Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia.

BACKGROUND: Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). METHODS AND RESULTS: Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. CONCLUSION: These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

Use of Fertility Drugs and Risk of Malignant Melanoma: Results from a Large Danish Population-Based Cohort Study.

Fertility drugs have not definitively been linked to malignant melanoma. By the use of data from a large nationwide cohort of women aged 20.0-45.0 years and living in Denmark between January 1, 1995 and December 31, 2011, we assessed the association between the use of fertility drugs and the risk of malignant melanoma. Information on fertility status and the use of fertility drugs was obtained from the population-based Danish Infertility Cohort. Cox proportional hazard regression models were applied to estimate hazard ratios and 95% confidence intervals with adjustment for potential confounders. The study population comprised 1,330,954 women, of whom 86,231 (6.5%) were treated with fertility drugs. During a median follow-up of 21.0 years, 6,139 women were diagnosed with malignant melanoma. Compared with fertile women, women with fertility challenges who had used any fertility drugs had an increased risk of malignant melanoma (hazard ratio = 1.14; 95% confidence interval = 1.02-1.27). Furthermore, the use of specific types of fertility drugs (clomiphene, gonadotropins, human chorionic gonadotropin, gonadotropin-releasing hormone preparations, and progesterone) was also associated with an increased risk of malignant melanoma, with hazard ratios ranging between 1.09 and 1.13; however, the association did not reach statistical significance. Our findings indicate that the use of fertility drugs was associated with a modestly increased risk of malignant melanoma.

Endometrial cancer risk after fertility treatment: a population-based cohort study.

PURPOSE: Using data from a large population-based cohort of women with fertility problems in Denmark, we examined the association between use of fertility drugs and endometrial cancer incidence. METHODS: Women aged 20-45 years living in Denmark during 1 January 1995-31 December 2017 and diagnosed with fertility problems (i.e., subfertile women) were identified from the Danish Infertility Cohort. Information on use of fertility drugs, endometrial cancer, covariates and vital status was obtained from various Danish national registers. Cox proportional hazard models were used adjusted for calendar year of study entry, highest level of education, parity status, hormonal contraceptive use, obesity and diabetes mellitus. RESULTS: Of the 146,104 subfertile women, 129,478 (88.6%) were treated with fertility drugs. During a median follow-up of 10.1 years, 119 women were diagnosed with endometrial cancer. Use of any fertility drugs was not associated with an increased rate of overall (HR 0.82; 95% CI 0.50-1.34) or type I endometrial cancer (HR 1.08; 95% CI 0.60-1.95). No associations between use of specific types of fertility drugs and endometrial cancer were observed. No marked associations were observed according to cumulative dose of specific fertility drugs, parity status, or with increasing follow-up time. CONCLUSIONS: No marked associations between use of fertility drugs and risk of endometrial cancer were observed. The relatively young age of the cohort at end of follow-up, however, highlights the need for longer follow-up of women after fertility drug use.

Emergency contraceptive pill use among women in Denmark, Norway and Sweden: Population-based survey.

INTRODUCTION: Emergency contraceptive pill (ECP) use is reported to have increased in several countries over time. In this multi-country population-based questionnaire study, we aimed to describe the patterns of ECP use and identify factors associated with its use. MATERIAL AND METHODS: In 2011-2012, women aged 18-45 years were randomly selected from national registers in Denmark, Norway and Sweden and invited to respond to questions related to lifestyle and contraceptive use. We used generalized logistic models to estimate odds ratios (ORs) and 95% confidence intervals (CI) comparing women who had used ECP with women who had never used ECP. RESULTS: Of the 45 445 women, 33.9% (Denmark = 32.3%, Norway = 35.1%, Sweden = 34.6%) had used ECP at least once in their lifetime. Among ECP users, 15.8% had used ECP within the last year and 50.0% had used ECP more than once in their life. After adjusting for country, age at response and response type, ECP use was associated with higher education (OR 2.09, 95% CI 1.54-2.84) and being single, divorced or widowed (OR 3.17, 95% CI 2.87-3.49). Binge drinking and smoking increased the odds of ECP use. Furthermore, early age at first intercourse (OR 1.29, 95% CI 1.08-1.55), having a new partner in the last 6 months (≥3 partners: OR 6.44, 95% CI 5.46-7.60) and lack of condom use with a recent new partner (OR 1.42, 95% CI 1.22-1.66) were found to be associated with ECP use. CONCLUSIONS: Our study shows that ECP use is common among Scandinavian women. Higher education and being single were associated with increased odds of ECP use. Risk behaviors such as smoking and early age at first sex were also associated with increased odds of ECP use. Since ECP use is not protective against sexually transmitted infections, our findings highlight the need to encourage awareness and regular use of condoms to prevent sexually transmitted diseases in women.

Risk of febrile seizures among children conceived following fertility treatment: A cohort study.

BACKGROUND: Studies have shown that fertility treatment in mothers is associated with neurological problems in children. However, knowledge about any association between maternal use of fertility treatment and febrile seizures in children is lacking. OBJECTIVE: To determine whether maternal use of fertility treatment is associated with febrile seizures in children. METHODS: All liveborn children in Denmark during 1996-2012 (n = 1 065 901) were linked with the Danish Infertility Cohort and the Danish national registers and were followed from one year of age until the first episode of a febrile seizure, death, emigration, loss to follow-up, or end of follow-up (December 2015). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. RESULTS: Approximately 16% children (n = 172 140) were conceived by infertile women, and approximately 3% (n = 34 082) were diagnosed with febrile seizures during follow-up. Compared with children conceived by fertile women, children conceived following any fertility treatment (HR 1.11, 95% CI 1.06, 1.16), following specific fertility treatment, for example IVF (HR 1.15, 95% CI 1.05, 1.25), ICSI (HR 1.20, 95% CI 1.10, 1.32), and following fertility drugs (HR 1.06, 95% CI 1.00, 1.11) had slight increase in risk of febrile seizures, after adjusting for calendar year of birth, parental age, education, parity status, and maternal smoking during pregnancy. The associations were unchanged when children conceived naturally by infertile women were used as the reference group. CONCLUSIONS: Children conceived following fertility treatment had slightly increased relative risk for febrile seizures.

Risk of epithelial ovarian cancer among women with benign ovarian tumors: a follow-up study.

PURPOSE: The importance of benign ovarian tumors as precursors or risk markers for ovarian cancer is not fully understood. Studies on the association between benign ovarian tumors and ovarian cancer have provided inconclusive results. We examined the overall and histological type-specific risk of ovarian cancer among 158,221 Danish women diagnosed with a benign ovarian tumor during 1978-2016. METHODS: The study cohort was linked to the Danish Cancer Register to identify all cases of epithelial ovarian cancer, and standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated. RESULTS: After excluding the first year of follow-up, women with benign ovarian tumors did not have an increased risk for overall epithelial ovarian cancer (SIR 1.02; 95% CI 0.93-1.11), as compared with women in the general population. However, we found an increased risk for mucinous ovarian cancer (SIR 2.06; 95% CI 1.67-2.52); both solid and cystic benign ovarian tumors were associated with an increased risk. The risk for mucinous ovarian cancer was increased irrespective of the age at benign ovarian tumors diagnosis and persisted for up to 20 years after the benign ovarian tumor diagnosis. No clear associations for other histological types of ovarian cancer were observed, except for an increased risk for serous ovarian cancer among women diagnosed with benign ovarian tumors at an young age. CONCLUSIONS: Benign ovarian tumors may be associated with long-term increased risk for mucinous ovarian cancer.

Chances of live birth after exposure to vitamin D-fortified margarine in women with fertility problems: results from a Danish population-based cohort study.

OBJECTIVE: To study the association between extra vitamin D from a mandatory margarine fortification program and chance of live birth among infertile women. DESIGN: Nationwide cohort study. SETTING: Not applicable. PATIENT(S): The study population consisted of 16,212 women diagnosed with infertility from June 1, 1980, to August 31, 1991. INTERVENTIONS(S): We took advantage of the mandatory vitamin D fortification program of margarine in Denmark that was abruptly stopped on May 31, 1985. The termination of the vitamin D fortification served as a cutoff point to separate the study population into various exposure groups. MAIN OUTCOME MEASURE(S): Odds ratios and 95% confidence intervals for the association between vitamin D exposure status and chance of a live birth within 12, 15, and 18 months after first infertility diagnosis. RESULT(S): Women who were diagnosed with infertility during the vitamin D-exposed period had an increased chance of a live birth compared with women diagnosed with infertility during the nonexposed period. For women diagnosed with infertility during the wash-out period, the chance of a live birth was also increased, but somewhat lower. Similar estimates were obtained with longer follow-up, in women with anovulatory infertility, and little seasonal variation was observed when calendar period of conception was applied. CONCLUSION(S): Our findings suggest that infertile women exposed to extra vitamin D from a margarine fortification program had an increased chance of live birth compared with women not exposed to extra vitamin D from fortification.

A Cohort Study of Breast Cancer Risk after 20 Years of Follow-Up of Women Treated with Fertility Drugs.

BACKGROUND: Using a nationwide cohort of Danish women, we investigated the association between use of fertility drugs and risk of breast cancer. METHODS: The study cohort included women ages 20 to 44 years and living in Denmark between January 1, 1995 and December 31, 2011. Information on fertility status, use of fertility drugs, breast cancer, covariates, and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were applied to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for potential confounders. RESULTS: Of the 1,330,852 women included, 96,782 (7.3%) were infertile, and 20,567 (1.5%) were diagnosed with breast cancer during a median follow-up of 20.9 years. Compared with fertile women, infertile women who had used any fertility drugs did not have an increased hazard for breast cancer overall (HR = 1.02; 95% CI, 0.95-1.10), or for any of the histologic types (ductal, lobular, or mucinous) of breast cancer. Furthermore, no associations were observed between use of specific types of fertility drugs and breast cancer. CONCLUSIONS: No convincing associations between use of fertility drugs and breast cancer were observed after two decades of follow-up. IMPACT: Our results do not support a marked association between fertility drugs and breast cancer and are therefore reassuring for infertile women treated with fertility drugs.

Risk of breast cancer among women with benign ovarian tumors: a Danish nationwide cohort study.

PURPOSE: To assess the association between benign ovarian tumors and subsequent risk of breast cancer, and to examine this association according to type of benign ovarian tumors. METHODS: This nationwide cohort study comprised all Danish women diagnosed with a benign ovarian tumor during 1978-2016 (n = 158,221) identified through the Danish National Patient Register. The cohort was linked to the Danish Cancer Registry to identify all cases of breast cancer, and standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated. RESULTS: Overall, women with a benign ovarian tumor were at significantly increased risk of breast cancer. The risk was confined to women with a solid ovarian tumor (SIR 1.09; 95% CI 1.05-1.13), particularly in women ≥ 50 years at benign tumor diagnosis (SIR 1.19; 95% CI 1.12-1.26). The risk remained increased up to 20 years or more after the diagnosis of a solid ovarian tumor (SIR 1.11; 95% CI 1.04-1.18), and women with a solid tumor were at increased risk of ductal, lobular, and other types of breast cancer, although most consistent for the lobular subtype. For cystic tumors, this association was confined to ductal breast cancer in women with the tumor diagnosed at age ≥ 50 years. CONCLUSIONS: Women with a benign ovarian tumor were at increased risk of breast cancer. This association was largely confined to women with a solid ovarian tumor, and the excess risk was present 20 years or more after the ovarian tumor diagnosis. The underlying mechanism is unknown and should be investigated further.

Human papillomavirus types in cervical high-grade lesions or cancer among Nordic women-Potential for prevention.

It is valuable to establish a population-based prevaccination baseline distribution of human papillomavirus (HPV) types among women with high-grade cervical intraepithelial neoplasia (CIN) grade 2 or 3 and cervical cancer in order to assess the potential impact of HPV vaccination. In four countries (Denmark, Norway, Sweden, and Iceland), we collected consecutive series of cervical cancers (n = 639) and high-grade precancerous cervical lesions (n = 1240) during 2004-2006 before implementation of HPV vaccination and subjected the specimens to standardized HPV genotyping. The HPV prevalence was 82.7% (95% confidence interval [CI] 79.0-86.4) in CIN2, 91.6% (95% CI 89.7-93.5) in CIN3, and 86.4% (95% CI 83.7-89.1) in cervical cancer. The most common HPV types in CIN2/3 were HPV16 (CIN2: 35.9%, 95% CI 31.2-40.6; CIN3: 50.2%, 95% CI 46.8-53.6) and HPV31 (CIN2: 10.9%, 95% CI 7.8-13.9; CIN3: 12.1%, 95% CI 9.9-14.3), while HPV16 and HPV18 were the most frequent types in cervical cancer (48.8%, 95% CI 44.9-52.7 and 15.3%, 95% CI 12.5-18.1, respectively). The prevalence of HPV16/18 decreased with increasing age at diagnosis in both CIN2/3 and cervical cancer (P < 0.0001). Elimination of HPV16/18 by vaccination is predicted to prevent 42% (95% CI 37.0-46.7) of CIN2, 57% (95% CI 53.8-60.5) of CIN3 and 64% (95% CI 60.3-67.7) of cervical cancer. Prevention of the five additional HPV types HPV31/33/45/52/58 would increase the protection to 68% (95% CI 63.0-72.2) in CIN2, 85% (95% CI 82.4-87.2) in CIN3 and 80% (95% CI 77.0-83.2) in cervical cancer. This study provides large-scale and representative baselines for assessing and evaluating the population-based preventive impact of HPV vaccination.

Contraceptive use at first intercourse is associated with subsequent sexual behaviors.

OBJECTIVE: Women's contraceptive use at first sexual intercourse (FSI) may be associated with subsequent sexual behaviors. We examined associations between contraceptive methods used at FSI and subsequent number of lifetime partners, induced abortions and sexually transmitted infections (STIs). STUDY DESIGN: During 2011-2012, we collected questionnaire data from a random sample of women aged 18-45 years from Denmark, Norway and Sweden. We used logistic regression and discrete-time proportional hazards models to estimate odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs), comparing different contraceptive methods used at FSI in the whole study sample and in women with FSI in 2001 or later [when emergency contraceptive pills (ECPs) were available without prescription]. RESULTS: Of 45,361 women in the study sample, those who did not use contraception at FSI (n=8155; 18.0%) were more likely than condom users to have ≥11 lifetime partners (OR=1.34; 95% CI 1.27-1.42), induced abortions (HR=1.62; 95% CI 1.53-1.71) and STIs (HR=1.15; 95% CI 1.10-1.20). ECP users (n=440, 1.0%) were more likely than condom users to have ≥11 lifetime partners (OR=1.76; 95% CI 1.40-2.22), induced abortions (HR=1.44; 95% CI 1.11-1.86) and STIs (HR=1.84; 95% CI 1.56-2.16). A similar pattern was seen in safe periods/withdrawal users. The associations did not change among women with FSI in 2001 or later (n=14,445). CONCLUSIONS: Compared with condom use, contraceptive nonuse, safe periods/withdrawal use and ECP use at FSI were associated with subsequent number of sexual partners, induced abortions and STIs. IMPLICATIONS: Contraceptive method used at first intercourse was associated with subsequent sexual behaviors in women. This study highlights the importance of early sexual behaviors and may help understand patterns of women's sexual behaviors.

Self-perceived risk of STIs in a population-based study of Scandinavian women.

OBJECTIVE: This study examined the associations between current behaviours/characteristics and self-perceived risk for STIs, among randomly selected women aged 18-45 years from Denmark, Norway and Sweden. METHOD: A population-based, cross-sectional, questionnaire study (paper based, web based and telephone based) was conducted during 2011-2012. We compared medium-high STI risk perception with no/low risk perception. The associations were explored for women who had ever had sexual intercourse and for women with a new partner in the last 6 months using multivariable logistic regression. RESULT: The overall prevalence of medium-high STI risk perception was 7.4%. It was highest among women aged 18-24 years (16.2%) and among the Danish women (8.8%). Number of new sexual partners in the last 6 months (≥3vs 0 partners, OR 14.94, 95% CI 13.20 to 16.94) was strongly associated with medium-high STI risk perception. Among women with a new partner in the last 6 months, lack of condom use increased medium-high STI risk perception (OR 1.73, 95% CI 1.52 to 1.96). Genital warts in the last year, binge drinking and being single were associated with increased risk perception and remained statistically significant after additional adjustments were made for number of new partners and condom use with new partners in the last 6 months. CONCLUSION: Subjective perception of risk for STI was associated with women's current risk-taking behaviours, indicating women generally are able to assess their risks for STIs. However, a considerable proportion of women with multiple new partners in the last 6 months and no condom use still considered themselves at no/low risk for STI.

Risk of borderline ovarian tumors among women with benign ovarian tumors: A cohort study.

OBJECTIVE: A growing number of studies suggest that some ovarian cancers can arise from benign and borderline ovarian tumors. However, studies on the association between benign and borderline ovarian tumors are lacking. We studied the overall- and histotype-specific risk of borderline ovarian tumors among women with a benign ovarian tumor. METHODS: This nationwide cohort study included all Danish women diagnosed with a benign ovarian tumor (n=139,466) during 1978-2012. The cohort was linked to the Danish Pathology Data Bank and standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated. RESULTS: Women with benign ovarian tumors had increased risks for subsequent borderline ovarian tumors (SIR 1.62, 95% CI 1.43-1.82), and this applied to both serous (SIR 1.69, 95% CI 1.39-2.03) and mucinous (SIR 1.75, 95% CI 1.45-2.10) histotypes of borderline ovarian tumors. The risk for borderline ovarian tumors was primarily increased for women diagnosed with a benign ovarian tumor before 40years of age. The risk remained increased up to 9years after a benign ovarian tumor diagnosis. Finally, the associations did not change markedly when analyzed for the different histotypes of benign (solid and cystic tumors) and borderline (serous and mucinous tumors) ovarian tumors. CONCLUSIONS: Women with benign ovarian tumors have a long-term increased risk for borderline ovarian tumors. However, as all associations in this study were only adjusted for age and calendar period of diagnosis, more studies that are able to adjust for additional potential confounding variables are required to further understand these associations.

Contraceptive non-use and emergency contraceptive use at first sexual intercourse among nearly 12 000 Scandinavian women.

INTRODUCTION: The aim of this study was to describe recent patterns of contraceptive use at first sexual intercourse and to examine whether selected factors are associated with non-use and emergency contraceptive pill use at first sexual intercourse, among 18- to 26-year-old women from Denmark, Norway and Sweden. MATERIAL AND METHODS: This was a population-based, questionnaire study of randomly chosen 18- to 26-year-old Scandinavian women. The prevalence of contraception methods used at first sexual intercourse was calculated. Factors associated with contraceptive non-use and emergency contraceptive pill use at first sexual intercourse were determined using log binomial models. RESULTS: The prevalence of contraceptive non-use and emergency contraceptive pill use was lowest in Denmark (9.6 and 2.1%, respectively) compared with Norway (14.1 and 4.4%) and Sweden (16.6 and 4.5%). The risk of contraceptive non-use increased in women who had first sexual intercourse at or before 14 years of age (13-14 years: prevalence ratio 1.40; 95% confidence interval 1.24-1.58). The risk of both non-use and emergency contraceptive pill use increased when the partner at first sexual intercourse was 20 years or older, and with increasing age difference between the partner and the woman at her first sexual intercourse. Smoking initiation prior to first sexual intercourse increased risk of contraceptive non-use (prevalence ratio 1.70; 95% confidence interval 1.50-1.92), and alcohol initiation prior to first sexual intercourse increased risk of emergency contraceptive pill use at first sexual intercourse (prevalence ratio 1.95; 95% confidence interval 1.49-2.54). CONCLUSIONS: Contraceptive non-use at first sexual intercourse was strongly associated with early age at first sexual intercourse. Emergency contraceptive pill and contraceptive non-use at first sexual intercourse were both strongly associated with increasing partner age and an increasing difference in age between the woman and her partner. Hence, young women should be educated to negotiate contraceptive use with their partners.

Primary peritoneal angiosarcoma: a case report.

Peritoneal angiosarcoma is an extremely rare sarcoma (0.01287% incidence per 100,000) with an aggressive clinical course and a poor prognosis. We herein report a case of a young man with diagnosis of angiosarcoma whose tumor adhering to the inferior wall of his bladder and omentum was initially thought to be rhabdomyosarcoma. His disease state progressively worsened, despite initiation of different types of chemotherapies. Blood was tested for cytokine and soluble receptor levels. Unexpectedly and never previously reported, very high levels of interleukin-6 (IL-6), osteopontin, and prolactin were found. Surprisingly, angiogenic cytokines levels were low. The patient died 5 months after initial presentation. In the present report, we discuss the difficulties in diagnosing this rare sarcoma and possible therapeutic targets, including the IL-6 pathway that may provide more effective ways in controlling this cancer in its metastatic stage.