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Background: Ovulation induction for in vitro fertilization (IVF) may increase intravascular thromboses among patients with antiphospholipid autoantibodies (aPLs) or antiphospholipid syndrome (APS) due to the high estrogen levels. While natural or modified natural IVF treatment cycles (MNC) are sometimes used instead of stimulated cycles with empiric anticoagulant treatment among these infertile patients, their efficacy is unclear., Materials and Methods: A retrospective cohort study including all IVF cycles of patients diagnosed with aPLs or APS in a tertiary, university-affiliated hospital between 2012 and 2022. The outcomes of stimulated cycles with anticoagulants and MNC and natural IVF cycle attempts were compared., Results: 121 oocyte retrievals from 38 women were analyzed: 93 stimulated and 28 MNC or natural IVF cycles. The rates of cycle cancellation (0 % vs. 17.9 %, p < 0.001) and cycles in which no oocytes were retrieved (0 % vs. 43.5 %, p < 0.001) were significantly lower following stimulated cycles vs. natural and MNC. In parallel, positive β-hCG (31.9 % vs. 10.9 %, p = 0.03), clinical pregnancy rate (23.6 % and 3.6 %, p < 0.001) and live birth rates (18.1 % vs. 3.6 %, p = 0.01) were significantly higher following stimulated cycles. No thrombotic events or bleeding occurred in any cycle., Conclusion: Ovarian stimulation for IVF is more effective for successful pregnancy and delivery than natural cycles and MNC and can be safely undertaken in aPLs or APS women undergoing IVF. Rates of complication from hormonal treatment are not increased when treated with LMWH during ovarian stimulation., Competing Interests: Declaration of competing interest We have confirmed that all manuscript authors contributed to the concept, design, results interpretation, and manuscript drafting. None of the authors of this study have any conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To study and compare the preimplantation genetic testing for monogenic disorders (PGT-M) results, and to evaluate the treatment cycle outcomes of embryos derived from a single pronucleus (1PN) vs. two pronuclei (2PN)., Design: A retrospective cohort study from January 2018 to December 2022 involving in vitro fertilization (IVF)-PGT-M treatment cycles., Setting: Single, academically affiliated fertility center., Patients: A total of 244 patients underwent 351 IVF-PGT-M treatment cycles., Intervention: Embryo biopsy with molecular testing for a monogenic disorder., Main Outcome Measures: The molecular diagnosis results and clinical outcomes after the transfer of embryos derived from 1PN and 2PN in IVF-PGT-M treatment cycles., Results: Embryos derived from 1PN have a significantly low developmental potential with a lower rate of embryos that underwent biopsy compared with 2PN-derived embryos; 1PN-derived embryos demonstrated a significantly lower number of blastocysts (24% vs. 37.9%) and top-quality blastocysts (22.3% vs. 48.1%) compared with 2PN-derived embryos. Lower successfully completed and unaffected PGT-M results were achieved in 1PN compared with 2PN-derived embryos (47.1% vs. 65.5% and 18.7% vs. 31.6%, respectively), with significantly higher abnormal molecular results (39.6% vs. 22.7%). The embryo transfer of 24 1PN-derived embryos with no affected genetic disorder resulted in 5 (20.8%) clinical pregnancies and 4 (16.7%) live births (LBs)., Conclusions: Within the limits of fewer embryos derived from 1PN that yielded unaffected embryos suitable for transfer, the clinical pregnancy and LB rate of 1PN embryos undergoing PGT-M are reassuring. We, therefore, suggest applying PGT-M to embryos derived from 1PN embryos to improve the cumulative clinical pregnancy and LB rates., Competing Interests: Declaration of Interests O.L. has nothing to disclose. M.N.-H. has nothing to disclose. S.T. has nothing to disclose. J.H. has nothing to disclose. E.Z. has nothing to disclose. R.N. has nothing to disclose. R.O. has nothing to disclose. A.A. has nothing to disclose., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Ovarian stimulation (OS) with high daily gonadotropin doses are commonly offered to patients attempting social/elective egg freezing. However, the optimal daily gonadotropin dose that would allow a higher oocyte yield in the successive IVF cycle attempt was not settled and should be determined., Patients and Methods: Data from all women admitted to our IVF unit for social/EEF, who underwent two consecutive IVF cycle attempts, with only those who used in the first attempt a starting daily gonadotropin dose of 300IU were analyzed. Patients characteristics and OS variables were used in an attempt to build a logistic model, helping in determining the daily gonadotropin dose that should be offered to patient during their second EEF attempt, aiming to further increase their oocyte yield., Results: Three hundred and thirteen consecutive women undergoing two successive IVF cycle attempts were evaluated. Using logistic regression model, two equations were developed using individual patient-level data that determine the daily gonadotropin dose needed aiming to increase the oocyte yield in the successive cycle. (a): X=-0.514 + 2.87*A1 + 1.733*A2-0.194* (E2/1000) and (b): P = EXP(X) / [1 + EXP(X)]., Conclusions: Using the aforementioned equations succeeded in determining the daily gonadotropin dose that might result in increasing oocyte yield, with an AUC of 0.85. Any additional oocyte retrieved to these EEF patients might get them closer to fulfil their desire to parenthood., (© 2024. The Author(s).)

Objective: We aim to investigate the effect of extreme emotional and psychological trauma following Hamas terrorist attack on October 7th, 2023, on IVF cycle outcome., Patients and Methods: The study population consisted of all couples undergoing 2 consecutive IVF attempts with ovum pick-up in our institute, before and during the week of October 8th to 12th, 2023. Embryological/ laboratory variables of the IVF cycles were assessed and compared between the patients' IVF cycle before and those that underwent OPU during the spoken week., Results: Twenty-three couples were eligible for analysis. There were no differences between the cycles in the length of ovarian stimulation, total dose of gonadotropin used, and the peak estradiol and progesterone levels. Furthermore, while no differences were observed in the number of oocytes and mature oocytes retrieved or fertilization rate, the mean number of top-quality embryos per OPU (1.1 ± 1.7 vs. 2.2 ± 2.9; p < 0.02) and ratio of top-quality embryos per number of fertilized oocytes (0.5 ± 0.3 vs. 0.7 ± 0.2; p < 0.01) were significantly lower during the spoken week. Semen total motile count was significantly reduced during the spoken week., Conclusions: In the present study, we are witness to the effect of acute emotional and psychological trauma on IVF outcome, as reflected by its detrimental effect on sperm and embryo quality., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: We aimed to compare the telomere length in granulosa cells of the young normal and poor ovarian responder patients and elderly patients undergoing ovarian stimulation for IVF., Methods: The main outcome measures granulosa cells telomere Length in the 3 study groups of patients undergoing IVF treatment in our center. 1) young normal responder patients (< 35 years); 2) young (< 35 years) poor ovarian responder patients; and 3) Elderly patients (40-45 years). Granulosa cells were obtained at the time of oocyte retrieval. Granulosa cells telomere length was assessed by absolute human telomere length quantification qPCR Assay., Results: The telomere length of the young normal responder was significantly longer as compared to young poor ovarian responder (15.5 vs 9.6 KB, p < 0.001) and the elderly patients (15.5 vs 10.66 KB, p < 0.002). No significant difference was observed in the telomere length between the young poor ovarian responder and the elderly patients., Conclusions: Granulosa cells telomere length of the young normal responder was found to be significantly longer than young poor ovarian responder or elderly patients, highlighting the role of telomere length as a predictor, or contributor to poor oocyte yield following IVF treatment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Double ovarian stimulation (DuoStim), initially only suggested for fertility preservation in cancer patients, is now increasingly also used in routine clinical IVF, especially in poor responders. The claimed rational for this is the alleged existence of multiple follicular waves in a single intermenstrual interval, allowing for retrieval of more oocytes in a single IVF cycle. This commentary argues that this expansion of purpose lacks rationale, evidence, and follow-up. Consequently, we suggest that, unless valid clinical indications have been established, DuoStim be only subject of controlled clinical trials with appropriate experimental consents., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Ovarian stimulation (OS) is one of the key factors in the success of in vitro fertilization-embryo transfer (IVF-ET), by enabling the recruitment of numerous healthy fertilizable oocytes and, thereby, multiple embryos. The Stop GnRH-agonist/GnRH-antagonist (GnRH-ag/GnRH-ant), which offers all the advantages of using long suppressive GnRH-ag, with GnRH-ant, is in my opinion a valuable addition to the armamentarium of OS protocols. It allows cycle programming, better follicular synchronization and offers successful outcome in a variety of challenging cases such as poor responders, Poseidon group 4 poor prognosis patients, those with elevated peak progesterone (P) serum levels, poor embryo quality or repeated IVF failures., (© 2023. The Author(s).)

Oocytes eligible for intracytoplasmic sperm injection (ICSI) are those that have progressed through meiosis to metaphase 2 (MII). The remaining delayed mature oocytes can be injected, aiming to achieve more embryos and a better chance to conceive. We aimed to assess the outcome of delayed matured oocytes, derived from either germinal vesicles or metaphase 1 (MI), that reached maturity (MII) 24 h following retrieval. The study population consisted of 362 women who underwent 476 IVF cycles. While fertilization rates were comparable between the sibling delayed mature oocyte group compared with injection on day 0 group (58.4% vs 62%, respectively, P = 0.07), the top-quality embryo rate per injected MII day 0 oocyte was significantly higher compared with day 1 injected oocyte (57.5% vs 43.9% respectively, P < 0.001). Moreover, following fresh transfer of embryos derived from delayed mature oocytes, implantation rate and the clinical pregnancy (CPR) and live-birth rates (LBR) per transfer were 3.9%, 3.3% and 1.6% respectively. When considering the following thawed embryo transfer cycles, implantation, pregnancy and LBR were non-significantly higher (10%, 8.3% and 8.3%, respectively). Although clinical outcomes are significantly lower when using embryos derived from delayed mature oocyte to mature day 0 oocytes, the additional embryos derived from delayed mature oocytes might contribute to the embryo cohort and increase the cumulative live-birth rate per retrieval. Moreover, the embryos derived from delayed mature oocyte favour a transfer in a frozen-thawed cycle rather than in a fresh cycle.

Background: Poor responders to ovarian stimulation are one of the most challenging populations to treat. As a failed cycle can cause a considerable emotional and economical loss, adequate fertility counseling addressing patients' expectations are highly important when facing patients with poor ovarian response. The study aimed to evaluate reproductive outcomes and to identify factors associated with live birth (LB) after fresh autologous IVF/intracytoplasmic sperm injection (ICSI) cycles of patients fulfilling the Bologna criteria for poor ovarian response (POR)., Methods: A retrospective study included 751 IVF/ICSI treatment cycles which yielded up to three retrieved oocytes, at a tertiary referral hospital between January 2016 and February 2020. A logistic regression analysis was used to adjust for confounders., Results: Clinical pregnancy and LB rate per cycle were significantly higher among women younger versus older than 40 years (9.8% and 6.8% vs 4.5% and 2.1%, p < 0.01, respectively). Patients who achieved LB were significantly younger, had higher number of oocytes retrieved, fertilization rate and top-quality embryos (p < 0.05). Multivariable regression analysis identified patient's age (OR 0.90; 95% CI 0.845-0.97; p = 0.005) and mean number retrieved oocytes (OR 1.95; 95% CI 1.20-3.16; p = 0.007) as factors significantly associated with the probability of a LB., Conclusions: The woman's age and the number of retrieved oocytes are both independent predicting factors of live birth in poor ovarian responders. Considering the risks, the high financial investment and poor reproductive outcomes involved in IVF treatments, raises questions regarding the adequacy of providing treatments in these patients' population. POR younger than 40 years may represent a possible exception due to acceptable probability for a LB., (© 2022. The Author(s).)

Ethical considerations are central to all medicine though, likely, nowhere more essential than in the practice of reproductive endocrinology and infertility. Through in vitro fertilization (IVF), this is the only field in medicine involved in creating human life. IVF has, indeed, so far led to close to 10 million births worldwide. Yet, relating to substantial changes in clinical practice of IVF, the medical literature has remained surprisingly quiet over the last two decades. Major changes especially since 2010, however, call for an updated commentary. Three key changes deserve special notice: Starting out as a strictly medical service, IVF in recent years, in efforts to expand female reproductive lifespans in a process given the term "planned" oocyte cryopreservation, increasingly became more socially motivated. The IVF field also increasingly underwent industrialization and commoditization by outside financial interests. Finally, at least partially driven by industrialization and commoditization, so-called add-ons, the term describing mostly unvalidated tests and procedures added to IVF since 2010, have been held responsible for worldwide declines in fresh, non-donor live birthrates after IVF, to levels not seen since the mid-1990s. We here, therefore, do not offer a review of bioethical considerations regarding IVF as a fertility treatment, but attempt to point out ethical issues that arose because of major recent changes in clinical IVF practice., (© 2022. The Author(s).)

Objective: No information exists in the literature regarding the effect of coronavirus disease 19 (COVID-19) infection on subsequent i n vitro fertilization (IVF) cycle attempt. We, therefore, aim to assess the influence of COVID-19 infection on IVF treatments., Design: An observational study., Setting: A tertiary, university-affiliated medical center., Patients and Methods: All consecutive couples undergoing ovarian stimulation (OS) for IVF, before and after recovering from COVID-19 infection, and reached the ovum pick-up (OPU) stage. The stimulation characteristics and embryological variables of couples undergoing IVF treatments after recovering from COVID-19 infection were assessed and compared to their IVF cycles prior to COVID-19 infection., Main Outcome Measures: Stimulation characteristics and embryological variables., Results: Nine couples (seven with the female partner infection and two with the male partner) resumed IVF treatment 8-92 d after recovering from the COVID-19 infection (negative polymerase chain reaction [PCR]). No in-between cycles differences were observed in OS and embryological variables between the cycles before and after recovering from the COVID-19 infection, except for a significantly lower proportion of top-quality embryos., Conclusions: COVID-19 infection did not affect patients' performance or ovarian reserve in their immediate subsequent IVF cycle, except for a reduced proportion of top-quality embryos (TQEs). We therefore suggest, to postpone IVF treatment for a least 3 months (duration of folliculogenesis and spermatogenesis) after recovering from COVID-19 infection, aiming to recruit healthy gametes that were not exposed to COVID-19 infection during their development.

Research Question: What are the cumulative clinical pregnancy rates (CPR) and live births rates (LBR) in intracytoplasmic sperm injection (ICSI) cycles using testicular motile compared with immotile spermatozoa, obtained from testicular sperm aspiration (TESA) or extraction (TESE)?, Design: A retrospective analysis of ICSI cycles using TESA or TESE over a period of 7 years. Cycles were divided into two groups according to the motility of the retrieved spermatozoa: Group A consisted of couples with motile spermatozoa; Group B of couples with immotile spermatozoa. Group B was subdivided into two groups: B1 consisted of couples with motile spermatozoa and B2 with immotile spermatozoa after the addition of pentoxifylline., Results: No differences in CPR and LBR per transfer was found between the study groups after fresh embryo transfer. No pregnancies were achieved by vitrified-warmed embryo transfer in group B2. Fertilization rates decreased when using immotile spermatozoa (64.4%, 56%, 37.9%, for groups A, B1 and B2, respectively, P < 0.001). Top-quality embryo rates were higher in groups A and B1 compared with B2 (40.7% and 40.1% versus 19.1%, respectively, P = 0.015). Cumulative CPR (53%, 41.7%, 13.6% for groups A, B1 and B2, respectively, P = 0.005) and LBR (42.4%, 30%, 13.6% for groups A, B1 and B2, respectively P = 0.03) per oocyte retrieval was significantly higher when using motile spermatozoa compared with motile or immotile spermatozoa after adding pentoxifylline., Conclusions: Although fertilization, top-quality embryo rates, cumulative CPR and LBR decreased when using immotile spermatozoa, ICSI is still valid; therefore, it should be considered and offered to couples before embarking on a donor sperm insemination cycle, or cryopreserving oocytes for future additional testicular sperm retrieval., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: No information exists in the literature regarding the effect of mRNA SARS-CoV-2 vaccine on subsequent IVF cycle attempt. We therefore aim to assess the influence of mRNA SARS-CoV-2 vaccine on IVF treatments., Design: An observational study., Setting: A tertiary, university-affiliated medical center., Patients and Methods: All couples undergoing consecutive ovarian stimulation cycles for IVF before and after receiving mRNA SARS-CoV-2 vaccine, and reached the ovum pick-up (OPU) stage. The stimulation characteristics and embryological variables of couples undergoing IVF treatments after receiving mRNA SARS-CoV-2 vaccine were assessed and compared to their IVF cycles prior to vaccination., Main Outcome Measures: Stimulation characteristics and embryological variables., Results: Thirty-six couples resumed IVF treatment 7-85 days after receiving mRNA SARS-CoV-2 vaccine. No in-between cycles differences were observed in ovarian stimulation and embryological variables before and after receiving mRNA SARS-CoV-2 vaccination., Conclusions: mRNA SARS-CoV-2 vaccine did not affect patients' performance or ovarian reserve in their immediate subsequent IVF cycle. Future larger studies with longer follow-up will be needed to validate our observations.

Background: A Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment., Methods: Ten experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed via an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%., Results: Eighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (1) Follicular development and stimulation with gonadotropins (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged <35 years. Oocyte number and live birth rate are strongly correlated; there is a positive linear correlation with cumulative live birth rate. Different r-hFSH preparations have identical polypeptide chains but different glycosylation patterns, affecting the biospecific activity of r-hFSH. r-hFSH plus recombinant human LH (r-hFSH:r-hLH) demonstrates improved pregnancy rates and cost efficacy versus human menopausal gonadotropin (hMG) in patients with severe FSH and LH deficiency. (2) Pituitary suppression (n = 2 statements): Gonadotropin releasing hormone (GnRH) antagonists are associated with lower rates of any grade ovarian hyperstimulation syndrome (OHSS) and cycle cancellation versus GnRH agonists. (3) Final oocyte maturation triggering (n=4 statements): Human chorionic gonadotropin (hCG) represents the gold standard in fresh cycles. The efficacy of hCG triggering for frozen transfers in modified natural cycles is controversial compared with LH peak monitoring. Current evidence supports significantly higher pregnancy rates with hCG + GnRH agonist versus hCG alone, but further evidence is needed. GnRH agonist trigger, in GnRH antagonist protocol, is recommended for final oocyte maturation in women at risk of OHSS. (4) Luteal-phase support (n = 3 statements): Vaginal progesterone therapy represents the gold standard for luteal-phase support., Conclusions: This Delphi consensus provides a real-world clinical perspective on the specific approaches during the key steps of ART treatment from a diverse group of international experts. Additional guidance from clinicians on ART strategies could complement guidelines and policies, and may help to further improve treatment outcomes., Competing Interests: TD and SL are employees of Merck KGaA, Darmstadt, Germany. RO received speaker fees/honoraria from Ferring and Merck KGaA, Darmstadt, Germany. CV is supported by a NHMRC Early Career Fellowship (GNT1147154). He also has equity interests in Virtus Health and reports grants, personal fees and non-financial support from Merck KGaA, Darmstadt, Germany, personal fees and non-financial support from MSD, grants and non-financial support from Ferring, personal fees from Besins Healthcare, and grants and non-financial support from Abbott. HF received speaker fees/honoraria/grants from MSD, Ferring, Besin, Merck KGaA, Darmstadt, Germany, and Sun Pharma. RF received consulting fees and honoraria from Merck KGaA, Darmstadt, Germany. YK received speaker fees/honoraria/grants from MSD, Merck KGaA, Darmstadt, Germany, Besins Healthcare, Gedeon Richter, Abbott, Bayer, and Sun Pharma. MH declares receipt of research grants from Merck KGaA, Darmstadt, Germany, and lecture fees from Merck KGaA, Darmstadt, Germany and Ferring. MG received fees from Merck KGaA, Darmstadt, Germany, Ferring, Gedeon Richter, MSD, IBSA. SE declares receipt of unrestricted research grants from Merck KGaA, Darmstadt, Germany, and lecture fees from Merck KGaA, Darmstadt, Germany, Gedeon Richter and Medical Education Academy. SS was speaker at non-promotional educational symposia by Merck KGaA, Darmstadt, Germany and Ferring in the last 12 months. YL received speaker fees/grants from Merck KGaA, Darmstadt, Germany, MSD, and Bayer. CA received consulting fees and payment/honoraria from Merck KGaA, Darmstadt, Germany., (Copyright © 2021 Orvieto, Venetis, Fatemi, D’Hooghe, Fischer, Koloda, Horton, Grynberg, Longobardi, Esteves, Sunkara, Li and Alviggi.)

With the recent increased utilization of oocyte vitrification for the purpose of fertility preservation, information regarding the future fertility potential of the frozen oocytes is mandatory. Nowadays, there is a relative lack of data about prediction of assisted reproductive technique (ART) success relying on the retrieved oocytes. In the present study, we therefore aimed to investigate whether oocyte diameter might predict the quality of the developing embryo. A retrospective, single-center cohort study. Oocytes retrieved following controlled ovarian hyperstimulation cycles during 2016 and incubated in a time-lapse incubator system were analyzed. Oocytes were grouped by mean oocyte diameter (MOD) and incubated for 5 days before the final morphological evaluation done by an expert embryologist. A total of 471 cycles which yielded 3355 metaphase II oocytes were included in the analysis. Embryos developed from oocytes with MOD close to the average (Average 1SD < MOD < Average + 1SD) had increased good-quality blastulation rates compared with embryos that developed from very small or very large oocytes. Oocytes with MOD between 105.96 and 118.69 μm have better probability of becoming top-quality D5 blastocysts (17.1-17.4% grade 1 embryos). There is a correlation between oocyte's MOD and the embryo quality at day 5. The oocytes with near average MOD have a better chance to develop to a good-quality embryo. Therefore, the study suggests that MOD might serve as a predictor for embryo grading at day 5.

Objectives: We aim to study the association of maternal age with maternal and neonatal complications in twin pregnancies., Methods: A retrospective cohort study of dichorionic-diamniotic twin pregnancies stratified into three groups according to maternal age ("A" <25, "B" 25-34 and "C" 35-44 years old). Outcome measures included pregnancy, delivery and neonatal complications. A sub-analysis of in vitro fertilization pregnancies only was conducted., Results: Compared with younger women (groups A [n=65] and B [n=783]), older women [group C (n=392)] demonstrated significantly higher rates of gestational diabetes mellitus (B 6.6% vs. A 0%, p =0.027, C 10.2% vs. B 6.6%, p =0.032), were more likely to undergo cesarean deliveries (C 66.6%, B 57.6%, A 52.3%, p =0.007), and were at increased risk of having more than 20% difference in weight between the twins (C 24.5%, B 17.4%, A 16.9%, p =0.013). Other outcomes, including preeclampsia, did not differ between the groups. A sub-analysis of the in vitro fertilization only pregnancies was performed. Compared with younger women (groups A [n=18] and B [n=388]), older women (group C [n=230]) underwent more cesarean deliveries (p=0.004), and had more than 20% difference in weight between the twins (p<0.004). Other outcomes, including gestational diabetes mellitus rates and preeclampsia, did not differ between the groups., Conclusions: Women at advanced maternal age with dichorionic twin pregnancies had significantly higher rates of gestational diabetes mellitus, cesarean deliveries and fetal weight discordancy as compared with younger women. In contrast, the incidence of preeclampsia was not affected by maternal age., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: We aim to estimate the future fertility of patient undergoing their first IVF cycle attempt with no oocyte retrieved, and to identify factors that might predict those who will conceive in subsequent IVF cycle attempt., Methods: A cohort retrospective study of all consecutive women attending our IVF unit, for their first IVF cycle attempt, between January 2013 to December 2019, who reached the ovum pick-up (OPU) stage with zero oocyte retrieved. Patients' characteristics and infertility-treatment-related variables in the first IVF cycle attempt were compared between those who conceived in a subsequent cycle and those who did not. Moreover, infertility-treatment-related variables during successful cycles resulting in pregnancy were compared to those without., Results: 59 met the study inclusion criteria, yielding zero oocytes. During the follow-up period, 12 (20.3%) women conceived (one conceived twice), and 8 (14%) gave birth to a live infant. Cumulative live-birth rate per OPU and per patients were 4% and 14%, respectively. Clinical pregnancies were achieved after 3.61+1.4 cycle attempts (range: 1-6), with no live-births following the fifth IVF cycle attempt. No in-between group differences were observed in ovarian stimulation variables of their first IVF cycle attempt. Moreover, in those cycles resulting in pregnancy, patients achieved a significantly higher number of fertilized oocytes (2.15+1.5 vs 0.94+1.5, respectively; p<0.01) and a higher mean top-quality embryos (TQE) (1.76+0.9 vs 0.73+1.2, respectively; p<0.003)., Conclusion: Women yielding zero oocytes at their first IVF cycle attempt, may achieve 14% cumulative live-birth rate after 5 IVF cycle attempts. Moreover, those who conceived in subsequent IVF cycle attempts were those achieving 2 or more fertilized oocytes/TQE., Competing Interests: The authors have declared that no competing interests exist.

Objective: The objective of this study was to examine whether the combined Stop GnRH-agonist (GnRH-ag), letrozole priming, and multiple-dose GnRH-antagonist (GnRH-ant) protocol may improve in vitro fertilization/intracytoplasmic sperm injection cycle in poor ovarian responders (PORs)., Design: This was a historical cohort, proof of concept study under tertiary setting at University affiliated Medical Center., Patients: Five PORs fulfilling the POSEIDON Group 4 criteria were included., Main Outcome Measures: Number of oocytes retrieved, number of top-quality embryos (TQEs), and controlled ovarian hyperstimulation (COH) variables were the main outcome measures., Results: The combined Stop GnRH-ag, letrozole priming, and multiple-dose GnRH-ant COH protocol revealed significantly higher number of follicles >13 mm on the day of hCG administration and higher number of oocytes retrieved, with non-significantly more TQEs and a reasonable clinical pregnancy rate., Conclusions: The combined Stop GnRH-ag, letrozole priming, and multiple-dose GnRH-ant COH protocol is a valuable tool in the armamentarium for treating POSEIDON Group 4 patients. Further large prospective studies are needed to elucidate its role in POR and to identify the specific characteristics of women (before initiating ovarian stimulation) that will aid both fertility specialists' counseling and their patients in adjusting the appropriate COH protocol., (© 2021 S. Karger AG, Basel.)

Objective: This study aimed to characterize those patients undergoing the stop gonadotropin-releasing hormone (GnRH)-agonist combined with multidose GnRH-antagonist protocol, with suboptimal response to GnRH-agonist trigger in in vitro fertilization (IVF) cycles., Design: This is a cohort study., Setting: The study was conducted in a university hospital., Patients: All consecutive women admitted to our IVF unit from February 2020 through November 2020 who reached the ovum pick-up stage were reviewed., Interventions: Triggering final oocyte maturation by GnRH-ag alone (GnRH-ag trigger group), or combined with hCG (dual trigger group), in patients undergoing the stop GnRH-agonist combined with multidose GnRH-antagonist protocol was performed., Main Outcome Measure: The main outcome measure was LH level 12 h after the trigger., Results: Five out of the 32 patients (15.6%) demonstrated suboptimal response as reflected by LH levels <15 IU/L 12 h after GnRH-agonist trigger. Moreover, while no differences were observed in oocyte recovery rate, maturity, or embryo quality between the different study groups (GnRH-ag trigger and dual trigger groups), those achieving a suboptimal response to the GnRH-agonist trigger (post-trigger LH <15 mIU/mL) demonstrated significantly higher number of follicles and peak estradiol levels at the day of trigger, compared to those with optimal response (post-trigger LH >15 mIU/mL)., Conclusions: The stop GnRH-agonist combined with GnRH-antagonist protocol enables the substitution of hCG with GnRH-ag for final oocyte maturation. However, caution should be taken in high responders, where the dual trigger with small doses of hCG (1,000-1,500 IU) should be considered, aiming to avoid suboptimal response (post-trigger LH levels <15 IU/L)., (© 2021 S. Karger AG, Basel.)

Purpose: To assess whether machine learning methods provide advantage over classic statistical modeling for the prediction of IVF outcomes., Methods: The study population consisted of 136 women undergoing a fresh IVF cycle from January 2014 to August 2016 at a tertiary, university-affiliated medical center. We tested the ability of two machine learning algorithms, support vector machine (SVM) and artificial neural network (NN), vs. classic statistics (logistic regression) to predict IVF outcomes (number of oocytes retrieved, mature oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births) based on age and BMI, with or without clinical data., Results: Machine learning algorithms (SVM and NN) based on age, BMI, and clinical features yielded better performances in predicting number of oocytes retrieved, mature oocytes, fertilized oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births, compared with logistic regression models. While accuracies were 0.69 to 0.9 and 0.45 to 0.77 for NN and SVM, respectively, they were 0.34 to 0.74 using logistic regression models., Conclusions: Our findings suggest that machine learning algorithms based on age, BMI, and clinical data have an advantage over logistic regression for the prediction of IVF outcomes and therefore can assist fertility specialists' counselling and their patients in adjusting the appropriate treatment strategy.

Objective: To investigate whether the addition of embryo biopsy performed during preimplantation genetic testing for monogenic diseases is associated with a higher risk of obstetric and neonatal complications compared with in vitro fertilization (IVF) without preimplantation genetic testing or spontaneously conceived pregnancies., Methods: This is a cohort study of all pregnancies conceived after preimplantation genetic testing for monogenic diseases (PGT-M group) from 2006 to 2018 at Sheba Medical Center, Israel. The control groups included patients who had conceived spontaneously (spontaneous conception group) or by IVF without preimplantation genetic testing (IVF group) and delivered at Sheba Medical Center. The obstetrics outcomes were compared among the groups. Multivariable regression modeling was performed, focusing on the relationship between preimplantation genetic testing and adverse outcomes., Results: Final analysis included 345 singleton and 76 twin deliveries in the PGT-M group. The spontaneous conception group included 5,290 singleton and 92 twin deliveries. The IVF group included 422 singleton and 101 twin deliveries. Among singleton pregnancies, patients in the PGT-M group had a higher rate of hypertensive disorders (6.9%) compared with those in the spontaneous conception group (2.3%; odds ratio [OR] 3.3; 95% CI 1.9-4.8; adjusted odds ratio [aOR] 14.8; 95% CI 7.4-29.8) and the IVF group (4.7%; OR 1.5; 95% CI 0.8-2.7; aOR 5.9; 95% CI 1.9-18.2). Likewise, patients in the PGT-M group had a higher rate of small-for-gestational age neonates (12.4%) compared with those in the spontaneous conception group (3.9%; OR 3.4; 95% CI 2.4-4.9; aOR 2.3; 95% CI 1.5-3.4) and the IVF group (4.5%; OR 3; 95% CI 1.7-5.2; aOR 2.5; 95% CI 1.7-5.2). Among twin pregnancies, patients in the PGT-M group also had an increased rate of hypertensive disorders compared with those in the spontaneous conception group (4.3%; OR 4.1; 95% CI 1.2-13.3; aOR 10.9; 95% CI 2.3-50) and the IVF group (4%; OR 4.5; 95% CI 1.4-14.7; aOR 3.7; 95% CI 1.1-12.8)., Conclusion: Pregnancies conceived after preimplantation genetic testing for monogenic disorders were associated with an increased risk of obstetric complications compared with pregnancies conceived spontaneously or by IVF without preimplantation genetic testing.

Background: Co-administration of letrozole during the first 5 days of ovarian stimulation was suggested to improve IVF outcomes in poor responders. We aimed to determine whether poor/sub-optimal responders might benefit from Letrozole co-treatment throughout the entire stimulation course., Methods: We retrospectively reviewed the medical files of women who demonstrated poor (oocyte yield ≤3) and sub-optimal (4 ≤ oocyte yield ≤9) ovarian response during conventional multiple-dose antagonist stimulation protocols and were co-treated in a subsequent cycle with 5 mg Letrozole from the first day of stimulation until trigger day. A self-paired comparison between gonadotropins-only and gonadotropins-letrozole cycles was performed., Results: Twenty-four patients were included. Mean patients' age was 39.83 ± 4.60 and mean day-3-FSH was 12.77 ± 4.49 IU/m. Duration of stimulation and total gonadotropins dose were comparable between the two cycle groups. Peak estradiol levels were significantly lower in gonadotropins-letrozole cycles (2786.74 ± 2118.53 vs 1200.13 ± 535.98, p < 0.05). Number of retrieved oocytes (3.29 ± 2.15 vs 6.46 ± 3.20, p < 0.05), MII-oocytes (2.47 ± 1.65 vs 5.59 ± 3.20, p < 0.05), 2PN-embryos (1.78 ± 1.50, 4.04 ± 2.74, p < 0.05) and top-quality embryos (0.91 ± 0.97 vs. 2.35 ± 1.66, p < 0.05) were significantly higher in the gonadotropins-letrozole cycles. Clinical pregnancy rate in gonadotropins-letrozole cycles was 31.5%., Conclusion: Letrozole co-treatment during the entire stimulation course improves ovarian response and IVF outcomes in poor/sub-optimal responders.

Objective: To examine whether the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol may improve conventional IVF/intracytoplasmic sperm injection (ICSI) cycle in poor ovarian response (POR) patients. Design: Cohort historical, proof of concept study. Setting: Tertiary, University affiliated Medical Center. Patient(s): Thirty POR patients, defined according to the Bologna criteria, who underwent a subsequent Stop GnRH-agonist combined with multiple-dose GnRH-antagonist controlled ovarian hyperstimulation (COH) protocol, within 3 months of the previous failed conventional IVF/ICSI cycle, were included. For the purposes of this study, we eliminated a bias in this selection by including only "genuine" poor responder patients, defined as those who yielded up to 3 oocytes following COH with a minimal gonadotropin daily dose of 300 IU. Main Outcome Measure(s): Number of oocytes retrieved, number of top-quality embryos, COH variables. Result(s): The Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol revealed significantly higher numbers of follicles >13 mm on the day of hCG administration, higher numbers of oocytes retrieved, and top-quality embryos (TQE) with an acceptable clinical pregnancy rate (16.6%). Moreover, as expected, patients undergoing the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol required significantly higher doses and a longer duration of gonadotropins stimulation. Conclusion(s): The combined Stop GnRH-ag/GnRH-ant COH protocol is a valuable tool in the armamentarium for treating "genuine" poor ovarian responders. Further, large prospective studies are needed to elucidate its role in POR and to characterize the appropriate patients subgroup (before initiating ovarian stimulation) that may benefit from the combined Stop GnRH-ag/GnRH-ant COH protocol., (Copyright © 2020 Orvieto, Kirshenbaum, Galiano, Elkan-Miller, Zilberberg, Haas and Nahum.)

Background: The presence of submucous fibroids strongly impacts on IVF results, therefore, these patients should be considered for surgical or medical treatment. The aim of this study was to assess the role of Ulipristal acetate (UPA), a selective progesterone receptor modulator, in restoring uterine cavity deformation due to submucous fibroids, in infertile patients attempting an IVF treatment. The secondary study outcome was to evaluate the impact of preconception UPA treatment on rate of biochemical pregnancy, ongoing pregnancy, and live birth compared to a control group without fibroids., Methods: Infertile patients with submucosal fibroid (Type 1 and Type 2 according to FIGO classification) were enrolled in the study as fibroids group and received 1 to 3 treatment cycles of UPA, according to their response, as reflected by fibroid volume reduction and restoration of normal uterine cavity. Patients in control group were randomly selected from a general IVF cohort by a ratio of 2:1 with fibroids group, matched by age, BMI, type and cause of infertility and antral follicle count. The impact of UPA on fibroids volume reduction was evaluated. IVF outcome was compared between groups., Results: Twenty-six patients underwent UPA treatment revealed a mean volume reduction of their fibroids of 41%. A total of 15 (57.6%) biochemical pregnancy were obtained, resulting in 13 (50%) ongoing pregnancy and 9 (34.6%) healthy babies were already delivered. Similar results were obtained in control group., Conclusion: Restoration of normal uterine cavity by UPA treatment prior to IVF treatment avoids surgery and establishes a pregnancy rate comparable to a control group without fibroids.

Research Question: To study gestational hypertensive disorders in oocyte donation pregnancies compared with other modes of conception at very advanced maternal age., Design: A historical cohort study of all women aged 45-47 years who gave birth to singletons at a tertiary medical centre between March 2011 and May 2018, at 24 weeks' gestation or later. Pregnancy outcomes were compared between donor oocyte (IVF-OD), IVF using autologous oocytes (IVF-A) and naturally conceived pregnancies. A multivariate logistic regression was used to evaluate the association between the mode of conception and gestational hypertensive disorders., Results: The final analysis included 159, 68 and 73 patients in the IVF-OD, IVF-A and natural conception groups, respectively. The rate of gestational hypertensive disorders was significantly higher among those who conceived by IVF compared with those who conceived naturally but did not differ between the two IVF groups (27.0% for IVF-OD, 19.1% for IVF-A, P = 0.204; 5.5% for natural conception, P < 0.001 and P = 0.013 compared with IVF-OD and IVF-A, respectively). The results remained similar in a multivariate logistic regression analysis. The rate of Caesarean deliveries was significantly higher in the IVF-OD and IVF-A groups compared with the natural conception group (83.6%, 70.6% and 37.0%, respectively, P < 0.001), but other pregnancy outcomes did not differ between the groups., Conclusions: IVF pregnancies in the late fifth decade of life were associated with significantly higher rates of gestational hypertensive disorders compared with naturally conceived pregnancies. No difference existed between the two IVF groups. These results may highlight the impact of IVF itself on gestational hypertensive disorders at very advanced maternal age., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The number of embryos transferred during an IVF cycle is directly related to the high incidence of multiple births, which is the culprit of perinatal morbidity. Therefore, single fresh embryo transfer (ET) strategy, or freeze-all, followed by a single frozen-thawed embryo transfer (FET) cycle, may dramatically reduce the rate of multiple births, without compromising the cumulative live birth rates (LBRs). A literature review was conducted for all available evidences assessing obstetrics and perinatal outcomes associated with FET compared to fresh ET and natural conception. While studies comparing fresh and FET cycles in normal responders have yielded conflicting results for pregnancy rate, FET was associated with lower risk of prematurity and low birth weight and increased risk of large for gestational age (LGA) and/or macrosomic in singletons, when compared with fresh ET. Macrosomic/LGA births have a higher risk of fetal hypoxia, stillbirth, shoulder dystocia, perineal lacerations, cesarean section, postpartum hemorrhage and neonatal metabolic disturbances at birth. Nonetheless, it seems that other than higher risk of fetal macrosomia, there are additional obstetric complications associated with FET. The relative risk of hypertensive disorders in pregnancy, as well as perinatal mortality were also demonstrated to be increased in FET compared with singletons from fresh ET and natural conception. Therefore, when considering elective freeze-all policy, in addition to LBR and the risk of ovarian hyperstimulation syndrome, physicians should consider the aforementioned increased FET cycles' pregnancy complications, including LGA/ macrosomia, hypertensive disorders of pregnancy, as well as perinatal mortality., (Copyright © 2020 Orvieto, Kirshenbaum and Gleicher.)

We aim to retrospectively evaluate the role of increasing the gonadotropin daily dose from 450 IU/day to 300 IU twice a day on IVF-ET outcome in poor responder patients. All consecutive women admitted to our IVF unit and underwent COH consisting of daily gonadotropin dose of 450 IU, followed by an IVF cycle using 300 IU twice a day, were included. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryo transferred and pregnancy rate was assessed. Twenty-three patients undergoing both cycles were evaluated. While there was no between-group difference in the duration of COH, number of 2PN embryos, fertilization rate and number of embryos transferred, patients receiving daily gonadotropin 300 IU twice a day achieved a significantly higher peak estradiol levels (3350.39 ± 2364.26 vs. 2223.74 ± 1299.91; p  < .03, respectively), and yielded significantly higher number of follicles >15 mm in diameter on day of hCG administration (3.2 ± 2.4 vs 1.8 ± 1; p  < .03, respectively) and higher number of oocytes retrieved (3.48 ± 2.54 vs 1.87 ± 1.1; p  < .02, respectively) with an acceptable live birth rate (5%). To conclude, in poor responders undergoing COH a daily gonadotropin dose of 450 IU, increasing the dose to 300 IU twice daily may result in higher oocyte yield, with the possible improvement in IVF outcome.

Many strategies are offered for the treatment of poor responders. However, no compelling advantage for one stimulation protocol over another has been hitherto established. In this study, we aimed to evaluate the role of different modes and timings of final follicular maturation trigger, on in vitro fertilization (IVF) cycle outcome of poor responder patients. In the present randomized controlled study, poor responder patients, according to the Bologna criteria, undergoing controlled ovarian hyperstimulation (COH) using the gonadotropin-releasing hormone (GnRH) antagonist protocol were randomly assigned to three different final follicular maturation trigger modes and timings: hCG 36 h before oocyte pick-up (OPU) (hCG trigger); GnRH agonist (GnRHag) 36 h before (OPU) and hCG on day of OPU (GnRHag trigger); and GnRHag and hCG, 40 and 34 h prior to OPU, respectively (double trigger). Pregnancy rate, number of oocytes, and top quality embryos (TQEs). Thirty-three poor responder patients were recruited and randomized to the different study groups. While there were no in-between groups' differences in patients' demographics and stimulation variables, patients in the double trigger group had a significantly higher number of TQE (1.1 ± 0.9 vs . 0.3 ± 0.8 and 0.5 + 0.7; p <.02) as compared to the hCG trigger and the GnRH-ag trigger groups, respectively, with an acceptable pregnancy rate. Double trigger offers an additional benefit to poor responder patients. Larger studies are required to support this new concept prior to its implementation to IVF practice.

Our aim was to assess the preimplantation embryos' sex ratios in couples with four or more children of same sex, undergoing sex selection for nonmedical reasons. We conducted a cohort-historical study of all consecutive patients admitted to the IVF-PGD program in a large tertiary center. We reviewed the computerized files of all consecutive women admitted to our IVF for sex selection for nonmedical reasons. Patients and their PGD cycle characteristics were compared according to the desired sex of their embryo and the mode of fertilization. Nine patients underwent a total of 19 PGD cycle attempts during the study period. Of the 77 embryos with complete molecular diagnosis, 41 revealed a male embryo and 36 a female embryo. Thirty-five percent of all the diagnosed embryos were of the desired sex. For couples desiring a boy, IVF cycles achieved a higher ratio of the desired embryonal sex compared to ICSI (52% vs 18.7%, p = .03). For couples desiring a girl, ICSI cycles had a higher percentage of the desired embryonal sex compared to IVF cycles (38% vs 23%). Moreover, 29.7% of ICSI and 40% of IVF embryos achieved the desired sex. In conclusion, PGD for sex selection results in a relatively low percentage (35%) of embryos demonstrating the desired sex. Nonetheless, selecting the mode of fertilization (ICSI/IVF) might improve the success rate. Further studies are required to explore the appropriate and cost-effective method for sex selection for nonmedical reasons.

Research Question: What pregnancy rates are achieved after transfer of cryopreserved double slow-frozen embryos in IVF cycles? Patients in whom surplus thawed cleaved embryos (day 2 or 3) were grown to the blastocyst stage, re-frozen and then re-thawed for transfer (double freezing) were included., Design: Data were collected on all patients who had undergone the above procedure at the IVF unit of Assuta Ramat Hachayal Hospital, Tel Aviv, during a 7-year period. For each patient in the study group, the two-consecutive, matched-by-age patients treated with frozen-thawed single blastocyst transfer were selected to form a 2:1 ratio control group. All embryos were frozen using the slow freeze protocol., Results: A total of 54 patients had 70 embryos that were re-frozen at the blastocyst stage. Twenty-eight of these blastocysts were thawed and 27 underwent transfer to 25 patients. A single embryo was transferred to 23 patients and two embryos were transferred to two patients. The survival rate of the second thawing was 96.4% (27/28). Clinical pregnancy rate was 16% (4/25) and implantation rate was 14.8% (4/27). In the study group, pregnancies were achieved in 22 out of the 25 patients using IVF treatment, indicating good receptivity of the uterus. In the control group, the implantation/pregnancy rates were significantly higher (44.2% [23/52]; P < 0.01)., Conclusion: The transfer of twice slow-frozen and thawed embryos does not seem to be a beneficial approach in the planned management of cryopreserved surplus embryos owing to the low pregnancy rate achieved after transfer of the re-frozen blastocyst embryos., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Backgroud: In order to maximize In vitro fertilization (IVF) success rates in advanced- age patients, it has been suggested to favor the use of intracytoplasmic sperm injection (ICSI) over conventional insemination (CI), with the notion that ICSI would serve as a tool to overcome interference in sperm oocyte interaction and sperm oocyte penetration issues that can be related to maternal age and are not due to sperm abnormalities. We therefore aim to evaluate the role of ICSI in the treatment of non-male factor infertile patients aged ≥35 in terms of fertilization and top-quality embryo rates., Methods: In this retrospective cohort study, data were collected and analyzed for all patients with non-male factor infertility, aged ≥35 treated, undergoing their first IVF cycle attempt with 6 or more oocytes yield, in whom a 50% ICSI-CI division was performed., Results: Five hundreds and four oocytes were collected from 52 eligible patients. Overall, 245 oocytes underwent ICSI and 259 oocytes underwent CI. The fertilization rate was 71.0% following ICSI, compared to 50.1% in the CI treated oocytes (P < 0.001). The top quality embryo rate was 62.8% following ICSI compared to 45.5% following CI (P < 0.001). Subdividing the study population to two age groups revealed that the above differences remained significant in patients aged 35-39 yrs., whereas in those aged 40-45 yrs., the differences were non-significant but still inclined in favor of ICSI., Conclusions: This study favors the use of ICSI in the older IVF population in order to increase both the fertilization rate and the number of top quality embryos that result per IVF cycle. Further studies are needed to establish our observations and use ICSI as the preferred approach to overcome egg sperm abnormal interactions related to advanced maternal age.

Background: Pregnancies in the fifth and sixth decades of life have been increasing, but current data are limited regarding the outcomes of twin compared with singleton pregnancies in this age group and to twin pregnancies at younger age., Objective: To compare obstetrical and neonatal outcomes of IVF conceived pregnancies, in twin gestations of women who were ≥45 years old at delivery to singletons at similar age and twin gestations at the age of <35 years, and to assess if the complications are mainly influenced by the very advanced maternal age or by the multifetal pregnancy., Study Design: A retrospective cohort study from a single tertiary medical center of women aged ≥45 at delivery between March 2011 and January 2018 and women aged <35 at delivery with twin pregnancies that conceived by IVF. Exclusion criteria were spontaneous pregnancies or pregnancies after ovulation induction, monochorionic twin pregnancies, higher order multiple gestations, or women that underwent fetal reduction. Pregnancy, delivery, postpartum and neonatal outcomes were compared between singleton and twin pregnancies. Multivariate logistic regression was used to evaluate the association between twin pregnancies and adverse outcomes., Results: Out of 67,355 deliveries, 612 were of women ≥45 years old, of whom 492 women conceived via IVF (395 singleton and 97 twin pregnancies). Of those, 60 women were ≥50 years old, 49 of them carried singleton and 11 carried twin pregnancies. Baseline characteristics were similar between groups. Women at the fifth and sixth decades with twins had significantly higher rates of preeclampsia (32.0% vs. 10.9%, p < 0.001), gestational diabetes mellitus (35.4% vs. 23.8%, p = 0.020), preterm deliveries <32 weeks of gestation (8.2% vs. 1.3%, p = 0.001), and fetal growth restriction (18.6% vs. 7.6%, p = 0.001) compared with singleton pregnancies at similar maternal age. After multivariate analysis adjusting for confounders, the odds ratio for the composite of preeclampsia, gestational hypertension, intrauterine fetal growth restriction, and placental abruption was 3.19 for twin compared with singleton pregnancies and 1.73 for gestational diabetes mellitus. Pregnancy complications among older women with twins were also significantly higher when compared with younger women with twins (<35 years old). Women in the fifth and sixth decades with twins had higher rates of cesarean deliveries (91.8% vs. 56.4%, p<0.001), gestational hypertension, preeclampsia, and gestational diabetes mellitus (10.3% vs. 4.2%., p=0.016; 32.0% vs. 6.2%, p<0.001; 35.1% vs. 8.1%, p<0.001, respectively) than the younger group carrying twins., Conclusions: Twin pregnancies in the fifth and sixth decades carry significantly higher complications rate compared with singleton pregnancies at the same age and twin pregnancies at younger age., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Research Question: What is the cumulative incidence of live birth (CILB) for high-order consecutive IVF cycles, and which factors are associated with live birth in women aged ≥41 years using autologous oocytes?, Design: A retrospective cohort study including 146 patients aged 41 years to <44 years who started their first IVF cycle attempt using autologous oocytes, between January 2006 and December 2013., Results: After 13 IVF cycles, CILB reached up to 33.6%. After six IVF cycles, 42 (28.8%) women delivered a live infant (85.7% of the total live birth). Mean live birth rate per cycle declined with age at the initial cycle (8% at 41 years; 5.8% at 42 years; and 4.1% at 43 years). Multivariable modified Poisson regression models identified patient's age (RR for 41 years versus 43 years: 0.47; 95% CI 0.25 to 0.87; P = 0.01), smoking status (RR 0.21; 95% CI 0.05 to 0.08; P = 0.02), and mean number of fertilized oocytes (RR 1.23; 95% CI 1.08 to 1.39; P < 0.01) as factors significantly associated with the probability of a live birth., Conclusions: Multiple repeat IVF cycles in women aged 41-44 years offers a reasonable long-term success rate. After six cycles of treatment, about 29% of women of advanced reproductive age using autologous oocytes expected to achieve a live birth. This information might assist in fertility counselling and managing patients' expectations by adjusting the appropriate treatment strategy and number of IVF cycle attempts, especially in countries in which egg donation is prohibited or when multiple repeated IVF cycles attempts are financially affordable., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the influence of seasonal variation on in vitro fertilization (IVF) outcome in a large cohort population., Methods & Materials: A total of 5,765 IVF cycles conducted in Sheba medical center between 2013 and 2016 were retrospectively analyzed. The treatment cycles included 4214 ovarian stimulation and ovum pick up (OPU) cycles of which 3020 resulted in fresh embryo transfer and 1551 vitrified- warmed cycles of which1400 resulted in warmed embryo transfer. Cycles were assigned to seasons according to the date of OPU for fresh embryo transfer cycles or according to the date of embryo warming for vitrified warmed embryo transfer cycles., Results: There were no statistically significant differences between the calendar months or seasons concerning the number of oocytes retrieved or fertilization rate in the fresh cycles. Throughout the 4 years of the study, the monthly clinical pregnancy rate fluctuated between 18.2% and 27.9% per fresh embryo transfer (mean 23.3%) and between 17.7% and 29.4% per vitrified warmed embryo transfer (mean 23%). These fluctuations did not follow any specific seasonal pattern., Conclusions: Our study did not demonstrate any significant influence of the calendar months or seasons on the clinical pregnancy rates of fresh or vitrified warmed embryo transfers. It might be speculated that the complete pharmaceutical control of the ovarian and endometrial function, as well as the homogeneous treatments, procedures and laboratory equipment used during the study period have lowered the influence of seasonal effect on IVF treatment outcome., Competing Interests: The authors have declared no competing interests exists.

Purpose: The aim of the present study was to determine the percentage of infertility patients who are diagnosed with a non-receptive endometrium according to the endometrial receptivity array (ERA) test and to examine whether adjusting the embryo transfer day according to the proposed shift in the window of implantation improves the pregnancy rate compared to non-ERA-tested patients., Methods: A single-center retrospective cohort study, including 53 consecutive good prognosis patients (0-2 previous frozen embryo transfers) admitted to our IVF unit for a mock cycle prior to their frozen day-5 embryo (blastocyst) transfer cycle. The mock cycle included an endometrial biopsy for both the ERA test and histological assessment by the Noyes criteria (study group). The next cycle frozen embryo transfer (FET) in the study group was adjusted according to the ERA results. The control group consisted of patients who underwent FET cycles at our clinic during the same period, without performing the endometrial biopsy and ERA testing., Results: During the study period, 503 patients (control group) underwent FET cycles without performing the ERA testing and 41 patients had FET following an ERA test. There were no between-group differences in patients' age, number of previous transfers, endometrial thickness, number of transferred embryos, and ongoing pregnancy rates (35.2 vs. 39%, respectively, p = NS). Out of the 53 patients who performed the ERA test before their first or second FET, five endometrial samples (9.4%) were found to be post-receptive, 29 (54.7%) pre-receptive, and only 19 samples (35.8%) were receptive. Women in the study group with pre- or post-receptive endometrium on ERA testing, the appropriate adjustment in timing of FET according to the ERA test resulted in a 33.3% pregnancy rate, which is comparable to the 35.2% background ongoing pregnancy rate of the control group., Conclusions: Performing the ERA test in a mock cycle prior to a FET does not seem to improve the ongoing pregnancy rate in good prognosis patients. Further large prospective studies are needed to elucidate the role of ERA testing in both good prognosis patients and in patients with recurrent implantation failure.

Objective: Intracytoplasmic sperm injection (ICSI) is commonly used during pre-implantation genetic diagnosis (PGD) in vitro fertilization (IVF), aiming to eliminate the risk of contamination from extraneous sperm DNA. Recently, ICSI "overuse" in non-male infertility has been doubted, since it does not offer an advantage over IVF. Prompted by the aforementioned observations, we sought to assess the accuracy of IVF vs ICSI in PGD cases, as might be reflected by a difference in the prevalence of discarded embryos as a consequent of parental contamination., Methods: Cohort-historical study of all consecutive patients admitted to the IVF-PGD program in a large tertiary center. The percentages of complete, incomplete diagnosis, PCR failure, abnormal embryos, and the contamination rate with paternal DNA in the IVF-only and the ICSI-only groups. We reviewed the computerized files of all consecutive women admitted to our IVF for a PGD-PCR cycle. Patients were divided accordingly into three groups: an IVF group-where all the oocytes underwent IVF only, an ICSI group-where all oocytes underwent ICSI, and a mixed group-where sibling oocytes underwent both IVF and ICSI. The laboratory data and the genetic diagnostic results were collected and compared between the different insemination groups., Results: Nine-hundred and twenty-seven patients underwent IVF-PGD cycles in our program, 315 in the IVF group, 565 in the ICSI group, and 47 in the mixed group. No differences were observed in fertilization rates, the percentage of embryos available for biopsy, and the percentages of complete, incomplete diagnosis, PCR failure, or abnormal embryos, between the IVF-only and the ICSI-only groups and between the IVF and the ICSI of sibling oocytes in the mixed group. Moreover, contamination with paternal DNA, through contamination with sperm cells, was negligible. Not one single case of misdiagnosis was encountered during the study period., Conclusion: It might be therefore concluded that IVF should be the preferred insemination methods in PGD cycles, and ICSI should be indicated only in cases of male-factor infertility.

Purpose: This study aims to report a case of ovarian hyperstimulation syndrome (OHSS) following GnRH agonist trigger for final follicular maturation., Methods: This study is a retrospective chart review., Results: We report the first case of OHSS following GnRH agonist trigger for final follicular maturation and freeze-all, masking extrauterine pregnancy (EUP). The present case report elucidates the feasibility of stimulating and recruiting ovarian follicles yielding mature oocytes during early pregnancy and the ability of GnRH agonist to trigger final follicular maturation during pregnancy, in the presence of high progesterone and hCG levels., Conclusions: Since OHSS almost always develops after hCG administration or in early pregnancy, its occurrence following GnRH agonist trigger should alert physician to search for either an inadvertent administration of exogenous hCG, or the endogenous secretion of hCG by pregnancy, e.g. EUP, or as part of a paraneoplastic syndrome.

So-called mild controlled ovarian hyperstimulation (mCOH) has in recent years increased in popularity, claiming to be safer and more patient-friendly, while also improving in vitro fertilization (IVF) outcomes. We here challenge the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) definition of mild stimulation, and especially address four fundamental issues, where our review found conventional COH (cCOH) advantageous over mCOH. They are: prevalence of severe ovarian hyperstimulation syndrome (OHSS), oocyte/embryo quality, pregnancy/live birth rates, and cost. We conclude that an objective review of the literature does not support the routine utilization of mCOH in assisted reproduction.

Purpose: Surrogacy remains the only option for having a biologic child for a unique population of women with severe medical conditions. However, no study has looked at surrogacy outcome as a result of the type of ovarian stimulation of the intended mother [controlled ovarian stimulation (COH), modified natural cycle (MNC), and in vitro maturation (IVM)] for oocyte retrieval., Methods: This is a retrospective study, including all intended mothers and gestational carriers in a tertiary, university affiliated, medical center, from 1998 to 2016., Results: Fifty-two women underwent 252 oocyte retrieval cycles. The pregnancy outcome of 212 embryo transfer cycles (64 gestational carriers) was reviewed according to the origin of the embryo. The number of retrieved oocytes was significantly higher following COH (n = 132) compared with IVM (n = 58) and MNC cycles (n = 62) (p = 0.013 and p < 0.0001, respectively). Pregnancy rates for embryos transferred according to each protocol were similar. All pregnancies that ended in live births when oocytes from IVM cycles were used derived from transfers of retrieved mature and mixed mature and immature oocytes. Pregnancies that involved embryos derived solely from immature oocytes that further matured in vitro and were transferred to gestational carriers were unsuccessful., Conclusions: MNC protocol is a good option to achieve pregnancy for intended mothers using gestational surrogacy who have contraindications to COH. The yield of IVM cycles in which immature oocytes are retrieved is inconclusive.

The hypothesis of preimplantation genetic diagnosis (PGS) was first proposed 20 years ago, suggesting that elimination of aneuploid embryos prior to transfer will improve implantation rates of remaining embryos during in vitro fertilization (IVF), increase pregnancy and live birth rates and reduce miscarriages. The aforementioned improved outcome was based on 5 essential assumptions: (i) Most IVF cycles fail because of aneuploid embryos. (ii) Their elimination prior to embryo transfer will improve IVF outcomes. (iii) A single trophectoderm biopsy (TEB) at blastocyst stage is representative of the whole TE. (iv) TE ploidy reliably represents the inner cell mass (ICM). (v) Ploidy does not change (i.e., self-correct) downstream from blastocyst stage. We aim to offer a review of the aforementioned assumptions and challenge the general hypothesis of PGS. We reviewed 455 publications, which as of January 20, 2017 were listed in PubMed under the search phrase < preimplantation genetic screening (PGS) for aneuploidy>. The literature review was performed by both authors who agreed on the final 55 references. Various reports over the last 18 months have raised significant questions not only about the basic clinical utility of PGS but the biological underpinnings of the hypothesis, the technical ability of a single trophectoderm (TE) biopsy to accurately assess an embryo's ploidy, and suggested that PGS actually negatively affects IVF outcomes while not affecting miscarriage rates. Moreover, due to high rates of false positive diagnoses as a consequence of high mosaicism rates in TE, PGS leads to the discarding of large numbers of normal embryos with potential for normal euploid pregnancies if transferred rather than disposed of. We found all 5 basic assumptions underlying the hypothesis of PGS to be unsupported: (i) The association of embryo aneuploidy with IVF failure has to be reevaluated in view how much more common TE mosaicism is than has until recently been appreciated. (ii) Reliable elimination of presumed aneuploid embryos prior to embryo transfer appears unrealistic. (iii) Mathematical models demonstrate that a single TEB cannot provide reliable information about the whole TE. (iv) TE does not reliably reflect the ICM. (v) Embryos, likely, still have strong innate ability to self-correct downstream from blastocyst stage, with ICM doing so better than TE. The hypothesis of PGS, therefore, no longer appears supportable. With all 5 basic assumptions underlying the hypothesis of PGS demonstrated to have been mistaken, the hypothesis of PGS, itself, appears to be discredited. Clinical use of PGS for the purpose of IVF outcome improvements should, therefore, going forward be restricted to research studies.

Study Objective: To investigate whether hysteroscopic proximal tubal occlusion with Essure microinserts (Conceptus Inc.; Bayer, AG, North Rhine-Westphalia, Germany) can improve pregnancy rates in patients with hydrosalpinges who had failed in vitro fertilization (IVF) treatment., Design: A prospective cohort study., Setting: University-affiliated tertiary centers., Patients: Twenty-four consecutive women with hydrosalpinges who had failed IVF treatment were included., Interventions: Hysteroscopic placement of Essure microinserts for hydrosalpinx blockage followed by IVF treatment., Measurements and Main Results: Ongoing pregnancy and live birth rates were recorded. Of the 24 patients undergoing a total of 42 IVF cycles after Essure insertion, 18 (75% of patients and 42.8% of IVF cycle attempts) conceived and 16 delivered live births (66.6% of patients and 38.1% of IVF cycle attempts)., Conclusion: Hysteroscopic proximal occlusion of hydrosalpinges with Essure microinserts is a valuable alternative to laparoscopic salpingectomy, resulting in reasonable pregnancy rates., (Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.)

The utilization of trophectoderm biopsy combined with comprehensive chromosome screening (CCS) tests for embryonic aneuploidy was recently suggested to improve IVF outcome, however, not without criticisms. The ongoing discussion on the unrestricted clinical adoption of preimplantation genetic screening (PGS) has called for a proper randomized controlled trial (RCT), aiming to further evaluate the cumulative live birth rates (LBRs) following a single oocyte retrieval, utilizing all fresh and frozen embryos. Since this study seems not to appear for various reasons, we present herewith, the hypothetical required RCT based on the hitherto published literature.After implementing data from the hitherto published literature on blastulation and aneuploidy rates, the rate of mosaicism and technical errors and implantation rates/LBRs of non-PGS day-3 and blastocyst and PGS blastocyst, we could clearly demonstrate the superiority of non-PGS embryo (day-3 and blastocyst) transfer over PGS blastocyst transfer, in terms of cumulative LBR (18.2-50 % vs 7.6-12.6 %, respectively).We therefore believe that until the proper, non-hypothetical RCT on the efficacy of this procedure will appear, PGS should be offered only under study conditions, and with appropriate informed consents.

Recently, several new promising modifications have been introduced to clinical practice that may simplify and optimize IVF outcome. In the present opinion paper we present a simplified approach to controlled ovarian hyperstimulation protocol (COH), which combines the benefits of the ultrashort flare GnRH agonist/GnRH antagonist protocol and the personalized tailored mode and timing of ovulation triggering, aiming to improve IVF outcome while eliminating of severe OHSS.In patients at risk to develop severe ovarian hyperstimulation syndrome (OHSS), GnRH agonist (GnRHa) trigger if offered for final follicular maturation. While in those achieving ≥20 oocytes, the freeze all policy with the subsequent frozen-thawed embryo transfers (ET) is recommended, in those where less than 20 oocytes are retrieved, patients are re-evaluated 3 days after oocyte retrieval (day of ET) for signs of early moderate OHSS. If no early signs of OHSS developed, one embryo was transferred, and the patients are instructed to inject 1500 IU of HCG. In cases where signs of early moderate OHSS appear, the freeze all policy is recommended.In Patients not at risk to develop severe OHSS- three different modes of concomitant administration of both GnRHa and a standard bolus of hCG (5000-10,000 units) prior to oocyte retrieval were suggested. Standard hCG dose concomitant with GnRHa (dual trigger), 35-37 h before oocyte retrieval is offered to normal responders patients, resulting in improved oocyte/embryo quality and IVF outcome. GnRHa 40 h and standard hCG added 34 h prior to oocyte retrieval (double trigger), respectively are offered to patients demonstrating abnormal final follicular maturation despite normal response to COH. The double trigger results in significantly higher number of oocytes retrieved, higher proportions of the number of oocytes retrieved to the number of follicles >10 mm and >14 mm in diameter on day of hCG administration, higher number of MII oocytes and proportion of MII oocytes per number of oocytes retrieved, with the consequent significantly increased number of top-quality embryos, as compared to the hCG-only trigger cycles. Standard hCG dose concomitant with GnRHa (dual trigger), 34 h before oocyte retrieval should be offered to poor responders patients, aiming to overcome premature luteinization, while achieving high yield of mature oocytes.Further studies are required to support this new concept prior to its implementation as a universal COH protocol to IVF practice.

We describe a case of normal responder patients with repeated implantation failure who was offered the combination of the ultrashort GnRH-ag/ GnRH-ant COH protocol, followed by endometrial injury and a subsequent natural cycle frozen-thawed embryos transfer. The patient conceived following the natural FET cycle that was supported by luteal daily progesterone, with the additional single injection of HCG and GnRH-agonist, on day of ET and 4 days later, respectively. This combined approach seems to be a valuable tool in the armamentarium for treating normal responder patients with repeated implantation failures and should be further examined in large randomized controlled trials.

Objective: We aim to evaluate the IVF-ET outcome in patients receiving a high daily dose (300 IU) of gonadotropins during controlled ovarian hyperstimulation (COH) for IVF and to assess the role of increasing the daily dose to 450 IU on improving outcome., Patients and Methods: All consecutive women admitted to our IVF unit during an 11 year period who underwent COH consisting of daily gonadotropin dose of 300 IU were included in the study. The ovarian stimulation characteristics, number of oocytes retrieved, number of embryo transferred and pregnancy rate were assessed. We also evaluated the subsequent cycle, using daily gonadotropin doses of 450 IU, among those patients who did not conceive using the 300 IU daily gonadotropin dose., Results: Nine hundred and forty-nine consecutive IVF cycles were evaluated. Patients who conceived using the daily gonadotropin dose of 300 IU (n = 133, 14% pregnancy rate) had significantly longer stimulation, yielded higher numbers of oocytes retrieved, fertilization rate and number of embryos transferred, compared to those who did not conceive. Moreover, while comparing IVF cycles using daily gonadotropin doses of 300 IU to 450 IU (n = 117), no in-between group differences were observed, except for significantly higher yields of oocytes retrieved. Moreover, cycles using daily gonadotropin doses of 450 IU resulted in a 7.7 live-birth rate., Conclusions: In poor responders undergoing COH with a daily gonadotropin dose of 300 IU, increasing the dose to 450 IU resulted in significantly higher oocyte yields and a reasonable live birth rate.