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Study question Are serum cytokines levels associated with ovarian response in IVF cycles? Summary answer The IL–6/IL–10 ratio is higher in patients with low ovarian response. What is known already Previous studies reported differences in the levels of IL–2, Il–6, IL–8, IL–10 and VEGF in follicular fluid between young patients with low ovarian response and normoresponder women. In addition, it is known that IL–6 plays an important role as a mediator of fever and acute phase reaction and IL–10 is the cytokine with the greatest anti-inflammatory power. Although there seems to be some evidence about the possible effect of the immune system on ovarian function and implantation, the role it plays in ART remains unknown. Our aim was to investigate the effect of cytokines in ovarian reserve and response. Study design, size, duration One hundred and fifty-two patients were included in a retrospective study between February 2016 and December 2020. Serum cytokines IL–2, IL–4, IL- 6, IL–8, IL–10, VEGF, IFN↖, TNF α, IL–1 α, IL–1 β, MCP–1 and EGF were measured previously to the ovarian stimulation cycle. Patients with altered karyotype, mutation or premutation in the FMR1 gene or endometriosis or with any other factor that could alter the ovarian reserve or response were excluded from the study. Participants/materials, setting, methods To measure the levels of the different cytokines, a sandwich immunoassay with specific antibodies for the cytokines IL–2, IL–4, IL–6, IL–8, IL–10, VEGF, IFN↖, TNF α, IL -1 α, IL–1 β, MCP–1 and EGF were used. The statistical analysis was performed with R Statistical Software, version 4.0.3 and the Software Statistical Product and Service Solutions, version 20.0 (SPSS, Chicago, IL, EE.UU.). Main results and the role of chance We found that the ratio between IL–6 and IL–10 cytokines is higher in those patients in whom four or fewer oocytes have been recovered after ovarian puncture (2.15 versus 1.55; p = 0.035; Mann-Whitney test). If we establish 0.9 as a cut-off point for the IL–6 / IL–10 ratio, we observed that above this value the risk of having a low response to ovarian stimulation is more than 3 times greater than below this value (22.9% versus 6.0%; p = 0.007; Fischer exact test). There were no statistically significant differences between both groups in terms of age (p = 0.136), dose of gonadotropin administered (p = 0.415) and duration of ovarian stimulation (p = 0.706). In addition, performing hierarchical cluster analysis with the analyzed cytokines and the associated variables to ovarian reserve and response, we observed that the antral follicle count, the total oocytes recovered and the MII recovered are grouped in the same cluster as the cytokines IL–2, IL–4, IL–6, IL–10, IL–1α, IL–1B, IFNγ y TNFα. We determined the number of clusters based on the tree diagram and k-means method. Limitations, reasons for caution The retrospective study design and the sample size could be a limitation. The study was performed in patients with suspected implantation failure. Wider implications of the findings: The ratio between IL–6 and IL–10 could be used as a potential biomarker to predict the ovarian response and provide real expectations regarding the success of IVF cycle. The action of IL–6 could be reduced by blocking its receptor using humanized monoclonal antibodies as Tocilizumab. Trial registration number Not applicable

Study question Are there any differences in clinical outcomes after SET of re-expanded versus non-re-expanded blastocysts? Summary answer The transfer of re-expanded thawed blastocysts is associated with improved clinical outcomes. What is known already Improvements in embryo culture conditions, endometrial receptivity protocols and vitrification as a revolutionary cryopreservation technique have allowed the expansion of blastocyst stage transfers (Lieberman and Tucker, 2006; Stanger et al., 2012; Rienzi et al., 2017), increasing clinical pregnancy and implantation rates in IVF cycles. The re-expansion of thawed blastocyst at the time of transfer has been considered as a good prognosis factor, but not always thawed embryos re-expand. To evaluate the relevance of this event, we compared the clinical results of the re-expanded embryos versus the collapsed ones after their thawing and transfer. Study design, size, duration A total number of 1.125 frozen-thawed blastocyst transfers were included in this retrospective observational study between January 2018 and December 2020. Seven hundred and eighty-six thawed blastocyst were fully expanded at the time of the transfer and 339 thawed blastocysts were non-re-expanded when they were transferred. Participants/materials, setting, methods 1.125 single frozen-thawed blastocyst embryo transfer (SET) cycles (802 from donated and 319 from autologous oocytes) were divided in two groups (re-expanded vs non-re-expanded). Positive beta human chorionic gonadotrophin (bHCG), pregnancy rate (PR), early miscarriage rate (EMR) and live birth rate (LBR) were compared between the two groups. Blastocysts were thawed using an Irvine Scientific® Thaw kit, Irvine Scientific® and were transferring in culture medium (Global® Total® LP, CooperSurgical®). Main results and the role of chance During 2018, 190 re-expanded blastocyst and 94 non-re-expanded were transferred. Statistical significant differences were found in the percentage of positive bHCG (48.4% vs 30.9%, p < 0,0048) and PR (39.5% vs 25.5%, p < 0,0203), respectively. In 2019, statistical differences were found in the LBR between 307 re-expanded blastocyst and 124 non-re-expanded (30.6% vs 12.9%; p < 0,00001). Differences were also found in positive bHCG (50.2% vs 21.8%, p < 0,00001) and PR (40.7% vs 15.3%, p < 0,00001), respectively. Finally, in 2020, 289 re-expanded blastocyst and 121 non-re-expanded were transferred, and significant differences were obtained in the percentage of positive bHCG (46.8% vs 22.3%, p < 0,00001) and PR (32.9% vs 15.7%, p < 0,00001), respectively. Globally, all the variables analysed were statistically significant in favour of the re-expanded embryo group: positive bHCG (48.7% vs 24.5%; p < 0,00001), PR (37.5% vs 18.3%; p < 0,00001) and LBR (20.1% vs 9.5%; p < 0,00001), except for EMR. Limitations, reasons for caution The inherent limitations to a retrospective design. Larger studies are warranted in order to reach robust conclusions on the subject. Wider implications of the findings: Transfer of re-expand blastocyst could be a positive indicator of clinical outcomes. In case of non-re-expand embryos, transfer of two could be reasonable. Trial registration number NONE