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To investigate the association between fertility drugs and tumors of the central nervous system (CNS).This cohort study was based on The Danish Infertility Cohort and included 148,016 infertile women living in Denmark (1995-2017). The study cohort was linked to national registers to obtain information on use of specific fertility drugs, cancer diagnoses, covariates, emigration, and vital status. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all CNS tumors and separately for gliomas, meningiomas and diverse benign tumors of the brain and other parts of the CNS.During a median 11.3 years of follow-up, 328 women were diagnosed with CNS tumors. No marked associations were observed between use of the fertility drugs clomiphene citrate, gonadotropins, gonadotropin-releasing hormone receptor modulators and progesterone and CNS tumors. However, use of human chorionic gonadotropin was associated with a decreased rate of meningiomas (HR 0.49 95% CI 0.28-0.87). No clear associations with CNS tumors were observed according to time since first use or cumulative dose for any of the fertility drugs.No associations between use of most types of fertility drugs and CNS tumors were observed. However, our findings only apply to premenopausal women and additional studies with longer follow-up time are necessary.

Objective: To study the association between use of fertility drugs and colorectal cancer among women with infertility. Design: Population-based cohort study. Setting: Not applicable. Patient(s): The study cohort was obtained from the Danish Infertility Cohort and consisted of all women with infertility aged 20–45 years living in Denmark during 1995–2017. Intervention(s): Information on the use of specific types of fertility drugs, colorectal cancer diagnoses, covariates, and vital status were obtained from the Danish Infertility Cohort and Danish national registers. Main Outcome Measure(s): Cox proportional hazard models adjusted for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer overall and rectal and colon cancer separately. Results(s): Among 148,036 women in the final study cohort, 205 women were diagnosed with colorectal cancer. Ever use of clomiphene citrate (CC) was associated with a lower rate of colorectal cancer (unadjusted HR, 0.67; 95% CI, 0.51–0.89; adjusted HR, 0.68; 95% CI, 0.50–0.93). However, the lower rate was only seen among women who first used CC >8 years ago (unadjusted HR, 0.56; 95% CI, 0.41-0.76; adjusted HR, 0.52; 95% CI, 0.36–0.75). No marked associations were found between the use of any of other types of fertility drugs and colorectal cancer. The results for colon and rectal cancer analyzed separately were similar, except for a suggestion of a decreased risk of rectal cancer associated with the use of gonadotropins (adjusted HR, 0.46; 95% CI, 0.20–1.08). Conclusion(s): Among women with infertility, the use of most types of fertility drugs was not associated with colorectal cancer. However, CC may decrease the risk of colorectal cancer and gonadotropins might decrease the risk of rectal cancer, but we cannot rule out that these findings may be more related to the underlying conditions in these women or are chance findings. Consequently, the results from this study should be investigated further in large epidemiological studies.

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

Asherman syndrome may be challenging to treat. This study presented the results after hysteroscopic treatment of Asherman syndrome in our clinic focusing on the reproductive outcome.A total of 43 women were operated in the course of a five-year period. The women were post-operatively treated with hyaluronic acid gel, intrauterine device (IUD) and hormonal supplementation. A second-look minihysteroscopy and removal of the IUD were conducted seven weeks later. Data concerning the results after one or more operations were obtained from a phone interview and from the medical records.The pregnancy rate among the 38 women who wished to conceive was 82%, and the live birth rate was 63%. Among the 31 women who became pregnant, 42% achieved spontaneous pregnancy, whereas 58% became pregnant after fertility treatments. An increased risk of obstetric complications was recorded, especially related to abnormal placentation and impaired placenta function.Hysteroscopic treatment of Asherman syndrome seems to be a safe procedure, but a risk possibly exists of obstetrical complications in the subsequent pregnancies. Pregnancies following hysteroscopic adhesiolysis should be considered high-risk pregnancies.none.not relevant.

OBJECTIVE: To study whether endometrial scratching in the luteal phase before ovarian stimulation increases clinical pregnancy rates in women with one or more previous implantation failures.DESIGN: A nonblinded multicenter randomized clinical trial.SETTING: Fertility clinics.PATIENT(S): Three hundred four eligible patients scheduled for IVF/intracytoplasmic sperm injection were randomized. The intervention group (n = 151) underwent endometrial scratching in the luteal phase before controlled ovarian stimulation, while no intervention was performed in the control group (n = 153).INTERVENTION(S): Endometrial scratching with a Pipelle de Cornier catheter in the luteal phase before ovarian stimulation.MAIN OUTCOME MEASURE(S): Clinical pregnancy rate and prenatal and birth data.RESULT(S): There was no overall significant improvement in clinical pregnancy rates between the control and intervention groups (38.5% vs. 44.4%; relative risk = 1.15; confidence interval [0.86-1.55]). However, subgroup analyses revealed that women with three or more previous implantation failures had a significant increase in clinical pregnancy rate (31.1% vs. 53.6%; relative risk = 1.72; confidence interval [1.05-2.83]) after scratching. No difference was seen as regards prenatal and birth data between the two groups.CONCLUSION(S): Endometrial scratching in the luteal phase before ovarian stimulation significantly enhances the clinical pregnancy rate in women with three or more prior implantation failures. This result seems to corroborate previous reports, which found that particularly women with repeated implantation failure seem to gain a positive effect from endometrial scratching. Importantly, there were no significant differences in prenatal data and birth data between the groups.CLINICAL TRIAL REGISTRATION NUMBER: NCT01963819.

Although assisted reproductive technology has reduced the need for surgery for women with infertility, there is evidence to support, that targeted reproductive surgery can improve fertility and pregnancy outcomes. In the last decades, increased access to minimal invasive surgery has brought a new era to reproductive surgery. An integration of reproductive surgery in the fertility treatment is therefore recommended. The patient should be offered detailed information regarding the pros and cons before the surgical treatment, as the evidence in the field is sparse, which is discussed in this review.

Introduction Today, it is widespread practice to postpone frozen embryo transfer (FET) in a modified natural cycle (mNC) for at least one menstrual cycle after oocyte retrieval and failed fresh embryo transfer or freeze-all. The rationale behind this practice is the concern that suboptimal ovarian, endometrial or endocrinological conditions following ovarian stimulation may have a negative impact on endometrial receptivity and implantation. However, two recent systematic reviews and meta-analyses based on retrospective data did not support this practice. As unnecessary delay in time to transfer and pregnancy should be avoided, the aim of this study is to investigate if immediate single blastocyst transfer in mNC-FET is non-inferior to standard postponed single blastocyst transfer in mNC-FET in terms of live birth rate. Methods and analysis Multicentre randomised controlled non-blinded trial including 464 normo-ovulatory women aged 18–40 years undergoing single blastocyst mNC-FET after a failed fresh or freeze-all cycle. Participants are randomised 1:1 to either FET in the first menstrual cycle following the stimulated cycle (immediate FET) or FET in the second or subsequent cycle following the stimulated cycle (postponed FET). The study is designed as a non-inferiority trial and primary analyses will be performed as intention to treat and per protocol. Ethics and dissemination Ethical approval has been granted by the Scientific Ethical Committee of the Capital Region of Denmark (J-nr.: H-19086300). Data will be handled according to Danish law on personal data protection in accordance with the general data protection regulation. Participants will complete written consent forms regarding participation in the study and storage of blood samples in a biobank for future research. The study will be monitored by a Good Clinical Practice (GCP)-trained study nurse not otherwise involved in the study. The results of this study will be disseminated by publication in international peer-reviewed scientific journals. Trial registration number NCT04748874; Pre-results.

STUDY QUESTION Do fertility drugs increase the risk of thyroid cancer among infertile women? SUMMARY ANSWER The use of most types of fertility drugs was not associated with an increased risk of thyroid cancer. WHAT IS KNOWN ALREADY The incidence of thyroid cancer is higher for women than men, especially during reproductive years, indicating that reproductive hormones may be involved in the development of thyroid cancer. Only a few previous studies have examined the association between the use of fertility drugs and incidence of thyroid cancer and the results are inconclusive. STUDY DESIGN, SIZE, DURATION A retrospective, population-based cohort study including all 146 024 infertile women aged 20–45 years and living in Denmark in the period 1995–2017. The women were followed from the date of entry in the cohort (i.e. date of first infertility diagnosis) until the occurrence of thyroid cancer or any other cancer (except non-melanoma skin cancer), death, emigration, total thyroidectomy or the end of follow-up (31 December 2018), whichever occurred first. The median length of follow-up was 11.3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 167 women were diagnosed with thyroid cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), thyroid cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for thyroid cancer overall and for papillary thyroid cancer. MAIN RESULTS AND THE ROLE OF CHANCE After adjustment for the calendar year of infertility diagnosis, the highest obtained level of education, parity status, obesity or thyroid disease and mutual adjustment for other registered fertility drugs, no marked associations were observed between the use of clomiphene citrate, hCG, gonadotropins or GnRH receptor modulators and risk of overall or papillary thyroid cancer. However, ever use of progesterone was associated with an increased rate of both overall (HR 1.63; 95% CI 1.07–2.48) and papillary (HR 1.66, 95% CI 1.04–2.65) thyroid cancer after mutual adjustment for other specific fertility drugs. For most specific fertility drugs, we observed a tendency toward higher associations with thyroid cancer within the first 5 years after the start of drug use than after 5 years from the start of use. No marked associations were detected according to the cumulative dose for any of the specific fertility drugs. 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 thyroid cancer cases. Although we were able to adjust for a number of potential confounders, residual and unmeasured confounding may potentially have affected the observed associations, as we could not adjust for some factors that may influence the association between fertility drugs and thyroid cancer, including age at menarche and BMI. WIDER IMPLICATIONS OF THE FINDINGS Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and thyroid cancer incidence, we observed a modest increased thyroid cancer incidence after the use of progesterone. However, we cannot rule out that this is a chance finding and the potential association between the use of progesterone and thyroid cancer should therefore be investigated further in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of infertility. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by research grants from the Jascha Foundation and the Aase and Ejner Danielsens Foundation. B.N. received honoraria and/or non-financial support by Gedeon Richter Nordics AB, IBSA Nordic APS and Merck KGAA. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBER N/A.

The ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) are suppressed in varying degree during the use of combined oral contraceptives (COC). Further, long-term use of COC can mask a condition of premature ovarian insufficiency. A desirable clinical tool that could distinguish true low ovarian reserve markers from COC-induced low levels

IntroductionAsthma is associated with prolonged time to pregnancy and a higher need for fertility treatment. However, the mechanism underlying this association remains incompletely understood. Previous research points to asthma-driven systemic inflammation also affecting the reproductive organs and thereby fertility. The aim of this study was to determine if treatment with omalizumab prior to fertility treatment will increase pregnancy rate among women with asthma by decreasing the systemic asthma-related inflammation and, by that, to provide insight into the underlying mechanisms.Methods and analysisThis is an ongoing prospective multicentre randomised controlled trial planned to enrol 180 women with asthma recruited from fertility clinics in Denmark. The patients are randomised 1:1 to either omalizumab or placebo. The primary endpoint is the difference in pregnancy rate confirmed with ultrasound at gestational week 7 of pregnancy. The secondary endpoints are change in sputum and blood eosinophil cell count, change in biomarkers, change in microbiota, together with rate of pregnancy loss, frequency of malformations, pre-eclampsia, preterm birth, birth weight, small for gestational age and perinatal death between groups.Ethics and disseminationThe methods used in this study are of low risk, but if successful, our findings will have a large impact on a large group of patients as infertility and asthma are the most common chronic diseases among the young population. The study has been approved by the Ethics Committee–Danish national research ethics committee (H-18016605) and the Danish Medicines Agency (EudraCT no: 2018-001137-41) and the Danish Data Protection Agency (journal number: VD-2018486 and I-Suite number 6745). The test results will be published regardless of whether they are positive, negative or inconclusive. Publication in international peer-reviewed scientific journals is planned.Trial registration numberNCT03727971.

Objective: The combined oral contraceptive pill is the most preferred contraceptive method worldwide. Despite high life-time prevalence of infertility of 16–26%, scarce data about concerns of future fertility among COC users are available. We aimed to study whether COC usage induces concerns about fertility. Methods: Online questionnaire-based survey included 1283 current COC users and 1006 past users. The questionnaire covered knowledge and concerns of various aspects of fertility with respect to COC usage. Results: Significantly, more current users (66%) than past users (52%) had considered whether or not COC usage could affect future fertility (OR = 1.6, 95% CI 1.3–1.9). Nearly 50% of both groups believed COC usage could impair conception rates after discontinuation. Furthermore, 28% current vs. 19% past users believed COC could diminish the ovarian reserve more permanently. Conversely, 14% current and 11% past users believed that lack of ovulation could ‘spare’ the eggs (OR = 0.9, 95% CI 0.7–1.3). Significantly fewer current users (22%) vs. past users (35%) had heard, primarily by female friends, that a short break of 1–2 months during long-term COC usage was healthy, (OR 0.72, 95%CI = 0.56–0.92). Conclusions: Health care professionals prescribing hormonal contraception should be aware of misapprehensions and concerns of fertility among users of COC.

Objectives: The aim of the study was to assess whether the ovarian reserve markers anti-Mullerian hormone (AMH) and antral follicle count (AFC) were lower among women using the progestin-on...

Objective To study whether infection with high-risk human papillomavirus (HPV), registered both as a single HPV positive test and as HPV persistence, increases the risk of female factor infertility in later reproductive life. Design Population-based cohort study. Setting Not applicable. Patient(s) A random sample of 11,088 women (20–29 years of age at enrollment) tested for cervical HPV at enrollment during 1991–93 and again after 2 years. Information on female factor infertility was obtained by linkage to the Danish Infertility Cohort. Intervention(s) None. Main Outcome Measure(s) Follow-up for each study participant was the period from the date of enrollment or date of the second visit until diagnosis of female factor infertility (main outcome), conception, death, emigration, disappearance, or end of study period. Data were analyzed by means of a Cox proportional hazards regression model. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HPV status and female factor infertility after adjustment for potentially confounding factors were determined. Result(s) After relevant exclusions, 10,595 women were eligible for analysis, 1,861 (17.6%) of whom were high-risk HPV positive at the first visit. There was no association between a positive HPV test at first visit (HR = 0.88; 95% CI, 0.75–1.02) or positivity for the same high-risk HPV type at the first and second visit (persistence; HR = 0.97; 95% CI, 0.66–1.44) and subsequent risk of female factor infertility in reproductive life. Conclusion(s) We found no association between a high-risk HPV infection and risk of female factor infertility, neither for a single HPV positive test nor for a persistent HPV infection.

It is crucial to understand the epidemiology and natural history of human papillomavirus (HPV) infection in both men and women, to prevent the increasing HPV-related disease burden in men. Data on HPV prevalence among men in the general population are limited. In this cross-sectional population-based study, we aimed to estimate genital HPV infection prevalence in Danish men using 2 different test methods.Penile swab samples from 2460 male employees and conscripts at military barracks in Denmark were tested for HPV DNA with the hybrid capture 2 (HC2) method, and a polymerase chain reaction (PCR) assay, Inno-LiPA. The overall and age- and type-specific prevalence of HPV infection with 95% confidence intervals (CIs) were estimated, and the correlation between the 2 assays was assessed.The overall HPV prevalence was 22.2% (95% CI, 20.6-23.9) in the HC2 test and 41.8% (95% CI, 39.9-43.8) with PCR. Of the PCR-positive samples, 50.9% were negative in the HC2 test. Of 183 PCR-positive samples that could not be genotyped (HPVX), 88.0% (95% CI, 83.2-92.7) were HC2 negative. The most prevalent types were HPV-51, HPV-16, HPV-66, HPV-53, and HPV-6. The prevalence of high-risk and low-risk HPV peaked among men aged 20 to 29 years, whereas the HPVX prevalence increased with age.Human papillomavirus is highly prevalent in the general male population of Denmark, with HPV-16 and HPV-51 being the most prevalent. Polymerase chain reaction detects twice as many positive samples as HC2 but includes HPVX, possibly representing cutaneous HPV types found on normal genital skin.

We investigated the effects of socioeconomic, demographic and health-related indicators on the incidence of and survival from cancers of the cervix, endometrium and ovary diagnosed in 1994-2003 with follow-up through 2006 in Denmark using information from nationwide registers. The analyses were based on the data on 3007 patients with cervical cancer, 3826 with endometrial cancer and 3855 with ovarian cancer in a cohort of 3.22 million persons born between 1925 and 1973 and aged >or=30 years. The incidence of cervical cancer increased with decreasing socioeconomic position; the incidences of endometrial and ovarian cancer were mostly associated with higher disposable income. Relative survival from cervical cancer was the highest among women of high socioeconomic position; increased excess mortality rates from endometrial and ovarian cancer were associated with low educational level, mainly during the first year after diagnosis. Socioeconomic position seemed to affect both the incidence of and the survival from cancers of the female genital organs.

To investigate the association between loop electrosurgical excision procedure (LEEP) and other potential risk factors, and subsequent preterm delivery (37 weeks), using data from a large cohort study of Danish women.The Danish prospective cohort study was initiated in 1991, with the original aim of investigating the role of human papillomavirus in the natural history of cervical neoplasia. The study included 11,088 women aged 20-29. The cohort was invited for 2 follow-up examinations in 1993-1995 and 1999-2000, respectively. At all 3 examinations, the women answered questions about a number of different lifestyle variables. We assessed the relationship between preterm delivery and potential risk factors, such as previous LEEP treatments, smoking during pregnancy, age, parity and previous preterm delivery. The cohort was followed until 2004, through linkages with the nationwide Pathology Data Bank and the Medical Birth Registry.Of the 14,982 deliveries in the cohort during follow up, 542 were preterm (21-37 weeks). Among deliveries with no previous LEEP, 3.5% ended as a preterm delivery, whereas this applied to 6.6% among deliveries following a LEEP, yielding a significantly increased risk of preterm birth after LEEP (OR=1.8; 95% CI: 1.1-2.9). The strongest risk factor for preterm delivery was a previous preterm delivery (OR=2.3; 95% CI: 1.4-3.7). Other significant risk factors were smoking during pregnancy and low educational status.Our study showed an almost 2-fold increase in the risk of preterm delivery after LEEP treatment. Thus, women in their reproductive age should be informed about the increased risk of preterm delivery, if treated with LEEP.

Describe smoking patterns in pregnancy in Denmark from 1997 to 2005 and make comparisons with the other Nordic countries, and further to analyze the influence of socio-demographic factors on smoking patterns in pregnancy.Register-based study.Denmark.All primiparous women giving birth in Denmark (n=261,029) in the period 1997-2005. Methods. Information about deliveries, smoking status and characteristics of the women were retrieved from the Danish National Birth Registry. Multiple logistic regression analysis was used to assess the importance of different factors in relation to the risk of smoking in pregnancy.Odds Ratios and associated 99% confidence intervals were used to assess the risk of smoking in pregnancy.The prevalence of women who smoked at some point in pregnancy declined significantly from 22% in 1997 to 16% in 2005. However, among women younger than 20 years at delivery, the pregnancy-related smoking prevalence increased from 37 to 43%. Time trends in smoking patterns were not confounded by socio-demographic factors. Women living in rural areas and women who did not have a partner had the highest risk of smoking in pregnancy.In this nationwide survey, a significant decline in the prevalence of primiparous women who smoked during pregnancy was observed from 1997 to 2005. Despite of this, pregnancy-related smoking prevalence in Denmark is still higher than in the other Nordic countries. Furthermore, the proportion of pregnant smokers was highest among young women, and future smoking cessation programs should bring this subgroup of women into focus.