How to talk to young adults about fertility.

RESEARCH QUESTION: How knowledgeable are Danish young adults about fertility and what are their attitudes towards learning about their reproductive biology? DESIGN: The study was conducted at different educational institutions with 11 focus-group discussions that included a total of 47 participants (aged 18-29 years). Qualitative content analysis was used. The participants' fertility knowledge score was measured using the Cardiff Fertility Knowledge Scale. RESULTS: The participants had an overall fertility knowledge score of 54%. Focus-group data showed that they thought it was important to learn about fertility and how to protect their fertility potential regardless of whether or not they wanted children. Providing knowledge is like planting a seed in the young adults. They wanted to hear about fertility in multifaceted ways and formats, and believed the information should be delivered by professionals, but developed in partnership with young people. The double-edged sword of knowledge and the consequence of knowledge made them hesitant or less open to learning. CONCLUSIONS: Recommendations from this study are to tailor fertility information to young people, with due cognisance of their developmental stage, and ideally from an earlier age.

Social disparities in the use of ART treatment: a national register-based cross-sectional study among women in Denmark.

STUDY QUESTION: How are educational level, labor market attachment and income associated with receiving a first ART treatment in either the public or private healthcare sector among women in Denmark? SUMMARY ANSWER: Higher educational level and income as well as labor market attachment were associated with higher probability of initiating ART treatment at public and private fertility clinics among women in Denmark. WHAT IS KNOWN ALREADY: Infertility is common in populations worldwide, and the approach to this issue differs between societies and healthcare systems. In the public Danish healthcare system, ART treatment is free of charge, and the direct cost for patients is therefore low. In the private healthcare sector in Denmark, ART treatment is self-financed. There is limited knowledge about the association between socioeconomic factors and seeking ART treatment, although previous studies have indicated that higher socioeconomic status is associated with seeking ART treatment. STUDY DESIGN, SIZE, DURATION: Women undergoing ART treatment during 1994-2016 registered in the Danish IVF register were individually linked with data from sociodemographic population registers using the Danish Personal Identification number. The study population consisted of 69 018 women treated with ART and 670 713 age-matched comparison women from the background population with no previous history of ART treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: The women included in the analyses were aged 18-45 years. The associations between attained educational level, labor market attachment and income and receiving a first ART treatment attempt were investigated for women either initiating treatment in the public sector or in the private sector, respectively. Information on age and origin was included as potential confounders, and odds ratios (ORs) were estimated in logistic regression models. In addition, analyses were stratified by age group to investigate potential differences across the age span. MAIN RESULTS AND THE ROLE OF CHANCE: Adjusted results showed increased odds of receiving a first ART treatment in either the public or private sector among women with a higher educational level. Furthermore, women in employment were more likely to receive a first ART treatment in the public or private sector compared to women outside the workforce. The odds of receiving a first ART treatment increased with increasing income level. Surprisingly, income level had a greater impact on the odds of receiving a first ART treatment in the public sector than in the private sector. Women in the highest income group had 10 times higher odds of receiving a first ART treatment in the public sector (OR: 10.53 95% CI: 10.13, 10.95) compared to women in the lowest income group. Sub-analyses in different age groups showed significant associations between ART treatment and income level and labor market attachment in all age groups. LIMITATIONS, REASONS FOR CAUTION: Our study does not include non-ART treatments, as the national IVF register did not register these types of fertility treatments before 2007. WIDER IMPLICATIONS OF THE FINDINGS: In Denmark, there is equal access to medically assisted reproduction treatment in the publicly funded healthcare system, and since there is no social inequality in the prevalence of infertility, social inequality in the use of ART treatment would not be expected as such. However, our results show that social inequality is found for a first ART treatment attempt across publicly and privately funded ART treatment across the socioeconomic indicators, educational level, labor market attachment and income. STUDY FUNDING/COMPETING INTEREST(S): The funding for the establishment of the Danish National ART-Couple II Cohort (DANAC II Cohort) was obtained from the Rosa Ebba Hansen Foundation. The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Does luteal phase progesterone supplementation affect physical and psychosocial well-being among women undergoing modified natural cycle-FET? A sub-study of a randomized controlled trial.

STUDY QUESTION: Are there any differences in physical and psychosocial well-being among women undergoing modified natural cycle frozen embryo transfer (mNC-FET) with or without vaginal progesterone as luteal phase support (LPS)? SUMMARY ANSWER: Women undergoing mNC-FET with vaginal progesterone supplementation were more likely to experience physical discomfort but there was no difference in psychosocial well-being between the two groups. WHAT IS KNOWN ALREADY: mNC-FET can be carried out with or without vaginal progesterone as LPS, which has several side-effects. It is commonly known that fertility treatment can cause stress and psychosocial strain, however, most studies on this subject are conducted in fresh cycle regimes, which differ from NC-FET and results may not be comparable. STUDY DESIGN, SIZE, DURATION: This is a sub-study of an ongoing RCT investigating whether progesterone supplementation has a positive effect on live birth rate in mNC-FET. The RCT is conducted at eight fertility clinics in Denmark from 2019 and is planned to end primo 2024. The sub-study is based on two questionnaires on physical and psychosocial well-being added to the RCT in August 2019. On the time of data extraction 286 women had answered both questionnaires. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had answered both questionnaires were included in the sub-study. Participants were equally distributed, with 143 in each of the two groups. Participants in both groups received the same questionnaires at two time-points: on cycle day 2-5 (baseline) and after blastocyst transfer. Participants in the progesterone group had administered progesterone for 7 days upon answering the second questionnaire. All items in the questionnaires were validated. Items on psychosocial well-being originate from the Copenhagen Multi-Centre Psychosocial Infertility-Fertility Problem Stress Scale (COMPI-FPSS) and from the Mental Health Inventory-5. MAIN RESULTS AND THE ROLE OF CHANCE: Women receiving progesterone experienced more vaginal itching and/or burning than women in the non-progesterone group (P < 0.001). Women in the progesterone group also experienced more self-reported vaginal yeast infection, this was, however, not significant after adjustment for multiple testing (P/adjusted P = 0.049/0.881). No differences regarding psychosocial well-being were found between the two groups. Within the progesterone group, a shift toward feeling less 'downhearted and blue' was found when comparing response distribution at baseline and after blastocyst transfer (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: All items on physical symptoms were self-reported. The item on vaginal yeast infection was therefore not diagnosed by a doctor. Inclusion in the study required a few extra visits to the clinic, participants who felt more burdened by fertility treatment might have been more likely to decline participation. Women who experienced a lot of side-effects to progesterone prior to this FET cycle, might be less likely to participate. WIDER IMPLICATIONS OF THE FINDINGS: Our results are in line with previous known side-effects to progesterone. Physical side-effects of progesterone should be considered before administration. STUDY FUNDING/COMPETING INTEREST(S): The RCT is fully supported by Rigshospitalet's Research Foundation and a grant from Gedeon Richter. Gedeon Richter were not involved in the design of protocol nor in the conduction of the study or analysis of results. A.P., L.P., and N.I.-C.F. report grants from Gedeon Richter, Ferring and Merck with no relations to this study. N.I.-C.F. has received travel support from Ferring, Merck A/S, & Gideon Richter, and is the head of the steering committee for the Danish Fertility Guidelines made by the members of from the Danish Fertility Society. A.P. reports consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, honoraria from Gedeon Richter, Ferring, Merck A/S, Theramex, and Organon, has received travel support from Gedeon Richter (payment to institution), participated on an advisory board for Preglem and was loaned an embryoscope from Gedeon Richter to their institution. A.L.S. has stock options for Novo Nordisk B A/S. B.A. have received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA, and Marckyrl Pharma. TRIAL REGISTRATION NUMBER: The RCT is registered on ClinicalTrials. gov (NCT03795220) and in EudraCT (2018-002207-34).

Psychosocial wellbeing shortly after allocation to a freeze-all strategy compared with a fresh transfer strategy in women and men: a sub-study of a randomized controlled trial.

STUDY QUESTION: Is the psychosocial wellbeing affected in women and men shortly after allocation to a freeze-all strategy with postponement of embryo transfer compared to a fresh transfer strategy? SUMMARY ANSWER: In general, psychosocial wellbeing (i.e. emotional reactions to the treatment, quality-of-life, infertility-related stress, and marital benefit) was similar in women and men allocated to a freeze-all versus those allocated to a fresh-transfer strategy 6 days after disclosure of treatment strategy (i.e. 4 days after oocyte retrieval), although women in the freeze-all group reported a slightly higher degree of depressive symptoms and mood swings compared to women in the fresh transfer group. WHAT IS KNOWN ALREADY: The use of a freeze-all strategy, i.e. freezing of the entire embryo cohort followed by elective frozen embryo transfer in subsequent cycles has increased steadily over the past decade in assisted reproductive technology (ART). This strategy essentially eliminates the risk of ovarian hyperstimulation syndrome and has proven beneficial regarding some reproductive outcomes in subgroups of women. However, patients experience a longer time interval between oocyte retrieval and embryo transfer, hence a longer time to pregnancy, possibly adding additional stress to the ART treatment. So far, little focus has been on the possible psychosocial strains caused by postponement of embryo transfer. STUDY DESIGN, SIZE, DURATION: This is a self-reported questionnaire based sub-study of a multicentre randomized controlled trial (RCT) including 460 women and 396 male partners initiating their first, second, or third treatment cycle of invitro fertilisation or intracytoplasmic sperm injection (ICSI) from May 2016 to September 2018. This sub-study was included in the primary project protocol and project plan for the RCT, as psychosocial wellbeing was considered a secondary outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women from eight public fertility clinics in Denmark and Sweden and one private clinic in Spain were randomized in a 1:1 ratio on the day of inclusion (menstrual cycle day 2 or 3) to either a freeze-all strategy with postponement of embryo transfer to a subsequent modified natural menstrual cycle or a fresh transfer strategy with embryo transfer in the hormone stimulated cycle. Treatment allocation was blinded until the day of the ovulation trigger. Women and their male partners were asked to complete a validated self-reported questionnaire 6 days after unblinding of treatment group allocation, corresponding to 4 days after oocyte retrieval, investigating their psychosocial wellbeing related to the treatment defined as emotional reactions to the treatment, quality-of-life, infertility-related stress, and marital benefit. The questionnaire included items from the Copenhagen Multi-Centre Psychosocial Infertility (COMPI) Fertility Problem Stress Scales and the COMPI Marital Benefit Measure. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were comparable between the two groups for both women and men. In total, response rates were 90.7% for women and 90.2% for men. In the freeze-all group, 207 women and 179 men completed the questionnaire compared with 204 women and 178 men in the fresh transfer group. Men in the two treatment groups did not differ in any of the explored aspects of psychosocial wellbeing (i.e. emotional reactions to the treatment, quality-of-life, infertility-related stress, and marital benefit) 6 days after disclosure of treatment strategy. Women in the freeze-all group reported a slightly higher degree of depressive symptoms (P = 0.045) and mood swings (P = 0.001) (i.e. variables included in 'emotional reactions to treatment') compared to women in the fresh transfer group. When adjusted for multiple testing, depressive symptoms were no longer significantly different between the two groups. No additional differences in psychosocial wellbeing were found. Self-reported quality-of-life during treatment was also rated as similar between the two groups in both women and men, but was slightly lower than they would rate their quality-of-life when not in fertility treatment. LIMITATIONS, REASONS FOR CAUTION: Although response rates were high, selection bias cannot be excluded. As this study was an RCT, we assume that psychosocial characteristics of the participants were equally distributed in the two groups, thus it is unlikely that the identified psychosocial differences between the freeze-all and fresh transfer group were present already at baseline. Furthermore, the questionnaire was completed as a one-time assessment 4 days after oocyte retrieval, thus not reflecting the whole treatment process, whereas an assessment after the full completed treatment cycle is needed to draw firm conclusions about the psychosocial consequences of the whole waiting period. However, a question posted that late would be highly biased on whether or not a pregnancy had been achieved. WIDER IMPLICATIONS OF THE FINDINGS: The results indicate that individuals in the freeze-all group exhibited slightly higher levels of depressive symptoms and mood swings compared to those in the fresh transfer group. Nevertheless, it is important to note that any worries related to potential emotional strains stemming from delaying embryo transfer should not overshadow the adoption of a freeze-all approach in cases where it is clinically recommended. As long as patients are provided with comprehensive information about the treatment strategy before initiating the process, it is worth emphasising that other aspects of psychosocial wellbeing were comparable between the two groups. STUDY FUNDING/COMPETING INTEREST(S): The study is part of the Reprounion collaborative study, co-financed by the European Union, Interreg V Öresund-Kattegat-Skagerrak. L.P. reports financial support from Merck A/S. H.S.N. reports grants from Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, Ministry of Education, Novo Nordic Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond and Independent Research Fund Denmark and personal fees from Ferring Pharmaceuticals, Merck A/S, Astra Zeneca, Cook Medical, IBSA Nordic and Gedeon Richter. H.S.N is founder and chairman of the Maternity Foundation and co-developed the Safe Delivery App (non-profit). N.C.F. reports grants from Gedeon Richter, Merck A/S, Cryos International and financial support from Ferring Pharmaceuticals, Merck A/S and Gedeon Richter. N.C.F. is chairman in the steering committee for the guideline groups for The Danish Fertility Society (non-profit). P.H. reports honoraria from Merch A/S, IBSA Nordic and Gedeon Richter. A.L.M.E. reports grants and financial support from Merck A/S and Gedeon Richter. A.P. reports grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and personal fees from Preglem S.A., Novo Nordic Foundation, Ferring Pharmaceuticals, Gedeon Richter, Cryos International, Merch A/S, Theramex and Organon and the lend of embryoscope to the institution from Gedeon Richter. All other authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT02746562.

Impact of the war in Ukraine and the COVID-19 pandemic on transnational surrogacy - a qualitative study of Danish infertile couples' experiences of being in 'exile'.

RESEARCH QUESTION: How did Danish permanently infertile couples experience surrogacy when going abroad and what impact did the war in Ukraine and the COVID-19 pandemic have on this? DESIGN: A qualitative study was performed between May and September 2022. The in-depth semi-structured interviews were conducted with 14 permanently infertile couples across Denmark who were in different stages of using surrogacy. The interviews were transcribed and analysed using systematic text condensation. RESULTS: All except one couple went abroad, mainly to Ukraine, to have an enforceable transparent contract, professionals to advise them and the possibility of using the eggs of the intended mother. They did not feel that this was a 'choice' but rather the only option they had to have the longed-for child. According to current Danish legislation, the intended mother could not obtain legal motherhood over the child, not even through stepchild adoption, and this increased the feeling of not being a 'worthy mother'. This study expanded on the term 'reproductive exile' by identifying four different forms of exile: the exiled Danish couple, the gestational carrier in exile, exile at home and, finally, the reproductive body in exile. CONCLUSIONS: Understanding infertile couples' experiences when crossing borders is important for several reasons. It may, among others, assist politicians and authorities in developing a sound Danish legal policy on surrogacy to address the current issues of legal parenthood and avoid missing reproductive opportunities for permanently infertile couples.

Infertility, pregnancy loss and assisted reproduction in women with asthma: a population-based cohort study.

STUDY QUESTION: Is the chance of childbirth, and risk of infertility, pregnancy loss and need for assisted reproduction different for women with asthma compared to women without asthma? SUMMARY ANSWER: Women with asthma had comparable chances of giving birth compared to the reference population, however, their risk of both infertility and pregnancy loss, as well their need for medically assisted reproduction, was higher. WHAT IS KNOWN ALREADY: Reproductive dysfunction has been reported among women with asthma, including longer time to pregnancy, increased risk of pregnancy loss and a higher need of medically assisted reproduction, but their risk of clinical infertility is unknown. STUDY DESIGN, SIZE, DURATION: This longitudinal register-based cohort study included all women with a healthcare visit for delivery, infertility, pregnancy loss or induced abortion in the southernmost county in Sweden, over the last 20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using the Skåne Healthcare Register, we identified all women aged 15-45 between 1998 and 2019, who received a diagnosis of asthma before their first reproductive outcome (n = 6445). Chance of childbirth and risk of infertility, pregnancy loss and assisted reproduction were compared to a healthcare seeking population of women without any asthma (n = 200 248), using modified Poisson regressions. MAIN RESULTS AND THE ROLE OF CHANCE: The chance of childbirth was not different between women with asthma versus those without, adjusted risk ratio (aRR) = 1.02, 95% CI: 1.01-1.03. The risk of seeking care for infertility was increased, aRR = 1.29, 95% CI: 1.21-1.39, and women with asthma more often needed assisted reproduction aRR = 1.34 95% CI: 1.18-1.52. The risk of suffering a pregnancy loss was higher, aRR = 1.21, 95% CI: 1.15-1.28, and induced abortions were more common, aRR = 1.15, 95% CI: 1.11-1.20, among women with asthma. LIMITATIONS, REASONS FOR CAUTION: The study was an observational study based on healthcare visits and lacked detailed anthropometric data, thus residual confounding cannot be excluded. Only women with a healthcare visit for a reproductive outcome were included, which cannot be translated into pregnancy intention. A misclassification, presumed to be non-differential, may arise from an incorrect or missing diagnosis of asthma or female infertility, biasing the results towards the null. WIDER IMPLICATIONS OF THE FINDINGS: This study points towards reproductive dysfunction associated with asthma, specifically in regards to the ability to maintain a pregnancy and the risk of needing medically assisted reproduction following clinical infertility, but reassuringly the chance of subsequently giving birth was not lower for these women. STUDY FUNDING/COMPETING INTEREST(S): This article is part of the ReproUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and Ferring Pharmaceuticals. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Effects of trying to conceive using an every-other-day strategy versus fertile window monitoring on stress: a 12-month randomized controlled trial.

STUDY QUESTION: Can animation videos on how to optimize the chances of pregnancy influence stress, anxiety, depression and sexual functioning of individuals trying to conceive (TTC)? SUMMARY ANSWER: There were no differences between those educated to have intercourse every other day, on the fertile window and a control group (CG), and depression and sexual dysfunction significantly increased over time for all arms. WHAT IS KNOWN ALREADY: Recent findings indicate that time to pregnancy can be significantly shortened by targeting the fertile period, but some reproductive care guidelines recommend instead the practice of intercourse every other day on the basis that it is less stressful to the couple. Evidence to support guidelines on how to preserve well-being and psychosocial adjustment and optimize pregnancy chances is lacking. STUDY DESIGN, SIZE, DURATION: We conducted a prospective, double-blinded, three-arm randomized controlled trial between July 2016 and November 2019. Participants were randomized to either not having any stimulus (CG) or visualizing a short animated video explaining how to improve chances of pregnancy by having intercourse every other day (EOD group), or by monitoring the fertile window (FWM group). Assessments were made before the intervention (T0), and 6 weeks (T1), 6 months (T2) and 12 months after (T3), with follow-ups censored in case of pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were childless individuals of reproductive age actively TTC and not diagnosed or unaware of a condition that could prevent spontaneous pregnancy. Individuals were excluded from recruitment if they had previous children or had a condition preventing spontaneous pregnancy. Our primary outcome was stress and secondary outcomes included anxiety, depression, sexual functioning and pregnancy. Primary analyses were performed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 450 randomized participants 127 were educated to use an every-other-day strategy, 135 to monitor the fertile window, and 134 received no intervention. Groups were similar regarding demographics and months TTC. Repeated measures analysis revealed that there were no significant interaction effects of psychological and sexual well-being between groups over time (P > 0.05). Significant time effects were revealed for stress (F(3,855) = 4.94, P < 0.01), depression (F(3,855) = 14.22, P < 0.01) and sexual functioning (time effects P values <0.001 for female sexual functioning dimensions and <0.002 for male dimensions), but not for anxiety (F(2,299) = 0.51, P > 0.05). Stress levels lowered after 6 months (P < 0.001) and returned to baseline levels at the 1-year follow-up. Depressive symptomatology significantly increased at 6 weeks (P = 0.023), and again 1 year after (P = 0.001). There were also significant decreases in all female sexual functioning dimensions (desire, satisfaction, arousal, pain, orgasm and lubrication). In men, there were significant variations in orgasm, intercourse satisfaction and erectile function, but not desire and sexual satisfaction. Revealed pregnancy rates were 16% for participants in the EOD group, 30% for the FWM group and 20% for the CG. Pregnancies were not significantly different between arms: EOD vs FWM (odds ratio (OR) 2.32; 95% CI 0.92-5.83); EOD vs CG (OR 0.74; 95% CI 0.30-1.87); and FWM vs CG (OR 1.71; 95% CI 0.70-4.18). LIMITATIONS, REASONS FOR CAUTION: Participants were recruited after transitioning to procreative sex. The study might be prone to bias as almost 30% of our sample fulfilled the chronological criterion for infertility, and other reproductive strategies could have been tried over time before recruitment. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that stress does not arise from feeling pressured on the fertile period and that advice on timing of intercourse might have to be personalized. The increasing levels of depression and sexual dysfunction over a year emphasize the crucial role of preconception care and fertility counseling in promoting psychological and sexual well-being. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by European Union Funds (FEDER/COMPETE-Operational Competitiveness Programme) and by national funds (FCT-Portuguese Foundation for Science and Technology) under the projects PTDC/MHC-PSC/4195/2012 and SFRH/BPD/85789/2012. TRIAL REGISTRATION NUMBER: NCT02814006. TRIAL REGISTRATION DATE: 27 June 2016. DATE OF FIRST PATIENT'S ENROLLMENT: 19 July 2016.

Meditation and mindfulness reduce perceived stress in women with recurrent pregnancy loss: a randomized controlled trial.

RESEARCH QUESTION: Can participating in a tailored 7-week meditation and mindfulness programme with additional standard supportive care versus standard supportive care only reduce perceived stress for women with recurrent pregnancy loss (RPL)? DESIGN: A two-armed randomized controlled trial (RCT) with 12-month follow-up. In total 76 patients were enrolled and randomly assigned to either standard supportive care or to a 7-week meditation and mindfulness programme led by an instructor in addition to standard supportive care. RESULTS: At intervention completion (after 7 weeks), perceived stress decreased significantly both in the intervention group (P = 0.001) and in the control group (P = 0.006). The decrease in perceived stress in the intervention group was significantly larger (P = 0.027) compared with the control group. At the 12-month follow-up perceived stress was still significantly decreased in both groups compared with baseline (P < 0.0001 in the intervention group and P = 0.002 in the control group). CONCLUSION: This first RCT of a tailored meditation and mindfulness intervention for women with RPL documents that a 7-week daily at-home meditation and mindfulness programme combined with group sessions reduced perceived stress significantly more than a standard supportive care programme. Future studies should address the most effective format and the 'dose' needed for an impact on perceived stress levels.

Perceived Threat of Infertility and Women's Intention to Anticipate Childbearing: The Mediating Role of Personally Perceived Barriers and Facilitators.

To study the role of perceived threat of infertility, barriers, and facilitators in intention to anticipate childbearing, a cross-sectional study was conducted with 240 women desiring to have children and committed in a heterosexual relationship. Participants answered an online survey between July 2016 and February 2018. Results showed that perceiving infertility as a strong barrier and being willing to use fertility treatment as a facilitator fully mediated the effect of perceived threat on intention to anticipate childbearing. In conclusion, women who perceive themselves at risk of being infertile will consider, to a higher degree, infertility as a strong barrier to achieve their reproductive life plan or will report higher willingness to use fertility treatments, which in turn would increase intentions to anticipate childbearing. Since evidence showed lack of fertility awareness, intervention initiatives should target these mediators.

Risk of hospitalization for early onset of cardiovascular disease among infertile women: a register-based cohort study.

STUDY QUESTION: Is female infertility predictive of a woman's future risk of early cardiovascular disease (CVD)? SUMMARY ANSWER: Female infertility does not seem to be predictive of early CVD during a mean follow-up of 9 years. WHAT IS KNOWN ALREADY: Associations between infertility and comorbidity have been found in several studies, but data on the association between female infertility and risk of CVD are scarce and inconclusive. STUDY DESIGN, SIZE, DURATION: In this nationwide cohort study, we included 87 221 women registered in the Danish National IVF register, undergoing medically assisted reproduction (MAR) between 1st of January 1994 and 31st of December 2015. The cohort was followed for incident hospitalization due to CVD in the Danish National Patient Register from enrollment to 31 December 2015. Women with a history of CVD prior to enrollment were excluded. Cox proportional hazard models with age as the underlying time scale were used to estimate hazard ratios (HR) with 95% CI of CVD among women with an infertility diagnosis, compared to women without an infertility diagnosis. All analyses were adjusted for educational attainment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female infertility and the reason for infertility was diagnosed and registered in the IVF register by specialists in Danish public and private fertility clinics since 1st of January 1994. In our cohort, 53 806 women (61.7%) were diagnosed with female factor infertility, while 33 415 (38.3%) did not have a female factor infertility diagnosis and made up the reference group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 686 (1.3%) infertile women were hospitalized for CVD compared to 250 (0.7%) among women without an infertility diagnosis during a mean follow-up time of 9 years. We found no increased risk of early CVD in our analyses (adjusted HR 0.98, 95% CI: 0.85;1.14). Likewise, analyses stratified by specific infertility diagnosis, showed no risk difference. LIMITATIONS, REASONS FOR CAUTION: We were unable to adjust for confounding parameters such as body mass index, cigarette smoking or alcohol consumption. These results may not be generalizable to infertile women who do not seek out fertility treatment, or infertile women with other lifestyle characteristics than Danish women. WIDER IMPLICATIONS OF THE FINDINGS: Diagnosing female infertility or the time of MAR does not seem to be a window of opportunity where early screening for cardiovascular disease risk factors can have a prophylactic potential. STUDY FUNDING/COMPETING INTEREST(S): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. None of the authors declare any conflict of interest.

Infertility-related stress and the risk of antidepressants prescription in women: a 10-year register study.

STUDY QUESTION: Is the first-time redeemed prescription of antidepressants predicted by the level of infertility-related stress in women seeking ART treatment? SUMMARY ANSWER: Infertility-related stress in the personal and marital domains and general physical stress reactions were significant predictors of a first redeemed prescription of antidepressants after ART treatment in this 10-year follow-up cohort study. WHAT IS KNOWN ALREADY: The literature has found inconsistent findings regarding the association between infertility-related stress and later psychological adjustment in fertility patients. The association between infertility-related stress and later prescription of antidepressants had never been explored in long-term cohort studies. STUDY DESIGN, SIZE, DURATION: All women (n = 1169) who participated in the Copenhagen Cohort Multi-centre Psychosocial Infertility (COMPI) cohort study in the year 2000 (questionnaire data) were linked with the register-based Danish National ART-Couple (DANAC) I cohort, which includes women and their partners having received ART treatment from 1 January 1994 to 30 September 2009. The study population were among other national health and sociodemographic registers further linked with the Danish National Prescription Registry. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women initiating ART treatment were followed until they had redeemed the first prescription of antidepressants or until 31 December 2009. Logistic regression analyses were conducted to test the association between general physical stress reactions and infertility-related stress in the personal, marital and social domains, respectively, and a future redeemed prescription of antidepressants. Age, education level, marital status, number of fertility treatments prior to study inclusion and female infertility diagnosis were included as covariates in the adjusted analyses. Further, the analysis was stratified according to childbirth or no childbirth during follow-up. MAIN RESULTS AND THE ROLE OF CHANCE: The final sample consisted of 1009 women with a mean age of 31.8 years. At study inclusion, women had tried to conceive for an average of 3.45 years. At 10-year follow-up, a total of 13.7% of women had a first redeemed prescription of antidepressant medication. The adjusted odds ratio (OR) showed that high general physical stress predicted the later prescription of antidepressants (adjusted (adj) OR = 2.85, 95% confidence interval (CI) 1.96-4.16). Regarding infertility-related stress domains, high personal stress (adj OR = 2.14, 95% CI 1.46-3.13) and high marital stress (adj OR = 1.80, 95% CI 1.23-2.64) were significantly associated with the later prescription of antidepressants. Social stress was not significantly associated with the future redeemed prescription of antidepressants (adj OR = 1.10, 95% CI 0.76-1.61). Among women not having achieved childbirth during follow-up, the risk of a first-time prescription of antidepressants associated with infertility-specific stress was higher compared to the risk among women having childbirth during follow-up. LIMITATIONS, REASONS FOR CAUTION: This study did not account for potential mediating factors, such as negative life events, which could be associated with the prescription of antidepressants. Second, we are not able to know if these women had sought psychological support during follow-up. Additionally, antidepressants might be prescribed for other health conditions than depressive disorders. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that women presenting high infertility-related stress in the personal and marital domains were at higher risk of redeemed first-time prescription of antidepressants after ART, independently of having delivered a child or not after initiation of ART treatment. Women would benefit from an initial screening specifically for high infertility-related stress. The COMPI Fertility Problem Stress Scales can be used by clinical staff in order to identify women in need of psychological support before starting ART treatments. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Portuguese Foundation for Science and Technology (FCT) under an individual doctoral grant attributed to the first author (SFRH/BD/103234/2014). The establishment of the DANAC I cohort was funded by Rosa Ebba Hansen's Fund. The COMPI Infertility Cohort project was supported by The Danish Health Insurance Fund (J.nr. 11/097-97), the Else and Mogens Wedell-Wedellsborgs Fund, the manager E. Danielsens and Wife's Fund, the merchant L.F. Foghts Fund, the Jacob Madsen and Wife Olga Madsens Fund. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: NA.

Male factor infertility and risk of death: a nationwide record-linkage study.

STUDY QUESTION: What is the risk of death among men with oligospermia, unspecified male factor and azoospermia in the years following fertility treatment? SUMMARY ANSWER: No significantly elevated risk was observed among men with oligospermia and unspecified male factor, while an increased risk was found among men with azoospermia. WHAT IS KNOWN ALREADY: Previous studies have shown associations between male factor infertility and risk of death, but these studies have relied on internal reference groups and the risk of death according to type of male infertility is not well characterized. STUDY DESIGN, SIZE, DURATION: In this prospective record-linkage cohort study, we identified men who had undergone medically assisted reproduction (MAR) between 1994 and 2015. Data was linked to the Danish causes of death register and sociodemographic registers through personal identification numbers assigned to all Danish citizens at birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men that had undergone MAR in Denmark (MAR Cohort; n = 64 563) were identified from the Danish IVF register, which includes data on whether infertility was due to male factor. For each man in the MAR cohort, five age-matched men who became fathers without fertility treatment were selected from the general population (non-MAR fathers; n = 322 108). Men that could not adequately be tracked in the Danish CPR register (n = 1259) and those that were censored prior to study entry (n = 993) were excluded, leaving a final population of 384 419 men. Risk of death was calculated by Cox regression analysis with age as an underlying timeline and adjustments for educational attainment, civil status and year of study entry. The risk of death was compared among men with and without male factor infertility identified from the IVF register (internal comparisons) as well as to the non-MAR fathers (external comparison). MAIN RESULTS AND THE ROLE OF CHANCE: The risk of death between the MAR cohort (all men, regardless of infertility) and the non-MAR fathers was comparable [hazard ratio (HR), 1.07; 95% CI, 0.98-1.15]. When the MAR cohort was limited to infertile men, these men were at increased risk of death [HR, 1.27; 95% CI, 1.12-1.44]. However, when stratified by type of male factor infertility, men with azoospermia had the highest risk of death, which persisted when in both the internal [HR, 2.30; 95% CI, 1.54-3.41] and external comparison [HR, 3.32; 95% CI, 2.02-5.40]. No significantly elevated risk of death was observed among men with oligospermia [HR, 1.14; 95% CI, 0.87-1.50] and unspecified male factor [HR, 1.10; 95% CI, 0.75-1.61] compared with the non-MAR fathers. The same trends were observed for the internal comparison. LIMITATIONS, REASONS FOR CAUTION: Duration of the follow-up was limited and there is limited generalizability to infertile men who do not seek fertility treatment. WIDER IMPLICATIONS OF THE FINDINGS: Using national health registers, we found an increased risk of death among azoospermic men while no increased risk was found among men with other types of infertility. For the azoospermic men, further insight into causal pathways is needed to identify options for monitoring and prevention. STUDY FUNDING/COMPETING INTEREST(S): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. C.G.'s research stay at Stanford was funded by grants from the University of Copenhagen, Kong Christian den Tiendes Fond, Torben og Alice Frimodt Fond and Julie Von Müllen Fond. M.E. is an advisor for Sandstone and Dadi. All other authors declare no conflict of interests. TRIAL REGISTRATION NUMBER: Not relevant.

The joint effect of unemployment and cynical hostility on all-cause mortality: results from a prospective cohort study.

BACKGROUND: It is hypothesised that hostility accentuates the association between stressful conditions and health. This study aims to test this hypothesis by analysing the joint effect of unemployment and hostility on all-cause mortality among men and women. METHODS: The population was 3677 men and 4138 women from the Danish workforce who participated in a survey in 2000. The joint exposure variable was defined as 1) employed, not hostile, 2) unemployed, not hostile, 3) hostile and employed, 4) unemployed and hostile. Outcome was defined as all-cause mortality between 2000 and 2014. Data was analysed with Cox proportional hazards models with age as the underlying time scale. The interaction between unemployment and hostility was studied using the synergy index. RESULTS: Compared to employed non-hostile men, men who were both hostile and unemployed were at markedly higher risk of premature death with a hazard ratio (HR) of 3.19 (95% CI 2.22-4.69). A similar picture was found for hostile and unemployed women, with a HR of 1.97 (95% CI 1.24-3.12). However, the mortality in men and women exposed to both did not exceed what was expected from the combination of their individual effects. Hence, we did not find that hostility enhances the association between unemployment and all-cause mortality. CONCLUSION: Men and women exposed to both unemployment and hostility were at markedly high risk of premature mortality. However, this study did not support the hypothesis that the deleterious health effect of the combination of unemployment and hostility exceeds their individual effects.

Concerns on future fertility among users and past-users of combined oral contraceptives: a questionnaire survey.

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.

Mortality in Women Treated With Assisted Reproductive Technology-Addressing the Healthy Patient Effect.

In previous studies, investigators have reported reduced mortality among women undergoing assisted reproductive technology (ART) treatment, possibly related to selection of healthy women into ART treatment. Our aim in this study was to explore the impact of relevant selection factors on the association between ART treatment and mortality and to explore effect modification by parity. Women treated with ART in fertility clinics in Denmark during 1994-2009 (n = 42,897) were age-matched with untreated women from the background population (n = 204,514) and followed until December 31, 2010. With adjustment for relevant confounders, the risk of death was lower among ART-treated women during the first 2 years after ART treatment (hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.63, 0.74), but there was no apparent difference after 10 years (HR = 0.92, 95% CI: 0.79, 1.07). Having children prior to ART treatment was associated with markedly reduced mortality (HR = 0.45, 95% CI: 0.38, 0.53), possibly due to better health among fertile women. While the frequencies of previous medical and psychiatric diagnoses among ART-treated and untreated women were similar, differences in disease severity could explain the reduced mortality among ART-treated women, as poor prognosis would make initiation of ART treatment unlikely. The survival advantage among ART-treated women is likely a selection phenomenon rather than a biological phenomenon.

The impact of ART on union dissolution: a register-based study in Denmark 1994-2010.

STUDY QUESTION: Are couples initiating ART treatment at higher risk for future union dissolution compared to other couples? SUMMARY ANSWER: There is no effect of ART treatments in future marital dissolution over a period of 16 years when adjusting for all confounders. WHAT IS KNOWN ALREADY: Findings regarding marital stability and infertility treatments have been sparse and controversial. While there is data showing higher divorce rates among women who go through infertility treatments, there is also some evidence of this experience bringing couples closer by forcing them to communicate more and to deal with the surrounding stigma. Using a population-based study and couple-level data, we investigated the extent to which ART treatment increases the risk for divorce/marital dissolution during up to 16 years of follow-up. STUDY DESIGN SIZE, DURATION: Register-based national cohort study including all women registered with ART treatment in Denmark between 1 January 1994 and 30 September 2009 (n = 42 845). Marital/cohabiting status was confirmed by matching these women to partners who they were married to or shared an address with. To account for having a significant relationship at baseline (2 years), marital/cohabiting status was confirmed by accessing this variable before the establishment of the cohort back to 1 January 1992. PARTICIPANTS/MATERIALS, SETTING, METHODS: A comparison group from the background population including five controls per case and matched to female age at baseline was prospectively sampled. Participants could change status during follow-up if they entered ART. The final sample had 148 972 couples, followed until marital dissolution, death of self/spouse, migration or until 31 December 2010. We used Cox regression models adjusting for female and male age, education, marriage, common child at baseline and live-born child during follow-up. MAIN RESULTS AND THE ROLE OF CHANCE: At baseline, the majority of couples were married (69%). More non-ART couples opted for marriage (70% versus 64%; P < 0.0001) and already had common children at study entry (43% versus 9%; P < 0.0001). During the 16 years of follow-up the majority of couples had children with their baseline partners (56% non-ART versus 65% ART), and 22% ended up separated or divorced (20% ART versus 22% non-ART). Findings revealed a lower risk of break-up among ART couples (crude HR 0.84, 95% CI 0.82-0.86), even after adjusting for both partners' age, education, partnership status and having a common child at baseline (adj HR 0.83, 95% CI 0.80-0.86). However, when subsequent common children (time-dependent) was added to the model, no difference in the risk of dissolution was found (adj HR 1.00, 95% CI 0.99-1.01). A significant interaction between ART status and common children showed that the risk of break-up was attributed to childlessness regardless of having gone through ART treatment. LIMITATIONS REASON FOR CAUTION: This study did not control for involuntary childlessness, non-ART fertility care (ovulation induction, IUI) and biological parenthood. Additionally, there are important predictors of divorce that were not considered. We were unable to adjust for religion, existence of previous marital relationships, income, employment, health status of parents and child(ren), and quality of relationship. WIDER IMPLICATION OF FINDINGS: The finding that going through ART does not increase the risk of break up per se is reassuring for couples who underwent ART and have children or are contemplating to start ART. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by FCT (Portuguese Foundation for Science and Technology), grant ref. SFRH/BPD/85789/2012. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Male factor infertility and risk of multiple sclerosis: A register-based cohort study.

BACKGROUND: Gender, possibly due to the influence of gonadal hormones, is presumed to play a role in the pathogenesis of multiple sclerosis (MS), but no studies have evaluated whether male infertility is associated with MS. OBJECTIVE: To study the association between male factor infertility and prevalent as well as incident MS. METHOD: Our cohort was established by linkage of the Danish National in vitro fertilization (IVF) registry to The Danish Multiple Sclerosis Registry and consisted of 51,063 men whose partners had undergone fertility treatment in all public and private fertility clinics in Denmark between 1994 and 2015. RESULTS: With a median age of 34 years at baseline, 24,011 men were diagnosed with male factor infertility and 27,052 did not have male factor infertility and made up the reference group. Men diagnosed with male factor infertility had a higher risk of prevalent (odds ratio (OR) = 1.61, 95% confidence interval (95% CI) 1.04-2.51) and incident MS (hazard ratio (HR) = 1.28, 95% CI 0.76-2.17) when compared to the reference group. CONCLUSION: This nationwide cohort study has shown, for the first time, an association between male infertility and MS which may be due to underlying common etiologies such as hypogonadism, shared genetics, or a joint autoimmune component.

Men's expectations and experiences of fertility awareness assessment and counseling.

INTRODUCTION: Men play an important role in couples' decisions about the timing of parenthood and they tend to delay parenthood. The reasons for delaying childbearing are multifaceted and complex. Their decisions may be based on a lack of accurate information about the reproductive life span and the consequences of delaying parenthood. The aim of this study was to explore men's expectations and experiences of fertility counseling. MATERIAL AND METHODS: Data were collected through semi-structured qualitative interviews with 21 men attending either the Fertility Assessment and Counseling Clinic in Copenhagen or in Horsens, Denmark. The men had no known fertility problems before going to the fertility counseling. They were interviewed before and after fertility counseling. RESULTS: The men were not concerned about their fertility before going to counseling. They believed they would be able to conceive whenever they wanted. Three of them had low semen quality and felt "punched in the gut" when they received these results at the fertility counseling. The study participants preferred clear and concrete information, and relevant knowledge at the right time was very important. The men felt empowered after the fertility counseling because they were equipped with concrete information that could inform their parenthood plans and decisions. Even the men who received unexpected bad news felt positive about the counseling. The participants perceived their knowledge and awareness of risk factors concerning fertility had increased. CONCLUSIONS: Men may benefit from an individualized approach where their fertility is assessed and they receive tailored fertility counseling specific to their personal fertility results. This type of intervention may be effective in increasing men's fertility awareness because it is personally relevant.

Low semen quality and experiences of masculinity and family building.

INTRODUCTION: Infertility is a concern for men and women. There is limited knowledge on how male factor infertility affects the couple in fertility treatment. The aim of this study was to explore how severe male factor infertility affects men's sense of masculinity, the couple's relationship and intentions about family formation. MATERIAL AND METHODS: Semi-structured qualitative interview study at the Fertility Clinic at Copenhagen University Hospital, Hvidovre, Denmark. Ten men with very poor semen quality initiating fertility treatment were interviewed between November 2014 and May 2015. Data were analyzed using qualitative content analysis. RESULTS: Three themes were identified: "Threatened masculinity", "Being the strong one: impact on the couple" and "Consideration of family building options: a chapter not willing to start". The men felt that they could not fulfill their role as a man. Some couples had conflicts and discussions because the women in general wanted to talk more about infertility than the men. The men focused on having a biological child. They wanted to focus on achieving biological parenthood and postpone consideration of other family building options such as adoption or the use of semen donation in order to become a parent. CONCLUSIONS: The consequence of severe male factor infertility was a threatened sense of masculinity. Fertility specialists and nurses should recognize the impact of male infertility and create space to give their patients an opportunity to verbalize their concerns and questions related to male factor infertility and the different challenges that the couple faces during the fertility treatment.

COMPI Fertility Problem Stress Scales is a brief, valid and reliable tool for assessing stress in patients seeking treatment.

STUDY QUESTION: Are the Copenhagen Multi-Centre Psychosocial Infertility research program Fertility Problem Stress Scales (COMPI-FPSS) a reliable and valid measure across gender and culture? SUMMARY ANSWER: The COMPI-FPSS is a valid and reliable measure, presenting excellent or good fit in the majority of the analyzed countries, and demonstrating full invariance across genders and partial invariance across cultures. WHAT IS KNOWN ALREADY: Cross-cultural and gender validation is needed to consider a measure as standard care within fertility. The present study is the first attempting to establish comparability of fertility-related stress across genders and countries. STUDY DESIGN SIZE, DURATION: Cross-sectional study. First, we tested the structure of the COMPI-FPSS. Then, reliability and validity (convergent and discriminant) were examined for the final model. Finally, measurement invariance both across genders and cultures was tested. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our final sample had 3923 fertility patients (1691 men and 2232 women) recruited in clinical settings from seven different countries: Denmark, China, Croatia, Germany, Greece, Hungary and Sweden. Participants had a mean age of 34 years and the majority (84%) were childless. MAIN RESULTS AND THE ROLE OF CHANCE: Findings confirmed the original three-factor structure of the COMPI-FPSS, although suggesting a shortened measurement model using less items that fitted the data better than the full version model. While data from the Chinese and Croatian subsamples did not fit, all other counties presented good fit (χ2/df ≤ 5.4; comparative fit index ≥ 0.94; root-mean-square error of approximation ≤ 0.07; modified expected cross-validation index ≤ 0.77). In general, reliability, convergent validity, and discriminant validity were observed in all subscales from each country (composite reliability ≥ 0.63; average variance extracted ≥ 0.38; squared correlation ≥ 0.13). Full invariance was established across genders, and partial invariance was demonstrated across countries. LIMITATIONS REASONS FOR CAUTION: Generalizability regarding the validation of the COMPI-FPSS cannot be made regarding infertile individuals not seeking treatment, or non-European patients. This study did not investigate predictive validity, and hence the capability of this instrument in detecting changes in fertility-specific adjustment over time and predicting the psychological impact needs to be established in future research. WIDER IMPLICATIONS OF THE FINDINGS: Besides extending knowledge on the psychometric properties of one of the most used fertility stress questionnaire, this study demonstrates both research and clinical usefulness of the COMPI-FPSS. STUDY FUNDING/COMPETING INTERESTS: This study was supported by European Union Funds (FEDER/COMPETE-Operational Competitiveness Program, and by national funds (FCT-Portuguese Foundation for Science and Technology) under the projects PTDC/MHC-PSC/4195/2012 and SFRH/BPD/85789/2012). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.