Depression risk in users of different doses of levonorgestrel intrauterine systems: a nationwide prospective cohort study.

Background: Use of the high-dose levonorgestrel-releasing intrauterine system (LNG-IUS) has been associated with increased risk of incident depression. Evidence is lacking on the influence of use of two recently marketed low-dose LNG-IUS on risk of depression. This study aims to examine associations between use of different doses of LNG-IUS and risk of depression. Methods: We conducted a nationwide prospective cohort study involving all first-time users of an LNG-IUS among all Danish nulliparous women aged 15-34 years with no medical history of depression, major psychiatric diseases, endometriosis, heavy menstrual bleeding, polyp, myoma, dysmenorrhoea, iron supplement use, abortion, and infertility treatment. Findings: A total of 46,565 first-time users of LNG-IUS were followed for 80,516 person-years with 1,531 incident initiations of antidepressant use observed during follow-up. Use of the high-dose LNG-IUS containing 52 mg levonorgestrel was initiated by 9,902 (21%) women, while 20,665 (44%), and 15,998 (34%) initiated use of the low-dose LNG-IUS containing 19·5 mg and 13·5 mg levonorgestrel, respectively.The age-, calendar-time-, and education-standardised incidence rates of first-time depression per 1,000 person-years at full LNG-IUS duration were 30.8 (95% CI 23·6-39·5) for the 52 mg LNG-IUS, 19·8 (95% CI 16·1; 24·0) for the 19·5 mg LNG-IUS, and 17·7 (95% CI 14·4-21·5) for the 13·5 mg LNG-IUS-. Compared to the high-dose 52 mg LNG-IUS, the adjusted number of avoided depressions per 1,000 person-years were 11·0 (95% CI 7·1-14·9) for the 19·5 mg LNG-IUS and 13·1 (95% CI 9·6-16·6) for the 13·5 mg LNG-IUS. The corresponding adjusted rate ratios were 0·77 (95% CI 0·68; 0·88) and 0·85 (95% CI 0·75-0·96). The reduced risk of depression with low-dose LNG-IUS compared to high-dose LNG-IUS was observable throughout duration of use. Interpretation: Use of low-dose LNG-IUS containing 19·5 mg and 13·5 mg levonorgestrel, respectively, were associated with a reduced risk of incident depression compared to use of the high-dose 52 mg LNG-IUS. The study suggests that low-dose LNG-IUS should be preferred over the high-dose LNG-IUS for contraceptive purpose. Funding: Sygeforsikringen "Danmark" grant: 2021-0128.

Sleep apnea, the risk of out-of-hospital cardiac arrest, and potential benefits of continuous positive airway pressure therapy: A nationwide study.

OBJECTIVE: Patients with sleep apnea (SA) are at increased cardiovascular risk. However, little is known about the risk of out-of-hospital cardiac arrest (OHCA) in patients with SA. Therefore, we studied the relation between SA patients who did and did not receive continuous positive airway pressure (CPAP) therapy with OHCA in the general population. METHODS: Using nationwide databases, we conducted a nested case-control study with OHCA-cases of presumed cardiac causes and age/sex/OHCA-date matched non-OHCA-controls from the general population. Conditional logistic regression models with adjustments for well-known OHCA risk factors were performed to generate odds ratio (OR) of OHCA comparing patients with SA receiving and not receiving CPAP therapy with individuals without SA. RESULTS: We identified 46,578 OHCA-cases and 232,890 matched non-OHCA-controls [mean: 71 years, 68.8% men]. Compared to subjects without SA, having SA without CPAP therapy was associated with increased odds of OHCA after controlling for relevant confounders (OR:1.20, 95%-Cl:1.06-1.36), while having SA with CPAP therapy was not associated with OHCA (OR:1.04, 95%-Cl:0.93-1.36). Regardless of CPAP therapy, age and sex did not significantly influence our findings. Our findings were confirmed in: (I) patients with neither ischemic heart disease nor heart failure (untreated SA, OR:1.24, 95%-CI:1.04-1.47; SA with CPAP, OR:1.08, 95%-CI:0.93-1.25); and (II) in patients without cardiovascular disease (untreated SA, OR:1.33, 95%-CI:1.07-1.65; SA with CPAP, OR:1.14, 95%-CI:0.94-1.39). CONCLUSION: SA not treated with CPAP was associated with OHCA, while no increased risk of OHCA was found for SA patients treated with CPAP.

Association between Glucagon-like Peptide-1 Receptor Agonists and the Risk of Glaucoma in Individuals with Type 2 Diabetes.

PURPOSE: To examine the association between Glucagon-like Peptide-1 Receptor Agonists (GLP-1RA) use and the development of glaucoma in individuals with type 2 diabetes. DESIGN: Nationwide, nested case-control study. PARTICIPANTS: From a nationwide cohort of 264708 individuals, we identified 1,737 incident glaucoma cases and matched them to 8685 glaucoma-free controls, all aged above 21 years old and treated with metformin and a second-line antihyperglycemic drug formulation, with no history of glaucoma, eye trauma or eye surgery. METHODS: Cases were incidence density matched to five controls by birth year, sex, and date of second-line treatment initiation. MAIN OUTCOME MEASURES: Conditional logistic regression was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for glaucoma, defined by first-time diagnosis, first-time use of glaucoma-specific medication, or first-time glaucoma-specific surgical intervention. RESULTS: Compared with the reference group, who received treatments other than GLP-1RA, individuals who were exposed to GLP-1RA treatment exhibited a lower risk of incident glaucoma (HR: 0.81, CI: 0.70 - 0.94, p = 0.006). Prolonged treatment extending beyond three years lowered the risk even further (HR: 0.71, CI: 0.55 - 0.91, p = 0.007). Treatment with GLP-1RA for 0 - 1 years (HR: 0.89, CI: 0.70 - 1.14, p = 0.35) and 1 - 3 years (HR: 0.85, CI: 0.67 - 1.06, p = 0.15) were not significant. CONCLUSIONS: GLP-1RA exposure was associated with a lower risk of developing glaucoma compared to receiving other second-line antihyperglycemic medication.

Association of vaginal oestradiol and the rate of breast cancer in Denmark: registry based, case-control study, nested in a nationwide cohort.

Objective: To estimate the rate of breast cancer associated with use of vaginal oestradiol tablets according to duration and intensity of their use. Design: Registry based, case-control study, nested in a nationwide cohort. Setting: Based in Denmark using the civil registration system, the national registry of medicinal product statistics, the Danish cancer registry, the Danish birth registry, and statistics Denmark. Participants: Women aged 50-60 years in year 2000 or turning 50 years during the study period of 1 January 2000 to 31 December 2018 were included. Exclusions were a history of cancer, mastectomy, use of systemic hormone treatment, use of the levonorgestrel releasing intrauterine system, or use of vaginal oestrogen treatments other than oestradiol tablets. To each woman who developed breast cancer during follow-up (18 997), five women in the control group (94 985) were incidence density matched by birth year. Main outcome measure: The main outcome was pathology confirmed breast cancer diagnosis. Results: 2782 (14.6%) women with breast cancer (cases) and 14 999 (15.8%) women with no breast cancer diagnosis (controls) had been exposed to vaginal oestradiol tablets with 234 cases and 1232 controls having been in treatment for at least four years at a high intensity (>50 micrograms per week). Increasing durations and intensities of use (cumulative dose/cumulative duration) of vaginal oestradiol tablets was not associated with increasing rates of breast cancer. Compared with never-use, cumulative use of vaginal oestradiol for more than nine years was associated with an adjusted hazard ratio of 0.87 (95% confidence interval 0.69 to 1.11). Results were similar in women who had long term use (≥four years) and with high intensity of use (>50-70 micrograms per week) with an adjusted hazard ratio 0.93 (95% confidence interval 0.81 to 1.08). Conclusions: Use of vaginal oestradiol tablets was not associated with increased breast cancer rate compared with never-use. Increasing duration and intensity of use was not associated with increased rates of breast cancer.

Dementia in Women Using Estrogen-Only Therapy.

This study examines the association between use of estrogen-only therapy for perimenopausal and menopausal women and risk of dementia.

Menopausal hormone therapy and central nervous system tumors: Danish nested case-control study.

BACKGROUND: Use of estrogen-containing menopausal hormone therapy has been shown to influence the risk of central nervous system (CNS) tumors. However, it is unknown how the progestin-component affects the risk and whether continuous versus cyclic treatment regimens influence the risk differently. METHODS AND FINDINGS: Nested case-control studies within a nationwide cohort of Danish women followed for 19 years from 2000 to 2018. The cohort comprised 789,901 women aged 50 to 60 years during follow-up, without prior CNS tumor diagnosis, cancer, or contraindication for treatment with menopausal hormone therapy. Information on cumulative exposure to female hormonal drugs was based on filled prescriptions. Statistical analysis included educational level, use of antihistamines, and use of anti-asthma drugs as covariates. During follow-up, 1,595 women were diagnosed with meningioma and 1,167 with glioma. The median (first-third quartile) follow-up time of individuals in the full cohort was 10.8 years (5.0 years to 17.5 years). Compared to never-use, exposure to estrogen-progestin or progestin-only were both associated with increased risk of meningioma, hazard ratio (HR) 1.21; (95% confidence interval (CI) [1.06, 1.37] p = 0.005) and HR 1.28; (95% CI [1.05, 1.54] p = 0.012), respectively. Corresponding HRs for glioma were HR 1.00; (95% CI [0.86, 1.16] p = 0.982) and HR 1.20; (95% CI [0.95, 1.51] p = 0.117). Continuous estrogen-progestin exhibited higher HR of meningioma 1.34; (95% CI [1.08, 1.66] p = 0.008) than cyclic treatment 1.13; (95% CI [0.94, 1.34] p = 0.185). Previous use of estrogen-progestin 5 to 10 years prior to diagnosis yielded the strongest association with meningioma, HR 1.26; (95% CI [1.01, 1.57] p = 0.044), whereas current/recent use of progestin-only yielded the highest HRs for both meningioma 1.64; (95% CI [0.90, 2.98] p = 0.104) and glioma 1.83; (95% CI [0.98, 3.41] p = 0.057). Being an observational study, residual confounding could occur. CONCLUSIONS: Use of continuous, but not cyclic estrogen-progestin was associated with increased meningioma risk. There was no evidence of increased glioma risk with estrogen-progestin use. Use of progestin-only was associated with increased risk of meningioma and potentially glioma. Further studies are warranted to evaluate our findings and investigate the influence of long-term progestin-only regimens on CNS tumor risk.

Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study.

OBJECTIVE: To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism. DESIGN: Nationwide cohort study. SETTING: Denmark through national registries. PARTICIPANTS: All 15-49 year old women living in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment (n=2 029 065). MAIN OUTCOME MEASURE: A first time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism. RESULTS: Among 2.0 million women followed for 21.0 million person years, 8710 venous thromboembolic events occurred. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 7.2 (95% confidence interval 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception. CONCLUSIONS: NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age. The number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception. Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.

Central nervous system tumours among users of vaginal oestradiol tablets: A nationwide population-based study.

BACKGROUND AND PURPOSE: It is currently unknown whether vaginal oestradiol is associated with development of meningioma and glioma. The aim of this study was to examine associations between cumulative use and treatment intensity of vaginally administered oestradiol tablets and incidence of meningioma and glioma in a nationwide, population-based study. METHODS: We conducted a nested case-control study within a nationwide cohort of Danish women followed from 2000 to 2018. The cohort consisted of 590,676 women aged 50-60 years at study start, without prior cancer diagnosis or use of systemic hormone therapy. Information on cumulative dose, duration, and intensity of vaginal oestradiol tablet use was assessed from filled prescriptions. Conditional logistic regression provided adjusted hazard ratios (HRs) for the association between vaginal oestradiol use and diagnosis of meningioma or glioma. RESULTS: We identified 1108 women with meningioma and 835 with glioma. Of these, 19.8% and 14.0% used vaginal oestradiol tablets, respectively. The HRs in those with ever-use of vaginal oestradiol tablets was 1.14 (95% confidence interval [CI] 0.97-1.34) for meningioma and 0.90 (95% CI 0.73-1.11) for glioma. The corresponding HRs for new users exclusively were 1.18 (95% CI 0.99-1.40) for meningioma and 0.89 (95% CI 0.71-1.13) for glioma. Intensity of vaginal oestradiol tablet use according to duration and user status yielded slightly elevated HRs for meningioma without an apparent dose-response pattern, while the HRs for glioma were generally below unity. Among new users, the HR with high intensity of current or recent vaginal oestradiol tablet use for 2+ years was 1.66 (95% CI 1.09-2.55) for meningioma and 0.77 (95% CI 0.41-1.44) for glioma. CONCLUSION: Use of vaginal oestradiol tablets was associated with a slightly increased incidence of meningioma but not of glioma. Owing to the observational nature of the study, residual bias cannot be ruled out.

Menopausal hormone therapy and dementia: nationwide, nested case-control study.

OBJECTIVES: To assess the association between use of menopausal hormone therapy and development of dementia according to type of hormone treatment, duration of use, and age at usage. DESIGN: Nationwide, nested case-control study. SETTING: Denmark through national registries. PARTICIPANTS: 5589 incident cases of dementia and 55 890 age matched controls were identified between 2000 and 2018 from a population of all Danish women aged 50-60 years in 2000 with no history of dementia or contraindications for use of menopausal hormone therapy. MAIN OUTCOME MEASURES: Adjusted hazard ratios with 95% confidence intervals for all cause dementia defined by a first time diagnosis or first time use of dementia specific medication. RESULTS: Compared with people who had never used treatment, people who had received oestrogen-progestogen therapy had an increased rate of all cause dementia (hazard ratio 1.24 (95% confidence interval 1.17 to 1.33)). Increasing durations of use yielded higher hazard ratios, ranging from 1.21 (1.09 to 1.35) for one year or less of use to 1.74 (1.45 to 2.10) for more than 12 years of use. Oestrogen-progestogen therapy was positively associated with development of dementia for both continuous (1.31 (1.18 to 1.46)) and cyclic (1.24 (1.13 to 1.35)) regimens. Associations persisted in women who received treatment at the age 55 years or younger (1.24 (1.11 to 1.40)). Findings persisted when restricted to late onset dementia (1.21 (1.12 to 1.30)) and Alzheimer's disease (1.22 (1.07 to 1.39)). CONCLUSIONS: Menopausal hormone therapy was positively associated with development of all cause dementia and Alzheimer's disease, even in women who received treatment at the age of 55 years or younger. The increased rate of dementia was similar between continuous and cyclic treatment. Further studies are warranted to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments.

Hormonal Contraceptives Are Associated With an Increase in Incidence of Asthma in Women.

BACKGROUND: Use of exogenous female sex hormones is associated with the development of asthma, but the question of whether the effect is protective or harmful remains unresolved. OBJECTIVE: To investigate whether initiation of hormonal contraceptive (HC) treatment was associated with development of asthma. METHODS: We performed a register-based, exposure-matched cohort study including women who initiated HC treatment of any kind between 10 and 40 years of age and compared the incidence of asthma with women who did not initiate HCs. Asthma was defined as 2 redeemed prescriptions of inhaled corticosteroids within 2 years. Data were analyzed using Cox regression models adjusted for income and urbanization. RESULTS: We included 184,046 women with a mean age of 15.5 years (SD 1.5 y), in which 30,669 initiated HC treatment and 153,377 did not. We found that initiation of HCs was associated with an increased hazard ratio (HR) of developing new asthma by 1.78 (95% CI 1.58-2.00; P < .001). The cumulative risk of new asthma was 2.7% after 3 years among users of HCs compared with 1.5% in nonusers. In the different subtypes of HCs, second- and third-generation contraceptives carried significant associations (second-generation HR 1.76; 95% CI 1.52-2.03; P < .001; third-generation HR 1.62 95% CI 1.23-2.12; P < .001). The association with increased incidence was seen only in women younger than 18 years. CONCLUSIONS: In this study, first-time users of HCs had an increased incidence of asthma compared with nonusers. Clinicians prescribing HCs should be aware that airway symptoms may develop.

Ectopic Pregnancy Risk in Users of Levonorgestrel-Releasing Intrauterine Systems With 52, 19.5, and 13.5 mg of Hormone.

This study assesses the association between use of levonorgestrel intrauterine systems containing 52, 19.5, and 13.5 mg of hormone and ectopic pregnancy in a nationwide cohort study.

Ultrasonographic features of the endometrium following successful medical termination of early pregnancy.

OBJECTIVE: Ultrasonographic features of the endometrium are often assessed when deciding the necessity of surgical intervention following early medical abortion. Knowledge is therefore needed on the ultrasonographic appearance of the endometrium following successful medical abortion in order to avoid unnecessary surgical interventions. We aimed to assess endometrial thickness and echogenicity at multiple time points following successful early medical abortion. STUDY DESIGN: We conducted a retrospective study in the largest office-based abortion providing clinic in Denmark. Using archived ultrasonographic images, we assessed endometrial thickness and echogenicity following all early medical abortions that did not need surgical intervention or repeated medication for completion during the years 2014-2017. RESULTS: Ultrasonographic endometrial features were assessed 1854 times following 1074 early medical abortions. Median endometrial thickness in the 1st week from induction was 13 milimeters (mm; lower-upper quartile 11-17 mm). For the 2nd, 3rd, 4th, and >4th week, the median endometrial thickness was found to be 11 mm (9-15 mm), 11 mm (8-14 mm), 12 mm (9-16 mm), and 11 mm (8-14 mm), respectively. Of the ultrasonographic examinations performed in the 1st week from medical induction, 24.7 % showed a heterogenous endometrium. For 2nd, 3rd, 4th, >4th week, the frequency of heterogeneity was 23.9 %, 16.3 %, 21.3 %, 18.9 %, respectively. A total of 151 abortions (14.1 %) were each examined three times, median time of examination being day 7, 15, and 26 following induction. Among these abortions, the three most common patterns of change in endometrial thickness were "decreasing" (37.7 %), "increasing-decreasing" (23.2 %), and "decreasing-increasing" (21.9 %). Further, 49.7 % of the 151 abortions showed a homogenous endometrium at all three examinations, 17.2 % showed a heterogenous endometrium at first examination and a homogenous endometrium the following two examinations, and 9.9 % showed a heterogenous endometrium at the first two examinations followed by a homogenous endometrium. CONCLUSION: In early medical abortions completed without secondary intervention, endometrial thickness and echogenicity varied clinically significantly for weeks following the medical induction. Every possible pattern of change in endometrial thickness and echogenicity was observed.

Hormonal contraception use before and after breast cancer diagnosis: A nationwide drug utilization study.

PURPOSE: To describe the use of hormonal contraceptives in Danish breast cancer patients. METHODS: Nationwide drug utilization study in Danish women diagnosed with breast cancer at ages 13-50 years during 2000-2015. User proportions were estimated in 6-months intervals from 2 years before to 2 years after diagnosis. RESULTS: Use of hormonal contraceptives declined sharply after breast cancer diagnosis. Still, 7% of patients aged 13-39 years filled hormonal contraceptive prescriptions within 6 months after the diagnosis. CONCLUSIONS: The majority of premenopausal breast cancer patients discontinues hormonal contraception at diagnosis. All prescribers of hormonal contraceptives should acknowledge that hormonal contraception is contraindicated for breast cancer patients. PLAIN LANGUAGE SUMMARY: Use of hormonal contraception is contraindicated among women with breast cancer. In this nationwide study, we assessed the use of hormonal contraceptives among all Danish premenopausal women diagnosed with breast cancer during 2000-2015. Hormonal contraceptive use was assessed within 2 years before and 2 years after breast cancer diagnosis. The majority of patients discontinued hormonal contraception at breast cancer diagnosis. However, 7% of patients aged 13-39 years filled hormonal contraceptive prescriptions within 6 months after the diagnosis.

Inhaled anti-asthma therapies following hormone therapy in women: a nationwide cohort study.

Research question: Does menopausal hormone therapy (HT) with exogenous oestrogens and progestogens change the use of inhaled anti-asthma medications in women with asthma? Methods: In a population-based matched cohort study using the Danish registries, we included women with asthma aged 45-65 years from 1 June 1995 to 30 June 2018. We investigated whether HT with oestrogen and/or progestogens was associated with changes in use of inhaled anti-asthma therapies in the 12 months following initiation. We used exposure density matching to match exposed subjects with unexposed subjects on age, household income and level of education. An exposed subject was defined as receiving HT. We calculated mean dose of medications and odds ratios of increases in the 12 months following HT initiation. Results: We included 139 483 women with asthma, of whom 116 014 (83.2%) were unexposed subjects and 23 469 (16.8%) exposed subjects. Mean±sd age was 53.0±5.2 years. Initiation of HT was not consistently associated with increased mean doses of inhaled corticosteroids (ICS), or long- and short-acting ß2-agonists. Women receiving systemic oestrogens had increased odds ratios of large increases (>100 µg) in ICS at 6 months (OR 1.09; 95% CI 1.04-1.13; p<0.001) and 9 months (OR 1.07; 95% CI 1.03-1.12; p<0.001). Progestogens were protective against increases in ICS at 6 and 9 months (OR 0.87; 95% CI 0.82-0.93; p<0.001; and OR 0.86; 95% CI 0.81-0.91; p<0.001). Conclusion: Initiation of HT did not change the use of inhaled medications in asthma. However, detrimental effects of oestrogen, as well as beneficial effects of progestogens, cannot be excluded.

Vaginal estrogen and association with dementia: A nationwide population-based study.

INTRODUCTION: Use of systemic hormone therapy has been positively associated with development of dementia. Little is known about the dose-dependent effect of vaginal estradiol on dementia risk. METHODS: We assessed associations between cumulative dose of vaginal estradiol tablets and dementia in a case-control study nested in a nationwide Danish cohort of women aged 50 to 60 years at study initiation, who did not use systemic hormone therapy. Each case was age-matched to 10 female controls. RESULTS: A total of 4574 dementia cases were matched to 45,740 controls. Cumulative use of vaginal estradiol tablets was not associated with all-cause dementia; adjusted hazard ratio 1.02 (95% confidence interval [CI] 0.89-1.18) for low dose (< 750 mcg), 1.07 (0.94-1.21) for medium dose (750-2000 mcg), and 0.93 (0.84-1.03) for high dose (> 2000 mcg). Similarly, Alzheimer's disease (AD) only was not associated with vaginal estradiol. DISCUSSION: Exposure to vaginal estradiol tablets was not associated with all-cause dementia or AD only.