Prediagnostic use of menopausal hormone therapy and long-term survival of localized epithelial ovarian cancer: The Extreme study.

Use of menopausal hormone therapy (MHT) prior to an epithelial ovarian cancer (EOC) diagnosis has been suggested to be associated with improved survival. In a recent nationwide cohort study, we found that prediagnostic long-term MHT use, especially estrogen therapy (ET), was associated with improved long-term survival in women with nonlocalized EOC. Our aim was to investigate the influence of prediagnostic MHT use on long-term survival among women with localized EOC in the same nationwide study. Our study cohort comprised all women aged 50 years or older with an EOC diagnosis in Denmark 2000-2014 (n = 2097) identified from the Extreme study. We collected information on usage of systemic ET and estrogen plus progestin therapy (EPT) from the Danish National Prescription Registry. By using pseudo-values, 5- and 10-year absolute and relative survival probabilities were estimated with 95% confidence intervals (CIs) while adjusting for histology, comorbidity, and income. Relative survival probabilities >1 indicate better survival. The 5-year absolute survival probabilities were 61% and 56%, respectively, among women who were nonusers and users of prediagnostic MHT, whereas these numbers were 46% and 41%, respectively, regarding 10-year survival. Use of MHT was not significantly associated with an improved 5- or 10-year survival in women with localized EOC (5-year relative survival probability = 0.95, 95% CI: 0.89-1.02; 10-year relative survival probability = 0.92, 95% CI: 0.84-1.02). Similar findings were seen for systemic ET or EPT use. Our findings do not suggest a positive benefit from prediagnostic MHT use on long-term survival of localized EOC.

TNM stage in the Nordic Cancer Registries 2004-2016: Registration and availability.

BACKGROUND AND PURPOSE: Stage at cancer diagnosis is an important predictor of cancer survival. TNM stage is constructed for anatomic solid cancer diagnoses from tumor size (T), nodal spread (N) and distant metastasis (M) and categorized in groups 0-I, II, II and IV. TNM stage is imperative in cancer diagnosis, management and control, and of high value in cancer surveillance, for example, monitoring of stage distributions. This study yields an overview of TNM availability and trends in stage distribution in the Nordic countries for future use in monitoring and epidemiologic studies. MATERIAL AND METHODS: TNM information was acquired from the cancer registries in Denmark, Norway, Sweden, and Iceland during 2004-2016 for 26 cancer sites in the three former countries and four in Iceland. We studied availability, comparability, and distribution of TNM stage in three periods: 2004-2008, 2009-2013, and 2014-2016, applying a previously validated algorithm of 'N0M0 for NXMX'. For cancers of colon, rectum, lung, breast, and kidney, we examined TNM stage-specific 1-year relative survival to evaluate the quality in registration of TNM between countries. RESULTS: Denmark, Sweden, and Iceland exhibited available TNM stage proportions of 75-95% while proportions were lower in Norway. Proportions increased in Sweden over time but decreased in Denmark. One-year relative survival differed substantially more between TNM stages than between countries emphasizing that TNM stage is an important predictor for survival and that stage recording is performed similarly in the Nordic countries. INTERPRETATION: Assessment and registration of TNM stage is an imperative tool in evaluations of trends in cancer survival between the Nordic countries.

Potential preventive properties of GLP-1 receptor agonists against prostate cancer: a nationwide cohort study.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been suggested to possess antineoplastic properties against prostate cancer. We examined the association between GLP-1RA use and prostate cancer risk in a real-world setting. METHODS: We performed a nationwide register-based cohort study using an active-comparator, new-user design. We included all men in Denmark aged ≥50 years who commenced use of GLP-1RAs or basal insulin during 2007-2019. HRs and 95% CIs for incident prostate cancer were estimated using multivariable Cox regression in 'intention-to-treat' (ITT)- and 'per-protocol'-like analyses. RESULTS: Among 14,206 initiators of GLP-1RAs and 21,756 initiators of basal insulin, we identified 697 patients with prostate cancer during a mean follow-up period of about 5 years from initiation of the study drugs. In comparison with basal insulin use, GLP-1RA use was associated with an adjusted HR of 0.91 (95% CI 0.73, 1.14) in the 'ITT' analysis and 0.80 (95% CI 0.64, 1.01) in the 'per-protocol' analysis. Stronger inverse associations were seen among older men (≥70 years) ('ITT' HR 0.56; 95% CI 0.38, 0.82; 'per-protocol' HR 0.47; 95% CI 0.30, 0.74), and in patients with CVD ('ITT' HR 0.75; 95% CI 0.53, 1.06; 'per-protocol' HR 0.60; 95% CI 0.39, 0.91). CONCLUSIONS/INTERPRETATION: GLP-1RA use was inversely associated with prostate cancer risk compared with use of basal insulin in the 'per-protocol' analysis. Older men and patients with CVD exhibited stronger inverse associations in both the 'ITT' and 'per-protocol' analyses. Our results may indicate that GLP-1RA use could protect against prostate cancer.

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.

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.

Influence of various assumptions for the individual TNM components on the TNM stage using Nordic cancer registry data.

BACKGROUND: The stage at diagnosis is one of the most important predictors for cancer survival. TNM stage is constructed from T (tumor size), N (nodal spread), and M (distant metastasis) components. In many notifications to cancer registries, TNM information is incomplete with unknown N and/or M. We aimed to evaluate the influence of various assumptions for recoding missing N (NX) and M (MX) as N0 and M0 on the proportion with available TNM stage, stage-distribution, and stage-specific relative survival. MATERIAL AND METHODS: We identified 140,201 patients diagnosed with incident cancer of the colon, rectum, lung, breast, or kidney during 2014-2016 in Denmark, Norway, Sweden, or Iceland. Information on TNM were obtained from cancer registry records used for an update of the Nordic cancer statistics database NORDCAN. Patients were followed for death or emigration through 2017. We calculated proportions of available TNM stage, stage distribution, and stage-specific relative survival under different approaches for each cancer site and country. RESULTS: Application of the assumptions yielded higher numbers of cases with available TNM stage for stages 0-I, II, and III. We observed only minor differences in stage-specific one-year relative survival when applying N0M0 for missing N and M, especially for high completeness of TNM registrations, whereas relative survival for remaining cases with missing TNM stage declined substantially. CONCLUSION: We found no major changes in stage-specific one-year relative survival applying N0M0 for NXMX. We conclude that complete TNM information is preferable to making assumptions, but it seems reasonable to consider assuming N0M0 for missing N and M in future studies based on the Nordic cancer registries. An automatic algorithm, though, is not recommended without considering potential area-specific reasons for frequent use of NX and MX. Clinicians should be urged to report complete TNM information to improve surveillance of the TNM stage.

Long-term survival of nonlocalized epithelial ovarian cancer among women using menopausal hormone therapy prior to diagnosis: The extreme study.

Prediagnostic use of menopausal hormone therapy (MHT) has been suggested to be associated with improved survival of epithelial ovarian cancer (EOC). We investigated the potential long-term survival benefit of prediagnostic MHT use in women ≥50 years with nonlocalized EOC using the Extreme study including all women in Denmark registered with nonlocalized EOC during 2000 to 2014 (N = 3776). We obtained individual-level information on prediagnostic use of systemic estrogen therapy (ET) and estrogen plus progestin therapy (EPT) from the National Prescription Registry and estimated absolute and relative 5- and 10-year survival probabilities with 95% confidence intervals (CIs) using pseudo-values, taking into account histology, comorbidity, income and residual disease. Among women not having used prediagnostic MHT, 5- and 10-year absolute survival probabilities were 19% and 11%, respectively. Compared to MHT nonusers, prediagnostic systemic ET use for 3 to 4 years and ≥ 5 years was associated with 1.43 (95% CI: 1.01-2.02) and 1.22 (95% CI: 0.96-1.55) times higher 5-year survival probabilities, respectively. Ten-year survival probabilities were also increased but not statistically significantly. Among prediagnostic EPT users, increased 5-year (1.14, 95% CI: 0.85-1.53) and 10-year (1.38, 95% CI: 0.91-2.08) survival probabilities were observed after use for 3 to 4 years compared to MHT nonuse, whereas EPT use for ≥5 years was not associated with long-term survival of nonlocalized EOC. Our findings may suggest a better long-term survival of nonlocalized EOC in women having used long-term prediagnostic ET. However, the statistical precision of our results did not allow firm conclusions and more studies are needed.

Association Between Maternal Hormonal Contraception Use and Central Nervous System Tumors in Children.

Importance: The incidence of central nervous system (CNS) tumors in children appears to be increasing, yet few risk factors are established. There is limited information regarding whether maternal hormonal contraception use increases this risk. Objective: To examine the association between maternal hormonal contraception use and CNS tumors in children (<20 years). Design, Setting, and Participants: In this nationwide cohort study based on population-based registry data, 1 185 063 children born in Denmark between January 1, 1996, and December 31, 2014, were followed up for a diagnosis of a CNS tumor (final follow-up on December 31, 2018). Exposures: Maternal hormonal contraception use was analyzed according to any use, regimen (combined/progestin only), and route of administration (oral/nonoral), categorized as recent use (≤3 months before start and during pregnancy), previous use (>3 months before start of pregnancy), and no use. For injections, implants, and intrauterine devices that are used for a different time period, the categorization was appropriately altered. Main Outcomes and Measures: Hazard ratio (HR) and incidence rate difference (IRD) of CNS tumors diagnosed at younger than 20 years. Results: After 15 335 990 person-years of follow-up (mean follow-up, 12.9 years), 725 children were diagnosed with a CNS tumor. The mean age at diagnosis was 7 years, and 342 (47.2%) of the diagnosed children were female. The adjusted incidence rate of CNS tumors per 100 000 person-years was 5.0 for children born to mothers with recent hormonal contraception use (n = 136 022), 4.5 for children born to mothers with previous use (n = 778 843), and 5.3 for children born to mothers with no use (n = 270 198). The corresponding HRs were 0.95 ([95% CI, 0.74-1.23]; 84 children with CNS tumors; IRD, -0.3 [95% CI, -1.6 to 1.0]) for recent use and 0.86 ([95% CI, 0.72-1.02]; 421 children with CNS tumors; IRD, -0.8 [95% CI, -1.7 to 0.0]) for previous use, compared with no use. No statistically significant associations were found for recent or previous use of oral combined, nonoral combined, oral progestin only, or nonoral products compared with no use of hormonal contraception. Conclusions and Relevance: Among Danish children, there was no statistically significant association between any maternal hormonal contraception use and CNS tumor risk.

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.

Maternal Medication Use and Childhood Cancer in Offspring-Systematic Review and Considerations for Researchers.

Cancer is an important cause of childhood mortality, yet the etiology is largely unknown. A combination of pre- and postnatal factors is thought to be implicated, including maternal medication use. We aimed to provide: 1) a systematic review of peer-reviewed publications on associations between maternal medication use and childhood cancer, with a focus on study design and methodology; and 2) suggestions for how to increase transparency, limit potential biases, and improve comparability in studies on maternal medication use and childhood cancer. We conducted a systematic search in the PubMed, Embase, Scopus, Cochrane, and Web of Science databases to June 8, 2020. Altogether, 112 studies were identified. The reviewed studies were heterogeneous in study design, exposure, and outcome classification. In 21 studies (19%), the outcome was any childhood cancer. Of the 91 papers that reported on specific types of cancer, 62% did not report the cancer classification system. The most frequently investigated medication groups were sex hormones (46 studies, excluding fertility medications), and antiinfectives (37 studies). Suggestions for strengthening future pharmacoepidemiologic studies on maternal medication use and childhood cancer relate to choice of cancer classification system, exposure windows, and methods for identification of, and control for, potential confounders.

The influence of marital status and partner concordance on participation in colorectal cancer screening.

BACKGROUND: Colorectal cancer screening program using a fecal immunochemical test aims to reduce morbidity and mortality through early detection. Although screening participation is free-of-charge, almost 40% of the invited individuals choose not to participate. To bring new insight into how non-participation can be identified and targeted, we examined the association between marital status and screening participation; with a focus on partner concordance in participation and sex differences. METHODS: This nationwide cross-sectional study included all Danish citizens aged 50-74 years, who were invited to colorectal cancer screening between 2014 and 2017. Logistic regression analysis was used to estimate odds ratio (OR) of participation while adjusting for sociodemographic variables. RESULTS: A total of 1 909 662 individuals were included in the analysis of which 62.7% participated in the screening program. Participation was highest among women. Stratified by marital status, screening participation was markedly lower in widowed (61.5%), divorced (54.8%) and single (47.3%), while participation reached 68.4% in married individuals. This corresponded to ORs of 0.59 (95% CI 0.58-0.59) for widowed, 0.56 (95% CI 0.55-0.56) for divorced and 0.47 (95% CI 0.47-0.48) for single, compared to married individuals. Individuals married to a participating partner were five times more likely to participate than married individuals with a non-participating partner, regardless of gender. CONCLUSIONS: Marital status was strongly associated with participation in colorectal cancer screening, and participation was even higher in married individuals with a participating partner. Future efforts to increase participation in colorectal cancer screening could potentially benefit from considering the role of partner concordance.

Contemporary Hormonal Contraception and the Risk of Breast Cancer.

BACKGROUND: Little is known about whether contemporary hormonal contraception is associated with an increased risk of breast cancer. METHODS: We assessed associations between the use of hormonal contraception and the risk of invasive breast cancer in a nationwide prospective cohort study involving all women in Denmark between 15 and 49 years of age who had not had cancer or venous thromboembolism and who had not received treatment for infertility. Nationwide registries provided individually updated information about the use of hormonal contraception, breast-cancer diagnoses, and potential confounders. RESULTS: Among 1.8 million women who were followed on average for 10.9 years (a total of 19.6 million person-years), 11,517 cases of breast cancer occurred. As compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26). This risk increased from 1.09 (95% CI, 0.96 to 1.23) with less than 1 year of use to 1.38 (95% CI, 1.26 to 1.51) with more than 10 years of use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer was still higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Risk estimates associated with current or recent use of various oral combination (estrogen-progestin) contraceptives varied between 1.0 and 1.6. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives (relative risk, 1.21; 95% CI, 1.11 to 1.33). The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person-years, or approximately 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year. CONCLUSIONS: The risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. (Funded by the Novo Nordisk Foundation.).

Rheumatoid arthritis and risk of spontaneous abortion: a Danish nationwide cohort study.

OBJECTIVES: To investigate the influence of RA or preclinical RA on the risk of spontaneous abortion (SA) while taking age and duration of RA into consideration. METHODS: By linkage of data from Danish national registries, we established a nationwide cohort of pregnancies in Denmark from 1 January 1977 to 31 December 2014. We used multiple logistic regression to estimate; odds ratios (OR) for SA in women with RA or preclinical RA, compared with women without, and OR for SA by maternal age in women with RA or preclinical RA. RESULTS: A total of 2 612 529 pregnancies were included. Women aged <35 years diagnosed with RA <5 years before pregnancy had an increased risk of SA (OR = 1.25 95% CI: 1.07, 1.48), compared with women without RA aged <35. Women at the same age diagnosed with RA ≥5 years before pregnancy had an OR of 1.14 (0.96-1.34), compared with women without. Among women with RA aged ≥35 years and women with preclinical RA at time of pregnancy, no increased risk of SA was found. The risk of SA increased by maternal age in both women with RA, preclinical RA and in women without. CONCLUSION: Among women aged <35 years, the risk of SA was higher in women with RA compared with women without. After the age of 35 years, the risk of SA was no different from that among women without RA, even though the risk of SA increased with increasing age.

Maternal use of hormonal contraception and risk of childhood ADHD: a nationwide population-based cohort study.

Although maternal use of hormones has been suspected of increasing the risk for childhood attention-deficit/hyperactivity disorder (ADHD), no study has examined hormonal contraception use in this context. We examined the association between maternal hormonal contraception use before or during pregnancy and ADHD risk in children. This nationwide population-based cohort study included 1,056,846 children born in Denmark between 1998 and 2014. Prescriptions for hormonal contraceptives redeemed by the mother was categorized as: no use, previous use (> 3 months before pregnancy), and recent use (≤ 3 months before or during pregnancy). Children were followed for ADHD, from birth until 31 December 2015. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). During 9,819,565 person-years of follow-up (median: 9.2), ADHD was diagnosed or a prescription for ADHD medication redeemed for 23,380 children (2.2%). The adjusted HR for ADHD was higher in children of mothers who had previously (HR 1.23; 95% CI 1.18-1.28) or recently (HR 1.30; 95% CI 1.24-1.37) used hormonal contraception than in those of mothers with no use. The highest estimates were seen for use of non-oral progestin products with HRs of 1.90 (95% CI 1.59-2.26) for previous use, 2.23 (95% CI 1.96-2.54) for recent use, and 3.10 (95% CI 1.62-5.91) for use during pregnancy. Maternal use of hormonal contraception was associated with an increased risk for ADHD in the offspring; more pronounced for non-oral progestin-only than other products.

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.

Maternal use of hormonal contraception and risk of childhood leukaemia: a nationwide, population-based cohort study.

BACKGROUND: Maternal hormonal contraception has been suspected of being linked to an increased risk of childhood cancer. The aim of this study was to assess the association between maternal use of hormonal contraception and diagnosis of leukaemia in their children. METHODS: In this cohort study, we followed a nationwide cohort of 1 185 157 liveborn children between 1996 and 2014 listed in the Danish Medical Birth Registry and identified those diagnosed with leukaemia in the Danish Cancer Registry. Redeemed prescriptions from the Danish National Prescription Registry provided information about maternal hormonal contraceptive use, categorised as: no use (never used contraception before birth; reference category), previous use (>3 months before start of pregnancy), and recent use (≤3 months before and during pregnancy). We also calculated risk estimates separately for maternal hormonal contraceptive use during pregnancy. The primary outcome of interest was a diagnosis of any leukaemia in the children. Secondary outcomes were diagnoses of lymphoid leukaemia and non-lymphoid leukaemia. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% CIs for risk of leukaemia in children. The Data Protection Agency registration number for this study is 2017-41-5221. FINDINGS: Between Jan 1, 1996, and Dec 31, 2014, the 1 185 157 liveborn children accumulated 11 114 290 person-years of follow-up (median 9·3 years, IQR 4·6-14·2), during which 606 children were diagnosed with leukaemia (465 with lymphoid leukaemia and 141 with non-lymphoid leukaemia). Children born to women with recent use of any type of hormonal contraception were at higher risk for any leukaemia than children of women who never used contraception (HR 1·46, 95% CI 1·09-1·96; p=0·011); and for exposure during pregancy the risk was 1·78 (0·95-3·31; p=0·070). No association was found between timing of use and risk for lymphoid leukaemia (HR 1·23, 95% CI 0·97-1·57, p=0·089, for previous use and 1·27, 0·90-1·80, p=0·167, for recent use); however, the HRs for non-lymphoid leukaemia were 2·17 (1·22-3·87; p=0·008) for recent use and 3·87 (1·48-10·15; p=0·006) for use during pregnancy. Hormonal contraception use close to or during pregnancy might have resulted in one additional case of leukaemia per about 50 000 exposed children, or 25 cases during the 9-year study period. INTERPRETATION: Our findings suggest the maternal hormonal use affects non-lymphoid leukaemia development in children. Since almost no risk factors have been established for childhood leukaemia, these findings suggest an important direction for future research into its causes and prevention. FUNDING: The Danish Cancer Research Foundation, the Arvid Nilssons Foundation, the Gangsted Foundation, the Harboe Foundation, and the Johannes Clemmesens Foundation.

Use of antidepressants and risk of epithelial ovarian cancer.

Antidepressants are widely prescribed among women to treat depression and anxiety disorders, but studies of their effects on gynecological cancer risk are sparse. We assessed associations between various antidepressants and risk of epithelial ovarian cancer. By using Danish nationwide registers, we identified all women (cases) aged 30-84 years with incident epithelial (serous, endometrioid, clear cell or mucinous) ovarian cancer during 2000-2011 (n = 4,103) and matched each case to 20 population controls (n = 58,706) by risk-set matching. Data on drug use (including tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants, and potential confounder drugs), medical and reproductive history and socioeconomic parameters, were obtained from nationwide registries. We used conditional logistic regression models to estimate adjusted odds ratios (ORs) and two-sided 95% confidence intervals (CIs) for epithelial ovarian cancer associated with antidepressive drug use. Compared with non-use, use of selective serotonin reuptake inhibitors was associated with a decreased risk of ovarian cancer (OR, 0.85; 95% CI, 0.74-0.96), whereas the associations for other antidepressants were close to unity [tricyclic and related antidepressants: OR, 0.99 (95% CI, 0.78-1.26); other antidepressants: OR, 1.05 (95% CI, 0.76-1.46)]. For individual types of SSRI, reduced ORs were observed for citalopram OR, 0.78 (95% CI, 0.66-0.93), paroxetine 0.79 (95% CI, 0.56-1.12) and sertraline 0.80 (95% CI, 0.60-1.08). Among postmenopausal women, the inverse association was restricted to users of menopausal hormone therapy. In conclusion, use of selective serotonin reuptake inhibitors was associated with a decreased risk of epithelial ovarian cancer; thereby implying potential chemopreventive properties of these drugs.

The influence of hormone therapies on type I and II endometrial cancer: A nationwide cohort study.

The influence of hormone therapy (HT) on risk for endometrial cancer is still casting which type of HT the clinicians recommend. It is unrevealed if HT has a differential influence on Type I versus Type II endometrial tumors, and little is known about the influence of, e.g., different routes of administration and about the influence of tibolone. We followed all Danish women aged 50-79 years without previous cancer or hysterectomy (n = 914,595) during 1995-2009. From the National Prescription Register, we computed HT exposures as time-dependent covariates. Incident endometrial cancers (n = 6,202) were identified from the National Cancer Registry: 4,972 Type I tumors and 500 Type II tumors. Incidence rate ratios (RRs) and 95% confidence intervals (Cls) were estimated by Poisson regression. Compared with women never on HT, the RR of endometrial cancer was increased with conjugated estrogen: 4.27 (1.92-9.52), nonconjugated estrogen: 2.00 (1.87-2.13), long cycle combined therapy: 2.89 (2.27-3.67), cyclic combined therapy: 2.06 (1.88-2.27), tibolone 3.56 (2.94-4.32), transdermal estrogen: 2.77 (2.12-3.62) and vaginal estrogen: 1.96 (1.77-2.17), but not with continuous combined therapy: 1.02 (0.87-1.20). In contrast, the risk of Type II tumors appeared decreased with continuous combined therapy: 0.45 (0.20-1.01), and estrogen therapy implied a nonsignificantly altered risk of 1.43 (0.85-2.41). Our findings support that continuous combined therapy is risk free for Type I tumors, while all other hormone therapies increase risk. In contrast, Type II endometrial cancer was less convincingly associated with hormone use, and continuous combined therapy appeared to decrease the risk.