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The improvements accomplished in assisted reproductive technology have emphasized more than ever the role played by chronological age, notably for predicting oocyte quality. Studies in cellular aging have directed research on telomere length measurements as possible markers of functional aging and, notably, female reproductive outcomes. Although further research is still needed, encouraging results are already available on the possibility that leucocyte telomere length may be a useful parameter for assessing reproductive potential in aging women. [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 narrative review of endometrial receptivity in adenomyosis and/or endometriosis revealed that this parameter is difficult to assess in natural conception because both disorders alter natural fertility. Recent data emanating from assisted reproductive technology have allowed the study of endometrial receptivity in women affected by adenomyosis and endometriosis. This has upended our views on the effects of these 2 disorders on embryo implantation. Today, the very existence of altered receptivity in assisted reproductive technology is questioned. In this context, we now know that frozen euploid blastocyst transfers in estradiol and progesterone cycles have unaltered outcomes in both adenomyosis and endometriosis. [ABSTRACT FROM AUTHOR]

The countercurrent opinion given in this paper is that the optimal management of frozen embryo transfers (FET) is not a one-size-fits-all matter, but rather one that should be decided after considering all the various parameters and options. This choice should notably encompass patients' individual characteristics – including variable risks of obstetric complications – and weigh out the respective advantages of each FET option in each case. While there may be real advantages for natural-cycle FET in many cases, these need to be balanced against both practical and clinical issues. Contrary to several prevailing, sometimes loudly expressed suggestions, there is not a one single effective approach when it comes to choosing a mode of scheduling FET. [ABSTRACT FROM AUTHOR]

Objective: To study the consequences of specific genotype profiles of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone choriogonadotropin receptor (LHCGR) on assisted reproductive technology outcomes when preimplantation genetic testing for aneuploidy is used for controlling the embryo ploidy status. The most common reported single-nucleotide polymorphisms in the amino acid position for the FSHR (N680S; N: asparagine, S: serine; [rs6166]) and the LHCGR (N312S variant; N: asparagine, S: serine [rs2293275]) were chosen for this study.Design: Retrospective cohort study.Setting: Private Fertility Clinic.Patient(s): All women aged 18-40 years undergoing their first assisted reproductive technology cycle with aneuploidy screening between 2006 and 2017 with body mass index of >18 and <40 kg/m2 were included.Intervention(s): All patients received both recombinant follicle-stimulating hormone and human menopausal gonadotropin or low dose human chorionic gonadotropin. Genomic DNA was isolated from patients' blood. Genotyping of the FSHR and LHCGR polymorphisms was performed using TaqMan genotyping assays. Associations between both receptor genotypes and clinical outcomes were assessed using generalized regression and ANOVA.Main Outcomes Measure(s): Live birth rate was the primary outcome. Secondary outcomes included oocyte yield, mature oocytes, blastulation rate, usable blastocyst rate, and implantation rate.Result(s): A total of 1,183 patients met the inclusion criteria and generated reliable genotype results. The overall genotype frequencies in the study population for the FSHR gene were as follows: 21.7% homozygous for S in codon 680, 29.2% homozygous for N680, and 48.1% heterozygous (N680S). As for the LHCGR, 15.6% were homozygous for N312, 38.5% homozygous for S312 and 45.9% heterozygous (N312S). Our study population consisted of 53.8% non-Hispanic white; 6.1% Hispanic white; 4.1% Afro-American; 15.4% Asian; and 20.6% other or unknown. No significant association was found with any of the studied variables (oocyte yield, usable blastocyst rate, implantation rate, live birth) when genotypes were analyzed per receptor or in combination with one another. There was a statistically significant but clinically irrelevant difference in the rate of mature oocytes across different variant combinations.Conclusion(s): Our findings suggest that the presence of gonadotropin receptor polymorphisms in both FSHR N680S and LHCGR N312S are not associated with assisted reproductive technology outcomes; therefore, these variants should not be considered reproductive predictors. [ABSTRACT FROM AUTHOR]

Endometriosis was classically diagnosed during diagnostic laparoscopies, which used to be routinely performed up until a decade ago or so. This practice fitted with the long-held belief that surgery was the gold standard for diagnosing endometriosis. Today, the abandon of routine diagnostic laparoscopies-in favor of assisted reproductive technology-first therapeutic approaches-has created a void for diagnosing endometriosis. Modern-day imaging techniques-ultrasound and magnetic resonance imaging-when used with a systematic approach have offered a reliable replacement option for diagnosing endometriosis. In infertility, endometriosis should be identified or excluded on the basis of past history or confirmation or exclusion suspicion on the basis of history and/or physical examination. [ABSTRACT FROM AUTHOR]

Gender-affirming hormone therapy (GAHT) is often provided to transgender people. In this review of the literature, the current knowledge of ovarian, breast, and metabolic changes (body composition, insulin resistance, bone density, cardiovascular risk factors such as lipids, blood pressure, and hematocrit) observed following GAHT in adult transgender men is discussed. A body of literature concurs to describe that long-term androgen therapy in transgender men exerts atrophic effects on the breast. There is currently no evidence of an increased risk of breast cancer. Long-term testosterone treatment induces ovarian effects that become visible after 6 months of therapy. These changes consist of both macroscopic and microscopic alterations of ovarian morphology that mimic the typical ovarian aspect encountered in women with polycystic ovary syndrome but without an effect on antral follicle count. Metabolic effects of long-term androgen treatment in transgender men put them at par with cisgender men in terms of lipid profile, insulin resistance, and overall mortality. Body composition changes as desired after testosterone administration in most transgender men, and insulin resistance decreases with virilization. There are no detrimental effects on bone mineral density. Cardiometabolic risk and morbidity data are currently reassuring, even if certain studies show conflicting results. An increase in blood pressure and a decrease in high-density lipoprotein cholesterol have been reported as risk factors, whereas polycythemia is rare and treatable. Most available data are observational and based on biochemical markers instead of the more direct measures of cardiovascular damage. An explanation for these observed changes is mostly lacking. Psychological stress and lifestyle factors are often forgotten in a much needed integrated approach. [ABSTRACT FROM AUTHOR]

Congenital and acquired uterine anomalies are associated with recurrent pregnancy loss (RPL). Relevant congenital Müllerian tract anomalies include unicornuate, bicornuate septate, and arcuate uterus. Recurrent pregnancy loss has also been associated with acquired uterine abnormalities that distort the uterine cavity such as, notably, intrauterine adhesions, polyps, and submucosal myomas. Initial evaluation of women with RPLs should include an assessment of the uterine anatomy. Even if proof of efficacy of surgical management of certain uterine anomalies is often lacking for managing RPLs, surgery should be encouraged in certain circumstances for improving subsequent pregnancy outcome. Uterine anomalies such as uterine septa, endometrial polyps, intrauterine adhesions, and submucosal myomas are the primary surgical indications for managing RPLs. [ABSTRACT FROM AUTHOR]

Chronic inflammatory processes affecting the endometrium, as encountered in endometriosis, adenomyosis, and chronic endometritis, alter endometrial receptivity. These disorders are associated with early pregnancy losses and possibly recurrent pregnancy losses (RPL). In the cases of endometriosis, other factors associated with the disease also are susceptible of causing miscarriages and possibly RPL, such as an impact of intrapelvic inflammatory processes affecting the oocyte and embryo in case of natural conception. Conversely these latter effects obviously are bypassed in case of assisted reproductive technology. Chronic inflammation of the endometrium in the condition known as chronic endometritis also causes early pregnancy losses and RPL with beneficial effects achieved when specific treatment is undertaken. [ABSTRACT FROM AUTHOR]

Objective: To study the true prevalence of recurrent implantation failure.Design: Retrospective cohort study.Setting: A private assisted reproductive technology center.Patient(s): Women (n = 4,429) with anatomically normal uterus who underwent up to three consecutive frozen euploid single embryo transfers (FE-SETs) were included in the study. Cycles with donor eggs or gestational carriers were excluded.Intervention(s): None.Main Outcome Measure(s): Cumulative outcomes from these cycles were analyzed. A logistic regression model was used to assess the differences of outcomes between first, second, and third FE-SET and a Kaplan-Meier curve as used to analyze cumulative implantation rate.Result(s): The mean age of the patients included in the study was of 35.4 years. The sustained implantation rates of the first, second, and third FE-SET were 69.9%, 59.8%, and 60.3% per transfer, respectively. The cumulative sustained implantation rate after up to three consecutive FE-SET was 95.2%. The live birth rates after the first, second, and third FE-SET were 64.8%, 54.4%, and 54.1% per transfer, respectively. The cumulative live birth rate after up to three consecutive FE-SET was 92.6%. The miscarriage rate after observing a positive heartbeat was not different between the first (7.2%), second (8.8%), and third (12.7%) FE-SET.Conclusion(s): Our findings suggest that true recurrent implantation failure is rare. For those patients with the ability to make euploid blastocysts, <5% would fail to achieve a clinical pregnancy with three embryos transferred. It remains to be further investigated whether this threshold identifies a truly recalcitrant group or simply a statistical certainty based on random variation. [ABSTRACT FROM AUTHOR]

Like all industries, fertility clinics should identify and follow reference markers of its activity-key performance indicators (KPI)-to allow assisted reproductive technology outcomes to be monitored and compared. Clinical KPIs revolve around following set parameters of the patient population, procedures, and outcome data. Moreover, KPIs should also include identified protocols and standard operating procedures followed in daily practice and should keep track of multiple pregnancy rates, a ruthless confounder of assisted reproductive technology outcomes. [ABSTRACT FROM AUTHOR]

The development of assisted reproductive technology (ART) through four decades has led to offer the ultimate treatment for nearly all forms of infertility. The only remaining factor of childlessness however that still eludes ART and its routine variants are the absolute uterine infertility factors, for which the only option is an experimental approach, uterus transplantation. Progresses has been made over the past few years, and more are underway for simplifying the process notably for simplifying the uterus extraction step performed in the uterus donor. Furthermore, as the technique is being better mastered, the original indications for uterus transplantation, the congenital or acquired absence of the uterus, are now widened to also include incurable uterine fibrosis, or Asherman's syndrome. The ART-related practicalities of uterus transplantation, ovarian stimulation and uterine priming are being discussed in the present review. [ABSTRACT FROM AUTHOR]

Endometriosis – a disease causing pain and infertility – is encountered in nearly 50% of infertile women. While medical treatment is effective on pain and recurrence of symptoms after surgical excision, it is of no help for treating infertility for which the only options considered are surgery and ART. Surgery enhances the chances of conceiving naturally during the 12–18 ensuing months irrespective of the stage of the disease. Surgery however is of no help when ART is considered, as it does not improve outcome and can only harm the ovarian response to stimulation. Today therefore, ART is commonly the primary option to be considered in women whose infertility is associated with endometriosis and whose ovarian reserve is compromised and/or who are over 35 years of age. When, ART is envisioned it is best to opt for a segmented ART approach with agonist trigger, freeze all and deferred embryo transfer. [ABSTRACT FROM AUTHOR]

Luteal phase support is mandatory in ovarian stimulation cycles in assisted reproductive technology owing to a deficit in LH pulsatility after the effects of exogenous hCG-used for triggering ovulation-vanish. This is classically accomplished by means of exogenous P administration, but emerging new options include microdoses of hCG and exogenous GnRH agonist. Although luteal phase support is commonly continued for up to 10 weeks into pregnancy, there is accumulating evidence that it can be stopped after the first ultrasound or even after a positive pregnancy test. [ABSTRACT FROM AUTHOR]

The authors review aberrations of uterine anatomy and physiology affecting pregnancy outcomes with IVF. In the case of endometriosis and hydrosalpinx, pathologies outside of the uterus alter the uterine endometrium. In the case of endometriosis, Dominique de Ziegler outlines the numerous changes in gene expression and the central role of inflammation in causing progesterone resistance. With endometriosis, the absence of ovarian function inherent in deferred transfer, with or without a more lengthy suppression of ovarian function, appears to be sufficient to restore normal function of eutopic endometrium. Because laparoscopy is no longer routine in the evaluation of infertility, unrecognized endometriosis then becomes irrelevant in the context of assisted reproductive technology. With hydrosalpinx and submucus myomas, the implantation factor HOXA-10 is suppressed in the endometrium and, with myomas, even in areas of the uterus not directly affected. Daniela Galliano reviews various uterine pathologies, the most enigmatic being adenomyosis, where the endometrium also manifests many of the changes seen in endometriosis and deferred transfer with extended suppression appears to provide the best outcomes. Ettore Cicinelli's group has extensively studied the diagnosis and treatment of endometritis, and although more definitive diagnosis and care of this covert disorder may await techniques such as sequencing of the endometrial microbiome, it undoubtedly is an important factor in implantation failure, deserving our attention and treatment. [ABSTRACT FROM AUTHOR]

Ovarian stimulation improves assisted reproductive technology outcome by increasing the number of oocytes available for insemination and in-vitro handling. A recent Duplex protocol features a dual stimulation, with the second stimulation started immediately after the first oocyte retrieval. Remarkably, the Duplex protocol is unexpectadly well tolerated by women and provides twice as many oocytes and embryos as a regular antagonist protocol in less than 30 days. [ABSTRACT FROM AUTHOR]

The assessments of oocyte quality and quantity and endocrine profile have traditionally been the cornerstone of the general workup of couples with infertility. Over the years, several clinical, hormonal, and functional biomarkers have been adopted to assess ovarian function and identify endocrine disorders before assisted reproductive technology. Furthermore, the genetic workup of patients has drastically changed, introducing novel markers. This not only allowed the prediction of response to ovarian stimulation but also contributed toward the development of a safer and more efficient management of women undergoing assisted reproductive technology. The scope of this review is to provide an overview of the current and novel strategies adopted for the assessment of ovarian function and ovulatory and endocrine disorders in women planning to conceive. Furthermore, it aims to provide an insight in the role of novel genetic biomarkers and use of expanded carrier screening as part of preliminary workup of women with infertility. [ABSTRACT FROM AUTHOR]

Uterus transplantation (UTx) is the first available treatment for absolute uterine factor infertility, a condition due to absence of the uterus or presence of a non-functional uterus. The proof-of-concept of UTx as an infertility treatment for this group of patients occurred in 2014 in Sweden by the first birth after human UTx. That and subsequent cases of the Swedish trial were live-donor UTx procedures with laparotomy of both donor and recipient. Although results of the initial Swedish clinical UTx trial were very favorable in terms of take-home-baby rate, the drawback was the long duration (>10 h) of donor surgeries and associated long recovery periods. There exist three later publications, with uterus procurements from live donors by laparotomy with a range of surgical durations of 5.3 hours to 13 hours. Our collaborative Swedish-French team has initiated efforts to introduce minimal invasive surgery in one trial in Sweden and one in France. The principle of these UTx trials is to use modern concepts of robotic-assisted laparoscopy primarily in the live donor. There also exists a small number of published UTx procedures with donor surgery by partial conventional laparoscopy and one published case with total robotic-assisted laparoscopy procedure. This review discusses open versus minimal invasive surgery in relation to the accumulated knowledge in the field. Moreover, we propose some future directions for the development of this surgery in UTx. [ABSTRACT FROM AUTHOR]

What is the reliability of Geri® Assess 2.0 software time-lapse technology for annotating kinetic events and identifying abnormal phenotypes in preimplantation human embryos? Embryos were annotated using Assess 2.0 for the appearance and fading of pronuclei, and for progression to the 2-, 3-, 4-, 5- and 6-cell stages and to three blastocyst stages. Identification of reverse cleavage and direct cleavage phenotypes was also recorded. Manual annotation was undertaken after these events in a blinded fashion. Embryo scores were compared between Assess 2.0 and manual annotation. A total of 513 oocytes from 34 women were included. Detection rates for Assess 2.0 versus manual annotation among the 10 kinetic events and including direct cleavage and reverse cleavage ranged between 0% and 94.4%. The percentage of discordant pairs was significantly different for all 12 events analysed (P -value range 0.036 to <0.0001). The sensitivity of Assess 2.0 ranged from 68.2% to 94.4% and specificity ranged from 63.8% to 97.3%. Assess 2.0 called for verification by the embryologist for at least one event in 55.2% of oocytes assessed. Of the 297 embryos scored by manual annotation, Assess 2.0 assigned the same score for only 125 (42.1%), although after manual corrections, concordance with manual annotation scores was raised to 66.0%. The results reveal striking differences between Assess 2.0 and manual annotation for kinetic annotations. Failure of Assess 2.0 to detect direct cleavage events and the low detection rate of reverse cleavage are further limitations. These collective findings highlight the importance of validating time-lapse annotation software before clinical implementation. Manual verification of Assess 2.0 outputs remains essential for accurate data interpretation. [ABSTRACT FROM AUTHOR]

Transgender males experience a disharmony between their birth sex and their intimate sense of gender belonging. Gender-affirming hormone therapy and gender-affirming surgery (GAS) are often inherently part of the gender-affirming process. In this context, we should ask whether it is better to keep or remove the uterus. Keeping the uterus and ovaries avoids a surgical procedure and a pubic scar that often results and preserves fertility and the possibility of carrying a baby. On the other hand, keeping the uterus is often psychologically unbearable for transgender males and the long-term effects of androgens on the uterus and ovaries remain uncertain. Conversely, hysterectomy and oophorectomy as part of the GAS process are part of gender reassignment. New mini-invasive surgery procedures for hysterectomies decrease the risks and limit the likelihood of scars to a minimum. In practice, the data suggest that very few transgender males carry a pregnancy and/or use their oocytes after gender-reaffirming treatment. Clinicians should counsel their transgender male patients on the definitive infertility consequences of hysterectomy and oophorectomy and discuss fertility preservation options before GAS. Individualized approaches must be preferred to systematic procedures regarding the personal decision to keep or not keep the uterus and ovaries. [ABSTRACT FROM AUTHOR]

Certain miscarriages result from immunologic factors, but there is no clear identification of the precise causes of recurrent pregnancy loss (RPL). Miscarriages and RPL can arise from a disruption of maternal-fetal immune homeostasis. Remodeling of the maternal uterine spiral arteries is one of the key steps for normal growth and development of the fetus. An adequate oxygen supply is necessary for correct placentation, and it is accomplished by proper vascular changes. The development of fetal tissues creates a potential immunologic problem since the fetus can express paternal antigens and, in some cases, antigens of a gamete donor. The maternal immune system actively responds to fetal antigens, and dysregulation of this crosstalk could partly explain pregnancy complications such as miscarriages and RPL. RPL resulting from thrombophilia is primarily due to acquired thrombophilia, and therefore screening and treatment should be focused on antiphospholipid antibody syndrome. [ABSTRACT FROM AUTHOR]

Is a symptom questionnaire as per the French IVF guidelines adequate for screening patients during the COVID-19 pandemic? Patients planning IVF from June 2020 to February 2021 were included in the study. In compliance with French IVF guidelines, all patients fever-free on the day of oocyte retrieval were screened for risk of COVID-19 by completing a symptom questionnaire after being counselled regarding the importance of a COVID-19-free medical practice. Patients with IVF planned between June and September 2020 only completed the questionnaire (group 1), while those planning IVF after September 2020 also underwent the RT-PCR test for SARS-CoV-2 RNA (group 2). Cycle cancellation rates between groups were compared. Group 1 patients consented for follicular fluid testing for SARS-CoV-2 and an interview after cycle completion to determine COVID-19 exposure during the 6 months before and after retrieval. Cycle cancellation rates for groups 1 and 2 were 0% (0/214) versus 1.4% (8/577), respectively, (P = 0.116). All 183 follicular fluid samples from group 1 were negative for SARS-CoV-2 RNA. Of 171 patients interviewed post-IVF, 16 (93.4%) developed COVID-19 symptoms or a positive real-time PCR (RT-PCR) RT-PCR test, but none within 2 months pre- or post-retrieval. These results provide reassurance that, consistent with the COVID-19 French IVF guidelines, use of a symptom questionnaire is effective in screening patients planning to undergo IVF. Failure to detect viral RNA in any follicular fluid sample does not negate the possibility that follicular fluid is a viral reservoir. However, the findings provide reassurance that the follicular environment in this study's carefully screened population was COVID-free. [ABSTRACT FROM AUTHOR]

Is T-shaped uterine cavity morphology associated with adverse pregnancy outcomes after transfer of a single thawed euploid blastocyst? In this secondary analysis of a prospective cohort study, 648 patients with three-dimensional ultrasound (3D-US) data obtained on the day before embryo transfer were categorized into three groups according to uterine cavity morphology: normal (n = 472), intermediate (n = 166) and T-shaped (n = 10). Quantitative uterine cavity dimensions were used to evaluate uterine cavity morphology. Pregnancy outcomes, including live birth, clinical miscarriage and ectopic pregnancy, were compared among the groups. The prevalence of a T-shaped uterus in this cohort was 1.5%. Uterine cavity morphology was strongly associated with the ratio of interostial distance and isthmic diameter (P < 0.01). Live birth rates were 66.5% for normal, 65.7% for intermediate and 40.0% for T-shaped cavity morphology. Women with a T-shaped uterus had an increased risk of clinical miscarriage (40.0% versus 7.0% for normal and 9.0% for intermediate cavity morphology, P < 0.01) and ectopic pregnancy (10.0% versus 1.1% for normal and 1.9% for intermediate cavity morphology, P = 0.05). When evaluating interostial distance and isthmic diameter ratio to determine pregnancy outcomes, a cut-off value of 2 was noted to have weak predictive value for live birth, but not clinical miscarriage or ectopic pregnancy. T-shaped uterine cavity morphology is associated with adverse pregnancy outcomes after transfer of a single thawed euploid blastocyst. Given the low prevalence of this condition, quantifying the magnitude of risk will require a larger cohort of patients. [ABSTRACT FROM AUTHOR]