Gonadotropin Releasing Hormone agonist (GnRHa) during chemotherapy and post-cancer childbirths - a Nationwide population-based cohort study of 24,922 women diagnosed with cancer in Sweden.

Background: Worldwide, an increasing number of women with cancer are receiving Gonadotropin Releasing Hormone agonist (GnRHa) co-treatment during chemotherapy aiming at ovarian protection. There is divergence among guidelines, and some have recommended GnRHa co-treatment for women with breast cancer, however, the effect of GnRHa on future fertility is uncertain. Methods: In this population-based cohort study we included all women diagnosed with cancer at ages 15-45 between July 2005 and March 2017 in Sweden, identified in the Swedish Cancer Register. Exposure to GnRHa co-treatment was captured using the Prescribed Drug Register. Post-cancer childbirth, extracted from the Medical Birth Register, was the main outcome. Secondary outcomes included childbirths achieved through natural conception (NC), infertility diagnosis and cancer mortality. For each outcome, adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using delayed-entry Cox models, stratified by age and cancer site. Findings: Among 24,922 women diagnosed with cancer, 1.5% had GnRHa co-treatment. Breast cancer diagnoses were found in 80.2% of GnRHa exposed women and the GnRHa exposure was not associated with higher rates of childbirth (aHR 1.23, 95% CI 0.80-1.89), or NC childbirth (aHR 1.02, 95% CI 0.62-1.67), whereas the rate of infertility was significantly higher (aHR 2.42, 95% CI 1.44-4.08). In women with lymphoma and other cancers, GnRHa exposure was not associated with higher rates of childbirth, NC childbirth or infertility. GnRHa exposure was not associated with higher cancer mortality for any cancer type. Interpretation: We did not find evidence of improved or maintained fertility, estimated as childbirth rates post-cancer, in women who received GnRHa during cancer treatment. Funding: This study was financed by research grants from The Swedish Cancer Society (CAN 2017/704; 190249Pj, 200170F), The Swedish Research Council (Dnr 2019-00446), the Nordic Cancer Union NCU (Grant 2017), The Swedish Childhood Cancer Fund (KP2016-0031), Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963).

Validation of diagnoses of liver disorders in users of systemic azole antifungal medication in Sweden.

BACKGROUND: Liver disorders are important adverse effects associated with antifungal drug treatment. However, the accuracy of Clinical International Classification of Diseases (ICD)-10 codes in identifying liver disorders for register based research is not well-established. This study aimed to determine the positive predictive value (PPV) of the ICD-10 codes for identifying patients with toxic liver disease, hepatic failure, and jaundice among patients with systemic antifungal treatment. METHODS: Data from the Swedish Prescribed Drug Register and the National Patient Register were utilized to identify adult patients who received systemic azole antifungal drugs and had a recorded diagnosis of toxic liver disease (K71.0, K71.1, K71.2, K71.6, K71.8, K71.9), hepatic failure (K72.0, K72.9), or jaundice (R17) between 2005 and 2016. The medical records of all included patients were reviewed. Prespecified criteria were used to re-evaluate and confirm each diagnosis, serving as the gold standard to calculate PPVs with 95% confidence intervals (95% CI) for each diagnostic group. RESULTS: Among the 115 included patients, 26 were diagnosed with toxic liver disease, 58 with hepatic failure, and 31 with jaundice. Toxic liver disease was confirmed in 14 out of 26 patients, yielding a PPV of 53.8% (95% CI 33.4-73.4%). Hepatic failure was confirmed in 26 out of 38 patients, resulting in a PPV of 62.1% (95% CI 48.4-74.5%). The highest PPV was found in jaundice, with 30 confirmed diagnoses out of 31, yielding a PPV of 96.8% (95% CI 83.3-99.9%). CONCLUSION: Among patients who received azole antifungal treatment and were subsequently diagnosed with a liver disorder, the PPV for the diagnosis of jaundice was high, while the PPVs for toxic liver disease and hepatic failure were lower.

Prenatal opioid exposure and risk of asthma in childhood: a population-based study from Denmark, Norway, and Sweden.

Background: Opioids may modulate the immune function through opioid receptors on immune cells. Long-term consequences of prenatal opioid exposure on the immune system, such as childhood asthma, are unknown. Objectives: To investigate whether prenatal opioid exposure is associated with the risk of childhood asthma. Methods: Cohort study using linked nationwide registers in Denmark (1996-2015), Norway (2005-2015), and Sweden (2006-2013). Children born by mothers who were chronic opioid analgesics users before pregnancy (n = 14,764) or who were receiving opioid maintenance therapy (OMT) before or during pregnancy (n = 1,595) were identified based on information from each of the medical birth registers and prescription registers. Long-term opioid analgesics exposed children were compared to short-term exposed or unexposed, whereas OMT exposed children were compared to OMT unexposed. Asthma among children ≥1 years of age was defined as two or more filled prescriptions of antiasthmatic medication within 365 days, or a diagnosis of asthma. Hazard ratios (HRs) were calculated using Cox proportional hazards regression with attained age as the time scale. Inverse probability of treatment weights based on propensity scores were applied to adjust for measured confounders. Individual level data from Norway and Sweden were pooled, whereas individual level data from Denmark were analyzed separately. For the opioid analgesics comparisons, adjusted HRs (aHR) from the combined Norwegian/Swedish data and the Danish data were pooled in a fixed-effects meta-analysis. Results: For the opioid analgesics cohort, no increased risk of asthma was observed in long-term exposed children neither compared with unexposed [aHR = 0.99 (95% CI 0.87-1.12)], nor compared with short-term exposed [aHR = 0.97 (0.86-1.10)]. No increased risk of asthma was observed in OMT exposed compared with OMT unexposed children [Norway/Sweden: aHR = 1.07 (0.60-1.92), Denmark: aHR = 1.25 (0.87-1.81)]. Results from sensitivity analyses, where potential misclassification of the outcome and misclassification of OMT exposure were assessed, as well as starting follow-up at 6 years of age, showed that the estimates of association were generally robust. Conclusion: We found no association between prenatal exposure to opioids and risk of childhood asthma. Results were consistent across two different opioid exposure groups with different confounder distributions.

Prenatal exposure to pregabalin, birth outcomes and neurodevelopment - a population-based cohort study in four Nordic countries.

INTRODUCTION: Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. OBJECTIVE: To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. METHODS: This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005-2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel-Haenszel (MH) meta-analyses. RESULTS: The total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98-1.34) for major congenital malformations and 1.72 (1.02-2.91) for stillbirth, which attenuated to 1.25 (0.74-2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03-1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67-1.42) for autism spectrum disorders, and 1.00 (0.78-1.29) for intellectual disability. CONCLUSIONS: Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis.

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.

In-utero antibiotic exposure and subsequent infections in infancy: a register-based cohort study with sibling analysis.

BACKGROUND: Prenatal antibiotic use, the ensuing maternal dysbiosis, and subsequent acquisition of altered microbiota in early life have been linked to the offspring's increased susceptibility to childhood infections. However, infection risks during the first year of life associated with in-utero antibiotic exposure have not been comprehensively explored. OBJECTIVE: To investigate the associations between exposure to antibiotics in utero and subsequent infections during infancy and whether such associations differ by antibiotic class. STUDY DESIGN: All data were retrieved from Swedish population-based registers. Singletons live-born between 2006 and 2018 were followed up from birth to their first birthday. Exposure was maternal filling of at least 1 antibiotic prescription between the last menstrual period and delivery. Outcomes were the infants' antimicrobial prescription fills, incident infections diagnosed in specialist care, and deaths with infections indicated as underlying or contributing causes ("infection-related deaths"). Birth year, birth season, maternal age, place of residence, parity, comorbidity indicator, body mass index, proxies for general health status, education level, and smoking status were considered covariates. Poisson regression was used to estimate crude and adjusted incidence rate ratios with 95% confidence intervals for the number of antimicrobial prescriptions filled to the infant. Cox regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for incident infections diagnosed in specialist care and at death. Sibling analyses were used to account for shared familial factors. Sensitivity of the results to exposure definition and perinatal factors prognostic for the outcomes were assessed in supplementary analyses. RESULTS: Of 1,347,018 infants in the full cohort, 294,657 (21.9%) were exposed to antibiotics in utero. There were 677,430 antimicrobial prescriptions filled (1.380 per 1000 person-days), 423,705 incident infections diagnosed in specialist care (0.870 per 1000 person-days), and 2800 infection-related deaths (0.006 deaths per 1000 person-days) during follow-up. Compared to unexposed, infants exposed to antibiotics in utero had higher rates of antimicrobial prescription fills (adjusted incidence rate ratio, 1.34; 95% confidence interval, 1.33-1.34), incident infections diagnosed in specialist care (adjusted hazard ratio, 1.28; 95% confidence interval, 1.27-1.29), and infection-related mortality (adjusted hazard ratio, 1.15; 95% confidence interval, 1.05-1.25). For antimicrobial prescriptions and infections diagnosed in specialist care, associations were consistent across most antibiotic classes but were attenuated in the sibling analyses: adjusted incidence rate ratio of 1.05 (95% confidence interval, 1.04-1.06) and adjusted hazard ratio of 1.05 (95% confidence interval, 1.03-1.07), respectively. No association with infant mortality was found in the sibling cohort (adjusted hazard ratio, 0.93; 95% confidence interval, 0.81-1.08). CONCLUSION: The minor associations between exposure to antibiotics in utero and infections during infancy were partly explained by shared familial factors and did not differ across frequently used antibiotic classes.

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.

Bleeding events among patients concomitantly treated with direct oral anticoagulants and macrolide or fluoroquinolone antibiotics.

Fluoroquinolones and macrolides may, due to a potential drug-drug interaction, increase the concentration of any concomitantly administered direct oral anticoagulant (DOAC) and thereby increase the risk of severe bleeding. However, clinical evidence for such an effect is scarce. The present study aimed to evaluate the association between the use of fluoroquinolones or macrolides and bleeding events in patients with concomitant DOAC use. This was a nationwide cohort study including 19 288 users of DOACs in 2008-2018 using information from Swedish national health registers. We compared the incidence of bleeding events associated with use of fluoroquinolones or macrolides using doxycycline as a negative control. Cox regression was used to calculate crude and adjusted hazard ratios (aHRs) in time windows of various length of follow-up after the start of antibiotic use. The incidence rates for fluoroquinolones and macrolides ranged from 12 to 24 and from 12 to 53 bleeding events per 100 000 patients in the investigated time windows. The aHRs (95% confidence interval) for use of fluoroquinolones and macrolides were 1.29 (0.69-2.44) and 2.60 (0.74-9.08) at the concomitant window, 1.31 (0.84-2.03) and 1.79 (0.75-4.29) at 30 days, and 1.34 (0.99-1.82) and 1.28 (0.62-2.65) at 150 days, respectively. With regard to fluoroquinolones, the present study suggests that the risk of bleeding when combined with DOACs, if any, is small. Codispensation of macrolides in patients on DOACs was not associated with an increased risk of bleeding. However, due to the small number of macrolide users, the results must be interpreted with caution.

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.

Method of Hormonal Contraception and Protective Effects Against Ectopic Pregnancy.

OBJECTIVE: To estimate the incidence rates for ectopic pregnancy by contraceptive method in a cohort of women using hormonal contraception in Sweden between 2005 and 2016. METHOD: Women aged 15-49 years with a filled prescription for a hormonal contraceptive in the Swedish Prescribed Drug Register between 2005 and 2016 were included. For each woman, all exposed woman-years were allocated to treatment episodes depending on the method of contraception. Treatment time started on the day the prescription was filled and ended on the first day of the end of supply, new eligible dispensing, pregnancy-related diagnosis and its associated estimated last menstrual period, or removal procedure. Ectopic pregnancy was defined as having at least two records of International Classification of Diseases, Tenth Revision code O00-, including O00.0, O00.1, O00.2, O00.8, O00.9, within 30 days or one episode of O00- and one surgical procedure for ectopic pregnancy (NOMESCO Classification of Surgical Procedures code LBA, LBC, LBD, LBE, LBW). Incidence rates per 1,000 woman-years and 95% CIs were calculated for each method of contraception. RESULTS: The study included 1,663,242 women and 1,915 events of ectopic pregnancy. The incidence rate (95% CI) for ectopic pregnancy per method of hormonal contraception was estimated: 13.5-mg levonorgestrel (LNG) hormonal intrauterine device (IUD), 2.76 (2.26-3.35) per 1,000 woman-years; 52-mg LNG hormonal IUD, 0.30 (0.28-0.33) per 1,000 woman-years; combined oral contraception, 0.20 (0.19-0.22) per 1,000 woman-years; progestogen implants, 0.31 (0.26-0.37) per 1,000 woman-years; oral medium-dose progestogen (desogestrel 75 mg), 0.24 per 1,000 woman-years, (0.21-0.27); and oral low-dose progestogen (norethisterone 0.35 mg and lynestrenol 0.5 mg), 0.81 (0.70-0.93) per 1,000 woman-years. CONCLUSION: Hormonal contraception lowers the risk of ectopic pregnancy markedly. The incidence rate of ectopic pregnancy among women using a low-dose hormonal IUD (13.5 mg LNG) was substantially higher than that in women using other types of hormonal contraception. This study provides real-world evidence to inform best clinical practice for women-centered contraceptive counseling.

Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder: a Nordic cohort study.

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

Temporal trends in lung cancer survival: a population-based study.

BACKGROUND: Lung cancer is the number one cancer-related cause of death in Sweden and worldwide. In most countries, five-year survival estimates vary between 10% and 20% with evidence of improved survival over time. Over the last decades, the management of lung cancer has changed including the introduction of national guidelines, new diagnostic procedures and treatments. This study aimed to investigate temporal trends in lung cancer survival both overall and in subgroups defined by established prognostic factors (i.e., sex, stage, histopathology and smoking history). MATERIALS AND METHODS: We estimated one-, two-, and five-year relative survival, and excess mortality, in patients diagnosed with squamous cell carcinoma or adenocarcinoma of the lung between 1995 and 2016 in Sweden. We used population-based information available in a national lung cancer research database (LCBaSe) generated by cross-linkage between the Swedish National Lung Cancer Register and several Swedish health and sociodemographic registers. RESULTS: We included 36,935 patients diagnosed with squamous cell carcinoma or adenocarcinoma of the lung between 1995 and 2016. The overall one-, two- and five-year survival estimates increased between 1995 and 2016, from 38% to 53%, 21% to 37%, and 14% to 24%, respectively. Over the study period, we also found improved survival in subgroups, for example in patients with stages III-IV disease, patients with adenocarcinoma, and never-smokers. The excess mortality decreased over the study period, both overall and in all subgroups. CONCLUSION: Lung cancer survival increased over time in the overall lung cancer population. Of special note was evidence of improved survival in patients with stage IV disease. Our results corroborate a previously observed global trend of improved survival in patients with lung cancer.

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.

Antibiotic use prior to a lung cancer diagnosis: a population-based study.

AIM: To examine patterns of recent pre-diagnostic fillings of antibiotics as an indicator of early symptoms of lung cancer. METHODS: Individuals diagnosed with lung cancer (cases) in 2009-2016 were identified in the Swedish National Lung Cancer Register, a population-based register, and randomly matched with up to five individuals free of lung cancer (controls) from the general population. Conditional logistic models were used to estimate odds ratios for the association between lung cancer and a recent history of filled antibiotic prescriptions. RESULTS: The study included 27,017 cases and 129,355 controls. The likelihood of recent exposure was approximately two times higher in cases compared to controls. The magnitude of the effect size became more pronounced with proximity to the diagnosis of lung cancer and an increasing number of filled prescriptions. While the magnitude of the effect size did not differ by sex or educational level, it became attenuated with increasing age. There was no evidence supporting a trend in the magnitude of the effect size for the association between lung cancer and a history of repeated fillings by cancer stage. CONCLUSION: Lung cancer was associated with an increased likelihood of a recent history of filled antibiotic prescriptions. However, there was no evidence of an association between repeated fillings and a diagnostic delay, as reflected by stage. Our findings underscore the importance of clinical reassessment to rule out lung cancer following pneumonia treatment, especially for patients with multiple treatment cycles.

Long-Term Risk of Skin Cancer and Lymphoma in Users of Topical Tacrolimus and Pimecrolimus: Final Results from the Extension of the Cohort Study Protopic Joint European Longitudinal Lymphoma and Skin Cancer Evaluation (JOELLE).

PURPOSE: Evidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately. PATIENTS AND METHODS: A cohort study in Denmark, Sweden, UK, and the Netherlands was conducted. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for nonmelanoma skin cancer (NMSC), melanoma, cutaneous T-cell lymphoma (CTCL), non-Hodgkin lymphoma (NHL) excluding CTCL, and Hodgkin lymphoma (HL) in new users of TCIs versus users of moderate/high-potency topical corticosteroids. RESULTS: The study included 126,908/61,841 adults and 32,605/27,961 children initiating treatment with tacrolimus/pimecrolimus, respectively. Follow-up was ≥10 years for 19% of adults and 32% of children. Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were <1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25-2.58) for cutaneous T-cell lymphoma. For pimecrolimus, IRRs in adults were <1 for non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and Hodgkin's lymphoma; and 1.21 (1.03-1.41) for melanoma; and 1.28 (1.20-1.35) for nonmelanoma skin cancer. In children, results were inconclusive due to few events. In adults, incidence rate ratios ≥5 years after first topical calcineurin inhibitor exposure were not higher than in overall analyses. CONCLUSION: Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results. Even if causal, the public health impact of these excess risks would be low and confined to the first years of exposure.

Association of Childhood Growth Hormone Treatment With Long-term Cardiovascular Morbidity.

Importance: Concerns about the cardiovascular safety of recombinant human growth hormone (rhGH) treatment in childhood have recently been raised; however, long-term studies are limited. Objective: To investigate the long-term risk of overall and severe cardiovascular events in patients previously treated with rhGH in childhood and whether there is an association with treatment duration or dose. Design, Setting, and Participants: This nationwide population-based cohort study included patients treated with rhGH during childhood from January 1, 1985, to December 31, 2010, in Sweden, with follow-up through December 31, 2014. Included patients were treated with rhGH owing to isolated growth hormone deficiency (GHD), small for gestational age (SGA), and idiopathic short stature (ISS). For each patient, 15 age-, sex-, and region-based matched control individuals were randomly selected from the general population as a comparison group. Data on cardiovascular outcomes and covariates including gestational age, birth weight, birth length, socioeconomic status, and height were obtained through linkage with several health care and population-based registers. Data were analyzed from January 1, 1985, to December 31, 2014. Exposures: Treatment with rhGH during childhood and adolescence (aged 0-18 years). Main Outcomes and Measures: The primary outcome was the first cardiovascular event recorded after the start of follow-up, and the secondary outcome was the first severe cardiovascular event. Results: A total of 53 444 individuals (3408 patients and 50 036 controls; 67.7% men; mean [SD] age at study end, 25.1 [8.2] years) were followed up for as long as 25 years (median follow-up, 14.9 [range, 0-25] years; total, 795 125 person-years). Among 1809 recorded cardiovascular events, the crude incidence rates were 25.6 events per 10 000 person-years for patients and 22.6 events per 10 000 person-years for controls. The adjusted hazard ratio (HR) for all cardiovascular events was higher in patients compared with controls (HR, 1.69; 95% CI, 1.30-2.19), especially for women (HR, 2.05; 95% CI, 1.31-3.20) compared with men (HR, 1.55; 95% CI, 1.12-2.13). All subgroups had increased HRs (SGA, 1.97 [95% CI, 1.28-3.04]; GHD, 1.66 [95% CI, 1.21-2.26]; and ISS, 1.55 [95% CI, 1.01-2.37]). Longer duration of rhGH treatment (HR, 2.08; 95% CI, 1.35-3.20) and total cumulative dose (HR, 2.05; 95% CI, 1.18-3.55) were associated with higher risk for overall cardiovascular disease. The adjusted HR for severe cardiovascular disease was 2.27 (95% CI, 1.01-5.12). Conclusions and Relevance: In this cohort study, treatment with rhGH during childhood due to GHD, SGA, or ISS was associated with increased risks of cardiovascular events in early adulthood, particularly in women; however, conclusions of causality are still limited and the absolute risk remains low.

Influence of statin-potency on the risk of kidney disease - A nationwide cohort study using laboratory data.

PURPOSE: To estimate the risk of kidney disease in high-potency statin users compared to those treated with low-potency statins without history of kidney disease at statin initiation, linking the Swedish national healthcare registers and laboratory data. METHODS: Incident users of statins, ≥40 years of age, with estimated Glomerular Filtration Rate (eGFR) >60 ml/min/1.73 m2 and no diagnosis of kidney disease at treatment initiation were identified between 2006 and 2007 and then followed for 2-years. The outcome was the incidence of kidney disease identified by the presence of the diagnostic code in the healthcare registers or eGFR <60 ml/min/1.73 m2 . We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with adjusted and propensity score (PS)-matched Cox proportional hazards models. RESULTS: A total of 27 385 patients were identified, 25.2% of which treated with a high-potency statin. During the follow-up, 68 (0.25%) patients were identified with a diagnosis of kidney disease from the registers. The number increased to 2498 (9.1%) when the criteria of eGFR <60 ml/min/1.73 m2 was added. The adjusted HR of kidney disease in high-potency statin users was 1.14 (95%CI 1.03-1.25) compared to low-potency users; the result was unchanged after the PS approach. CONCLUSIONS: Adding information from laboratory data to those from the national health registers, a slightly increased risk for kidney disease was found in high-potency statin users without pre-existing kidney disease at treatment initiation compared to those treated with low-potency statins.

Assessing Safety of Direct Thrombin Inhibitors, Direct Factor Xa Inhibitors and Vitamin K Antagonists in Patients with Atrial Fibrillation: A Nation-Wide Propensity Score Matched Cohort from Sweden.

PURPOSE: To evaluate associations between first-time use of direct oral anticoagulants or vitamin K antagonists and bleeding risk or mortality in the elderly with atrial fibrillation in a real-world setting in Sweden. PATIENTS AND METHODS: The study population comprises first-time users, above age 60, of dabigatran, apixaban, rivaroxaban, or warfarin, with first atrial fibrillation occurrence within 6 months before dispensing (2012-2016). Outcomes were gastrointestinal, any, or intracranial bleeding, and mortality. Exposure started at first dispensing of a study drug. Follow-up continued until outcome, end of drug supply, dispensing of another study drug, death or end of study (December 2016). We conducted a propensity score matched, nationwide register-based cohort study including three treatment groups: direct thrombin inhibitors, direct factor Xa inhibitors and vitamin K antagonists, each compared to the other two, focusing on subgroups of age and sex. Cox proportional hazard models adjusted for CHA2DS2VASc and HAS-BLED scores provided hazard ratios with 95% confidence intervals. RESULTS: The matched study populations consisted of 7,264 patients for the direct thrombin inhibitors vs vitamin K antagonists comparison, 12,566 patients for the direct factor Xa inhibitors vs vitamin K antagonists comparison and 6,606 patients for the direct factor Xa inhibitors vs direct thrombin inhibitors comparison, in total 26,436 patients. Numerically high, but imprecise, hazard ratios for gastrointestinal bleeding were observed for women aged 75-80, 80-85, or above 85 years, eg 6.00 (1.02, 113.47) for direct thrombin inhibitors vs vitamin K antagonists. For both sexes, numerically high hazard ratios for any bleeding were observed in ages 80-85, or above 85 years, eg 2.90 (1.01, 10.41) for direct thrombin inhibitors vs vitamin K antagonists. Numerically high HRs for intracranial bleeding were observed for women aged 75-80 or 80-85 years, eg 2.70 (0.65, 18.19) for direct factor Xa inhibitors vs vitamin K antagonists. Excess mortality was observed in both sexes, across age groups, for naive and experienced anticoagulant users. CONCLUSION: The observed increased gastrointestinal bleeding risk in first-time users of direct thrombin inhibitors or direct factor Xa inhibitors is consistent with previous studies. The possible risk of excess mortality merits further studies.

Metformin versus insulin use for treatment of gestational diabetes and delivery by caesarean section: A nationwide Swedish cohort study.

OBJECTIVE: Pregnant women who develop gestational diabetes (GDM) are more likely to deliver by caesarean section (CS). Over the last decade, the use of metformin has increased as an alternative to insulin but it's unknown how this shift in treatment has influenced the mode of delivery. Therefore, the aim of this study was to determine the association between metformin use and CS and delivery of a large-for-gestational age (LGA) infant compared to insulin use for GDM. STUDY DESIGN: The Swedish population health registers were linked to identify pregnant women from 2012 to 2016 without preexisting diabetes and with a first filled prescription of insulin or metformin in trimester 2 or 3 (n = 2467), categorized into those treated with insulin only (88%), metformin only (7.6%), or both insulin and metformin (4.3%). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Analyses were adjusted for relevant covariates and stratified by history of CS. RESULTS: The proportion of women using metformin to treat GDM increased from 2.5% in 2012 to over 30% in 2016. Comparing insulin only to metformin only use, no association with delivery by CS (adjusted OR 0.79, 95% CI; 0.54-1.16) and lower odds of delivering a LGA infant (adjusted OR 0.44, 95% CI; 0.26-0.76) was found. Treatment with both insulin and metformin was associated with an increased risk of CS (adjusted OR 1.65, 95% CI; 1.06-2.56), which were more often unplanned. Estimates were further elevated in nulliparous (adjusted OR 2.32, 95% CI; 0.95-5.65) and multiparous women with a history of CS (adjusted OR 2.29, 95% CI; 0.60-8.74) but conclusions could not be drawn given the wide CIs. CONCLUSION: There was no evidence of a higher association of metformin use alone with CS compared to insulin use for treatment of GDM but a protective effect for delivery of a LGA infant was shown. Women requiring treatment with both insulin and metformin had increased odds for delivery by CS which in turn may indicate that the need for the use of both medications to treat GDM suggests a pregnancy at higher risk.