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Study Question: Are there differences in psychosocial and physical wellbeing among women and male partners undergoing modified natural cycle (mNC) frozen embryo transfer (FET) in immediate compared to postponed cycles after ovarian stimulation (OS) and oocyte pick-up (OPU)?, Summary Answer: Significantly more women in the immediate group reported physical symptoms than women in the postponed group whilst fewer were emotionally affected by waiting time, although the latter difference lost statistical significance after adjustment for multiple testing., What Is Known Already: Infertility and fertility treatment are known to cause psychosocial distress in women and couples longing for a child. The treatment may be long-term and delayed for various reasons, such as the elective postponement of FET after a fresh transfer without pregnancy or an elective freeze-all cycle, possibly further increasing the level of distress., Study Design, Size, Duration: Sub-study of an ongoing multicentre randomized controlled, non-inferiority trial assessing the optimal timing for mNC-FET treatment after OS and OPU. Participants were randomized 1:1 to mNC-FET in the cycle immediately following OS or mNC-FET in a subsequent cycle. The study is based on data from the first women (N = 300) and male partners (N = 228) invited to answer a self-reported questionnaire assessing psychosocial and physical wellbeing. Data were collected from April 2021 to March 2024., Participants/materials, Setting, Methods: Questionnaires were distributed to all randomized women and their male partners on cycle day 2-5 of mNC-FET cycles and returned before the administration of ovulation trigger. The questionnaire consisted of validated items originating from the Copenhagen Multicentre Psychosocial Infertility-Fertility Problem Stress Scale (COMPI-FPSS) and Marital Benefit Measure (COMPI-MBM). Emotional reactions to waiting time in fertility treatment, mental health, general quality-of-life, and physical symptoms were also assessed., Main Results and the Role of Chance: Questionnaire response rates were 90.3% for women and 80.0% for male partners in the immediate group, and 82.3% for women and 57.3% for male partners in the postponed group. Approximately 90% of all women worried to some or a great extent about whether the treatment would be successful. More women in the postponed group reported that they were emotionally affected by the waiting time from OPU to blastocyst transfer to some or to a great extent (57.4% versus 73.9% in the immediate versus postponed group, P = 0.014), but the results were not significant after adjustment for multiple testing (P = 0.125). For male partners, no difference in emotional reactions to waiting time between groups was found. There was no significant difference in total infertility-related stress or symptoms of severe depression between the immediate and the postponed group for women or male partners, but women were generally more distressed than their partners. There was a significantly higher incidence of stomach and/or pelvic pain (24.0% versus 9.4%, adjusted P = 0.013), feeling of being bloated (33.8% versus 15.1%, adjusted P = 0.010) and swollen or tender breasts (24.8% versus 0.9%, P < 0.001) in the immediate group., Limitations, Reasons for Caution: All items were self-reported. No assessment of psychosocial or physical wellbeing was performed before participant enrolment. The sample size of male partners was relatively small, and female partners were not included in this sub-study due to a very small number of participants in this group., Wider Implications of the Findings: If immediate mNC-FET proves to be effective, physical and emotional factors may play a key role in choosing treatment strategy for the individual patient. This study demonstrated more physical symptoms related to OS in the immediate cycles., Study Funding/competing Interest(s): The RCT was supported by Rigshospitalet's Research Foundation and an independent research grant from Merck A/S (MS200497&#95;0024). Merck A/S had no role in the design of this study and will not have any role during its execution, analyses, interpretation of data, or decision to submit results. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and Cryos as payment to the institution. A.P. received consulting fees from IBSA, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, and honoraria from Organon, Ferring Pharmaceuticals, Gedeon Richter and Merck A/S. A.P. received support for meeting attendance from Gedeon Richter. M.S. benefitted from a grant from Gedeon Richter. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. N.C.F. received grants from Gedeon Richter, Merck A/S and Cryos as payment to the institution. N.C.F. received consulting fees from Merck A/S and support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, IBSA, and Gedeon Richter. N.C.F. is chair of the steering committee for the guideline groups for The Danish Fertility Society. E.L. received a radiometer contract on blood gas validation as a payment to the institution. E.L. received honoraria from Pfizer and support for meeting attendance from Astella. B.N. received grants from IBSA, Ferring Pharmaceuticals, Merck A/S, and Gedeon Richter as payment to the institution. B.N. received honoraria from Merck A/S and Organon and support for meeting attendance from IBSA and Gedeon Richter. B.N. and L.P. participate in an Advisory Board at Ferring Pharmaceuticals. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk., Trial Registration Number: ClinicalTrials.gov NCT04748874., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The effect of late-follicular phase progesterone elevation (LFPE) during ovarian stimulation on reproductive outcomes in ART treatment remains controversial, but recent studies indicate lower pregnancy rates with rising progesterone levels. This study aims to investigate the prevalence of late-follicular phase progesterone elevation (LFPE) and possible impact on ongoing pregnancy rate after fresh or frozen blastocyst transfer in a sub-study setting of a randomised controlled trial. A total of 288 women were included (n=137 and n=151 in the fresh transfer and freeze-all group, respectively). Among these 11(3.8%) had a progesterone level ≥1.5 ng/ml, and 20(6.9%) had a progesterone level ≥1.2 ng/ml on trigger day . Spline regression analysis showed no significant effect of late follicular phase progesterone levels on ongoing pregnancy. In the multivariate regression analysis ( n  = 312) only age, but not progesterone level on trigger day was significantly associated with ongoing pregnancy. In conclusion, in a clinical setting with moderate gonadotrophin stimulation and well-defined trigger and fresh transfer cancellation criteria, the prevalence of women with LFPE ≥1.5 ng/ml was low and did not indicate the clinical value of routine measurement of progesterone in the late follicular phase.

Managing asthma during pregnancy is crucial for both the mother and the developing child. Adequate control lowers risks as do continuation of prescribed medication and maintaining of regular check-ups. Signs of deterioration should not be ignored and treating asthma during pregnancy should follow guidelines for non-pregnant women with asthma as described in this review. Effective medication and counseling are essential for a safe pregnancy, emphasizing that well-controlled asthma is key., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect the male reproductive system as it uses angiotensin-converting enzyme (ACE)2, which is expressed in testicular tissue, as an entry point into the cell. Few studies have evaluated the long-term effects of mild coronavirus disease 2019 (COVID-19) on testicular function, and insulin-like factor 3 (INSL3) levels have not previously been assessed during acute SARS-CoV-2 infection., Objectives: The aim of the study was to assess the impact of acute SARS-CoV-2 infection on testicular function including INSL3 and the presence of SARS-CoV-2 RNA in semen in non-hospitalised men with mild COVID-19., Materials and Methods: This longitudinal study included 36 non-hospitalised SARS-CoV-2-positive men (median age 29 years). Inclusion was within seven days following a positive SARS-CoV-2 reverse-transcription polymerase chain reaction test. Reproductive hormone levels, semen parameters, and the presence of SARS-CoV-2 RNA in oropharyngeal and semen samples were assessed during acute SARS-CoV-2 infection (baseline) and at three- and six-month follow-up. Wilcoxon matched-pair signed-rank (two samples) test was used to assess time-related alterations in reproductive hormone levels and semen parameters., Results: Lower plasma testosterone (T) (total and calculated free (c-fT)) and higher luteinising hormone (LH) concentrations were observed during acute SARS-CoV-2 infection (baseline) compared to three- and six-month follow-up. Consequently, ratios of c-fT/LH were lower at baseline compared to three- and six-month follow-up (p < 0.001 and p = 0.003, respectively). Concomitantly, lower INSL3 concentrations were observed at baseline compared to three-month follow-up (p = 0.01). The total number of motile spermatozoa was also lower at baseline compared to six-month follow-up (p = 0.02). The alterations were detected irrespective of whether the men had experienced SARS-CoV-2-related fever episodes or not. No SARS-CoV-2 RNA was detected in semen at any time point., Discussion and Conclusion: This study showed a reduction in testicular function, which was for the first time confirmed by INSL3, in men mildly affected by SARS-CoV-2 infection. The risk of transmission of SARS-CoV-2 RNA via semen seems to be low. Febrile episodes may impact testicular function, but a direct effect of SARS-CoV-2 cannot be excluded., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Purpose: The SmartSleep Study is established to comprehensively assess the impact of night-time smartphone use on sleep patterns and health. An innovative combination of large-scale repeated survey information, high-resolution sensor-driven smartphone data, in-depth clinical examination and registry linkage allows for detailed investigations into multisystem physiological dysregulation and long-term health consequences associated with night-time smartphone use and sleep impairment., Participants: The SmartSleep Study consists of three interconnected data samples, which combined include 30 673 individuals with information on smartphone use, sleep and health. Subsamples of the study population also include high-resolution tracking data (n=5927) collected via a customised app and deep clinical phenotypical data (n=245). A total of 7208 participants are followed in nationwide health registries with full data coverage and long-term follow-up., Findings to Date: We highlight previous findings on the relation between smartphone use and sleep in the SmartSleep Study , and we evaluate the interventional potential of the citizen science approach used in one of the data samples. We also present new results from an analysis in which we use 803 000 data points from the high-resolution tracking data to identify clusters of temporal trajectories of night-time smartphone use that characterise distinct use patterns. Based on these objective tracking data, we characterise four clusters of night-time smartphone use., Future Plans: The unprecedented size and coverage of the SmartSleep Study allow for a comprehensive documentation of smartphone activity during the entire sleep span. The study has been expanded by linkage to nationwide registers, which allow for further investigations into the long-term health and social consequences of night-time smartphone use. We also plan new rounds of data collection in the coming years., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Objectives: To explore the relationship among night-time smartphone use, sleep duration, sleep quality, and menstrual disturbances in young adult women., Methods: Women aged 18-40 years were included in the SmartSleep Study in which they objectively tracked their smartphone use via the SmartSleep app between self-reported sleep onset and offset times ( n = 764) and responded to a survey ( n = 1068), which included background characteristics, sleep duration, sleep quality (Karolinska Sleep Questionnaire), and menstrual characteristics (International Federation of Gynecology and Obstetrics' definitions)., Results: The median tracking time was four nights (interquartile range: 2-8). Higher frequency ( p = .05) and longer duration ( p = .02) of night-time smartphone use were associated with long sleep duration (≥9 h), but not with poor sleep quality or short sleep duration (<7 h). Short sleep duration was associated with menstrual disturbances (OR = 1.84, 95% confidence interval [CI] = 1.09 to 3.04) and irregular menstruation (OR = 2.17, 95% CI = 1.08 to 4.10), and poor sleep quality was associated with menstrual disturbances (OR = 1.43, 95% CI = 1.19 to 1.71), irregular menstruation (OR = 1.34, 95% CI = 1.04 to 1.72), prolonged bleedings (OR = 2.50, 95% CI = 1.44 to 4.43) and short-cycle duration (OR = 1.40, 95% CI = 1.06 to 1.84). Neither duration nor frequency of night-time smartphone use was associated with menstrual disturbances., Conclusions: Night-time smartphone use was associated with longer sleep duration, but not with menstrual disturbances in adult women. Short sleep duration and sleep quality were associated with menstrual disturbances. Further investigation of the effects of night-time smartphone use on sleep and female reproductive function in large prospective studies is needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Research Question: Is low-grade inflammation, detected by C-reactive protein (CRP), a marker of IVF outcome addressing both blastocyst quality and pregnancy outcome?, Design: This sub-study of a multicentre randomized controlled trial included 440 women undergoing IVF treatment with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Serum CRP was measured on cycle day 2-3 (baseline) and on the day of ovulation triggering. The association between CRP concentrations and reproductive outcomes (number of retrieved oocytes, number of good-quality blastocysts, pregnancy, pregnancy loss and live birth), were analysed, adjusting for relevant confounders., Results: A negative association was found between higher baseline CRP concentrations and live birth rate (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.62-0.96, P = 0.02) and higher CRP concentrations at baseline were associated with pregnancy loss among women who conceived (OR 1.37, 95% CI 1.07-1.76, P = 0.01). When testing for a specific cut-off, CRP concentrations above 2.34 (the highest quartile) were more likely to be associated with pregnancy loss (P = 0.02) and a lower chance of live birth (P = 0.04) compared with the lowest quartile. No associations were found between CRP concentrations and pregnancy outcomes on the day of ovulation triggering, and there were no associations between CRP concentrations and the number of good-quality blastocysts., Conclusions: Higher CRP concentrations at cycle day 2-3, before starting ovarian stimulation, are negatively associated with chance of live birth, possibly because of an increased risk of pregnancy loss. No association was found between the number of good-quality blastocysts and CRP concentration. More studies are needed to investigate the impact of low-grade inflammation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Study Question: How does nucleus status at the two-cell stage predict blastocysts formation and clinical outcome after single blastocyst transfer?, Summary Answer: Binucleated embryos at the two-cell stage (2BI) show higher rates of good quality blastocyst formation, pregnancy and live birth compared to those with one nucleus in each blastomere (2MONO), whereas true multinucleated embryos at the two-cell stage (2MULTI) show lower rates of good quality blastocyst formation and pregnancy compared to 2MONO embryos., What Is Known Already: The introduction of time-lapse culture has made it possible to study nucleus status at the two-cell stage more consistently and it shows that multinucleation at the two-cell stage (2MN) is a common event. The effect of 2MN is still unclear. High numbers of 2MN with the potential to develop to blastocysts that become clinical pregnancies and result in birth of healthy babies with no impaired perinatal outcome have been reported. However, some studies have found 2MN to be associated with impaired implantation and live birth. Furthermore, knowledge on how the different subgroups of multinucleation affects the IVF outcome is limited., Study Design Size Duration: A non-interventional retrospective study was performed in a public fertility clinic. Blastocyst formation data from 223 women attending their first IVF cycle between May 2016 and December 2018, and clinical outcome data from 1314 single blastocyst transfers between May 2014 and December 2018 were used for the study. Fresh and frozen-thawed embryo transfers were included., Participants/materials Setting Methods: Embryos were cultured until the blastocyst stage in a time-lapse incubator and nucleus status at the two-cell stage, the Gardner score and other morphokinetic parameters were annotated. We compared blastocyst development and clinical outcome, including positive hCG, ongoing pregnancy and live birth, of embryos with 2BI and/or 2MULTI blastomeres to 2MONO embryos., Main Results and the Role of Chance: Embryos with 2BI in one blastomere (2BI1) were twice as likely to develop to good quality blastocysts (odds ratio (OR) 2.54, 95% CI 1.30-4.95, P  = 0.006) compared to 2MONO embryos. Embryos with 2MULTI in both blastomeres (2MULTI2) were significantly less able to develop to good quality blastocysts (OR 0.38, 95% CI 0.23-0.63, P  < 0.001) compared to 2MONO embryos. Embryos with 2BI in both blastomeres (2BI2) had a significantly better chance of resulting in a positive hCG (OR 2.40, 95% CI 1.11-5.20, P  = 0.027), ongoing pregnancy (OR 2.79, 95% CI 1.29-6.04, P  = 0.009) and live birth (OR 3.16, 95% CI 1.43-6.95, P  = 0.004) compared to 2MONO blastocysts after single blastocyst transfer. In contrast, 2MULTI2 embryos were significantly less likely to result in a positive hCG (OR 0.58, 95% CI 0.35-0.97, P  = 0.036) and ongoing pregnancy (OR 0.51, 95% CI 0.28-0.94, P  = 0.030) compared to 2MONO blastocysts., Limitations Reasons for Caution: Discrepancies among the existing studies regarding the definition of multinucleation may lead to different conclusions. Even though the distinction between binucleation and true multinucleation was a strength in our study design, a further distinction between true multinucleated and micronucleated embryos could be interesting to investigate in future studies. Also, we included any anucleated embryos in the 2MONO group. For the study of clinical outcomes, the patients were allowed to be included with more than one transfer cycle. Both fresh and thawed transfers were included., Wider Implications of the Findings: We find it important to discriminate between binucleation and true multinucleation when evaluating embryo nucleus status at the two-cell stage. Embryos displaying 2BI1 and 2BI2 have significantly better good quality blastocyst formation rates and clinical outcome after single blastocyst transfers, respectively. 2MULTI2 embryos have impaired blastocyst development potential and poorer clinical outcomes., Study Funding/competing Interests: H.S.N. received an unrestricted grant from Merck for 3 months' normal salary for a medical Doctor (A.L.T.) to write the manuscript. Merck was not involved in the study design, analysis, interpretation of data, writing the paper or the decision to submit the manuscript for publication. H.S.N. has received speaker's fees from Ferring Pharmaceuticals, Merck Denmark A/S, Astra Zeneca, Cook Medical and Ibsa Nordic (outside the submitted work). N.l.C.F. has received a grant from Gedeon Richter (outside the submitted work). The other authors did not report any potential conflicts of interest. All authors declared no conflicts of interest regarding this work., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

The freeze all strategy has become a promising alternative to fresh embryo transfer in fertility treatment almost eliminating late ovarian hyperstimulation syndrome (OHSS) in the segmented cycle. There is a lack of in-depth knowledge regarding patients' attitudes towards the freeze all strategy. The aim of this study was to explore the attitudes towards a freeze all strategy compared with fresh embryo transfer in assisted reproductive technology (ART) treatment among couples in a public health care setting. We conducted semi-structured qualitative interviews with ten couples already participants in a randomised controlled trial (RCT) and undergoing ART treatment. The couple's responses showed five themes: (i) Starting treatment provides needed relief; (ii) Treatment must be provided with humanity; (iii) Provision of information instigates positive attitudes towards treatment; (iv) Fresh treatment - 'The normal way'; and (v) Freeze all treatment - 'The new black'. When thorough information about treatment procedures and safety aspects regarding both the freeze all and fresh embryo transfer strategy is given prior to initiation of treatment, couples feel secure and content, regardless of which treatment strategy is finally applied. This qualitative study found that starting treatment could prompt longed-for relief, as professionals would now 'take over' and assist in meeting the couple's family building goals.

This article reviews the current studies published on the transmission of SARS-CoV-2 in semen and the potential effect of COVID-19 on male fertility. The aim was to provide insight into different possible mechanisms of involvement of the male reproductive system by SARS-CoV-2 infection and to evaluate the studies investigating the presence of virus in semen. It is concluded that the likelihood of SARS-CoV-2 transmission through semen is low and that COVID-19 may negatively affect semen parameters, but that the impairment is probably short-termed.

In Denmark, intrauterine insemination (IUI) with or without ovarian stimulation is a common treatment for infertility. If strict cancellation criteria are met to reduce the risk of multiple pregnancies in ovarian stimulation cycles, IUI can be considered safe, less invasive and less costly compared to in vitro fertilisation. In 2019, a total of 9,322 homologous IUIs and 8,433 IUIs using donor sperm were performed in Denmark, and 2,000 children were expected to be born after the use of IUI. Thus, in this review we conclude that IUI is an effective treatment for infertility in selected patients.

Background: Infertility affects 15%-25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth., Objectives: Three overall questions will be studied: (1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? (2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And (3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up?, Material and Methods: ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skåne University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of biospecimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem., (© 2021 American Society of Andrology and European Academy of Andrology.)

Background: Failed gonadotropin-releasing hormone (GnRH) agonist trigger with no oocyte retrieved during aspiration of several follicles is a rare but recurrent situation that can be rescued by the termination of the aspiration procedure, retriggering by human chorion gonadotropin (hCG), and repeated oocyte pickup 36 h later. Failed GnRH agonist trigger is frustrating and unsatisfactory, and fertility doctors must be aware of possible hCG retriggering and retained opportunity for successful cycle outcome. Objective: In this case report, we present a woman who experienced failed GnRH agonist trigger and rescue hCG retrigger followed by two consecutive live births after frozen-thawed single blastocyst transfers. Methods: A case report. Results: Two healthy children were born in 2018 and 2020, respectively as a result of controlled ovarian stimulation for IVF, failed GnRH agonist trigger followed by hCG re-trigger, and successful retrieval of 25 oocytes. Conclusion: Retriggering with hCG after failed GnRH agonist trigger can result in consecutive live births, and such knowledge can prevent cycle cancellation and patient discouragement. Knowledge on retriggering with hCG and consecutive live births after failed GnRH agonist trigger can prevent cycle cancellation and patient discouragement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liest, Riishede Christiansen, Prætorius, Bogstad, Freiesleben, Pinborg and Løssl.)

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., Competing Interests: Competing interests: ABP and KL has received a research grant from Merck supporting the present study. SJB has received a research grant from Rigshospitalet’s research fund supporting the present study. As a partner of Reprounion, ABP has received a grant from Ferring as well as a research grant from Gedeon Richter. ABP has received consulting fees from Novo Nordisk, honoraria from Merck and Ferring, honoraria as well as support for attending meetings from Gedeon Richter. KL has received honoraria from pharmakon and support for attending meetings from Gedeon Richter. PH has received unrestricted grants from Merck, Gedeon Richter, IBSA, Ferring and MSD as well as honoraria for lectures from Merck and Gedeon Richter. MF has received a research grant from Gedeon Richter. NLCF has received an unrestricted grant from Gedeon Richter, honoraria for lectures from Merck and support for attending meetings by Ferring, Merck and Gedeon Richter. Since 2018, NLCF is head of the steering committee for Danish fertility guidelines., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Over the last decades, the use of intracytoplasmic sperm injection (ICSI) has increased, even among patients without male factor infertility. The increase has happened even though there is no evidence to support that ICSI results in higher live birth rates compared with conventional in vitro fertilisation (IVF) in cases with nonmale factor infertility. The lack of robust evidence on an advantage of using ICSI over conventional IVF in these patients is problematic since ICSI is more invasive, complex and requires additional resources, time and effort. Therefore, the primary objective of the IVF versus ICSI (INVICSI) study is to determine whether ICSI is superior to standard IVF in patients without severe male factor infertility. The primary outcome measure is first live birth from fresh and frozen-thawed transfers after one stimulated cycle. Secondary outcomes include fertilisation rate, ongoing pregnancy rate, birth weight and congenital anomalies., Methods and Analysis: This is a two-armed, multicentre, randomised, controlled trial. In total, 824 couples/women with infertility without severe male factor will be recruited and allocated randomly into two groups (IVF or ICSI) in a 1:1 ratio. Participants will be randomised in variable block sizes and stratified by trial site and age. The main inclusion criteria are (1) no prior IVF/ICSI treatment, (2) male partner sperm with an expected count of minimum 2 million progressive motile spermatozoa following density gradient purification on the day of oocyte pick up and (3) age of the woman between 18 and 42 years., Ethics and Dissemination: The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committee of the Capital Region of Denmark. Study findings will be presented, irrespectively of results at international conferences and submitted for publication in peer-reviewed journals., Trial Registration Number: NCT04128904. Pre-results., Competing Interests: Competing interests: SB and NLCF received a research grant from the Capital Region of Denmark and two unrestricted grants from Gedeon Richter to support the INVICSI study as mentioned under ‘Funding’. Outside the submitted work authors have received grants/fees/funding or declare relationships with the following third parties: SB: Gedeon Richter, the Capital Region of Denmark. NLCF: Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, Head of the steering committee for the Danish Fertility Guidelines made by members of the Danish Fertility Society (no payment), Guerbet, Advisory Board (personal fee). AP: Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, Theramex. UBK: IBSA, Ferring Pharmaceuticals, Merck A/S. LFA: Gedeon Richter. BN: Gedeon Richter, IBSA, Merck A/S. HSN: Ferring Pharmaceuticals, Merck A/S, AstraZeneca, Cook Medical, Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, Danish Ministry of Education. MLG: Gedeon Richter, Merck A/S. LP: Gedeon Richter, Merck A/S., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Asthma 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 Analysis: This 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 Dissemination: The 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 Number: NCT03727971., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Recent studies in in vitro fertilisation (IVF) patients have associated abnormal vaginal microbiota (AVM) with poor clinical pregnancy rates of 6%-9% per embryo transfer. The biological plausibility for this finding is hypothesised to be ascending infection to the endometrium which in turn hampers embryo implantation. New molecular based diagnosis may offer advantages compared to microscopical diagnosis of AVM which has huge inter-study variability ranging from 4 to 38%; however, the important question is whether screening and treatment of AVM would improve reproductive outcomes in IVF patients. Herein, we describe a protocol for an ongoing double-blind, placebo-controlled multicentre trial of IVF patients diagnosed with AVM and randomised in three parallel groups 1:1:1., Methods and Analysis: This is a drug intervention study where IVF patients will be screened for AVM, using a qPCR assay targeting Atopobium vaginae and Gardnerella vaginalis . If positive, patients will be randomised to one of the three study arms. The first arm consists of clindamycin 300 mg ×2 daily for 7 days followed by vaginal Lactobacillus crispatus CTV-05 until clinical pregnancy scan week 7-9. The second arm consists of clindamycin and placebo L. crispatus CTV-05, whereas patients in the third arm will be treated with placebo/placebo. We used a superiority design to estimate that active treatment in both arms will increase the primary outcome, clinical pregnancy rate per embryo transfer, from 20% to 40%. A potential difference between the two active arms was considered exploratory. With a power of 80% and an alpha at 5%, the sample size is estimated to be 333 patients randomised. A pre-planned interim analysis is scheduled at 167 patients randomised., Ethics and Dissemination: All patients have to give informed consent. Dissemination of results is ensured in clinical trial agreements whether they be positive or not. Ethics committee, Central Denmark Region approved this protocol., Trial Registration Number: ICH-GCP monitored trial, EudraCT 2016-002385-31; Pre-results., Competing Interests: Competing interests: PH, JSJ, NU, TP and TH are listed as inventors in an international patent application (PCT/US2018/040882), involving the therapeutic use of vaginal lactobacilli to improve IVF outcomes. TP is an employee of Osel, Inc. Not related to this trial, TH received honoraria for lectures from Ferring, IBSA, Besins and Merck. PH received unrestricted research grants from MSD, Merck and Ferring as well as honoraria for lectures from MSD, Merck, Gedeon-Richter, Theramex and IBSA. JSJ received speaker’s fee from Hologic, BD, SpeeDx and Cepheid and serves on the scientific advisory board of Roche Molecular Systems, Abbott Molecular and Cepheid. NLCF received unrestricted research grant from Gedeon Richter and honoraria for lectures from Merck. HSN received unrestricted research grant from Ferring and honoraria for lectures from Merck, IBSA and Ferring., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Androgen receptors are expressed by all stages of growing follicles, and follicular fluid androgen levels are positively correlated to granulosa cell androgen receptor and follicle-stimulating hormone (FSH) receptor expression. Thus, androgens may promote follicular growth, accumulation and/or responsiveness to gonadotropins. This is explored therapeutically in the concept of androgen priming, to improve the ovarian response to stimulation in assisted reproduction. Androgen effects may be achieved in two different ways, either directly by providing exogenous androgen or by providing luteinizing hormone (LH) activity [i.e., LH or human chorionic gonadotropin (hCG)] to stimulate local ovarian production of androgen. The androgen concentrations in follicular fluid by far exceed the levels in female circulation and it has recently been shown that there was no correlation between serum testosterone levels and follicular fluid androgen levels. There is some evidence that administration of exogenous dehydroepiandrosterone or testosterone increases live birth rates, but an optimal protocol has not been established and such adjuvant treatment should be considered experimental. Furthermore, studies exploring long-term administration of LH activity, achieving LH levels comparable to those seen in women with polycystic ovary syndrome, are awaited. The aim of the present review is to discuss critically the most suitable approach for androgen priming from a biological and clinical standpoint, and to evaluate current approaches and results obtained in clinical trials., (Copyright © 2020 Løssl, Freiesleben, Wissing, Birch Petersen, Holt, Mamsen, Anderson and Andersen.)

Study Question: Does women's age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells?, Summary Answer: Accumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile., What Is Known Already: The mechanisms underlying the decline in women's fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa)., Study Design, Size, Duration: This study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden., Participants/materials, Setting, Methods: Blood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package., Main Results and Role of Chance: Using established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7 years) compared to chronological age (average: 33.9 years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4 years) and leukocytes (average: 38.8 years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P = 0.003) but predicted telomere lengths unaffected by age (Pearson's correlation coefficient = -0.1, P = 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n = 335) and in leukocytes (n = 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P = 3.96 × 10-08) and gene expression (152 genes, P = 2.3 × 10-06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle., Large Scale Data: N/A., Limitations, Reasons for Caution: No gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found., Wider Implications of the Findings: Our findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age., Study Funding/competing Interest(s): This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Introduction: Despite the high number of frozen embryo transfer (FET) cycles being conducted (190 000 cycles/year) in Europe, the timing of blastocyst transfer and the use of luteal phase progesterone support in modified natural cycle FET (mNC-FET) in assisted reproductive technologies are controversial. In mNC-FET, the timing of blastocyst warming and transfer is determined according to the time of implantation in a natural cycle, aiming to reach blastocyst endometrial synchronicity. However, the optimal day of blastocyst transfer following ovulation trigger is not determined. In addition, the value of luteal phase support to maintain the endometrium remains uncertain. Thus, there is a need to identify the optimal timing of blastocyst warming and transfer and the effect of luteal phase support in a randomised controlled trial design. The aim of this randomised controlled trial is to investigate if progesterone supplementation from the early luteal phase until gestational age 8 weeks is superior to no progesterone supplementation and to assess if blastocyst warming and transfer 6 days after ovulation trigger is superior to 7 days after ovulation trigger in mNC-FET with live birth rates as the primary outcome., Methods and Analysis: Multicentre, randomised, controlled, single-blinded trial including 604 normo-ovulatory women aged 18-41 years undergoing mNC-FET with a high-quality blastocyst originating from their first to third in vitro fertilisation/intracytoplasmic sperm injection cycle. Participants are randomised (1:1:1:1) to either luteal phase progesterone or no luteal phase progesterone and to blastocyst warming and transfer on day 6 or 7 after human chorionic gonadotropin trigger. Only single blastocyst transfers will be performed., Ethics and Dissemination: The study is approved by the Danish Committee on Health Research Ethics (H-18025839), the Danish Medicines Agency (2018061319) and the Danish Data Protection Agency (VD-2018-381). The results of the study will be publicly disseminated., Trial Registration Number: The study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To explore the effect of adding simulation-based transvaginal ultrasound training to trainees' clinical training compared with only clinical training on quality of and efficiency of care., Background: Simulation-based ultrasound training may be an effective adjunct to clinical training, but no studies have examined its effects on quality and efficiency of care., Methods: Trainees from 4 University Hospitals in East Denmark were included (N = 54). Participants were randomized to either simulation-based ultrasound training and clinical training (intervention group, n = 28), or to clinical training only (control group, n = 26).The primary outcome was patient-reported discomfort during transvaginal ultrasound examinations performed by study participants. Secondary outcomes included patient-reported perceived safety and confidence in ultrasound provider. Finally, the need for trainee supervision or repeated patient examinations was recorded., Results: In total, 1150 patient ratings were collected. The intervention was associated with a reduction of patient discomfort by 18.5% [95% confidence interval (CI), 10.7-25.5; P < 0.001), and with a 7.9% (95% CI, 0.5-14.7; P = 0.04) increase in perceived safety. The intervention group participants received 11.1% (95% CI, 2.5-18.9) higher scores on patients' confidence compared with control group participants (P = 0.01). When the number of days of clinical training was doubled, the odds for trainee supervision or repeated patient examination was reduced by 45.3% (95% CI, 33.5-55.1) and 19.8% (95% CI, 4.1-32.9) in the intervention and control group, respectively (P = 0.005)., Conclusions: Simulation-based ultrasound training improved quality of care and reduced the need for repeated patient examination and trainee supervision.