Polycystic ovary syndrome and endometrial cancer risk: results from a nationwide cohort study.

Most previous studies have found an elevated risk of endometrial cancer among women with polycystic ovary syndrome (PCOS). However, these have highly varying methods for ascertainment of PCOS diagnoses and have limitations such as few exposed women and short follow-up. In this cohort study, we investigated the association between PCOS and endometrial cancer among women born in Denmark between January 1, 1940, and December 31, 1993 (N=1,719,121). Data in this study, including PCOS and endometrial cancer diagnoses and covariates, were derived from nationwide registers. We used cox proportional hazard regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7862 endometrial cancer cases were identified during 23.7 years of follow-up (inter quartile range 37.7-61.9). We found an increased risk of endometrial cancer among women with PCOS compared with women without PCOS (HR: 3.02, 95% CI; 2.03-4.49). The risk was increased for premenopausal women (HR5.82, 95% CI: 3.64-9.30) whereas no marked association was seen for postmenopausal women. However, for postmenopausal women, results were limited by few cases and young age at end of follow-up. Mounting evidence of an increased risk for endometrial cancer among women with PCOS reinforces the need for prevention and early detection.

Trends in survival of epithelial ovarian/tubal cancer by histology and socioeconomic status in Denmark 1996-2017.

OBJECTIVES: To examine time trends in ovarian/tubal cancer relative survival, excess mortality, and all-cause mortality for different histological types and levels of socioeconomic position. METHODS: Women with ovarian/tubal cancer diagnosed 1996-2017 were identified in the Danish Cancer Registry (n = 11,755). Age-standardized 5-year relative survival over time was estimated by histology, socioeconomic status, and stage. Furthermore, 5-year excess mortality rate ratios (EMRR) according to calendar time for all categories of histology and socioeconomic status were calculated using a Poisson regression model. Finally, all-cause mortality by histology and socioeconomic status was estimated in multivariate Cox proportional hazards regression models. RESULTS: Statistically significant improvements in 5-year relative survival occurred for all histological types over time except mucinous tumors (5-year EMRR, localized: 0.92 (95% CI: 0.71-1.16); advanced: 0.96 (95% CI: 0.85-1.08). Increase in relative survival over time and corresponding decrease in excess mortality was observed for all categories of socioeconomic status except for women with localized disease in the lowest income group (5-year EMRR = 0.91 (95% CI:0.76-1.10)). The impact of histology and socioeconomic status on all-cause mortality depended on time since diagnosis. Among the socioeconomic factors, especially low educational level and living alone were associated with increased all-cause mortality, particularly in the first year after diagnosis. CONCLUSIONS: Ovarian/tubal cancer survival generally increased over time across histological types and socioeconomic factors. However, the lack of improvement for mucinous tumors needs further research. Additionally, the results for women with low income and education shows that continued focus on social equality in survival is necessary.

Maternal use of hormonal contraception and epilepsy in offspring.

STUDY QUESTION: Is maternal use of hormonal contraception associated with the development of epilepsy in the offspring? SUMMARY ANSWER: We found that maternal use of hormonal contraception was associated with a slightly increased risk of epilepsy in the offspring. WHAT IS KNOWN ALREADY: Foetal exposure to exogenous hormones has been associated with changes in brain development. However, little is known about maternal hormonal contraception use and development of epilepsy in the offspring. STUDY DESIGN, SIZE, DURATION: A nationwide cohort of all live born children born in Denmark between 1 January 1998 and 31 December 2014, was followed from day 29 after birth for epilepsy (first diagnosis of epilepsy or first redeemed prescription for anti-epileptic medication) to censoring (emigration, death) or 31 December 2015, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diagnoses of epilepsy were obtained from the National Patient Registry. The Danish National Prescription Registry supplied information on redeemed prescriptions for hormonal contraception and anti-epileptic medication. Maternal hormonal contraception use was categorized as never use (reference group), previous use (prescriptions redeemed >3 months before pregnancy start) and recent use (prescriptions redeemed ≤3 months before or during pregnancy). MAIN RESULTS AND THE ROLE OF CHANCE: The data show that 17 585 children developed epilepsy during a median follow-up of 9.2 years (9 732 635 person-years). The hazard ratio (HR) for epilepsy was 1.07 (95% CI 1.02-1.13) in children of mothers who had used any type of hormonal contraception recently, compared with children of mothers who had not used hormonal contraception. The HR was similar for recent use of oral combined products, while the HRs for recent or previous use of non-oral combined products were 1.32 (95% CI 0.98-1.77) and 1.16 (95% CI 1.02-1.32), respectively. For non-oral progestin-only products, the HRs were 1.19 (95% CI 1.04-1.38) and 1.53 (95% CI 1.31-1.80), respectively, for recent and previous use. LIMITATIONS, REASONS FOR CAUTION: There may be some misclassification of maternal hormonal contraception use, as some women may not have used the redeemed prescriptions or used them at a different point in time; potentially leading to an attenuation of the estimates. In addition, although we were able to account for known risk factors for epilepsy, unknown or residual confounding cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are based on nationwide population-based data and can therefore be applied to other similar populations. However, as this is the first study in this field, further studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study, which was supported by internal funding at the Unit of Virus, Lifestyle and Genes. All authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

A Danish nationwide study of risk factors associated with Type I and Type II endometrial cancer.

OBJECTIVE: To examine risk factors for Type I and Type II endometrial cancer (EC) and to directly compare the influence of risk factors for Type II with Type I tumors. Furthermore, to examine whether risk factors for high-grade Type I and Type II tumors differed from low-grade Type I tumors. METHODS: Women with EC diagnosed during 2000-2016 were identified in the Danish Cancer Registry. A case-control analysis was conducted with 1:15 random population controls matched on age and gender. Using conditional logistic regression, odds ratios and 95% confidence intervals on risk factors for Type I and II tumors were estimated. In case-case analyses, risk factors were evaluated in a direct comparison of cases grouped by tumor type and grade. RESULTS: We identified 6958 women with Type I EC and 1206 women with Type II EC. In the case-control analysis, nulliparity and diabetes were associated with increased risk of both tumor types, whereas hormone replacement therapy only increased the risk of Type I EC. When directly comparing Type I and II tumors, the influence of BMI ≥ 30, current smoking, and parity ≥ 3 was strongest for Type I EC. The associations for the majority of risk factors were similar for Type II and high-grade Type I tumors compared with low-grade Type II tumors. CONCLUSIONS: Risk factors for Type I and II tumors were overlapping suggesting that Type II tumors may be less estrogen-independent than previously anticipated. High-grade Type I tumors seemed to resemble Type II tumors more than low-grade Type I tumors.

Non-epithelial ovarian cancer in Denmark - Incidence and survival over nearly 40 years.

OBJECTIVE: To examine trends in incidence and survival of non-epithelial ovarian cancer in Denmark over nearly 40 years, using nationwide, population-based cancer registry data. METHODS: From 1978 to 2016, we identified the non-epithelial ovarian cancer cases among all ovarian malignancies in the Danish Cancer Registry. Age-specific incidence rates, age-standardized incidence rates, and average annual percentage change (AAPC) were estimated with 95% confidence intervals (CIs). Overall and 5-year relative survival analyses were conducted and supplemented with Cox regression to explore the effect of different characteristics on overall mortality. RESULTS: A total of 720 non-epithelial ovarian cancers were identified, corresponding to 3.4% of all ovarian malignancies. The majority of non-epithelial ovarian cancers were germ cell tumors (49.9%) and sex cord-stromal tumors (38.6%). The age-standardized incidence rate of germ cell tumors was stable over the study period, ranging between 0.33 and 0.39 per 100,000 woman-years. In contrast, the age-standardized incidence rate of sex cord-stromal tumors declined from 0.30 (1978-1987) to 0.09 (2008-2016) per 100,000 woman-years (AAPC = -5.15%; 95% CI: -7.29, -2.96). The 5-year relative survival of germ cell tumors and sex cord-stromal tumors was 94% and 79%, respectively, in the most recent period (2008-2011). Cox regression showed that overall mortality was associated with calendar year, age, and stage. CONCLUSIONS: The incidence of germ cell tumors was stable over calendar time, whereas the incidence of sex cord-stromal tumors decreased significantly. Non-epithelial ovarian cancer overall mortality has decreased during the study period and this could not be explained by taking stage and age at diagnosis into account.

Risk of endometrial cancer among women with benign ovarian tumors - A Danish nationwide cohort study.

OBJECTIVE: The few studies on the association between benign ovarian tumors and endometrial cancer have been inconclusive. Using data from a large Danish register-based cohort study, we assessed the overall and type-specific risk of endometrial cancer among women with a benign ovarian tumor. METHODS: We identified all Danish women diagnosed with a benign ovarian tumor during 1978-2016 in the Danish National Patient Register (n = 149,807). The study population was followed for subsequent development of endometrial cancer by linkage to the Danish Cancer Register and standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) were calculated after correction for hysterectomy. RESULTS: After a one-year delayed study entry, women with benign ovarian tumors had a decreased incidence of endometrial cancer (SIR = 0.74, 95% CI: 0.68-0.81) compared with women in the general Danish population. Both solid benign ovarian tumors (SIR = 0.79, 95% CI 0.70-0.88) and cystic benign ovarian tumors (SIR = 0.68, 95% CI 0.58-0.78) were associated with decreased incidences of endometrial cancer. Likewise, women with benign ovarian tumors had decreased incidences of both type I and type II endometrial cancer. The incidence of endometrial cancer was decreased to virtually the same magnitude irrespective of the age at diagnosis of a benign ovarian tumor and the reduction persisted throughout the follow-up period. CONCLUSIONS: The risk of endometrial cancer was decreased beyond the first year after a benign ovarian tumor and the decrease persisted for 20 or more years. The possible underlying mechanisms are not known and should be investigated further.

Risk of juvenile idiopathic arthritis among children conceived after fertility treatment: a nationwide registry-based cohort study.

STUDY QUESTION: Is the risk of juvenile idiopathic arthritis (JIA) increased in children conceived after fertility treatment, and is an observed association caused by specific types of fertility treatment or by factors associated with the underlying infertility? SUMMARY ANSWER: The risk of JIA in children conceived after fertility treatment (any and specific types of fertility treatment) was not convincingly affected when compared with children born to fertile women. WHAT IS KNOWN ALREADY: It has been suggested that fertility treatment may affect the development of the immune system and thereby increase the risk of developing autoimmune diseases, including JIA. STUDY DESIGN, SIZE, DURATION: This retrospective population-based cohort study included all live-born children in Denmark between 1 January 1996 and 31 December 2012 (n = 1 084 184). The study population was followed from date of birth until first diagnosis of JIA as registered in the Danish National Patient Registry, date of 16th birthday, date of emigration, date of death or end of follow-up (31 December 2014), whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study cohort was linked to the Danish Infertility Cohort in order to identify children born to women with fertility problems (n = 174 702) and fertility treatment (n = 89 931). Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: During a median follow-up period of 10.3 years, 2237 children were diagnosed with JIA. Children born to women with fertility problems had an increased risk of JIA (HR 1.18, 95% CI 1.05-1.32) compared with children born to fertile women. However, the risk was not increased in children conceived after any fertility treatment (HR 1.11; 95% CI 0.95-1.29), or after specific types of fertility treatment being ART (HR 1.05; 95% CI 0.83-1.33), IVF (HR 1.01; 95% CI 0.73-1.38), ICSI (HR 0.98; 95% CI 0.64-1.50) or any fertility drugs (HR 1.10; 95% CI 0.94-1.28) compared with children born to fertile women. The associations between fertility treatment and JIA were also assessed by using children born to women with fertility problems without fertility treatment in the index pregnancy as a reference group, however, the findings did not change substantially. LIMITATIONS REASONS FOR CAUTION: Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of JIA cases. There may be some misclassification of fertility problems, as some women have undiagnosed fertility problems and are therefore not included in the Danish Infertility Cohort; potentially leading to slight attenuation of the association between fertility problems and JIA. WIDER IMPLICATIONS OF THE FINDINGS: The results are based on national data and our findings can therefore be applied to other similar populations. Our results indicate that fertility treatment per se do not increase the risk of JIA but merely that the increased risk of JIA observed among children born to women with fertility problems may be due to underlying factors related to both infertility and JIA. However, as this is the first large study in this field, further studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants from the Jascha Foundation, the Aase and Ejner Danielsens Foundation and The Danish Rheumatism Association. All authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

High-grade cervical intraepithelial neoplasia in human papillomavirus self-sampling of screening non-attenders.

BACKGROUND: Self-sampling for human papillomavirus (HPV) offered to women who do not participate in cervical cancer screening is an increasingly popular method to increase screening coverage. The rationale behind self-sampling is that unscreened women harbour a high proportion of undetected precancer lesions. Here, we compare the cervical intraepithelial neoplasia grade 2 or worse (⩾CIN2) detection rate between non-attenders who participated in self-sampling and women attending routine screening. METHODS: A total of 23 632 women who were qualified as non-attenders in the Copenhagen Region were invited for HPV-based self-sampling. Of these, 4824 women returned a self-sample, and HPV-positive women were referred for cytology and HPV co-testing as follow-up. The entire cohort and a reference cohort (3347 routinely screened women) were followed for histopathology confirmed ⩾CIN2. Odds ratio (OR) and the relative positive predictive value of ⩾CIN2 detection between the two populations were estimated. RESULTS: Women participating in self-sampling had a higher ⩾CIN2 detection than women undergoing routine cytology-based screening (OR=1.83, 95% CI: 1.21-2.77) and a similar detection as routinely screened women tested with cytology and HPV testing (OR=1.03, 95% CI: 0.75-1.40). The positive predictive value for ⩾CIN2 was higher in screening non-attenders than in routinely HPV- and cytology-screened screened women (36.5% vs 25.6%, respectively). CONCLUSIONS: Self-sampling offered to non-attenders showed higher detection rates for ⩾CIN2 than routine cytology-based screening, and similar detection rates as HPV and cytology co-testing. This reinforces the importance of self-sampling for screening non-attenders in organised cervical cancer screening.

Prevalence of Human Papillomavirus in Self-Taken Samples from Screening Nonattenders.

The Copenhagen Self-Sampling Initiative (CSi) has shown how human papillomavirus (HPV)-based self-sampling can be used to increase screening participation among 23,632 nonattenders in the Capital Region of Denmark. In this study, we describe HPV prevalence and genotype frequency in 4,824 self-samples as determined by three HPV assays (the CLART, Onclarity, and Hybrid Capture 2 [HC2] assays) and compare the results with those for physician-taken follow-up samples. The HPV self-sample findings were also compared to the findings for a reference population of 3,347 routinely screened women from the Horizon study, which had been undertaken in the same screening laboratory. Nonattenders had an HPV prevalence of 11.3% as determined by the CLART assay, which was lower than that for women from the Horizon study (18.5%). One-third of the CSi women who tested HPV positive by self-sampling tested HPV negative on the physician-taken follow-up sample. The CLART and Onclarity assays agreed on 64% (95% confidence interval [CI], 60 to 68%) of the HPV-positive self-taken samples. When the HC2 assay results were added into a three-way comparison, the level of agreement decreased to 27% (95% CI, 24 to 29%). Our findings suggest that further validation of HPV assays on self-taken samples is needed for optimal HPV detection and correct clinical management of HPV-positive women.

Risk of head-and-neck cancer following a diagnosis of severe cervical intraepithelial neoplasia: a nationwide population-based cohort study in Denmark.

OBJECTIVE: Women with a history of cervical intraepithelial neoplasia grade 3 including adenocarcinoma in situ (CIN3/AIS) may be more prone to develop cancers of the ano-genital region and head-and-neck cancers. The current literature is, however, limited. METHODS: We established a nationwide cohort of approximately 2,500,000 Danish women born in 1918-1990. By linking the cohort to population-based health registries, we obtained information on CIN3/AIS, cancer, migration, death, education, and smoking. Cox proportional hazards models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) for the association between CIN3/AIS and risk of head-and-neck squamous cell carcinoma (HNSCC). HRs were presented for any HNSCC and for four subgroups categorized by their anticipated degree of association with human papillomavirus (HPV). RESULTS: A history of CIN3/AIS was significantly associated with an increased overall relative risk of HNSCC after adjustment for year of birth, attained age, and length of education. The risk was especially high for sites anticipated to be strongly associated with HPV (e.g. base of tongue, tonsils) (HR, 2.49; 95% CI, 1.84-3.36). Lower risks were found for sites anticipated to be not or weakly associated with HPV (e.g. nasal cavity, middle ear, sinuses) (HR, 1.29; 95% CI, 0.61-2.76). CONCLUSION: Women with a history of CIN3/AIS have a significantly higher risk of HNSCC than women without such a history. The increased relative risk persisted for at least 20years after the CIN3/AIS diagnosis. Women with CIN3/AIS may be more susceptible to the consequences of HPV and/or may have higher risk behavior, such as smoking.

Statin use and risk for ovarian cancer: a Danish nationwide case-control study.

BACKGROUND: Limited data suggest that statin use reduces the risk for ovarian cancer. METHODS: Using Danish nationwide registries, we identified 4103 cases of epithelial ovarian cancer during 2000-2011 and age-matched them to 58,706 risk-set sampled controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for epithelial ovarian cancer overall, and for histological types, associated with statin use. RESULTS: We observed a neutral association between ever use of statins and epithelial ovarian cancer risk (OR=0.98, 95% CI=0.87-1.10), and no apparent risk variation according to duration, intensity or type of statin use. Decreased ORs associated with statin use were seen for mucinous ovarian cancer (ever statin use: OR=0.63, 95% CI=0.39-1.00). CONCLUSIONS: Statin use was not associated with overall risk for epithelial ovarian cancer. The inverse association between statin use and mucinous tumours merits further investigation.

Increasing incidence of base of tongue cancers from 2000 to 2010 due to HPV: the largest demographic study of 210 Danish patients.

BACKGROUND: We assessed the development in the number of new base of tongue squamous-cell carcinoma (BSCC) cases per year in eastern Denmark from 2000 to 2010 and whether HPV may explain any observable increased incidence. METHODS: We performed HPV DNA PCR and p16 immunohistochemistry analysis for all (n=210) BSCCs registered in the Danish Head and Neck Cancer Group (DAHANCA) and the Danish Pathology Data Bank, and genotyped all HPV-positive specimens with amplicon-based next-generation sequencing. RESULTS: The overall crude incidence of BSCCs increased significantly (5.4% per year) during the study period. This was explained by a significant increase in the number of HPV-positive BSCCs (8.1% per year), whereas the number of HPV-negative BSCCs did not increase significantly. The overall HPV prevalence was 51%, with HPV16 as the predominant HPV type. CONCLUSIONS: The increased number of HPV-positive BSCCs may explain the increasing incidence of BSCCs in eastern Denmark, 2000-2010.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Low-dose aspirin use and the risk of ovarian cancer in Denmark.

BACKGROUND: A comprehensive body of evidence has shown that aspirin has cancer-preventive effects, particularly against gastrointestinal cancer, but its effects on the risk of ovarian cancer are less well established. This nationwide case-control study examined the association between low-dose aspirin and the risk of ovarian cancer. PATIENTS AND METHODS: We identified all patients in the Danish Cancer Registry aged 30-84 years old with a histologically verified first diagnosis of epithelial ovarian cancer during 2000-2011. Each patient was sex- and age-matched to 15 population controls using risk-set sampling. Prescription use, comorbidity, reproductive history, and demographic characteristics data were obtained from nationwide registries. The use of low-dose (75-150 mg) aspirin was defined according to the dose as well as the duration and consistency of use. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between low-dose aspirin use and the risk of epithelial ovarian cancer, both overall and for specific histological types. RESULTS: For 4103 ovarian cancer cases and 58 706 population controls, the adjusted OR for epithelial ovarian cancer associated with ever use (≥2 prescriptions) of low-dose aspirin was 0.94 (95% CI 0.85-1.05). ORs for epithelial ovarian cancer were lower with the use of 150 mg aspirin tablets (OR = 0.82; 95% CI 0.68-0.99) and with long-term use (≥5 years) of low-dose aspirin (OR = 0.77; 95% CI 0.55-1.08). Continuous long-term use of low-dose aspirin, defined as close consecutive prescriptions, was associated with a further reduction in OR (0.56; 95% CI 0.32-0.97). For histological types of epithelial ovarian cancer, the strongest inverse associations with low-dose aspirin use were seen for mucinous and endometrioid tumours. CONCLUSION: This nationwide case-control study indicates that low-dose aspirin use may be associated with a reduced risk of epithelial ovarian cancer.

Mental disorders in childhood and young adulthood among children born to women with fertility problems.

STUDY QUESTION: Is the risk of hospital admission or outpatient contact for mental disorders increased in children born to women with fertility problems compared with children born to women without fertility problems? SUMMARY ANSWER: We found an increased risk of hospital admission or outpatient contact for mental disorders in children born to women with fertility problems. WHAT IS KNOWN ALREADY: Few studies have investigated the risk of mental disorders in children born after fertility treatment and although some studies have pointed to an increased risk, others found no association. The inconsistent results may be due to methodological constraints in many previous studies, including small sample size and short follow-up, resulting in imprecise risk estimates and lack of information on risk patterns of mental disorders in adulthood. STUDY DESIGN, SIZE, DURATION: This nationwide retrospective register-based cohort study included all 2 412 721 children born in Denmark between 1969 and 2006. All children were followed from date of birth until date of hospital contact for a mental disorder, date of emigration, date of death or 31 December 2009, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Information concerning maternal fertility status for all children in the cohort was obtained by linkage to the Danish Infertility Cohort, which contains data on nearly all women with fertility problems in Denmark since 1963. A total of 124 269 (5%) children were born to women with fertility problems and 2 288 452 (95%) to women without fertility problems. To identify children hospitalized for a mental disorder, the cohort was linked to the Danish Psychiatric Central Research Registry. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between maternal fertility status and the risk of hospital admission or outpatient contact for various groups of mental disorders, including any mental disorder and all 11 main discharge diagnostic groups, classified according to the International Classification of Diseases, version 10. MAIN RESULTS AND THE ROLE OF CHANCE: During a mean follow-up period of 21 years (range, 0-40 years), 168 686 (7%) children were admitted to hospital or had an outpatient contact for a mental disorder. Children born to women with fertility problems had a significantly higher risk of any mental disorder (HR 1.23; 95% CI 1.20-1.26) and for most of the 11 main discharge groups, including schizophrenia (HR 1.16; 95% CI 1.07-1.27), mood (affective) disorders (HR 1.21; 95% CI 1.15-1.28) and disorders of psychological development (HR 1.15; 95% CI 1.09-1.21) as well as the subgroup of attention-deficit/hyperactivity disorders (HR 1.36; 95% CI 1.29-1.45) compared with children born to women without fertility problems. The risk estimates did not change markedly when analyses were performed separately for mental disorders diagnosed during childhood (0-19 years) and in young adulthood (20-40 years). LIMITATIONS, REASON FOR CAUTION: The true risk of mental disorders may be somewhat underestimated, as only severe disorders requiring hospital admission or outpatient contact were considered as events. Furthermore, we could not determine whether the increased risks observed were due to factors related to the underlying infertility or to fertility treatment procedures. WIDER IMPLICATIONS OF THE FINDINGS: This is the first report on mental disorders in adulthood among children born to women with fertility problems. Furthermore, we have assessed the risk of several severe mental disorders not previously studied (e.g. neurotic, stress-related and somatoform disorders and disorders of adult personality and behaviour). These important findings should be investigated further in large epidemiological studies designed to differentiate between factors related to fertility treatment and to the underlying infertility. STUDY FUNDING/COMPETING INTERESTS: The study was supported by internal funding from the Unit of Virus, Lifestyle and Genes at the Danish Cancer Society Research Center. All authors report no conflicts of interest.

Parity as a cofactor for high-grade cervical disease among women with persistent human papillomavirus infection: a 13-year follow-up.

BACKGROUND: Several environmental factors have been associated with increased risks for cervical cancer. We examined whether reproductive history, contraceptive use, or sexual behaviour increase the risk for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among women with persistent human papillomavirus (HPV) infection. METHODS: A population-based cohort of women participated in a personal interview and underwent a gynaecological examination at which cervical specimens were obtained for HPV DNA testing. Follow-up information (~13 years) on cervical lesions was obtained from the Danish Pathology Data Bank. Women who had a high-risk HPV infection comprised the overall study population (n=1353). A subgroup of women with persistent high-risk HPV infection (n=312) was identified. Hazard ratios (HRs) for a diagnosis of CIN3+ and the corresponding 95% confidence intervals (CIs) were calculated. RESULTS: Women with persistent HPV infection who had given birth had a significantly increased risk for CIN3+ (HR=1.78; 95% CI: 1.07-2.94). No association was found with pregnancy, use of intrauterine devices, or sexual behaviour. Based on small numbers, women with persistent HPV infection had a decreased risk for CIN3+ with any use of oral contraceptives (HR=0.54; 95% CI: 0.29-1.00). CONCLUSION: Childbirth increases the risk for subsequent CIN3+ among women with persistent HPV infection.

Socioeconomic position and survival after cervical cancer: influence of cancer stage, comorbidity and smoking among Danish women diagnosed between 2005 and 2010.

BACKGROUND: In an attempt to decrease social disparities in cancer survival, it is important to consider the mechanisms by which socioeconomic position influences cancer prognosis. We aimed to investigate whether any associations between socioeconomic factors and survival after cervical cancer could be explained by socioeconomic differences in cancer stage, comorbidity, lifestyle factors or treatment. METHODS: We identified 1961 cases of cervical cancer diagnosed between 2005 and 2010 in the Danish Gynaecological Cancer database, with information on prognostic factors, treatment and lifestyle. Age, vital status, comorbidity and socioeconomic data were obtained from nationwide administrative registers. Associations between socioeconomic indicators (education, income and cohabitation status) and mortality by all causes were analysed in Cox regression models with inclusion of possible mediators. Median follow-up time was 3.0 years (0.01-7.0). RESULTS: All cause mortality was higher in women with shorter rather than longer education (hazard ratio (HR), 1.46; 1.20-1.77), among those with lower rather than higher income (HR, 1.32; 1.07-1.63) and among women aged<60 years without a partner rather than those who cohabited (HR, 1.60; 1.29-1.98). Socioeconomic differences in survival were partly explained by cancer stage and less by comorbidity or smoking (stage- and comorbidity-adjusted HRs being 1.07; 0.96-1.19 for education and 1.15; 0.86-1.52 for income). CONCLUSION: Socioeconomic disparities in survival after cervical cancer were partly explained by socioeconomic differences in cancer stage. The results point to the importance of further investigations into reducing diagnosis delay among disadvantaged groups.

Oral contraceptive use and impact of cumulative intake of estrogen and progestin on risk of ovarian cancer.

PURPOSE: Oral contraceptive use decreases the risk of ovarian cancer, but no previous studies have assessed the impact of cumulative intake of estrogen and progestin on ovarian cancer risk. METHODS: We used data from a population-based case­control study conducted in Denmark in 1995­1999 among women aged 35­79 years; 554 women with epithelial ovarian cancer and 1,564 age-matched controls were included in the analyses. Data were analyzed in multiple logistic regression models. RESULTS: The use of combined oral contraceptives only and the mixed use of combined and progestin-only pills decreased the risk of ovarian cancer, while no association was found with exclusive use of progestin-only pills. No major differences in risk were found for users of combined oral contraceptives with high- and low-potency estrogen and progestin. There was no effect of cumulative progestin intake, but decreased risks of ovarian cancer with increasing cumulative intake of estrogen (OR = 0.82; 95 % CI 0.67­0.99, per 100 mg estrogen) and increasing duration of oral contraceptive use (OR = 0.95; 95 % CI 0.92­0.98, per year of use) were found. No effect of cumulative estrogen intake was found, however, after adjustment for duration of oral contraceptive use. CONCLUSIONS: The protective effect of oral contraceptives against ovarian cancer may be sufficiently explained by duration of anovulation. This suggests that if the estrogen and progestin doses are sufficient to cause anovulation, a higher intake of estrogen or progestin confers no extra protection against ovarian cancer.

Psychiatric disorders in women with fertility problems: results from a large Danish register-based cohort study.

STUDY QUESTION: Do women who don't succeed in giving birth after an infertility evaluation have a higher risk of psychiatric disorders compared with women who do? SUMMARY ANSWER: The results indicated that being unsuccessful in giving birth after an infertility evaluation could be an important risk factor for psychiatric disorders. WHAT IS KNOWN ALREADY: Several studies have investigated the association between fertility treatment and psychological distress, but the results from these studies show substantial variation and lack of homogeneity that may be due to methodological limitations. STUDY DESIGN, SIZE AND DURATION: A retrospective cohort study was designed using data from a cohort of 98 320 Danish women evaluated for fertility problems during 1973-2008 and linked to several Danish population-based registries. All women were followed from the date of first infertility evaluation until date of hospitalization for the psychiatric disorder in question, date of emigration, date of death or 31 December 2008, whichever occurred first. Owing to the precise linkage between the infertility cohort and the Danish population-based registries, using the unique Danish personal identification number, virtually no women were lost to follow-up. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Information on reproductive status for all women in the infertility cohort was obtained by linkage to the Danish Medical Birth Registry. A total of 53 547 (54.5%) women gave birth after the initial infertility evaluation, whereas 44 773 (45.5%) women did not gave birth after the evaluation. To determine psychiatric disorders diagnosed in the women after enrolment in the infertility cohort, the cohort was linked to the Danish Psychiatric Central Registry. A total of 4633 women were hospitalized for a psychiatric disorder. The Cox proportional hazard regression model was applied to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between parity status after the initial infertility evaluation and risk of hospitalization for various groups of psychiatric disorders, including 'all mental disorders' and six main discharge subgroups labelled: 'alcohol and intoxicant abuse', 'schizophrenia and psychoses', 'affective disorders', 'anxiety, adjustment and obsessive compulsive disorders', 'eating disorder' and 'other mental disorders'. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence rate for all mental disorders was 393 cases per 100 000 person-years among women who did not succeed in giving birth after the infertility evaluation but only 353 cases per 100 000 person-years among women who succeeded in giving birth after the infertility evaluation. Women not giving birth after the infertility evaluation had an increased risk of hospitalization for all mental disorders (HR 1.17, 95% CI 1.11; 1.25), alcohol and intoxicant abuse (HR 2.02, 95% CI 1.69; 2.41), schizophrenia and psychoses (HR 1.46, 95% CI 1.17; 1.82) and other mental disorders (HR 1.42, 95% CI 1.27; 1.58) compared with women who gave birth after the infertility evaluation. In contrast, the risk of affective disorders (HR 0.90, 95% CI 0.81; 0.99) was decreased among women not giving birth after the infertility evaluation. Finally, the risk of anxiety, adjustment and obsessive compulsive disorders (HR 1.07, 95% CI 0.97; 1.17) as well as of eating disorders (HR 1.40, 95% CI 0.88; 2.22) was not significantly affected by parity status after the infertility evaluation. LIMITATIONS, REASON FOR CAUTION: As only psychiatric conditions warranting hospitalization could be included in the present study, the true incidence of all psychiatric disorders among women with fertility problems is likely to be somewhat underestimated. Furthermore, since detailed information on fertility treatment was not available for all cohort members the association between different modalities of assisted reproductive techniques and risk of psychiatric disorders was not assessed. WIDER IMPLICATIONS OF THE FINDINGS: Clinicians and other healthcare personnel involved in diagnosis and treatment of women with fertility problems should be aware of the potential risk modification of psychiatric disorders associated with unsuccessful fertility treatment. Hence, our results may point to new aspects of follow-up of women with fertility problems who are unsuccessful in giving birth in order to prevent or identify and treat these possible psychological side effects. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Danish Cancer Society (award number: 96 222 54). All authors report no conflicts of interest.

Thyroid cancer in Denmark 1943-2008, before and after iodine supplementation.

Thyroid cancer incidence has increased worldwide during the previous decades. In this nationwide study, we aimed to identify the overall incidence of thyroid cancer in Denmark during 66 years (1943-2008) and incidences of the four main histological types of thyroid cancer from 1978 to 2008. Data were obtained from the nationwide Danish Cancer Registry, and we focused especially on the period after implementation of compulsory iodine supplementation, which was established on a national level in 2000. We calculated age-standardized incidence rates per 100,000 person-years, and age-period-cohort models were fitted to describe trends in incidence. To quantify trends in incidence over time, log-linear Poisson models were used to estimate annual percentage change. From 1943 to 2008, 1,947 men (29%) and 4,682 women (71%) were diagnosed with thyroid cancer. The age-standardized incidence increased in both sexes; in men from 0.41 to 1.57 per 100,000 and from 0.90 to 4.11 per 100,000 in women, corresponding to a significant average annual percentage change of 1.7 and 1.8%, respectively. The incidence increased with younger birth cohorts. The rise was almost exclusively caused by papillary carcinomas, and it was particularly present during the last decades of the study period. It cannot be ruled out that iodine supplementation may play a role for the risk of thyroid cancer, but as the strongest increase in incidence began in the years before the implementation, it is likely that improvement in diagnostic modalities increased diagnostic activity, and/or new unknown risk factors are also important contributors to the increase.