In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90

Abstract Study question Does blastocyst-stage embryo transfer in fresh and frozen cycles improve the cumulative live birth rate (cLBR) compared with cleavage-stage embryo transfer in IVF/ICSI treatments? Summary answer In good prognosis IVF patients (≥4 available embryos), a blastocyst-stage transfer policy did not result in a significant higher cLBR compared to cleavage-stage transfer policy. What is known already A recent Cochrane systematic review and meta-analysis concluded that fresh blastocyst-stage transfer in IVF/ICSI treatments is associated with higher rates of pregnancy in comparison to fresh transfer of cleavage-stage embryos. However, it is unknown whether a blastocyst-transfer policy also improves the cumulative live birth rate, i.e. the live birth rate derived from fresh and frozen-thawed embryo transfers following a single oocyte retrieval, in comparison to a cleavage-stage transfer policy in IVF/ICSI. Study design, size, duration In this multicenter randomized controlled trial women were randomly allocated to blastocyst-stage transfers (blastocyst group - fresh embryo transfer on day 5 after oocyte retrieval followed by vitrification of remnant blastocysts on day 5 and 6 following local criteria) or cleavage-stage transfers (cleavage-stage group - fresh embryo transfer on day 3 after oocyte retrieval followed by embryo cryopreservation on day 3 or 4). Randomization was stratified for age (≥36 or < 36 years). Participants/materials, setting, methods Women with a good prognosis after IVF/ICSI (defined as presenting ≥4 available embryos on day 2 of embryo culture), during their first, second, or third treatment cycle, were included. The primary outcome was the cLBR per oocyte retrieval, including associated frozen-thawed embryo transfers within 12 months after randomization (or 17 months during the COVID pandemic). Risk ratios (RR) with 95% CI adjusted for age group were calculated using log-linear binominal regression. Main results and the role of chance A total of 1202 women from 21 Dutch centers were randomly assigned to blastocyst-stage transfers (N = 599) or cleavage stage transfers (N = 603) between 2018 and 2021. At submission of this abstract, data on the primary outcome was available for 1153 (95.9%) women, 577 women in the blastocyst-stage group and 576 women in the cleavage-stage group. The cumulative live birth rate was 58.2% (336/577 women) in the blastocyst-stage group and 57.3% (330/576 women) in the cleavage stage group (RR 1.022, 95% CI 0.844-1.237; p = 0.825). The live birth rate after fresh embryo transfer was 38.0% (219/577 women) versus 29.9% (172/576 women) in the blastocyst-stage group and cleavage-stage group respectively (RR 1.282, 95% CI 1.017-1.615 p = 0.035). Interaction was found between age and day of transfer with a higher cumulative live birth rate and a higher live birth rate after fresh transfer in women of 36 years or older in the blastocyst group. Analyses on other IVF treatment outcomes, obstetrical or neonatal outcomes, patient burden, and cost effectiveness are ongoing. Limitations, reasons for caution Outcomes are only applicable for treatments of women with at least four embryos available on day two of embryo culture. Wider implications of the findings A blastocyst-stage embryo transfer policy did not result in a significant higher cumulative live birth rate in comparison to a cleavage-stage embryo transfer policy in IVF/ICSI treatments. Further research into the interaction of age with outcomes is warranted. Trial registration number NTR7034

STUDY QUESTION:Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER:In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY:We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION:We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS:In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0-10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE:In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0-6.8) (oil group (n = 199) 4.8 (IQR 3.0-6.4); water group (n = 201) 5.0 (IQR 3.0-6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1-2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66-1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7-15.0) in the oil group versus 8.0 ml (IQR 5.9-13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION:This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS:The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S):The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers' fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER:The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE:1 February 2012. DATE OF FIRST PATIENT’S ENROLMENT:3 February 2012.

STUDY QUESTION Do the quality of life (QoL) and the risk factors for emotional problems during and after treatment of infertile women differ from their partners? SUMMARY ANSWER Women have lower levels of fertility-related QoL, and more and differing risk factors for emotional problems during and after treatment than their partners. WHAT IS KNOWN ALREADY?: The psychological impact of infertility in patients negatively affects their QoL and is also related to increased discontinuation of treatment. Moreover, psychological factors might positively affect pregnancy rates. However, it is still unclear if differences in QoL and emotional status exist between infertile women and their partners. So far, research mainly focused on generic instruments to measure patients' QoL in the area of fertility care. STUDY DESIGN, SIZE, DURATION A cross-sectional study of infertile couples within 32 Dutch fertility clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS We included infertile women and their partners (both heterosexual and lesbian couples) under any treatment and at any stage of treatment in one of the 32 participating clinics. Per clinic, 25-75 patients were randomly selected depending on clinic size. In total, 1620 women and their partners were invited separately to complete the FertiQoL and SCREENIVF questionnaires to measure their level of QoL and risk factors for emotional problems during and after treatment, respectively. MAIN RESULTS AND THE ROLE OF CHANCE A total of 946 women (response rate 58%) and 670 partners (response rate 41%) completed the questionnaire set. As 250 women and 150 partners were already pregnant, questionnaires from 696 women and 520 partners could be analysed. Women scored significantly lower on the FertiQoL total scores [B = -6.31; 95% confidence interval (CI) = -7.63 to 4.98] and three of the FertiQoL subscales (Emotional, Mind-Body and Social) than their partners, indicating lower QoL. Scores on the SCREENIVF questionnaire were significantly higher for women (B = 0.22; 95% CI = 0.06-0.38), indicating that women are more at risk for developing emotional problems (and these factors differed from those of their partners) during and after fertility treatment than their partners. LIMITATIONS, REASONS FOR CAUTION Although the number of participants is high (n = 1216), the relatively low response rate, especially for partners (41%), may have influenced the results through selection bias. An analysis of non-responders could not be performed. The FertiQoL and SCREENIVF questionnaires, which have been validated only in women starting a first IVF cycle, should also be validated for studying partners. In addition, the SCREENIVF questionnaire has been validated in Dutch women only and further research in an international setting is also required. WIDER IMPLICATIONS OF THE FINDINGS Our study results represent the Dutch infertile population as more than one-third of all Dutch clinics participated in the study. As the FertiQoL questionnaire is an internationally validated questionnaire already, these results can be put in a more broader and international perspective. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Merck Sharp & Dohme (MSD), The Netherlands. There are no competing interests.

STUDY QUESTION:Are clinic factors, including patients' experiences with patient-centred care, associated with dropout in fertility care?SUMMARY ANSWER:Clinic factors, including patients' experiences with patient-centred care, are not related to dropout.WHAT IS KNOWN ALREADY:In fertility care, a significant proportion of patients do not achieve pregnancy because they discontinue treatment prematurely. Many studies have tried to identify factors predicting dropout, showing incompatible results. However, these studies mainly focus on factors at the treatment and patient level, while clinic factors have received little attention.STUDY DESIGN, SIZE, DURATION:This prospective, longitudinal study was nested within a large RCT, which aims to improve the level of patient-centredness of Dutch fertility care. Of the 1620 infertile women who were invited to participate, the baseline measurement of the study (T0) included 693 women who completed a questionnaire about their experiences with patient-centred fertility care. The follow-up of the patients was 1 year (T1).PARTICIPANTS/MATERIALS, SETTING, METHODS:All included women suffered from infertility and were undergoing treatment in one of the 32 Dutch clinics involved in the trial. Levels of patient-centredness were determined using the Patient-Centredness Questionnaire-Infertility (PCQ-Infertility) at T0. Meanwhile, a professionals' questionnaire was used to gather additional information on characteristics of the clinic (e.g. the number of patients per year or the presence of a fertility nurse). After 1 year, at T1 measurement, patients completed a questionnaire on their current status in fertility care, including their main reason for discontinuation if applicable.MAIN RESULTS AND THE ROLE OF CHANCE:A total of 693 non-pregnant women completed the questionnaire set at T0 and 534 women (77.1%) provided consent for follow-up. At T1 measurement, 434 women (81.3%) completed the questionnaire and 153 of these women (35.2%) continued treatment while 76 women (17.5%) dropped out. Another 175 women (40.3%) had achieved pregnancy and 30 patients (7.9%) were advised to discontinue treatment for medical reasons. Neither levels of patient-centredness nor the additional clinic characteristics differed significantly between dropouts and compliers. However, patients who did not receive assisted reproduction treatment (ART; e.g. underwent intrauterine insemination, IUI) before they dropped out had significantly lower scores on the PCQ-Infertility subscale 'Respect for patients' values' than patients who continued their treatment [odds ratio (OR) 0.57; 95% confidence interval (CI) 0.34-0.95]. Patients who received ART and, subsequently, dropped out had higher scores on the PCQ-Infertility subscale 'Patient involvement' than those receiving non-ART (OR 2.39; 95% CI 1.02-5.59).LIMITATIONS, REASONS FOR CAUTION:We were not able to follow-up a significant proportion (ca. 19%) of the 1620 women who were invited for T0 measurement, which might have biased our results. We also excluded patients who were still in the diagnostic work-up stage and this might have influenced our results as it is known that patients dropout at this stage. As the PCQ-Infertility was validated in patients who were already undergoing treatment, we decided to focus on this patient group only.WIDER IMPLICATIONS OF THE FINDINGS:The results of this study provide a better insight into those factors influencing dropout from the perspective of factors in the clinic itself. Although most clinic factors were not related to dropout, clinic factors might be of use when predicting dropout for specific patient groups, such as patients receiving ART and non-ART. Future research should involve an exploration of more specific predictors of dropout at the patient, treatment and clinic levels.STUDY FUNDING/COMPETING INTERESTS:This work was supported by Merck Serono, the Netherlands. No competing interests declared.

STUDY QUESTION Is patient screening for emotional risk factors before starting IVF treatment feasible? SUMMARY ANSWER Introduction of screening for emotional risk factors by a validated instrument (SCREENIVF) in couples treated by IVF or ICSI is feasible, indicated by a moderate to high and stable uptake rate, a high acceptance of the process of SCREENIVF, and a high acceptability of the presented risk profile by the patients. WHAT IS KNOWN ALREADY SCREENIVF is a validated screening tool to identify women at risk for emotional maladjustment preceding the start of their IVF/ICSI treatment. STUDY DESIGN, SIZE AND DURATION This was a prospective cohort study, including data of two cohorts of patients (304 and 342 patients), with a duration of 3 months per cohort. For the first cohort, we sent a process evaluation to 210 patients and it was completed by 91 patients. PARTICIPANTS/MATERIALS, SETTING AND METHODS All 304 patients (male and female) who started IVF/ICSI between 1 December 2009 and 28 February 2010 in our tertiary IVF clinic were eligible. The uptake rate of SCREENIVF was assessed as the response rate to the screening questionnaire. One year later, we re-assessed the uptake rate in 342 new patients to assess the stability of the uptake rate. A non-responder assessment in patients who did not complete SCREENIVF was carried out. Finally, patients' characteristics and their experiences with SCREENIVF as well as their consequent actions were assessed by an additional process evaluation questionnaire sent some months later to 210 patients. MAIN RESULTS AND THE ROLE OF CHANCE The uptake rate of SCREENIVF was 78-80%. One-third of the responders were found to be at risk for emotional maladjustment, which was comparable with previous studies using SCREENIVF. Of 27 non-responders to SCREENIVF, 41% explained non-response by 'no actual need for psychological help' and 19% forgot to complete the screening. The response rate to the process evaluation was 43% (n = 91). Of these, 90% found the screening was useful, and almost all patients were positive about the SCREENIVF questionnaire. Furthermore, 93% recognized themselves in the risk profile based on SCREENIVF. Of the patients at risk, 21% reported planning to seek professional help, but 46% of the at-risk patients experienced travelling distance as an obstacle to seek psychological help. We concluded that screening patients for emotional risk factors is feasible. In future, psychosocial care offered by the Internet may be promising in meeting the barrier of travelling distance. LIMITATIONS, REASONS FOR CAUTION People were asked to fill in SCREENIVF for clinical purposes pretreatment. There might be a selection bias in the people who did not fill in SCREENIVF, which may be due to already existing psychological problems or language problems. The low response rate of the process evaluation questionnaire and the mono-centre evaluation may be confounders and may have influenced our analysis opportunities. WIDER IMPLICATIONS OF THE FINDINGS The generalizability of this data is unknown with respect to other ethnic groups. Furthermore, more research is needed to evaluate psychosocial factors in male partners. Future research should also focus on the barriers and facilitators for help-seeking behaviour. STUDY FUNDING/COMPETING INTEREST(S) There was no funding for this study and no conflict of interest.