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In this study, women with OASIS had a more than doubled risk of longer-term bothersome symptoms of AI compared with controls. Symptoms were experienced as bothersome and as having an influence on QoL.

STUDY QUESTION What outcomes are important for women to decide on the day of embryo transfer in IVF? SUMMARY ANSWER The highest cumulative live birth rate per treatment (cLBR) was the most important treatment outcome for women undergoing an IVF treatment, regardless of the number of transfers needed until pregnancy and impact on quality of life. WHAT IS KNOWN ALREADY Cleavage stage (day three) and blastocyst stage (day five) embryo transfers are common transfer policies in IVF. The choice for one or the other day of embryo transfer differs between clinics. From the literature, it remains unclear whether the day of transfer impacts the cLBR. Patient preferences for the day of embryo transfer have not been examined yet. STUDY DESIGN, SIZE, AND DURATION A discrete choice experiment (DCE) was performed to investigate female patients’ preferences and their values concerning various aspects of an IVF treatment, with a particular focus on embryo transfer policy. A multicenter DCE was conducted between May 2020 and June 2020 in which participants were asked to choose between different treatments. Each treatment was presented using hypothetical scenarios containing the following attributes: the probability of a healthy live birth per IVF treatment cycle, the number of embryos available for transfer (for fresh and frozen-thawed embryo transfer), the number of embryo transfers until pregnancy, and the impact of the treatment on the quality of life. PARTICIPANTS/MATERIALS, SETTING, METHODS Women (n = 445) were asked to participate in the DCE at the start of an IVF treatment cycle in 10 Dutch fertility clinics. Participating women received an online questionnaire. The attributes’ relative importance was analyzed using logistic regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE A total of 164 women participated. The most important attribute chosen was the cLBR. The total number of embryos suitable for transfer also influenced women’s treatment preferences. Neither the number of transfers needed until pregnancy, nor the impact on quality of life influenced the treatment preferences in the aggregated data. For women in the older age group (age ≥36 years) and the multipara subgroup the impact on quality of life was more relevant. Naive patients (patients with no prior experience with IVF treatment) assigned less value to the number of embryo transfers needed until pregnancy and assigned more value to the cLBR than the patients who had experienced IVF. LIMITATIONS REASONS FOR CAUTION An important limitation of a DCE study is that not all attributes can be included, which might be relevant for making choices. Patients might make other choices in real life as the DCE scenarios presented here are hypothetical and might not exactly represent their personal situation. We tried to avoid potential bias by selecting the attributes that mattered most to the patients obtained through patient focus groups. Final selection of attributes and the assigned levels was established using the input of an expert panel of professionals and by performing a pilot study to test the validity of our questionnaire. Furthermore, because we only included women in our study, we cannot draw any conclusions on preferences for partners. WIDER IMPLICATIONS OF THE FINDINGS The results of this study may help fertility patients, clinicians, researchers, and policy makers to prioritize the most important attributes in the choice for the day of embryo transfer. The present study shows that cLBR per IVF treatment is the most important outcome for women. However, currently there is insufficient information in the literature to conclude which day of transfer is more effective regarding the cLBR. Randomized controlled trials on the subject of day three versus day five embryo transfers and cLBR are needed to allow evidence-based counseling. STUDY FUNDING/COMPETING INTEREST(S) This work received no specific funding and there are no conflicts of interest. TRIAL REGISTRATION NUMBER None.

IntroductionIn vitro fertilisation (IVF) has evolved as an intervention of choice to help couples with infertility to conceive. In the last decade, a strategy change in the day of embryo transfer has been developed. Many IVF centres choose nowadays to transfer at later stages of embryo development, for example, transferring embryos at blastocyst stage instead of cleavage stage. However, it still is not known which embryo transfer policy in IVF is more efficient in terms of cumulative live birth rate (cLBR), following a fresh and the subsequent frozen–thawed transfers after one oocyte retrieval. Furthermore, studies reporting on obstetric and neonatal outcomes from both transfer policies are limited.Methods and analysisWe have set up a multicentre randomised superiority trial in the Netherlands, named the Three or Fivetrial. We plan to include 1200 women with an indication for IVF with at least four embryos available on day 2 after the oocyte retrieval. Women are randomly allocated to either (1) control group: embryo transfer on day 3 and cryopreservation of supernumerary good-quality embryos on day 3 or 4, or (2) intervention group: embryo transfer on day 5 and cryopreservation of supernumerary good-quality embryos on day 5 or 6. The primary outcome is the cLBR per oocyte retrieval. Secondary outcomes include LBR following fresh transfer, multiple pregnancy rate and time until pregnancy leading a live birth. We will also assess the obstetric and neonatal outcomes, costs and patients’ treatment burden.Ethics and disseminationThe study protocol has been approved by the Central Committee on Research involving Human Subjects in the Netherlands in June 2018 (CCMO NL 64060.000.18). The results of this trial will be submitted for publication in international peer-reviewed and in open access journals.Trial registration numberNetherlands Trial Register (NL 6857).

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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

age groups. TL was similar in young groups while in older groups TL was statistically significantly different (134.6 AE 15.95 a.u vs 113.6 AE 12,99 a.u, NZ and OAZ respectively, p ¼ 0.035). Moreover, an accumulation of critically short telomeres was found in older OAZ (3.28 % vs 11.68 %, NZ and OAZ respectively; p ¼ 0.043). To analyse telomere protection, TRF1 levels were studied. In blood, younger OAZ showed lower levels of TRF1 (317.3 AE 49.93 a.u vs 267.7 AE 40.02 a.u, NZ and OAZ respectively; p ¼ 0.010) and accumulated a higher percent of low TRF1 levels at telomeres (16.9% vs 25.22 %, p ¼ 0.001). Regarding ART outcomes, a lower rate of fertilization per Metaphase II oocytes (0.358 AE 0.072 vs 0.811 AE 0.019, p < 0.0001) and a higher rate of abortion (0.277 AE 0.188 vs 0.014 AE 0.014, p ¼ 0.032) was found in older OAZ after intracytoplasmic sperm injection using donor oocytes and transfer.CONCLUSIONS: OAZ patients have a shorter systemic TL already detectable at young age and also patent in sperm at older ages, possibly due to telomere unprotection with low levels of TRF1. Therefore, in OAZ patients, alteration of telomere biology could cause the premature aging of the reproductive system. Additionally, older OAZ had worse ARToutcomes in contrast with NZ, suggesting that correct TL maintenance is a potential molecular marker of sperm quality to consider at older ages, before performing ART.