BACKGROUND:IVF and IUI with ovarian stimulation (IUI-OS) are widely used in managing unexplained infertility. IUI-OS is generally considered first-line therapy, followed by IVF only if IUI-OS is unsuccessful after several attempts. However, there is a growing interest in using IVF for immediate treatment because it is believed to lead to higher live birth rates and shorter time to pregnancy. OBJECTIVE AND RATIONALE:Randomized controlled trials (RCTs) comparing IVF versus IUI-OS had varied study designs and findings. Some RCTs used complex algorithms to combine IVF and IUI-OS, while others had unequal follow-up time between arms or compared treatments on a per-cycle basis, which introduced biases. Comparing cumulative live birth rates of IVF and IUI-OS within a consistent time frame is necessary for a fair head-to-head comparison. Previous meta-analyses of RCTs did not consider the time it takes to achieve pregnancy, which is not possible using aggregate data. Individual participant data meta-analysis (IPD-MA) allows standardization of follow-up time in different trials and time-to-event analysis methods. We performed this IPD-MA to investigate if IVF increases cumulative live birth rate considering the time leading to pregnancy and reduces multiple pregnancy rate compared to IUI-OS in couples with unexplained infertility. SEARCH METHODS:We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, and the Cochrane Gynaecology and Fertility Group Specialised Register to identify RCTs that completed data collection before June 2021. A search update was carried out in January 2023. RCTs that compared IVF/ICSI to IUI-OS in couples with unexplained infertility were eligible. We invited author groups of eligible studies to join the IPD-MA and share the deidentified IPD of their RCTs. IPD were checked and standardized before synthesis. The quality of evidence was assessed using the Risk of Bias 2 tool. OUTCOMES:Of eight potentially eligible RCTs, two were considered awaiting classification. In the other six trials, four shared IPD of 934 women, of which 550 were allocated to IVF and 383 to IUI-OS. Because the interventions were unable to blind, two RCTs had a high risk of bias, one had some concerns, and one had a low risk of bias. Considering the time to pregnancy leading to live birth, the cumulative live birth rate was not significantly higher in IVF compared to that in IUI-OS (4 RCTs, 908 women, 50.3% versus 43.2%, hazard ratio 1.19, 95% CI 0.81-1.74, I2 = 42.4%). For the safety primary outcome, the rate of multiple pregnancy was not significantly lower in IVF than IUI-OS (3 RCTs, 890 women, 3.8% versus 5.2% of all couples randomized, odds ratio 0.78, 95% CI 0.41-1.50, I2 = 0.0%). WIDER IMPLICATIONS:There is no robust evidence that in couples with unexplained infertility IVF achieves pregnancy leading to live birth faster than IUI-OS. IVF and IUI-OS are both viable options in terms of effectiveness and safety for managing unexplained infertility. The associated costs of interventions and the preference of couples need to be weighed in clinical decision-making.

STUDY QUESTION Does offering the Pleasure&Pregnancy (P&P) programme rather than expectant management improve naturally conceived ongoing pregnancy rates in couples diagnosed with unexplained infertility?SUMMARY ANSWER The P&P programme had no effect on the ongoing pregnancy rates of couples with unexplained infertility.WHAT IS KNOWN ALREADY Underpowered studies suggested that face-to-face interventions targeting sexual health may increase pregnancy rates. The impact of an eHealth sexual health programme had yet to be evaluated by a large randomized controlled trial.STUDY DESIGN, SIZE, DURATION This is a nationwide multi-centre, unblinded, randomized controlled superiority trial (web-based randomization programme, 1:1 allocation ratio). This RCT intended to recruit 1164 couples within 3 years but was put on hold after having included 700 couples over 5 years (2016-2021). The web-based P&P programme contains psychosexual information and couple communication, mindfulness and sensate focus exercises aiming to help maintain or improve sexual health, mainly pleasure, and hence increase pregnancy rates. The P&P programme additionally offers information on the biology of conception and enables couples to interact online with peers and via email with coaches.PARTICIPANTS/MATERIALS, SETTING, METHODS Heterosexual couples with unexplained infertility and a Hunault-prognosis of at least 30% chance of naturally conceiving a live-born child within 12 months were included, after their diagnostic work-up in 41 Dutch secondary and tertiary fertility centres. The primary outcome was an ongoing pregnancy, defined as a viable intrauterine pregnancy of at least 12 weeks duration confirmed by an ultrasound scan, conceived naturally within 6 months after randomization. Secondary outcomes were time to pregnancy, live birth, sexual health, and personal and relational well-being at baseline and after 3 and 6 months. The primary analyses were according to intention-to-treat principles. We calculated relative risks (RRs, pregnancy rates) and a risk difference (RD, pregnancy rates), Kaplan-Meier survival curves (live birth over time), and time, group, and interactive effects with mixed models analyses (sexual health and well-being).MAIN RESULTS AND THE ROLE OF CHANCE Totals of 352 (one withdrawal) and 348 (three withdrawals) couples were allocated to, respectively the P&P group and the expectant management group. Web-based tracking of the intervention group showed a high attrition rate (57% of couples) and limited engagement (i.e. median of 16 visits and 33 min total visitation time per couple). Intention-to-treat analyses showed that 19.4% (n = 68/351) of the P&P group and 22.6% (n = 78/345) of the expectant management group achieved a naturally conceived ongoing pregnancy (RR = 0.86; 95% CI = 0.64-1.15, RD = -3.24%; 95% CI -9.28 to 2.81). The time to pregnancy did not differ between the groups (Log rank = 0.23). Live birth occurred in 18.8% (n = 66/351) of the couples of the P&P group and 22.3% (n = 77/345) of the couples of the expectant management group (RR = 0.84; 95% CI = 0.63-1.1). Intercourse frequency decreased equally over time in both groups. Sexual pleasure, orgasm, and satisfaction of women of the P&P group improved while these outcomes remained stable in the expectant management group. Male orgasm, intercourse satisfaction, and overall satisfaction decreased over time with no differences between groups. The intervention did not affect personal and relational well-being. Non-compliance by prematurely starting medically assisted reproduction, and clinical loss to follow-up were, respectively, 15.1% and 1.4% for the complete study population. Per protocol analysis for the primary outcome did not indicate a difference between the groups. Comparing the most engaged users with the expectant management group added that coital frequency decreased less, and that male sexual desire improved in the intervention group.LIMITATIONS, REASONS FOR CAUTION The intended sample size of 1164 was not reached because of a slow recruitment rate. The achieved sample size was, however, large enough to exclude an improvement of more than 8% of the P&P programme on our primary outcome.WIDER IMPLICATIONS OF THE FINDINGS The P&P programme should not be offered to increase natural pregnancy rates but may be considered to improve sexual health. The attrition from and limited engagement with the P&P programme is in line with research on other eHealth programmes and underlines the importance of a user experience study.STUDY FUNDING/COMPETING INTEREST(S) Funded by The Netherlands Organisation for Health Research and Development (ZonMw, reference: 843001605) and Flanders Research Foundation. C.B.L. is editor-in-chief of Human Reproduction. H.W.L. received royalties or licences from Prometheus Publishers Springer Media Thieme Verlag. J.B. received support from MercK for attending the ESHRE course 'The ESHRE guideline on ovarian stimulation, do we have agreement?' J.v.D. reports consulting fees and lecture payments from Ferring, not related to the presented work, and support for attending ESHRE from Goodlife and for attending NFI Riga from Merck. A.H. reports consulting fees by Ferring Pharmaceutical company, The Netherlands, paid to institution UMCG, not related to the presented work. H.V. reports consulting fees from Ferring Pharmaceutical company, The Netherlands, and he is a member of the ESHRE guideline development group unexplained infertility and Chair of the Dutch guideline on unexplained infertility (unpaid). M.G. declares unrestricted research and educational grants from Ferring not related to the presented work, paid to their institution VU Medical Centre. The other authors have no conflicts to declare.TRIAL REGISTRATION NUMBER NTR5709.TRIAL REGISTRATION DATE 4 February 2016.DATE OF FIRST PATIENT'S ENROLMENT 27 June 2016.

Abstract Study question How is the sexual functioning of newly diagnosed unexplained infertile couples and which factors are associated? Summary answer At least 25% of couples are at risk of sexual dysfunction. Sexual functioning is associated with age, infertility duration, sperm quality, personal and relational wellbeing. What is known already A large proportion of unexplained infertile couples have the ability to conceive naturally over time. Sexual functioning is important for natural conception rates, but infertility is associated with reduced sexual functioning. Surprisingly, sexual functioning and its risk-factors are still understudied in unexplained infertility. Knowing the risk factors for reduced sexual functioning would enable fertility specialists to timely diagnose, prevent or treat sexual dysfunction, and in this way improve natural conception rates. The current literature is mainly based on individual-level data, neglecting the fact that observations, such as sexual functioning, arising from couples are not independent. Study design, size, duration Cross-sectional digital survey data and medical chart factors, which also served as the baseline assessment of a randomized controlled trial (Pleasure&Pregnancy, trial registration number NTR5709), were subjected to a dyadic analysis followed by linear regression. A total of 700 heterosexual couples recently diagnosed with unexplained infertility in secondary or tertiary fertility clinics were addressed between 2016 and 2021. Participants/materials, setting, methods Heterosexual couples (female age 18-38 year) with unexplained infertility and who were able to have coitus were eligible. Sexual functioning was assessed with the Female Sexual Function Index (FSFI) and International Index of Erectile Function (IIEF). Determinants included demographic, lifestyle and diagnostic and wellbeing factors as assessed with the Hospital Anxiety and Depression Scale (HADS) and the Revised Dyadic Adjustment Scale (R-DAS). B represents the impact on sexual functioning when a factor changes 1 unit. Main results and the role of chance A total of 581 (83%) women and 478 (68%) men filled out questionnaires. Survey data and medical chart factors were available for 451 couples. About one in four women (24.3%) and one in fourteen men (7.3%) were at risk of respectively female sexual dysfunction and erectile dysfunction after fertility work-up. Couples had a mean coital frequency of 7 times per month (SD 2.7). Higher female and male sexual desire (B: 0.04, p<0.01 and B: 0.02, p<0.02) and satisfaction (B: 0.03, p<0.01 and B: 0.06, p<0.01), but not orgasm were significantly associated with increased coital frequency. Own age (B: -0.64), anxiety (B: -9.47), depression (B: -7.61) and relationship distress (B: -8.97), and partners’ relationship distress (B: -5.08) and total motility sperm count (B: -4.88) were associated with lower female sexual functioning. Own age (B: -0.17), anxiety (B: -5.03), depression (B: -3.65), relationship distress (B: -5.77), and partners’ age (B: -0.46) and relationship distress (B: -3.14) and couples’ duration of infertility (B: -0.24) were associated with lower male sexual functioning. Limitations, reasons for caution The study is prone to selection bias given the inclusion of couples seeking medical help, consenting to a RCT and were having coitus. Not all previous identified determinants of sexual functioning were studied due to factors as missing data, low case numbers or not being assessed in the Pleasure&Pregnancy RCT. Wider implications of the findings Clinicians advising couples with unexplained infertility to continue natural conception, need to be aware that at least 25% of couples are at risk of sexual dysfunction. Clinicians should consider risk factors of reduced sexual functioning, take a sexual anamnesis and advice sexual counselling and treatment if indicated. Trial registration number Baseline assessment of RCT (Pleasure&Pregnancy) with trial registration number NTR5709

Abstract Study question Is the sexual desire of infertile women and men correlated with their intercourse frequency and sexual satisfaction? Summary answer Both partner’s sexual desire is moderately correlated to intercourse frequency and their own sexual satisfaction and weakly correlated to the sexual satisfaction of their partner. What is known already Reviews showed that infertile couples have worse sexual health than the general population. Qualitative studies explained that infertile patients feel less attractive and consider intercourse a ‘duty’, associated with failure. Fertility clinics offer diagnosis and treatments but have yet to start caring for sexual health. The Pleasure&Pregnancy-programme, combining psychosexual education with communication, mindfulness and sensate focus exercises, recently proved to increase the sexual desire of infertile women pursuing natural conception. Whether improving sexual desire can be expected to increase the intercourse frequency and sexual satisfaction of women and men about to start fertility treatment had yet to be explored. Study design, size, duration A cross-sectional cohort of 140 heterosexual couples (n = 280; response rate 51%) was surveyed between 2019 and 2022. Couples filled out a package questioning their sexual health over the past four weeks at a chosen moment between their first fertility clinic consultation and the end of their diagnostic workup. This package included a questionnaire to be filled out by each partner individually and a couple questionnaire. Non-responders received were reminded. Participants/materials, setting, methods Sexual desire and satisfaction of women and men was assessed with subscales of the following valid and reliable questionnaires: Female Sexual Function Index in women (FSFI; the higher, the better) or International Index of Erectile Function in men (IIEF; the higher, the better). Intercourse frequency of couples was assessed with a sexual activity event log. Spearman rho’s correlations assessed associations between sexual desire, sexual satisfaction and coital frequency. Main results and the role of chance Responding women and men were in their early thirties and had tried to conceive naturally for 18.2 months, on average. The sexual desire of women (and of men was not correlated (r = 0.116, p = 0.178). Couples had sexual intercourse seven times per month (7.12±4.03), on average. The sexual desire of both women and men was moderately correlated to couple’s intercourse frequency (♀: r = 0.402, p < 0.001; ♂: r = 0.426, p < 0.001). The sexual desire of women was also moderately correlated to their own sexual satisfaction (r = 0.481, p < 0.001) and weakly correlated to the sexual satisfaction of their male partner (r = 0.270, p = 0.001). The sexual desire of men was significantly but weakly correlated to their own sexual satisfaction (r = 0.361, p < 0.001) and the sexual satisfaction of their female partner (r = 0.239, p = 0.005). Limitations, reasons for caution The sexual health of the included couples is currently followed-up during fertility treatment. Linear mixed models, taking account of dyads and of multiple assessments, would allow analysing the impact over time of women’s sexual desire whilst taking account of the sexual desire of her male partner and vice-versa. Wider implications of the findings Sexual desire seems important for a couple’s coital frequency and both partner’s sexual satisfaction. Examining whether a six-month sexual health programme that improves women’s sexual desire, could in the longer term improve intercourse frequency and especially sexual satisfaction or prevent the deterioration thereof would be interesting. Trial registration number not applicable

STUDY QUESTION:What are the experiences and the support and sexual advice needs of subfertile couples continuing to attempt natural conception after the diagnostic fertility work-up? SUMMARY ANSWER:Exploration of the experiences of couples showed that couples would have appreciated fertility clinic staff embedding expectant management into the fertility clinic trajectory, supportive staff with female and male patient interactions and advice on common experiences of peers and on managing their lifestyle, distress and subfertility-related sexual challenges. WHAT IS KNOWN ALREADY:Dutch and British professional guidelines advise newly diagnosed subfertile couples with a 'good prognosis' to continue to attempt natural conception and do not require fertility clinic staff to interact with patients. Fertility clinic staff and subfertile couples struggle to follow these guidelines as they feel an urgent need for action. Subfertile couples might benefit from sexual advice, as subfertility is negatively associated with sexual functioning, which is important for natural conception. STUDY DESIGN SIZE DURATION:Twelve one-time in-depth interviews (2015-2017) were conducted with 10 heterosexual couples and 2 women whose partners did not participate, then the interviews were subjected to inductive content analysis, reaching inductive thematic saturation. PARTICIPANTS/MATERIALS SETTING METHODS:The 22 interviewees had experienced 3-18 months of expectant management after their diagnostic fertility work-up in a Belgian or a Dutch tertiary fertility clinic. The face-to-face in-depth interviews explored positive and negative experiences and unmet needs. The transcribed interviews were subjected to inductive content analysis, by two researchers discussing initial disagreements. MAIN RESULTS AND THE ROLE OF CHANCE:Couples would appreciate fertility clinic staff embedding expectant management in the fertility clinic trajectory, by starting off with reassuring couples that their very thorough diagnostic fertility work-up demonstrated their good chance of natural conception, and by involving couples in deciding on the duration of expectant management and by planning the follow-up appointment after expectant management up front. Couples had encountered sexual challenges during expectant management and had an interest in sexual advice, focused on increasing pleasure and partner bonding and preventing the rise of dysfunctions. The couples agreed that a (secured) website with evidence-based, non-patronizing text and mixed media would be an appropriate format for a novel support programme. Couples were keen for interactions with fertility clinic staff which addressed both partners of subfertile couples. Couples also valued advice on managing their lifestyle and distress and would have liked information on the experiences of their peers. LIMITATIONS REASONS FOR CAUTION:Recall bias is plausible given the retrospective nature of this study. This explorative interview study was not designed for examining country or gender differences in experiences and needs but it did generate new findings on inter-country differences. WIDER IMPLICATIONS OF THE FINDINGS:Rather than simply advising expectant management, fertility clinics are encouraged to offer couples who continue to attempt natural conception after their diagnostic fertility work-up, supportive patient-staff interactions with advice on common experiences of peers and on managing their lifestyle, distress and sexual challenges related to subfertility. STUDY FUNDING/COMPETING INTERESTS:Funded by Flanders Research Foundation and the University of Amsterdam. There are no competing interests. TRIAL REGISTRATION NUMBER:N/A.

Abstract Study question Is coital frequency (CF) influenced by intrauterine insemination with ovarian stimulation (IUI-OS) or expectant management in couples diagnosed with unexplained subfertility and a poor prognosis? Summary answer Couples allocated to expectant management had a higher CF than those allocated to IUI-OS. We found no evidence for associations with live birth. What is known already In couples with unexplained subfertility and a poor prognosis for natural conception, IUI-OS is generally first line treatment. Not much is known about the CF of these couples and to what extend they are still trying to conceive naturally and whether allocation to treatment or no treatment has an influence on CF. It is often postulated that the effect of IUI-OS might be derived from replacing coitus, especially in couples with longstanding subfertility i.e., over 24 months. Keeping a sex diary can provide insight on this. Study design, size, duration We performed a multicentre randomised-controlled-trial in couples with unexplained subfertility and a poor prognosis of conceiving naturally within one year. The couples were allocated in a 1:1 ratio to six months IUI-OS or six months expectant management. CF was assessed with diaries on moment of coitus in relation to the menstrual cycle. We intended to include 1091 couples but after almost 4 years, the study was stopped due to slow inclusion and lack of funding. Participants/materials, setting, methods We recruited 178 women; 86 women were assigned IUI-OS and 92 women expectant management. All participating Dutch-reading women were eligible for the online diaries (CASTOREDC). We defined the fertile window as 7 days before and 2 days after the estimated ovulation date for all cycles. We used the Mann Whitney U test for differences in CF and timing and logistic regression for the estimated association with live birth, adjusting for cycle number and treatment allocation. Main results and the role of chance After IUI-OS 28/86 women (33%) had a live birth and 12/92 (13%) after expectant management, yielding a relative risk of 2.5 (90%CI 1.49 to 4.17). Of the 178 recruited women 79 (44%) filled out at least one monthly diary on sex and/or menstruation dates, 35 after IUI-OS and 44 after EM. Of these10/35 (29%) had a live birth after IUI-OS and 3/44 (7%) after expectant management. In a total of 497 cycles, the 79 couples reported 2023 dates of coitus (average of 4.1 per cycle). The median CF was 3 (IQR: 0 to 7) in the IUI-OS group and 4 (1 to 6) in the expectant management group (p for difference: 0.08). The median CF that took place within the fertile window was 1 (0 to 3) in the IUI-OS group and 2 (0 to 3) in the expectant management group (p for difference: <0.01). No interaction was found between intercourse frequency or timing and treatment on live birth rate. The adjusted odds ratio for intercourse frequency was 0.93 (95%CI: 0.78-1.09). The adjusted odds ratio for intercourse timing was 0.94 (95%CI: 0.64-1.37). The odds ratio for allocated treatment was unaffected by these adjustments for intercourse frequency or timing. Limitations, reasons for caution Only 44% of trial population returned the CF and menstruation diaries which could have induced selection bias. We estimated the day of ovulation based on the date of the next menstrual period in the expectant management group of this pragmatic trial. Wider implications of the findings Even though the duration of subfertility was longstanding, couples in both groups still had coitus and the median CF was higher in the expectant management group. Trial registration number NTR5599

Abstract Study question Does offering the ‘Pleasure&Pregnancy programme’ rather than expectant management affect sexual desire, pleasure and satisfaction, intercourse frequency and ongoing pregnancy rates in subfertile couples? Summary answer The ‘Pleasure&Pregnancy programme’ limits the decline in sexual desire and intercourse frequency but does not affect sexual pleasure and satisfaction and ongoing pregnancy rates. What is known already Dutch guidelines advise six months of non-interactive expectant management, in couples with unexplained subfertility and Hunault-prognosis of minimally 30%, rather than immediately starting assisted reproduction. Adherence to this advice is limited as both couples and fertility clinic staff feel an urge for action. Underpowered studies indicated that face-to-face sex-counselling may increase the pregnancy rates of these couples. Interactive eHealth programmes proved as effective as face-to-face sex counselling in other patient populations. Our group developed the interactive six months Pleasure&Pregnancy web-based programme, aiming to help couples maintain or improve sexual pleasure and activity and consequently increase chances on naturally conceived pregnancies. Study design, size, duration This multi-centre trial randomised 701 couples between six months of the Pleasure&Pregnancy programme (n = 349) or expectant management, the current standard of care (n = 353) from 2016 to 2021. The Pleasure&Pregnancy web-based programme contains eight modules combining psychosexual education with couple communication, mindfulness and sensate focus exercises and additionally enables couples to interact with professionals and peers. Sexual outcomes were assessed with a diary and reliable questionnaires at baseline, three and six months. Participants/materials, setting, methods Heterosexual couples with unexplained subfertility and a Hunault-prognosis of minimally 30% were included after their diagnostic work-up in 41 Dutch fertility clinics. All analyses were according to intention-to-treat principles. Differences between groups in ongoing pregnancy rates (naturally conceived within six months after randomization; primary outcome) were expressed as relative risks (RR). Linear mixed models assessed time, group and interactive effects on female/male sexual desire, pleasure and satisfaction, and intercourse frequency; mean differences (MD) are provided. Main results and the role of chance Response rates at baseline, three and six months for the diaries assessing sexual pleasure (Quality of Sexual Experience; QSE) were, respectively: 55.8%, 33.9% and 16.8%. For the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI) questionnaires assessing intercourse frequency, sexual desire and satisfaction response rates were, respectively: 83.2%, 50.8% and 41.2%. The probability of a naturally conceived ongoing pregnancy within six months after randomization did not differ between the randomized groups, and was 22% (n = 78/349) in the Pleasure&Pregnancy-group and 24% (n = 83/353) in the control group (RR 0.94; 95% CI 0.67 to 1.32). Neither did the groups differ in time to pregnancy (log rank p = 0.46). Both female and male sexual pleasure and satisfaction was comparable in both groups and did not change over time. Male sexual desire (scale 2-10) remained over time in the Pleasure&Pregnancy-group but decreased in the control group (MD 0.47, 95%CI 0.28 to 0.67, p < 0.001) and a similar trend was observed in females (MD 0.16, 95%CI -0.02 to 0.33, p = 0.086). Intercourse frequency declined over time in both groups (MD over 6 months -1.05, 95% CI -1.47 to -0.62, p < 0.01), but less in the Pleasure&Pregnancy- group (MD 0.3, 95% CI 0-0.6; p = 0.05). Limitations, reasons for caution The intended sample size of 1164 was not reached, although the inclusion period was doubled. Web-based tracking showed limited intervention adherence, indicating the need for per protocol analysis in addition to this intention-to-treat analysis. Examining user experiences with the Pleasure&Pregnancy programme would be of interest and might explain adherence rate. Wider implications of the findings Clinics are advised to offer the Pleasure&Pregnancy or similar programme to care for the sexual health of couples with unexplained subfertility. The Pleasure&Pregnancy programme did not increase naturally conceived ongoing pregnancy rates but did help couples maintain their sexual desire and intercourse frequency, while continuing to attempt natural conception. Trial registration number NTR5709

Abstract Study question How do infertility patients, endometriosis patients and health care providers rate the virtual care that was provided during the first lockdown of the COVID-19 pandemic? Summary answer Patients and health care providers rate telephone- and video consultations as good alternatives during the pandemic but it cannot replace future physical consultations. What is known already Virtual alternatives to regular care such as telephone and video consultations are gaining more attention as replacement for physical consultations and are ideal for use in a social distancing situation as the COVID-19 pandemic. However, infertility and endometriosis patients often rely on physical consultations for reassurance as well as for treatments such as artificial reproductive technology and surgery. Not being able to receive these reassurances and treatments may cause stress especially as infertility patients are known to experience a high sense of urgency to obtain treatment. For patients with endometriosis, regular follow-up visits are important for continuity of care. Study design, size, duration: A cross-sectional cohort study was performed, including 555 patients and 101 health care providers in the field of infertility and endometriosis in the Netherlands. Online questionnaires were sent between May and October 2020. Participants/materials, setting, methods Patients with infertility and endometriosis patients from a university hospital and members of the respective national patients organizations, as well as health care providers in the fields of infertility and endometriosis were asked to participate. The questionnaires consisted of demographics, appraisal of telephonic and video consultations (TCs and VCs) and assessment of fertility related quality of life (FertiQoL) and patient-centeredness of endometriosis care (ENDOCARE). Main results and the role of chance The questionnaires were completed by 374 infertility patients, 181 endometriosis patients and 101 health care providers. 75.9% of the infertility patients, 64.8% of the endometriosis patients and 82.7% of the health care providers rated TCs as a good alternative for physical consultations during the COVID-19-pandemic. Only 21.3%, 14.8% and 21.3% rated TCs as a good replacement of physical consultations in general. 76.6% and 35.9% of the infertility and endometriosis patients reported to experience an increase in stress due to the altered care during the COVID-19 pandemic. 38.7% and 58.0% reported to have received sufficient information from their care givers. Infertility patients scored lower on the FertiQoL than the reference population, while the ENDOCARE results of endometriosis patients were comparable to the reference. Limitations, reasons for caution This study was limited to the Dutch population. As the organization of infertility care varies internationally, the results will not be directly applicable to other countries or health care systems. Wider implications of the findings: Virtual care options are a good alternative for infertility and endometriosis patients in situations where physical consultations are not possible. Self-reported stress is especially high in infertility patients during the COVID-19-pandemic. Health care providers should provide more information to patients in order to increase their ability to cope with stress. Trial registration number N/A

Research question: How do infertility patients, endometriosis patients and health-care providers rate virtual care as an alternative to physical consultations during the first lockdown of the coronavirus disease 2019 (COVID-19) pandemic in the Netherlands, and how does this influence quality of life and quality of care? Design: Infertility patients and endometriosis patients from a university hospital and members of national patient organizations, as well as healthcare providers in infertility and endometriosis care, were asked to participate between May and October 2020. The distributed online questionnaires consisted of an appraisal of virtual care and an assessment of fertility-related quality of life (FertiQol) and patient-centredness of endometriosis care (ENDOCARE). Results: Questionnaires were returned by 330 infertility patients, 181 endometriosis patients and 101 healthcare providers. Of these, 75.9% of infertility patients, 64.8% of endometriosis patients and 80% of healthcare providers rated telephone consultations as a good alternative to physical consultations during the COVID-19-pandemic. Only 21.3%, 14.8% and 19.2% of the three groups rated telephone consultations as a good replacement for physical consultations in the future. A total of 76.6% and 35.9% of the infertility and endometriosis patients reported increased levels of stress during the pandemic. Infertility patients scored lower on the FertiQol, while the ENDOCARE results care seem comparable to the reference population. Conclusions: Virtual care seems to be a good alternative for infertility and endometriosis patients in circumstances where physical consultations are not possible. Self-reported stress is especially high in infertility patients during the COVID-19-pandemic. Healthcare providers should aim to improve their patients' ability to cope.

STUDY QUESTION Can we develop a web-based sex education programme (programme running in a web browser) that addresses the needs of subfertile couples who are advised expectant management for at least 6 months? SUMMARY ANSWER The ‘Pleasure & Pregnancy’ programme addresses couples’ needs, is likely to improve couples’ sexual functioning, and is subsequently hypothesised to improve the chance of natural pregnancy. WHAT IS KNOWN ALREADY According to professional guidelines (e.g. the Netherlands and UK) couples with unexplained subfertility and a good chance of natural pregnancy, should be advised at least 6 months of expectant management. Adherence to expectant management is challenging as couples and gynaecologist prefer a more active approach. Targeting sexuality may be useful as subfertility is a risk factor for decreased sexual functioning. STUDY DESIGN, SIZE, DURATION A novel programme was developed according to the three steps of the Medical Research Councils’ (MRC) framework. First, relevant literature was explored. Second, an interdisciplinary expert panel developed a theory (based on a systematic literature review and patient interviews) on how the chance of natural conception can be improved. Third, the expected process and outcomes were modelled. PARTICIPANTS/MATERIALS, SETTING, METHODS Two licenced clinical sexologists, two gynaecologists, a clinical embryologist and two midwife-researchers, all from Belgium and the Netherlands, proposed components for the sex education programme. PubMed was searched systematically for randomised controlled trials (RCTs) evaluating the proposed components in different patient populations. The needs of 12 heterosexual Dutch or Belgian couples who were advised expectant management were explored with in-depth interviews. The content and delivery characteristics of the novel programme were described in detail with the aid of ‘Intervention Taxonomy’. To model the outcomes, a protocol for an RCT was designed, registered and submitted for publication. MAIN RESULTS AND THE ROLE OF CHANCE To help maintain or improve sexual functioning, mainly pleasure, and hence increase pregnancy rates, the web-based Pleasure & Pregnancy programme contains a combination of psychosexual education and couple communication, mindfulness and sensate focus exercises. Information on the biology of conception and interaction with fertility clinic staff and peers were added based on couples’ needs to increase potential acceptability. LIMITATIONS AND REASON FOR CAUTION This paper outlines the development phase of a sex education programme according to the MRC-framework. Whether the Pleasure & Pregnancy programme actually is acceptable, improves sexual functioning, increases pregnancy rates and is cost-effective remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS No previous interactive web-based sex education programme has aimed to increase the natural pregnancy rate of subfertile couples by targeting their sexual pleasure. The Pleasure & Pregnancy programme addresses couples’ needs and its effect on sexual functioning and pregnancy rate is plausible but remains to be demonstrated by an RCT which is currently ongoing. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by The Netherlands Organisation for Health Research and Development (ZonMw), Flanders Research Foundation and the University of Amsterdam. C.B.L. is editor-in-chief of Human Reproductionbut was blinded to all parts of the peer review process. The remaining authors have no conflict of interest to report. TRIAL REGISTRATION NUMBER Not applicable.

STUDY QUESTION:What is the rate of natural conception leading to ongoing pregnancy or livebirth over 6-12 months for infertile women of age ≥35 years?SUMMARY ANSWER:Natural conception rates were still clinically relevant in women aged 35 years and above and were significantly higher in women with unexplained infertility compared to those with other diagnoses.WHAT IS KNOWN ALREADY:In recent years, increasing numbers of women have attempted to conceive at a later age, resulting in a commensurate increase in the need for ART. However, there is a lack of data on natural fertility outcomes (i.e. no interventions) in women with increasing age.STUDY DESIGN, SIZE, DURATION:A systematic review with individual participant data (IPD) meta-analysis was carried out. PubMed, MEDLINE, EMBASE, the Cochrane Library, clinicaltrials.gov were searched until 1 July 2018 including search terms 'fertility service', 'waiting list', 'treatment-independent' and 'spontaneous conception'. Language restrictions were not imposed.PARTICIPANTS/MATERIALS, SETTING, METHODS:Inclusion criteria were studies (at least partly) reporting on infertile couples with female partner of age ≥35 years who attended fertility services, underwent fertility workup (e.g. history, semen analysis, tubal status and ovulation status) and were exposed to natural conception (e.g. independent of treatment such as IVF, ovulation induction and tubal surgery). Studies that exclusively studied only one infertility diagnosis, without including other women presenting to infertility services for other causes of infertility, were excluded. For studies that met the inclusion criteria, study authors were contacted to provide IPD, after which fertility outcomes for women of age ≥35 years were retrieved. Time to pregnancy or livebirth and the effect of increasing age on fertility outcomes after adjustment for other prognostic factors were analysed. Quality of studies was graded with the Newcastle-Ottawa Scale (non-randomised controlled trials (RCTs)) or the Cochrane Risk of Bias tool (for RCTs).MAIN RESULTS AND THE ROLE OF CHANCE:We included nine studies (seven cohort studies and two RCTs) (n = 4379 women of at least age 35 years), with the observed composite primary outcome of ongoing pregnancy or livebirth occurring in 429 women (9.8%) over a median follow-up of 5 months (25th to 75th percentile: 2.5-8.5 months). Studies were of moderate to high quality. The probability of natural conception significantly decreased with any diagnosis of infertility, when compared with unexplained infertility. We found non-linear effects of female age and duration of infertility on ongoing pregnancy and tabulated the predicted probabilities for unexplained infertile women aged 35-42 years with either primary or secondary infertility and with a duration of infertility from 1 to 6 years. For a 35-year-old woman with 2 years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or livebirth was 0.15 (95% CI 0.11-0.19) after 6 months and 0.24 (95% CI 0.17-0.30) after 12 months. For a 42-year-old woman, this decreased to 0.08 (95% CI 0.04-0.11) after 6 months and 0.13 (95% CI 0.07-0.18) after 12 months.LIMITATIONS, REASONS FOR CAUTION:In the studies selected, there were different study designs, recruitment strategies in different centres, protocols and countries and different methods of assessment of infertility. Data were limited for women above the age of 40 years.WIDER IMPLICATIONS OF THE FINDINGS:Women attending fertility services should be encouraged to pursue natural conception while waiting for treatment to commence and after treatment if it is unsuccessful. Our results may aid in counselling women, and, in particular, for those with unexplained infertility.STUDY FUNDING/COMPETING INTEREST(S):S.J.C. received funding from the University of Adelaide Summer Research Scholarship. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437), B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. B.W.M. reports research support by Merck and Guerbet.PROSPERO REGISTRATION NUMBER:CRD42018096552.

STUDY QUESTION:What are the moral considerations held by donors, recipients and professionals towards the ethical aspects of the intake and distribution of donor bank oocytes for third-party assisted reproduction? SUMMARY ANSWER:Interviews with oocyte donors, oocyte recipients and professionals demonstrate a protective attitude towards the welfare of the donor and the future child. WHAT IS KNOWN ALREADY:The scarcity of donor oocytes challenges the approach towards the many ethical aspects that arise in establishing and operating an oocyte bank for third-party assisted reproduction. Including experiences and moral considerations originating from practice provides useful insight on how to overcome these challenges. STUDY DESIGN, SIZE, DURATION:The project was set-up as a qualitative interview study and took place between October 2016 and August 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS:We conducted 25 semi-structured interviews with professionals engaged in the practice of oocyte banking (n = 10), recipients of donor oocytes (n = 7) and oocyte donors (n = 8). Key themes were formulated by means of a thematic analysis. MAIN RESULTS AND THE ROLE OF CHANCE:Based on the interviews, we formulated four main themes describing stakeholders' views regarding the ethical aspects of the intake and distribution of donor bank oocytes. First, respondents articulated that when selecting donors and recipients, healthcare workers should prevent donors from making a wrong decision and safeguard the future child's well-being by minimizing health risks and selecting recipients based on their parental capabilities. Second, they proposed to provide a reasonable compensation and to increase societal awareness on the scarcity of donor oocytes to diminish barriers for donors. Third, respondents considered the prioritization of recipients in case of scarcity a difficult choice, because they are all dependent on donor oocytes to fulfil their wish for a child. They emphasized that treatment attempts should be limited, but at least include one embryo transfer. Fourth and finally, the importance of good governance of oocyte banks was mentioned, including a homogenous policy and the facilitation of exchange of experiences between oocyte banks. LIMITATIONS, REASONS FOR CAUTION:The possibility of selection bias exists, because we interviewed donors and recipients who were selected according to the criteria currently employed in the clinics. WIDER IMPLICATIONS OF THE FINDINGS:Respondents' moral considerations regarding the ethical aspects of the intake and distribution of donor oocytes demonstrate a protective attitude towards the welfare of the donor and the future child. At the same time, respondents also questioned whether such a (highly) protective attitude was justified. This finding may indicate there is room for reconsidering strategies for the collection and distribution of donor bank oocytes. STUDY FUNDING/COMPETING INTEREST(S):This study was funded by ZonMw: The Dutch Organization for Health Research and Development (Grant number 70-73000-98-200). A.M.E.B. and B.C.J.M.F. are the initiators of the UMC Utrecht oocyte bank. J.J.P.M.P. is the director of the MCK Fertility Centre. IMC is working as a gynaecologist at the AMC Amsterdam oocyte bank. During the most recent 5-year period, BCJM Fauser has received fees or grant support from the following organizations (in alphabetic order): Actavis/Watson/Uteron, Controversies in Obstetrics & Gynaecologist (COGI), Dutch Heart Foundation, Dutch Medical Research Counsel (ZonMW), Euroscreen/Ogeda, Ferring, London Womens Clinic (LWC), Merck Serono (GFI), Myovant, Netherland Genomic Initiative (NGI), OvaScience, Pantharei Bioscience, PregLem/Gedeon Richter/Finox, Reproductive Biomedicine Online (RBMO), Roche, Teva and World Health Organization (WHO). The authors have no further competing interests to declare. TRIAL REGISTRATION NUMBER:N/A.

STUDY QUESTIONDoes starting IUI with ovarian stimulation (IUI-OS) within 1.5 years after completion of the fertility workup increase ongoing pregnancy rates compared to expectant management in couples with unexplained subfertility?SUMMARY ANSWERIUI-OS is associated with higher chances of ongoing pregnancy compared to expectant management in unexplained subfertile couples, specifically those with poor prognoses of natural conception, i.e. <15% over 6 months or <25% over 1 year.WHAT IS KNOWN ALREADYIUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found conflicting results. A cohort of couples with unexplained subfertility exposed to expectant management and IUI-OS offers an opportunity to determine the chances of conception after both strategies and to evaluate whether the effect of IUI-OS depends on a couple's prognosis of natural conception.STUDY DESIGN, SIZE, DURATIONA prospective cohort study on couples with unexplained or mild male subfertility who could start IUI-OS at any point after completion of the fertility workup, recruited in seven Dutch centres between January 2002 and February 2004. Decisions regarding treatment were subject to local protocols, the judgement of the clinician and the wishes of the couple. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. Follow up was censored at the start of IVF, after the last IUI cycle or at last contact and truncated at a maximum of 1.5 years after the fertility workup.PARTICIPANTS/MATERIALS, SETTING, METHODSThe endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting.MAIN RESULTS AND THE ROLE OF CHANCEData from 1896 couples were available. There were 800 couples whom had at least one IUI-OS cycle within 1.5 years post fertility workup of whom 142 couples conceived (rate: 0.50 per couple per year, median follow up 4 months). The median period between fertility workup completion and starting IUI-OS was 6.5 months. Out of 1096 untreated couples, 386 conceived naturally (rate: 0.31 per couple per year, median follow up 7 months). Starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.96 (95% CI: 1.47-2.62) compared to expectant management. The effect of treatment was modified by a couple's prognosis of achieving natural conception (P = 0.01), with poorer prognoses or additional failed natural cycles being associated with a stronger effect of treatment. The predicted 6-month ongoing pregnancy rate for a couple with a prognosis of 25% at completion of the fertility workup over the next six cycles (~40% over 1 year) was 25% (95% CI: 21-28%) for expectant management and 24% (95% CI: 9-36%) when starting IUI-OS directly. For a couple with a prognosis of 15% (25% over 1 year), these predicted rates were 17% (95% CI: 15-19%) for expectant management and 24% (95% CI: 15-32%) for starting IUI-OS.LIMITATIONS, REASONS FOR CAUTIONThe effect estimates are based on a prospective cohort followed up for 1.5 years after completion of the fertility workup. Although we balanced the known predictors of conception between treated and untreated couples using inverse probability weighting, observational data may be subject to residual confounding. The results need to be confirmed in external datasets.WIDER IMPLICATIONS OF THE FINDINGSThese results explain the discrepancies between previous trials that compared IUI-OS to expectant management, but further studies are required to establish the threshold at which IUI-OS is (cost-)effective.STUDY FUNDING/COMPETING INTEREST(S)This study was facilitated by (Grant 945/12/002) from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. S.B. reports acting as Editor-in-Chief of HROpen. The other authors have no conflicts of interest.

Introduction Many subfertile couples are diagnosed with (relatively) unexplained subfertility and a good prognosis. National professional guidelines (eg, the Netherlands and UK) advise ‘expectant management (EM)’ for 6–12 months, in which no interaction with healthcare staff is offered. Underpowered studies indicate that face-to-face sex-counselling increases the ongoing pregnancy rates of these couples. In patients with other conditions, web-based interactive educational programmes have the same effect on sexual functioning as face-to-face sex counselling. The ‘Pleasure&Pregnancy randomised controlled trial (RCT)’ will examine in couples with unexplained subfertility and a good prognosis whether a new web-based interactive educational programme results in a higher chance of naturally conceiving an ongoing pregnancy within 6 months as compared with EM.Methods and analysis A multicentre RCT with cost-effectiveness analysis will include heterosexual couples diagnosed with (relatively) unexplained subfertility and a good prognosis in Dutch and Belgian secondary or tertiary fertility clinics. Couples will be randomised between 6 months of EM and 6 months of the Pleasure&Pregnancy-programme. This new web-based interactive educational programme includes eight progressive modules of information (on the biology of conception and pleasurable sex) and sensate focus, couple communication and mindfulness exercises. Couples are offered interaction with their coaches via email and can take part in three moderated chat sessions with peers. The primary outcome of this RCT is the probability of naturally conceiving an ongoing pregnancy within 6 months after randomisation. Secondary outcomes include time-to-pregnancy, live birth rate, costs, sexual functioning and personal and relational well-being. Analysis will be according to intention to treat.Ethics and dissemination This study has been approved by the Medical Ethical Committees of the Academic Medical Centre (the Netherlands) and the Leuven University Hospital (Belgium). The findings of this RCT will be disseminated through presentations at international scientific meetings and peer-reviewed publications.Trail registration number NTR5709; Pre-results.

Many couples are diagnosed with unexplained subfertility and a good prognosis (i.e. ≥30%) on naturally conceiving a child. National guidelines (e.g. Netherlands, UK) advise ‘expectant management’ (EM) for 6-12 months, without offering interaction with staff. Underpowered studies indicate that face-to-face sex counselling could increase pregnancy rates. Interactive web-based educational programs had the same effect as face-to-face sex counselling on the sexual functioning of patients with other condition. We designed a randomized controlled trial (RCT) to examine whether a new interactive web-based educational program is more effective than EM in couples with unexplained subfertility and a good prognosis. The RCT compares 6-months of EM to a newly developed 6-month interactive web-based educational program aiming to maintain or improve pleasurable sex. The program includes information and eight progressive modules with sensate focus, couple communication and mindfulness exercises and interaction with coaches and peers. Ongoing pregnancy rate was selected as the as primary outcome of the RCT. Secondary outcomes include time-to-pregnancy, life birth rate, costs, sexual functioning and personal and relational wellbeing. A sample size of 582 couples per arm was calculated based on an expected effect size of 8% and drop-out rate of 10% and based on testing a two-sided effect with an alpha of 5% and a power of 80%. The study will be conducted in a consortium of Dutch and Belgian gynaecologists.

Centre for Reproductive Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ 9 Amsterdam, the Netherlands Department of Biostatistics and Research Support, Julius 10 Centre, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the 11 Netherlands Medical Statistics, Department of Biomedical Sciences, Leiden University 12 Medical Centre, Einthovenweg 20, 2333 ZC Leiden, the Netherlands Medical Statistics 13 Team, Institute of Applied Health Sciences, University of Aberdeen, AB24 3FX Aberdeen, 14 United Kingdom Department of Obstetrics and Gynaecology, Jeroen Bosch Ziekenhuis, 15 Henri Dunantstraat 1, 5223 GZ Den Bosch, the Netherlands Cardiff University School of 16 Medicine, Heath Park Cardiff CF14 4XN, United Kingdom Department of Obstetrics and 17 Gynaecology, Monash University, Scenic Blvd, VIC 3800 Clayton, Australia 18