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STUDY QUESTION What are the clinical pregnancy and live birth rates in women who underwent up to two more euploid blastocyst transfers after three failures in the absence of another known factor that affects implantation? SUMMARY ANSWER The fourth and fifth euploid blastocyst transfers resulted in similar live birth rates of 40% and 53.3%, respectively, culminating in a cumulative live birth rate of 98.1% (95% CI = 96.5–99.6%) after five euploid blastocyst transfers. WHAT IS KNOWN ALREADY The first three euploid blastocysts have similar implantation and live birth rates and provide a cumulative live birth rate of 92.6%. STUDY DESIGN, SIZE, DURATION An international multi-center retrospective study was conducted at 25 individual clinics. The study period spanned between January 2012 and December 2022. A total of 123 987 patients with a total of 64 572 euploid blastocyst transfers were screened for inclusion. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients with a history of any embryo transfer at another clinic, history of any unscreened embryo transfer at participating clinics, parental karyotype abnormalities, the use of donor oocytes or a gestational carrier, untreated intracavitary uterine pathology (e.g. polyp, leiomyoma), congenital uterine anomalies, adenomyosis, communicating hydrosalpinx, endometrial thickness <6 mm prior to initiating of progesterone, use of testicular sperm due to non-obstructive azoospermia in the male partner, transfer of an embryo with a reported intermediate chromosome copy number (i.e. mosaic), preimplantation genetic testing cycles for monogenic disorders, or structural chromosome rearrangements were excluded. Ovarian stimulation protocols and embryology laboratory procedures including trophectoderm biopsy followed the usual practice of each center. The ploidy status of blastocysts was determined with comprehensive chromosome screening. Endometrial preparation protocols followed the usual practice of participating centers and included programmed cycles, natural or modified natural cycles. MAIN RESULTS AND THE ROLE OF CHANCE A total of 105 (0.085% of the total population) patients met the criteria and underwent at least one additional euploid blastocyst transfer after failing to achieve a positive pregnancy test with three consecutive euploid blastocyst transfers. Outcomes of the fourth and fifth euploid blastocyst transfers were similar across participating centers. Overall, the live birth rate was similar with the fourth and fifth euploid blastocysts (40% vs 53.3%, relative risk = 1.33, 95% CI = 0.93–1.9, P value = 0.14). Sensitivity analyses excluding blastocysts biopsied on Day 7 postfertilization, women with a BMI >30 kg/m2, cycles using non-ejaculate or donor sperm, double-embryo transfer cycles, and cycles in which the day of embryo transfer was modified due to endometrial receptivity assay test result yielded similar results. Where data were available, the fourth euploid blastocyst had similar live birth rate with the first one (relative risk = 0.84, 95% CI = 0.58–1.21, P  = 0.29). The cumulative live birth rate after five euploid blastocyst transfers was 98.1% (95% CI = 96.5–99.6%). LIMITATIONS, REASONS FOR CAUTION Retrospective design has its own inherent limitations. Patients continuing with a further euploid embryo transfer and patients dropping out from treatment after three failed euploid transfers can be systematically different, perhaps with regard to ovarian reserve or economic status. WIDER IMPLICATION OF THE FINDINGS Implantation failure seems to be mainly due to embryonic factors. Given the stable and high live birth rates up to five euploid blastocysts, unexplained recurrent implantation failure should have a prevalence of <2%. Proceeding with another embryo transfer can be the best next step once a known etiology for implantation failure is ruled out. STUDY FUNDING/COMPETING INTEREST(s) None. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Latent Agents in Networks: Estimation and Targeting In "Latent Agents in Networks: Estimation and Targeting," Baris Ata, Alexandre Belloni, and Ozan Candogan address the problem of estimating network effects in a setting in which data only on a subset of agents is available. In this setting, the observable agents influence each other's outcomes both directly and indirectly through their influence on the latent agents. Even in sparse networks, the combination of direct and indirect network effects yields a nonsparse influence structure that makes estimation challenging. The authors overcome this challenge and provide an estimation algorithm that performs well in high-dimensional settings. They also establish convergence rates for their proposed estimator and show that their performance guarantees are valid for a large class of networks. Finally, the authors demonstrate the application of their algorithm to a targeted advertising problem, in which it can be used to obtain asymptotically optimal advertising decisions despite the presence of latent agents. We consider a platform that serves (observable) agents, who belong to a larger network that also includes additional agents who are not served by the platform. We refer to the latter group of agents as latent agents. Associated with each agent are the agent's covariate and outcome. The platform has access to past covariates and outcomes of the observable agents, but no data for the latent agents is available to the platform. Crucially, the agents influence each other's outcome through a certain influence structure. In particular, observable agents influence each other both directly and indirectly through the influence they exert on the latent agents. The platform doesn't know the inference structure of either the observable or the latent parts of the network. We investigate how the platform can estimate the dependence of the observable agents' outcomes on their covariates, taking the presence of the latent agents into account. First, we show that a certain matrix succinctly captures the relationship between the outcomes and the covariates. We provide an algorithm that estimates this matrix using historical data of covariates and outcomes for the observable agents under a suitable approximate sparsity condition. We also establish convergence rates for the proposed estimator despite the high dimensionality that allows more agents than observations. Second, we show that the approximate sparsity condition holds under the standard conditions used in the literature. Hence, our results apply to a large class of networks. Finally, we illustrate the applications to a targeted advertising problem. We show that, by using the available historical data with our estimator, it is possible to obtain asymptotically optimal advertising decisions despite the presence of latent agents. Funding: O. Candogan acknowledges NSF award 2216912 for "Institute for Data, Econometrics, Algorithms and Learning". Supplemental Material: The online appendix is available at https://doi.org/10.1287/opre.2023.2485. [ABSTRACT FROM AUTHOR]

A study published in the journal Human Reproduction analyzed the outcomes of 123,987 patients from 26 clinics in three continents to investigate the prevalence of recurrent implantation failure (RIF). The study found that RIF is much less common than previously believed. The study included patients who had undergone up to five euploid blastocyst transfers, ruling out known causes of implantation failure. The results were consistent across multiple sensitivity analyses and were unaffected by factors such as the number of eggs retrieved, BMI, or the use of preimplantation genetic testing for aneuploidy (PGT-A) or endometrial receptivity array (ERA). The study does not recommend or discourage the use of PGT-A or ERA, but rather provides evidence against the presence of an obscure endometrial/uterine/maternal factor in cases of implantation failure. The authors of the study have no conflicts of interest to declare. [Extracted from the article]

The article discusses a study on progestin-primed ovarian stimulation (PPOS) and its effects on aneuploidy (abnormal number of chromosomes) in blastocysts. The study compared two cycles in the same patients, one using a GnRH antagonist and the other using a PPOS protocol. The results showed similar rates of euploidy (normal number of chromosomes) between the two cycles, with slightly higher oocyte yield in the PPOS cycle. The article also addresses previous studies that have reported conflicting results on the effectiveness of PPOS, emphasizing the need for high-quality studies to determine its true impact. Overall, the study supports the use of PPOS as a safe and effective method for ovarian stimulation. [Extracted from the article]

The ultimate measure of success of assisted reproductive technology (ART) is the cumulative live birth rate (CLBR) per ovarian stimulation cycle, which increases with every oocyte collected. However, the adverse effects of ovarian stimulation on endometrial receptivity, as well as the risks of ovarian hyperstimulation syndrome (OHSS) and adverse obstetric and neonatal outcomes, are observed to increase with ovarian response to stimulation. To mitigate these risks, mild stimulation has been hailed as the safer patient-friendly approach with the additional benefit of cutting the cost of gonadotrophins. Yet accumulating data demonstrate the absence of an adverse effect of ovarian stimulation on oocytes as well as on obstetric and neonatal outcomes, and multiple preventive strategies have been introduced for OHSS. The widespread use of vitrification revolutionized ART by enabling the liberal use of cycle segmentation to minimize the risk of OHSS and avoid impaired endometrial receptivity due to ovarian stimulation. Vitrification also allowed every oocyte to contribute to the CLBR. Thus, it is questionable whether the cost savings from gonadotrophins during the index ovarian stimulation offset the cost saving by preventing repeat ovarian stimulation and repeat laboratory procedures per live birth. This paper aims to prove by contradiction that ovarian stimulation should be aimed to maximize oocyte yield. [ABSTRACT FROM AUTHOR]

Background: In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART activities to resume. Still, questions on the impact of the virus on human gametes and fertility remain.Objective and Rationale: This article summarizes published data, aiming to clarify the impact of SARS-CoV-2 and the COVID-19 disease on human fertility and assisted reproduction, as well as the impact of vaccination, and from this, provide answers to questions that are relevant for people contemplating pregnancy and for health care professionals.Search Methods: PUBMED/MEDLINE and the WHO COVID-19 database were searched from inception to 5 October 2022 with search terms focusing on 'SARS-CoV-2' and gametes, embryos, reproductive function, fertility and ART. Non-English studies and papers published prior to 2020 were excluded, as well as reviews and non-peer reviewed publications. Full papers were assessed for relevance and quality, where feasible.Outcomes: From the 148 papers included, the following observations were made. The SARS-CoV-2-binding proteins, angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), are expressed in the testis, but co-expression remains to be proven. There is some evidence of SARS-CoV-2 RNA in the ejaculate of COVID-19 patients with severe disease, but not in those with mild/moderate disease. SARS-CoV-2 infection can impair spermatogenesis, but this seems to resolve after one spermatogenic cycle. Testosterone levels seem to be lower during and after COVID-19, but long-term data are lacking; disease severity may be associated with testosterone levels. COVID-19 cannot be considered a sexually transmitted disease. There is no co-expression of ACE2 and TMPRSS2 in the myometrium, uterus, ovaries or fallopian tubes. Oocytes seem to have the receptors and protease machinery to be susceptible to SARS-CoV-2 infection; however, viral RNA in oocytes has not been detected so far. Women contemplating pregnancy following COVID-19 may benefit from screening for thyroid dysfunction. There is a possible (transient) impact of COVID-19 on menstrual patterns. Embryos, and particularly late blastocysts, seem to have the machinery to be susceptible to SARS-CoV-2 infection. Most studies have not reported a significant impact of COVID-19 on ovarian reserve, ovarian function or follicular fluid parameters. Previous asymptomatic or mild SARS-CoV-2 infection in females does not seem to negatively affect laboratory and clinical outcomes of ART. There are no data on the minimum required interval, if any, between COVID-19 recovery and ART. There is no evidence of a negative effect of SARS-CoV-2 vaccination on semen parameters or spermatogenesis, ovarian function, ovarian reserve or folliculogenesis. A transient effect on the menstrual cycle has been documented. Despite concerns, cross reactivity between anti-SARS-CoV-2 spike protein antibodies and Syncytin-1, an essential protein in human implantation, is absent. There is no influence of mRNA SARS-CoV-2 vaccine on patients' performance during their immediate subsequent ART cycle. Pregnancy rates post-vaccination are similar to those in unvaccinated patients.Wider Implications: This review highlights existing knowledge on the impact of SARS-CoV-2 infection or COVID-19 on fertility and assisted reproduction, but also identifies gaps and offers suggestions for future research. The knowledge presented should help to provide evidence-based advice for practitioners and couples contemplating pregnancy alike, facilitating informed decision-making in an environment of significant emotional turmoil. [ABSTRACT FROM AUTHOR]