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To investigate whether endometrial thickness (ET) independently affects the live birth rate (LBR) after embryo transfer. Retrospective study. Private assisted reproductive technology center. A total of 959 single euploid frozen embryo transfers. Vitrified euploid blastocyst transfer. Live birth rate per embryo transfer. The conditional density plots did not demonstrate either a linear relationship between the ET and LBR or a threshold below which the LBR decreased perceivably. Receiver operating characteristic curve analyses did not suggest a predictive value of the ET for the LBR. The area under the curve values were 0.55, 0.54, and 0.54 in the overall, programmed, and natural cycle transfers, respectively. Logistic regression analyses with age, embryo quality, day of trophectoderm biopsy, body mass index, and ET did not suggest an independent effect of the ET on the LBR. We did not identify a threshold of the ET that either precluded live birth or under which the LBR decreases perceivably. Common practice of cancelling embryo transfers when the ET is <7 mm may not be justified. Prospective studies, in which the management of the transfer cycle would not be altered by ET, would provide higher-quality evidence on the subject. [ABSTRACT FROM AUTHOR]

Progestin-primed ovarian stimulation (PPOS) is being increasingly used for ovarian stimulation in assisted reproductive technology. Different progestins have been used with similar success. The available studies suggest a similar response to ovarian stimulation with gonadotrophin-releasing hormone (GnRH) analogues. Any differences in the duration of stimulation or gonadotrophin consumption are minor and clinically insignificant. PPOS has the advantage of oral administration and lower medication costs than GnRH analogues. As such it is clearly more cost-effective for fertility preservation and planned freeze-all cycles, but when fresh embryo transfer is intended PPOS can be less cost-effective depending on the local direct and indirect costs of the additional initial frozen embryo transfer cycle. Oocytes collected in PPOS cycles have similar developmental potential, including blastocyst euploidy rates. Frozen embryo transfer outcomes of PPOS and GnRH analogue cycles seem to be similar in terms of both ongoing pregnancy/live birth rates and obstetric and perinatal outcomes. While some studies have reported lower cumulative live birth rates with PPOS, they have methodological issues, including arbitrary definitions of the cumulative live birth rate. PPOS has been used in all patient types (except progesterone receptor-positive breast cancer patients) with consistent results and seems a patient friendly and cost-effective choice if a fresh embryo transfer is not intended. [ABSTRACT FROM AUTHOR]

Objective: To present a definition of recurrent implantation failure that accounts for the effects of female age and anticipated blastocyst euploidy rates on cumulative implantation rates.Design: Mathematical modeling.Setting: Not applicable.Patient(s): Not applicable.Intervention(s): Mathematical modeling of cumulative implantation probability on the basis of published blastocyst euploidy rates across categories of female age.Main Outcome Measure(s): The number of blastocysts required to achieve 95% cumulative implantation probability under the assumption of the absence of any other factor affecting implantation.Result(s): When the euploidy status of the transferred embryo is unknown (i.e., not subjected to preimplantation genetic testing for aneuploidies), our simulation shows that no age category reaches 95% cumulative probability of implantation of at least one embryo until after transfer of seven blastocysts. The number of blastocysts required to reach the same threshold is higher for older patients. For example, women older than 38 years require transfer of more than 10 untested blastocysts for the upper range of predictive probability to meet the threshold of 95%. On the other hand, if the implantation rate for a euploid blastocyst is assumed to be 55%, then 4 blastocysts are enough to reach a cumulative probability rate greater than 95%, regardless of age.Conclusion(s): The term "recurrent implantation failure" should be a functional term guiding further management. We suggest that recurrent implantation failure should not be called until implantation failure becomes reasonably likely to be caused by factors other than embryo aneuploidy, the leading cause of implantation failure. We propose a new definition that factors in anticipated blastocyst euploidy rates across categories of female age, euploid blastocyst implantation rate, and a specified threshold of cumulative probability of implantation. [ABSTRACT FROM AUTHOR]

To date, recurrent implantation failure (RIF) has no clear definition and no clearly identified impaired function. Hence, the term RIF is currently used somewhat haphazardly, on the basis of clinicians' judgment. International experts in reproductive medicine met on July 1, 2022, in Lugano, Switzerland, to review the different facets of RIF and define the diagnosis and its appropriate management. A systematic review without meta-analysis of studies published in English from January 2015 to May 2022. Data indicated that RIF has been largely overevaluated, overdiagnosed, and overtreated without sufficient critical assessment of its true nature. Our analyses show that true RIF is extremely uncommon—occurring in <5% of couples with infertility—and that reassurance and continued conventional therapies are warranted in most cases of assisted reproductive technology (ART) failure. Although the true biologic determinants of RIF may exist in a small subset of people with infertility, they elude the currently available tools for assessment. Without identification of the true underlying etiology(ies), it is reasonable not to assign this diagnosis to a patient until she has failed at least 3 euploid blastocyst transfers (or the equivalent number of unscreened embryo transfers, adjusted to the patient's age and corresponding euploidy rate). In addition, other factors should be ruled out that may contribute to her reduced odds of sustained implantation. In such cases, implantation failure should not be the only issue considered in case of ART failure because this may result from multiple other factors that are not necessarily repetitive or persistent. In reality, RIF impacting the probability of further ART success is a very rare occurrence. True RIF is extremely uncommon, occurring in <5% of couples with infertility. Reassurance and continued conventional therapies are warranted in most cases. It would seem reasonable not to assign this diagnosis to a patient until she has failed at least 3 euploid embryo transfers (or the equivalent number of unscreened embryos, adjusted to her age). Given the number of internationally recognized experts in the field present at the Lugano meeting 2022, our publication constitutes a consensus statement. [ABSTRACT FROM AUTHOR]

A 30-year-old woman with premature ovarian insufficiency had two follicles measuring 17 mm and 14 mm on day 3 of her menstrual cycle. Serum oestradiol concentration was 210 pg/ml. Recombinant human chorionic gonadotrophin was given and 5 mg/day letrozole started orally. One metaphase II oocyte was collected 36 h later. A 4-cell embryo was vitrified on the second day after fertilization. Letrozole was stopped on cycle day 8 due to absence of any other visible antral follicles. Oestradiol valerate 6 mg/day was started and the endometrium was 9.2 mm on cycle day 11. The embryo was warmed and transferred on cycle day 13, the 8th day after oocyte retrieval. Luteal phase support with progesterone, oestradiol and low molecular weight heparin was started on the day of transfer and continued until the 10th gestational week. A healthy girl weighing 3200 g was born at term. Early follicular phase oocyte collection did not result in early opening of the implantation window. Apparently secretory transformation was not started until luteal phase support, enabling a cleavage stage embryo transferred 8 days later to implant. Either corpus luteum formation could be disrupted or the endometrium could remain unresponsive to progesterone during the early follicular phase. [ABSTRACT FROM AUTHOR]

Most proposed definitions of recurrent implantation failure (RIF) are based on clinical judgement, probably affected by patients' demands. They are not based on robust statistical considerations. As a result, a diagnosis of RIF is commonly made too early, exposing couples to the risk of overdiagnosis and overtreatment. However, the situation is changing, and three statistical approaches have recently been proposed. The first is a probability model based on the chances of success per cycle and suggests for the definition three failed oocyte retrieval cycles with all embryos being transferred in women younger than 40 years of age. The second approach suggests an individualized diagnosis that takes into consideration multiple factors, while the third is also based on individualization but mainly relies on anticipated euploidy rates across the female age range. All these approaches have their pros and cons. Regardless of the specific peculiarities, they represent steps in the right direction, with the intent of providing a statistically sound definition. However, these attempts will not be useful unless endorsed by the scientific community in general. There is a pressing need for a rigorous and shared definition of RIF that will be widely accepted by researchers, scientific societies and other stakeholders, including patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the predictive value of endometrial thickness (EMT) for live birth when a lower threshold of EMT is not employed for embryo transfer (ET).Design: Retrospective study SETTING: Academic assisted reproduction center PATIENT(S): All women who underwent fresh or frozen-thawed ET at the Koç University Hospital Assisted Reproduction Unit between October 2016 and August 2019 INTERVENTION(S): After ruling out endometrial pathology, blastocyst transfer was planned regardless of the EMT in the absence of increased serum progesterone level on the trigger day in fresh embryo transfer cycles or before commencing progesterone treatment in artificially prepared frozen-thawed ET cycles.Main Outcome Measure(s): The primary outcome was live birth. Live birth and miscarriage rates per ET were stratified according to fresh and frozen-thawed ET cycles for each millimeter of endometrial thickness. Receiver operator characteristic curve analyses were performed to evaluate the predictive value of EMT for live birth.Result(s): A total of 560 ET cycles, 273 fresh and 287 frozen-thawed, were included in the study. Relevant patient characteristics as well as EMTs were similar between women who achieved a live birth and those who did not after fresh or frozen-thawed ET. There was no linear association between EMT and live birth or miscarriage rates. Area under the curve values for EMT to predict live birth after fresh, frozen-thawed, and all ETs were 0.56, 0.47, and 0.52, respectively.Conclusion(s): Our results showed that the EMT was not predictive for live birth in either fresh or frozen-thawed ET cycles. Once intracavitary pathology and inadvertent progesterone exposure were excluded, women with thinner EMTs should not be denied their potential for live birth because it is comparable to that of those with thicker EMT. [ABSTRACT FROM AUTHOR]

The study explores the factors influencing the implantation success rate of euploid embryos. We primarily aim to understand the relationship between morphokinetics and implantation outcomes, considering potential confounding variables such as maternal age and morphological features of the embryos. Additionally, we intend to elucidate the role of morphological grading in the interplay between morphokinetics and implantation rates in euploid single embryo transfers. The present retrospective study was conducted between January-2016 and January-2023 in a tertiary university hospital's IVF clinic. Forty-four patients who were followed up in time-lapse incubation (Embryoscope, VitroLife) after intracytoplasmic sperm injection (ICSI) procedure were included. All embryos were individually cultured in a time-lapse incubator from ICSI up to the stage of trophectoderm biopsy. Images were recorded with the use of the integrated microscope in every 15 minutes from seven different focal planes. All annotations were made in a prospective fashion by single experienced senior embryologist. A longitudinal dataset containing information on individuals over time was used with a multilevel modeling approach. A linear mixed-effects model was used to analyze the data. The outcome variable (implantation) was modeled as a function of the time intervals, with random effects for the individual. The significance of the fixed effects was tested using a likelihood ratio test. A p-value of less than 0.05 was considered statistically significant. In 44 transferred single euploid embryos, 30 were implanted (68.1%). There was no marked disparity in demographic distributions between the failure or successful implantation groups (for female age, median (IQR) 39.0 (35.5 to 40.0) vs. 39.0 (34.0 to 40.0), p =.751; for male age, median (IQR) 41.5 (38.2 to 43.8) vs. 39.5 (36.0 to 42.8), p=.318; for BMI median (IQR) 23.3 (21.5 to 25.9) vs. 24.7 (23.3 to 28.2), p=.212). Regarding morphological factors, a significant correlation between inner cell mass (ICM) grade and implantation rate was found (p=.001), but it was not observed in trophectoderm grades (p=.103). In the LME (both fixed and random effects were used) model (fixed effects coefficients were the morphokinetic parameters, random effects were the individual embryos, and the outcome was implantation), a significant negative trend was demonstrated between the delay in the last quartile of embryo timeline and implantation. Specifically, a 50% decline in implantation rates was observed in the last quartile with a 9-hour delay (p=.0369, standard error=.3692). However, adding ICM grades to the LME model diminishes the negative trend (p=.99575). The study indicates that morphokinetics may play a role in the success of euploid single embryo transfer procedures, especially within specific temporal windows might impact implantation rates in euploid SET. However, association is diminished when considered with morphological grading of the embryo. [ABSTRACT FROM AUTHOR]

Does subcutaneous progesterone provide similar live birth or ongoing pregnancy rates as vaginal progesterone in frozen embryo transfer (FET) cycles? Retrospective cohort study (n = 214 women), consisting of 107 women who received subcutaneous progesterone for FET in artificial cycles and 107 women receiving vaginal progesterone who were matched for age and treatment cycle rank acted as controls. All embryos were transferred in an artificial cycle with 6 mg per day oral oestradiol valerate starting on the second or third day of the menstrual cycle. Patients underwent transvaginal ultrasound on the 10th day of priming, and subcutaneous progesterone (50 mg/day) or vaginal progesterone (180 mg/day) was started if the endometrium had a trilinear pattern regardless of its thickness. Embryo transfer was carried out on the sixth day of progesterone administration. Oestradiol and progesterone were continued until a negative pregnancy test, 10 days after the transfer, or until the completion of 10th gestational week. Main outcome measures were live birth or ongoing pregnancy rates. Baseline characteristics were similar between the groups. Positive pregnancy test rates (64.5% versus 58.9%; P = 0.40; RR 1.1; 95% CI 0.89 to 1.35), live birth or ongoing pregnancy rates (39.3% versus 35.5%; P = 0.57; RR 1.11; 95% CI 0.78 to 1.56) and miscarriage rates (29% versus 25.5%; P = 0.68; RR 1.08; 95% CI 0.76 to 1.55) were similar in the subcutaneous progesterone and vaginal progesterone groups, respectively. Subcutaneous progesterone seems to be an effective alternative to vaginal progesterone in patients undergoing FET. Randomized controlled trials comparing it with different progesterone preparations, routes and protocols are needed to better define its role. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis of comparative studies investigated whether progestins are as effective as gonadotrophin releasing hormone (GnRH) analogues for pituitary suppression in assisted reproduction. The primary outcome was live birth rate per woman. Secondary outcomes were live birth or ongoing pregnancy per woman and per embryo transfer, ongoing pregnancy, clinical pregnancy, numbers of oocytes and metaphase-two oocytes, duration of stimulation and gonadotrophin consumption. Adverse events included miscarriage, ectopic pregnancy and multiple pregnancy rates. The GRADE system was used to assess the quality of evidence. Seven studies involving a total of 2047 women were included. Three studies compared a progestin with a GnRH antagonist and four studies compared a progestin with a GnRH agonist. Most studies are non-randomized and report outcomes per embryo transfer, rather than per woman. Although progestins were similar to GnRH antagonists in effectiveness and safety parameters, they were associated with significantly higher live birth or ongoing pregnancy per embryo transfer compared with the short GnRH agonist protocol (RR 1.49, 95% CI 1.16 to 1.91). Progestin primed stimulation lasted significantly longer (mean difference 0.61 days, 95% CI 0.33 to 0.89) and required significantly more gonadotrophins (mean difference 433.2 IU, 95% CI 311.11 to 555.19) than the short GnRH agonist protocol, but the differences were clinically negligible. Safety parameters were similar between progestins and GnRH agonists. In conclusion, progestins can effectively prevent premature ovulation in assisted reproductive technology cycles. If larger and well-designed studies confirm these findings, progestins may be an effective and low-cost alternative to GnRH analogues when a fresh embryo transfer is not planned owing to a medical indication. [ABSTRACT FROM AUTHOR]

A receptive endometrium is required for successful embryo implantation. Endometrial thickness, as measured by ultrasonography, is the most commonly used marker of endometrial receptivity in assisted reproductive technology cycles. Several factors simultaneously affect both endometrial thickness and probability of live birth, including age, oestradiol concentration and oocyte number, among others. Most of the studies investigating a relationship between endometrial thickness and embryo transfer outcomes are retrospective and do not adequately address confounding factors, in addition to other limitations. Despite multiple meta-analyses and studies with large numbers of cycles, controversy still exists. The difference between the results from prospective and retrospective studies is also striking. This article presents a critical appraisal of the studies on endometrial thickness and embryo transfer outcomes in order to highlight methodological issues and how they can be overcome in future studies. Currently available evidence does not seem to support a modification of management just because endometrial thickness is below an arbitrary threshold. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical outcome of single-embryo transfer (SET) with double-embryo transfer (DET) in in vitro maturation (IVM) cycles performed in patients with polycystic ovary syndrome (PCOS), and to determine which factors predict those outcomes.Design: A retrospective analysis.Setting: Private assisted reproduction center.Patient(s): One hundred and fifty-nine women with PCOS.Intervention(s): In vitro maturation with elective SET or DET conducted between September 2007 and May 2014.Main Outcome Measure(s): Live-birth rates.Result(s): Single-embryo transfer was performed in 83 patients (52.2%), and DET was performed in 76 patients (47.7%). When compared with the patients who had DET, the patients who had SET were statistically significantly younger (32.4 ± 3.5 vs. 24.1 ± 4.2 years) and had a shorter infertility duration (9.2 ± 4.5 vs. 4.4 ± 2.1 years), fewer previous ART cycles (<2 prior attempts, 39.5% vs. 6%; ≥2 prior attempts, 60.5% vs. 0), fewer collected oocytes (15.1 ± 4.6 vs. 12.6 ± 3.8), fewer metaphase II oocytes (9.0 ± 4.1 vs. 5.7 ± 2.9), fewer fertilized oocytes (8.2 ± 3.7 vs. 3.6 ± 2.3), and a higher implantation rate (27% vs. 47%). The SET and DET groups had similar embryo quality and similar clinical pregnancy (44.6% vs. 44.7%) and live-birth rates (34.9% vs. 34.2%). Twin pregnancy rates were statistically significantly higher in the DET compared with the SET groups (9.2% vs. 2.4%).Conclusion(s): In vitro maturation is a successful assisted reproduction technique that can be an alternative to conventional in vitro fertilization in women presenting with PCOS-related infertility. Our observations suggest that SET is a feasible option to prevent multiple pregnancies while maintaining the live-birth rate. [ABSTRACT FROM AUTHOR]

Objective: To compare two commonly used protocols (fresh vs. vitrified) used to transfer euploid blastocysts after IVF with preimplantation genetic screening.Design: Randomized controlled trial.Setting: Private assisted reproduction center.Patient(s): A total of 179 patients undergoing IVF treatment using preimplantation genetic screening.Intervention(s): Patients were randomized at the time of hCG administration to either a freeze-all cycle or a fresh day 6 ET during the stimulated cycle.Main Outcome Measure(s): Implantation rates (sac/embryo transferred), ongoing pregnancy rates (PRs) (beyond 8 weeks), and live birth rate per ET in the primary transfer cycle.Result(s): Implantation rate per embryo transferred showed an improvement in the frozen group compared with the fresh group, but not significantly (75% vs. 67%). The ongoing PR (80% vs. 61%) and live birth rates (77% vs. 59%) were significantly higher in the frozen group compared with the fresh group.Conclusion(s): Either treatment protocol investigated in the present study can be a reasonable option for patients. Freezing all embryos allows for inclusion of all blastocysts in the cohort of embryos available for transfer, which also results in a higher proportion of patients reaching ET. These findings suggest a trend toward favoring the freeze-all option as a preferred transfer strategy when using known euploid embryos.Clinical Trial Registration Number: NCT02000349. [ABSTRACT FROM AUTHOR]