Prevalence of drugs used for chronic conditions after diagnosis of thyroid cancer: a register-based cohort study.

OBJECTIVE: Little is known about thyroid cancer survivors' risk of chronic conditions. We, therefore, investigated the prevalence of drugs used for chronic conditions among thyroid cancer patients using population-wide register data. METHODS: We linked data from the Cancer Registry of Norway to the Norwegian Prescription Database and other databases for a study population of 3.52 million individuals, including 3486 individuals with thyroid cancer diagnosed during 2005-2019. Prevalence ratios (PRs) with 95% CIs of reimbursed prescribed drugs in thyroid cancer patients up to 15 years after thyroid cancer diagnosis were estimated by log-binomial regression, with the cancer-free population as reference. RESULTS: Individuals (both males and females) with thyroid cancer had higher use of drugs for several chronic conditions in the years after diagnosis; eg, 5 years after thyroid cancer diagnosis, there was elevated use of drugs for hypoparathyroidism (PRmales = 35.4, 95% CI, 25.2-49.7; PRfemales = 42.8, 95% CI, 34.2-53.6), hypertension (PRfemales = 1.20, 95% CI, 1.12-1.28), anxiety and tension (PRmales = 4.01, 95% CI, 1.80-8.92; PRfemales = 2.01, 95% CI, 1.15-3.52), gastric acid disorders (PRmales = 1.52, 95% CI, 1.22-1.91; PRfemales = 1.45, 95% CI, 1.27-1.66), and pain (PRmales = 1.48, 95% CI, 1.11-1.97; PRfemales = 1.24, 95% CI, 1.08-1.42) as compared with the cancer-free population. In addition, males with thyroid cancer had long-term elevated use of drugs for depression (eg, year 10+, PRmales = 1.66, 95% CI, 1.06-2.59). Individuals with thyroid cancer also had higher use of drugs for several conditions prior to the thyroid cancer diagnosis, eg, hypertension, gastric acid disorders, and pain. CONCLUSIONS: Individuals diagnosed with thyroid cancer had elevated long-term use of drugs for several chronic conditions, as compared with the cancer-free population.

Incidence trends of adult glioma in Norway and its association with occupation and education: A registry-based cohort study.

BACKGROUND: Gliomas constitute 75 % of all malignant primary adult brain tumors. Being the most frequent histologic subtype, glioblastomas (GBMs) cause substantial morbidity and mortality worldwide and the Nordic countries have some of the highest incidence rates in the world. Therefore, we investigated the incidence of gliomas in Norway including time trends and associations with education and occupation. METHODS: We retrieved individual-level data from databases at Statistics Norway containing information on education and occupation and linked them to data on adult glioma patients diagnosed during 2004-21 from the Cancer Registry of Norway. Age-standardized incidence rates (ASIRs) (World Standard Population) were calculated and analyzed with regards to sex and morphology. Poisson regression was used to test for time-trends, and to analyze the associations between education, occupation and glioma incidence, adjusted for age, sex, and calendar year. Estimates were reported as incidence rate ratios (IRRs) with 95 % confidence intervals (CIs). RESULTS: The overall ASIR of gliomas (per 100,000 person-years) was 7.1 (95 % CI 6.9-7.3), with no specific time trend during the study period. The incidence increased with age. Compared to the other subtypes, GBMs were diagnosed at older ages. The risks of developing glioma overall and GBM were associated with occupation but not with educational level. The relative risk of glioma and GBM were respectively 1.17 (95 % CI 1.05-1.31) and 1.17 (95 % CI 1.02-1.35) among high-skilled white-collar workers compared to blue-collar workers. CONCLUSIONS: The overall and sex-specific ASIRs of gliomas and GBMs did not show any noticeable time trends. The higher risk of developing glioma overall and GBM in high-skilled white-collar workers compared to blue-collar workers calls for further investigations.

ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases.

BACKGROUND: Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice. METHODS: We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available. FINDINGS: 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex. INTERPRETATION: Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use. FUNDING: European Union Horizon 2020 Research and Innovation Programme.

Body mass index, triglyceride-glucose index, and prostate cancer death: a mediation analysis in eight European cohorts.

BACKGROUND: Insulin resistance is a hypothesised biological mechanism linking obesity with prostate cancer (PCa) death. Data in support of this hypothesis is limited. METHODS: We included 259,884 men from eight European cohorts, with 11,760 incident PCa's and 1784 PCa deaths during follow-up. We used the triglyceride-glucose (TyG) index as indicator of insulin resistance. We analysed PCa cases with follow-up from PCa diagnosis, and the full cohort with follow-up from the baseline cancer-free state, thus incorporating both PCa incidence and death. We calculated hazard ratios (HR) and the proportion of the total effect of body mass index (BMI) on PCa death mediated through TyG index. RESULTS: In the PCa-case-only analysis, baseline TyG index was positively associated with PCa death (HR per 1-standard deviation: 1.11, 95% confidence interval (CI); 1.01-1.22), and mediated a substantial proportion of the baseline BMI effect on PCa death (HRtotal effect per 5-kg/m2 BMI: 1.24; 1.14-1.35, of which 28%; 4%-52%, mediated). In contrast, in the full cohort, the TyG index was not associated with PCa death (HR: 1.03; 0.94-1.13), hence did not substantially mediate the effect of BMI on PCa death. CONCLUSIONS: Insulin resistance could be an important pathway through which obesity accelerates PCa progression to death.

Associations between pregnancy-related factors and birth characteristics with risk of rare uterine cancer subtypes: a Nordic population-based case-control study.

PURPOSE: Uterine sarcomas are a rare group of uterine malignancies. Due to the low incidence and changes in uterine sarcoma classification, risk factors are not well characterized. Our objective was to evaluate risk factors for uterine sarcoma and compare risk factors between uterine sarcoma, malignant mixed Mullerian tumors (MMMTs), and type I endometrial carcinomas. METHODS: This nested case-control study utilized linked data from population-based medical birth and cancer registries in Denmark, Finland, Norway, and Sweden. Up to 10 controls were matched on country and birth year for each uterine cancer case. Using multivariable adjusted multinomial logistic regression, estimates of the associations between pregnancy-related factors and risk of uterine sarcoma, MMMTs, and type I endometrial carcinomas were determined. RESULTS: Having a very-low-birth-weight infant (< 1500 vs. 2500-3999 g: OR [95% CI] 2.83 [1.61-4.96]) was associated with an increased risk of uterine sarcoma. Whereas, having a more recent pregnancy was associated with reduced risks of MMMT (< 10 vs. ≥ 30 years: 0.66 [0.20-2.23]) and type 1 endometrial carcinomas (0.35 [0.30-0.41]) but not uterine sarcomas (1.33 [0.90-1.98], p-heterogeneity < 0.01). CONCLUSION: Our study provides evidence that risk factors for uterine sarcoma and MMMT, previously grouped with uterine sarcomas, vary substantially. Additionally, MMMT and type I endometrial carcinomas are more similar than uterine sarcoma in that pregnancy complications like gestational hypertension and preeclampsia were associated with reduced risks of both but not uterine sarcoma, suggesting different etiologies.

Fetal Exposure to Preeclampsia and Later Risk of Cardiometabolic Disorders: A Population-Based Cohort Study.

BACKGROUND: Fetal preeclampsia exposure has been associated with later cardiometabolic disease. However, this association has been investigated in few large population-wide studies, and it is unknown whether the association represents a causal relationship or is the result of shared etiological factors. METHODS: To further investigate the relationship between preeclampsia exposure and later cardiometabolic disease, we identified 1 692 944 singleton infants born in Norway during 1967 to 1997, where 44 299 were exposed to preeclampsia in utero. The individuals were followed for hypertension, diabetes, and dyslipidemia as defined by dispensed medication. We used Cox regression models to calculate the association between preeclampsia exposure and cardiometabolic outcomes adjusting for measured confounders. We also used full sibling comparisons and stratified Cox regression to control for unmeasured familial confounders. RESULTS: On the population level, exposed individuals had increased risk of hypertension (adjusted hazard ratio [aHR] 1.51 [95% CI, 1.41-1.63]), diabetes (aHR 1.33 [95% CI, 1.24-1.43], and dyslipidemia (aHR 1.28 [95% CI, 1.13-1.45]) compared with unexposed individuals. In sibling data, individuals not exposed to preeclampsia, but with an exposed sibling, had higher risk of hypertension and diabetes than individuals where no siblings were exposed to preeclampsia. Moreover, when comparing siblings discordant on preeclampsia exposure, there were no associations between preeclampsia and hypertension (aHR 1.05 [95% CI, 0.88-1.26]), diabetes (aHR 0.96 [95% CI, 0.80-1.14]), and dyslipidemia (aHR 0.86 [95% CI, 0.62-1.20]). CONCLUSIONS: Fetal preeclampsia exposure was associated with adult life hypertension, diabetes, and dyslipidemia, but these associations were likely due to shared etiological factors, rather than exposure to the preeclamptic condition itself.

Cancer risk in the siblings of individuals with major birth defects: a large Nordic population-based case-control study.

BACKGROUND: Individuals with major birth defects are at increased risk of developing cancer, indicating a common aetiology. However, whether the siblings of individuals with birth defects are also at an increased risk of cancer is unclear. METHODS: We used nationwide health registries in four Nordic countries and conducted a nested case-control study. We included 40 538 cancer cases (aged 0-46 years) and 481 945 population controls (matched by birth year and country), born between 1967 and 2014. The relative risk of cancer among individuals whose siblings had birth defects was computed with odds ratios (OR) and 95% confidence intervals (CIs), using logistic regression models. RESULTS: In the total study population (aged 0-46 years), we observed no overall difference in cancer risk between individuals whose siblings had birth defects and those who had unaffected siblings (OR 1.02; 95% CI 0.97-1.08); however, the risk of lymphoid and haematopoietic malignancies was elevated (1.16; 1.05-1.28). The overall risk of childhood cancer (0-19 years) was increased for siblings of individuals who had birth defects (1.09; 1.00-1.19), which was mainly driven by lymphoma (1.35; 1.09-1.66), neuroblastoma (1.51; 1.11-2.05) and renal carcinoma (5.03; 1.73-14.6). The risk of cancer also increased with the number of siblings with birth defects (Ptrend = 0.008). CONCLUSION: Overall risk of cancer among individuals (aged 0-46 years) whose siblings had birth defects was not elevated, but the risk of childhood cancer (ages 0-19 years) was increased. Our novel findings are consistent with the common aetiologies of birth defects and cancer, such as shared genetic predisposition and environmental factors.

Metformin Versus Insulin and Risk of Major Congenital Malformations in Pregnancies With Type 2 Diabetes: A Nordic Register-Based Cohort Study.

OBJECTIVE: To assess the risk of major congenital malformations with metformin versus insulin in pregnancies with type 2 diabetes. RESEARCH DESIGN AND METHODS: This cohort study used four Nordic countries' nationwide registers of live and stillborn infants exposed to metformin or insulin during first trimester organogenesis. Main exclusion criteria were type 1 diabetes, polycystic ovary syndrome, fertility treatment, and exposure to other diabetes drugs. Adjusted risk ratios (RRs) and 95% CIs were estimated for any and cardiac malformations. RESULTS: Of 3,734,125 infants in the source population, 25,956 were exposed to metformin or insulin in the first trimester, and 4,023 singleton infants were included. A malformation was diagnosed in 147 (4.7%) of 3,145 infants with exposure to any metformin (alone or in addition to insulin) and 50 (5.7%) of 878 infants with exposure to insulin alone (RR 0.84, 95% CI 0.46-1.54). Among 2,852 infants exposed to metformin alone and 293 infants exposed to metformin in addition to insulin 127 (4.4%) and 20 (6.8%), respectively, had a malformation. The adjusted risk was not increased for either metformin alone (0.83, 0.44-1.58) or both metformin and insulin (0.98, 0.56-1.69) versus insulin alone. Corresponding RRs for cardiac malformations were 1.01 (0.55-1.84) for any metformin, 0.92 (0.47-1.81) for metformin alone, and 1.72 (0.76-3.91) for both metformin and insulin. CONCLUSIONS: No evidence of an increased malformation risk with metformin versus insulin in the first trimester was found. Results should be interpreted with caution since information on glycemic control was missing.

Atomoxetine in Early Pregnancy and the Prevalence of Major Congenital Malformations: A Multinational Study.

Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure.Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors.Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16).Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations.

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

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

Metabolically (un)healthy obesity and risk of obesity-related cancers: a pooled study.

BACKGROUND: Studies of obesity with or without metabolic aberrations, commonly termed metabolically unhealthy or healthy obesity, in relation to cancer risk are scarce. METHODS: We investigated body mass index (normal weight, overweight, obesity) jointly and in interaction with metabolic health status in relation to obesity-related cancer risk (n = 23 630) among 797 193 European individuals. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to define metabolically healthy and unhealthy status. Hazard ratios (HRs) and multiplicative interactions were assessed using Cox regression, and additive interactions were assessed using the relative excess risk for interaction. All statistical tests were 2-sided. RESULTS: Metabolically unhealthy obesity, with a baseline prevalence of 7%, was, compared with metabolically healthy normal weight, associated with an increased relative risk of any obesity-related cancer and of colon, rectal, pancreas, endometrial, liver, gallbladder, and renal cell cancer (P < .05), with the highest risk estimates for endometrial, liver, and renal cell cancer (HR = 2.55-3.00). Metabolically healthy obesity showed a higher relative risk for any obesity-related cancer and colon (in men), endometrial, renal cell, liver, and gallbladder cancer, though the risk relationships were weaker. There were no multiplicative interactions, but there were additive, positive interactions between body mass index and metabolic health status on obesity-related and rectal cancer among men and on endometrial cancer (P < .05). CONCLUSIONS: This study highlights that the type of metabolic obesity phenotype is important when assessing obesity-related cancer risk. In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.

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.

Maternal Health, Pregnancy and Offspring Factors, and Maternal Thyroid Cancer Risk: A Nordic Population-Based Registry Study.

Thyroid cancer incidence is higher in women than men, especially during the reproductive years, for reasons that remain poorly understood. Using population-based registry data from 4 Nordic countries through 2015, we examined associations of perinatal characteristics with risk of maternal thyroid cancer. Cases were women diagnosed with thyroid cancer ≥2 years after last birth (n = 7,425, 83% papillary). Cases were matched to controls (n = 67,903) by mother's birth year, country, and county of residence. Odds ratios (ORs) were estimated using conditional logistic regression models adjusting for parity. Older age at first pregnancy, postpartum hemorrhage (OR = 1.18, 95% (confidence interval) CI: 1.08, 1.29), and benign thyroid conditions (ORs ranging from 1.64 for hypothyroidism to 10.35 for thyroid neoplasms) were associated with increased thyroid cancer risk, as were higher offspring birth weight (per 1-kg increase, OR = 1.17, 95% CI: 1.12, 1.22) and higher likelihood of offspring being large for gestational age (OR = 1.26, 95% CI: 1.11, 1.43). Unmarried/noncohabiting status (OR = 0.91, 95% CI: 0.84, 0.98), maternal smoking (OR = 0.75, 95% CI: 0.67, 0.84), and preterm birth (OR = 0.90, 95% CI: 0.83, 0.98) were associated with reduced risk. Several factors (e.g., older age at first pregnancy, maternal smoking, goiter, benign neoplasms, postpartum hemorrhage, hyperemesis gravidarum, and neonatal jaundice) were associated with advanced thyroid cancer. These findings suggest that some perinatal exposures may influence maternal thyroid cancer risk.

Sex differences in childhood cancer risk among children with major birth defects: a Nordic population-based nested case-control study.

BACKGROUND: Childhood cancer is more common among children with birth defects, suggesting a common aetiology. Whether this association differs by sex is unclear. METHODS: We performed a population-based nested case-control study using nationwide health registries in four Nordic countries. We included 21 898 cancer cases (0-19 years) and 218 980 matched population controls, born 1967-2014. Associations between childhood cancer and major birth defects were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression models. Effect modification was evaluated using a counterfactual framework to estimate confidence intervals and P-values for the natural indirect effects. RESULTS: Birth defects were present for 5.1% (1117/21 898) of childhood cancer cases and 2.2% (4873/218 980) of controls; OR of cancer was higher for chromosomal (OR = 10, 95% CI = 8.6-12) than for non-chromosomal defects (OR = 1.9, 95% CI = 1.8-2.1), strongest between genetic syndromes/microdeletion and renal tumours, Down syndrome and leukaemia, and nervous system defects and central nervous system tumours. The association between birth defects and cancer was stronger among females (OR = 2.8, 95% CI = 2.6-3.1) than males (OR = 2.1, 95% CI = 1.9-2.2, Pinteraction <0.001). Male sex was an independent risk factor for childhood cancer, but very little of the overall association between sex and childhood cancer was mediated through birth defects (4.8%, PNIE <0.001), although more at younger ages (10% below years and 28% below 1 year). CONCLUSIONS: The birth defect-cancer associations were generally stronger among females than males. Birth defects did not act as a strong mediator for the modest differences in childhood cancer risk by sex, suggesting that other biological pathways are involved.

Labor epidural analgesia and subsequent risk of offspring autism spectrum disorder and attention-deficit/hyperactivity disorder: a cross-national cohort study of 4.5 million individuals and their siblings.

BACKGROUND: A recent study has suggested that labor epidural analgesia may be associated with increased rates of offspring autism spectrum disorder. Subsequent replication attempts have lacked sufficient power to confidently exclude the possibility of a small effect, and the causal nature of this association remains unknown. OBJECTIVE: This study aimed to investigate the extent to which exposure to labor epidural analgesia is associated with offspring autism spectrum disorder and attention-deficit/hyperactivity disorder following adjustments for unmeasured familial confounding. STUDY DESIGN: We identified 4,498,462 singletons and their parents using the Medical Birth Registers in Finland (cohorts born from 1987-2005), Norway (1999-2015), and Sweden (1987-2011) linked with population and patient registries. These cohorts were followed from birth until they either had the outcomes of interest, emigrated, died, or reached the end of the follow-up (at mean ages 13.6-16.8 years), whichever occurred first. Cox regression models were used to estimate country-specific associations between labor epidural analgesia recorded at birth and outcomes (eg, at least 1 secondary care diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder or at least 1 dispensed prescription of medication used for the treatment of attention-deficit/hyperactivity disorder). The models were adjusted for sex, birth year, birth order, and unmeasured familial confounders via sibling comparisons. Pooled estimates across all the 3 countries were estimated using inverse variance weighted fixed-effects meta-analysis models. RESULTS: A total of 4,498,462 individuals (48.7% female) were included, 1,091,846 (24.3%) of which were exposed to labor epidural analgesia. Of these, 1.2% were diagnosed with autism spectrum disorder and 4.0% with attention-deficit/hyperactivity disorder. On the population level, pooled estimates showed that labor epidural analgesia was associated with increased risk of offspring autism spectrum disorder (adjusted hazard ratio, 1.12; 95% confidence interval, 1.10-1.14, absolute risks, 1.20% vs 1.07%) and attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.20; 95% confidence interval, 1.19-1.21; absolute risks, 3.95% vs 3.32%). However, when comparing full siblings who were differentially exposed to labor epidural analgesia, the associations were fully attenuated for both conditions with narrow confidence intervals (adjusted hazard ratio [autism spectrum disorder], 0.98; 95% confidence interval, 0.93-1.03; adjusted hazard ratio attention-deficit/hyperactivity disorder, 0.99; 95% confidence interval, 0.96-1.02). CONCLUSION: In this large cross-national study, we found no support for the hypothesis that exposure to labor epidural analgesia causes either offspring autism spectrum disorder or attention-deficit/hyperactivity disorder.

Interaction of leisure-time physical activity with body mass index on the risk of obesity-related cancers: A pooled study.

Physical activity (PA) has been associated with a lower risk of some obesity-related cancers, but the combined association and interaction of PA and body weight on obesity-related cancer risk is less clear. We examined the association of leisure-time PA (high/low) and its combination with body mass index (BMI, <25 [low]/≥25 [high] kg/m2 ) on obesity-related cancer risk in 570 021 individuals, aged 43 years on average at baseline, in five Scandinavian cohorts. We used Cox regression to calculate hazard ratios of obesity-related cancers (n = 19 074) and assessed multiplicative and additive interactions between PA and BMI on risk. High leisure-time PA, recorded in 19% of the individuals, was associated with a 7% (95% confidence interval [CI] 4%-10%) lower risk of any obesity-related cancer compared to low PA, with similar associations amongst individuals with a low and a high BMI (6% [1%-11%] and 7% [2%-11%]). High PA was also associated with decreased risks of renal cell (11% [9%-31%]) and colon cancer (9% [2%-16%]). When high PA and low BMI were combined, the relative risk reduction for all obesity-related cancers was 24% (95% CI 20%-28%); endometrial cancer, 47% (35%-57%); renal cell cancer, 39% (27%-51%); colon cancer, 27% (19%-35%); multiple myeloma, 23% (2%-40%) and pancreatic cancer, 21% (4%-35%), compared to low PA-high BMI. There were no additive or multiplicative interactions between PA and BMI on risk. The result of our study suggests a reduced risk of obesity-related cancer by leisure-time PA in both normal weight and overweight individuals, which further decreased for PA and normal weight combined.

Association between medical androgen deprivation therapy and long-term cardiovascular disease and all-cause mortality in nonmetastatic prostate cancer.

Studies have suggested that prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) are at increased risk of developing or exacerbating cardiovascular disease (CVD). We aimed to explore the association between ADT for PCa and subsequent CVD and all-cause mortality in this nationwide, longitudinal study. We also evaluated the role of cardiovascular risk and ADT duration to determine effect modification. Norwegian registry data were used to identify patients with PCa from 2008-18 and who received primary ADT in the first year after diagnosis. The associations between ADT and composite cardiovascular events, and the individual components of myocardial infarction, stroke and heart failure, in addition to atrial fibrillation and all-cause mortality, were explored using time-varying Cox regression models. We included 30 923 PCa patients, of whom 8449 (27%) received primary ADT. Mean follow-up was 2.9 and 3.8 years for CVD events and mortality, respectively. We found an association between ADT and composite CVD (adjusted HR 1.13: 95% CI 1.05-1.21), myocardial infarction (1.18: 1.05-1.32), stroke (1.21: 1.06-1.38), heart failure (1.23: 1.13-1.35) and all-cause mortality (1.49: 1.39-1.61). These associations persisted in those with low and moderate CVD risk and ADT longer than 7 months. A relationship between ADT and composite CVD and all-cause mortality was observed, especially in those with moderate CVD risk and longer treatment duration. Future studies with more detailed cancer data are needed to verify the clinical relevance of these results, especially when considering all-cause mortality within the context of treatment guidelines and benefits of ADT.

Male to female ratios in autism spectrum disorders by age, intellectual disability and attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine the gender distribution in ASD in adults compared with children and the impact of comorbid intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD) on the male to female ratio (MFR). METHODS: We estimated the MFR and the male prevalence ratio (PR) for ASD in adults and children using the Medical Birth Registry of Norway, including all individuals born during 1967-2011. We examined variation with age, comorbid ID and ADHD as defined by diagnoses in the Norwegian Patient Registry during 2008-2015 and/or a dispensed prescription for ADHD medication. RESULTS: The sample included 1,701,206 adults and 804,146 children, including 8,995 (0.5%) adults and 8,056 (1.0%) children with ASD, 53,822 (3.2%) adults and 26,967 (3.4%) children with ADHD and 9,178 (0.5%) adults and 5,038 (0.6%) children with ID. The MFR for ASD was 3.67 in children and 2.57 in adults, corresponding to a male PR in ASD of 1.54 (95% CI 1.53-1.56) and 1.41 (1.39-1.24), respectively. Comorbid ID decreased the MFR and the male PR in both adults and children, whereas comorbid ADHD significantly increased the male PR in children. The MFR and the population prevalence of ASD, ADHD and ID decreased from children to younger adults and yet further to older adults. CONCLUSION: We found a lower MFR and male PR in adults than in children. Findings suggest the strong male predominance seen in childhood/clinical studies of ASD diminishes in adult samples, possibly reflecting the influence of non-aetiological factors such as later diagnosis in females, diagnostic biases and diagnostic trends.

Use of sildenafil and other phosphodiesterase type 5 inhibitors among pregnant women in Scandinavia.

INTRODUCTION: For phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, the only approved indication in women is for pulmonary arterial hypertension. These drugs are increasingly being proposed and tested for treatment of female infertility and complications in pregnancy. However, the extent of use of PDE5 inhibitors in the general pregnant population over the last decades is unknown. Therefore, we conducted a descriptive cohort study using data from the population health registers in the Scandinavian countries. MATERIAL AND METHODS: By linking the Medical Birth Registers and the Prescribed Drug Registers in Denmark (1997-2017), Norway (2004-2017), and Sweden (2006-2016), women with filled prescriptions of PDE5 inhibitors in outpatient settings in the 90 days before the date of last menstrual period and/or during pregnancies were identified. With additional linkage to the National Patient Registers, information on maternal, pregnancy, and infant characteristics, co-morbidities, and co-medication was collected and described. RESULTS: Among over 3 million singleton pregnancies, only 77 were pregnancies in women who had at least one filled prescription of a PDE5 inhibitor within the 90 days before the start of pregnancy to delivery. Prescription fills most often occurred before the last menstrual period and in the first trimester, with very few occurring later in pregnancy. Sildenafil was the most used PDE5 inhibitor. Among pregnant women using PDE5 inhibitors, 44% were 35 years of age or older, eight had a cardiovascular diagnosis, and three specifically had a diagnosis of pulmonary arterial hypertension. Among the infants born to mothers using PDE5 inhibitors, nine were born preterm, six were small-for-gestational age, five had an Apgar score at 5 minutes below 8, 18 were admitted to the Neonatal Intensive Care Unit, and eight had respiratory and cardiovascular conditions. CONCLUSIONS: Few women used PDE5 inhibitors in outpatient settings before or during pregnancy in the Scandinavian countries in the last decades. Only a small proportion had a diagnosis for pulmonary arterial hypertension, suggesting off-label use in the remaining users. Use was predominantly in mothers over age 35 years. The safety of fetal exposure to sildenafil and other PDE5 inhibitors in pregnancy has not been established. As maternal age continues to increase and additional uses of PDE5 inhibitors are investigated, the safety of these drugs in pregnancy should be thoroughly evaluated.

The Inverse Association of Body Mass Index with Lung Cancer: Exploring Residual Confounding, Metabolic Aberrations and Within-Person Variability in Smoking.

BACKGROUND: The inverse observational association between body mass index (BMI) and lung cancer risk remains unclear. We assessed whether the association is explained by metabolic aberrations, residual confounding, and within-person variability in smoking, and compared against other smoking-related cancers. METHODS: We investigated the association between BMI, and its combination with a metabolic score (MS) of mid-blood pressure, glucose, and triglycerides, with lung cancer and other smoking-related cancers in 778,828 individuals. We used Cox regression, adjusted and corrected for within-person variability in smoking (status/pack-years), calculated from 600,201 measurements in 221,958 participants. RESULTS: Over a median follow-up of 20 years, 20,242 smoking-related cancers (6,735 lung cancers) were recorded. Despite adjustment and correction for substantial within-person variability in smoking, BMI remained inversely associated with lung cancer [HR per standard deviation increase, 0.87 (95% confidence interval 0.85-0.89)]. Individuals with BMI less than 25 kg/m2 and high MS had the highest risk [HR 1.52 (1.44-1.60) vs. BMI ≥25 with low MS]. These associations were weaker and nonsignificant among nonsmokers. Similar associations were observed for head and neck cancers and esophageal squamous cell carcinoma, whereas for other smoking-related cancers, we generally observed positive associations with BMI. CONCLUSIONS: The increased lung cancer risk with low BMI and high MS is unlikely due to residual confounding and within-person variability in smoking. However, similar results for other cancers strongly related to smoking suggest a remaining, unknown, effect of smoking. IMPACT: Extensive smoking-adjustments may not capture all the effects of smoking on the relationship between obesity-related factors and risk of smoking-related cancers.