Clinical Management of Infertility Associated with Endometriosis.

OBJECTIVE: This study aimed to review recent data that affected the clinical management of infertility associated with endometriosis. DATA SOURCES: We completed a PubMed review of all articles that included the following keywords: endometriosis, infertility, IVF, and ART. STUDY SELECTION: A study was selected based on the pertinence of the topic addressed in relation to the study's set objectives. DATA EXTRACTION AND SYNTHESIS: All identified articles were first assessed based on a review of the abstract. Pertinent articles were reviewed in depth. CONCLUSION: Endometriosis interferes with natural conception primarily by altering the quality of gametes-oocytes and sperm-and early-stage embryos. On the contrary, recent data indicate that gametes and early-stage embryos are not altered in the case of ART. Surgery-a classical approach in yesteryears-does appear to improve ART outcomes and may affect ovarian reserve and the number of oocytes retrieved in ART. Surgery is thus more rarely opted for today and only when necessary; proceeding to fertility preservation prior to surgery is recommended. When ART is performed in women with endometriosis, it is recommended to use an antagonist or progesterone-primed ovarian stimulation approach followed by deferred embryo transfer. In this case, GnRH (gonadotropin releasing hormone) agonist is preferred for triggering ovulation, as it limits the risk of cyst formation as well as ovarian hyperstimulation syndrome. Frozen embryo transfers are best performed in E2 (estradiol) and progesterone replacement cycle.

Do IVF culture conditions have an impact on neonatal outcomes? A systematic review and meta-analysis.

PURPOSE: Are embryo culture conditions, including type of incubator, oxygen tension, and culture media, associated with obstetric or neonatal complications following in vitro fertilization (IVF)? METHODS: A systematic search of MEDLINE, EMBASE, and Cochrane Library was performed from January 01, 2008, until October 31, 2021. The studies reporting quantitative data on at least one of the primary outcomes (birthweight and preterm birth) for the exposure group and the control group were included. For oxygen tension, independent meta-analysis was performed using Review Manager, comparing hypoxia/normoxia. For culture media, a network meta-analysis was carried out using R software, allowing the inclusion of articles comparing two or more culture media. RESULTS: After reviewing 182 records, 39 full-text articles were assessed for eligibility. A total of 28 studies were kept for review. Meta-analysis about the impact of incubator type on perinatal outcomes could not be carried out because of a limited number of studies. For oxygen tension, three studies were included. The pairwise meta-analysis comparing hypoxia/normoxia did not show any statistical difference for birthweight and gestational age at birth. For culture media, 18 studies were included. The network meta-analysis failed to reveal any significant impact of different culture media on birthweight or preterm birth. CONCLUSION: No difference was observed for neonatal outcomes according to the embryo culture conditions evaluated in this review. Further research is needed about the safety of IVF culture conditions as far as future children's health is concerned.

Successful ART outcome in a woman with McCune-Albright syndrome: a case report and literature review.

McCune-Albright syndrome (MAS) is a rare genetic disease affecting multiple organs, including endocrine tissues. This endocrinopathy is sometimes responsible for infertility, as it may induce an independent functioning of the ovaries leading to anovulatory cycles. This case report describes the infertility journey of a 22-year-old female who had early puberty and irregular periods with high estrogen and progesterone levels, low FSH and LH (on day 3 of her menstrual cycle), and a multi-cystic right ovary. She received several infertility treatments: initially in vitro oocyte maturation (IVM) followed by cyst transvaginal ultrasound-guided aspiration, all unsuccessful. A right hemi-ovariectomy was performed that eventually restored regular cycles and made it possible to perform ovarian stimulation (OS) and in vitro fertilization (IVF). Live birth was obtained after the first embryo transfer.

Limits imposed by the experimental design of a large prospective non-inferiority study on PGT-A invalidate many of the conclusions.

The New England Journal of Medicine recently published a large study addressing the efficacy of preimplantation genetic testing for aneuploidy (PGT-A). The 14-centre randomized control non-inferiority trial used cumulative live birth rate (CLBR) as a clinical endpoint to examine the value of PGT-A and concluded that conventional IVF was not inferior to IVF with PGT-A. Unfortunately, the experimental design was highly flawed; and in fact, the data generated in the study do not support the major conclusions presented in the publication. The embryos in each patient's three-embryo pool, which were available for transfer, were selected solely by morphology. The investigators then randomized patients to either the PGT-A group or the control group. It is important to note that PGT-A screening in the study group was done only after the embryos were selected. PGT-A was not really used in a meaningful way, which would have been for the PGT-A results to help in selecting which embryos would be in the three-embryo group. Thus, the outcomes were wholly determined prior to the study intervention. The ultimate delivery rate for each group of three embryos was determined when they were selected by morphology. The randomization, which occurred after embryo selection, would assure equal distribution of those cohorts destined to deliver and those destined to fail to the two study groups, the PGT-A and control groups. Thus, there was no potential for PGT-A to enhance selection and thus no possible way to improve the cumulative outcomes. Since there was no possible way for the control group to be inferior, the experimental design precluded any chance of evaluating the primary endpoint of the study. The primary question of the study was never evaluated. Another serious flaw was that the study was initiated prior to knowing how to interpret the data provided in the PGT-A analytical result. Specifically, the design excluded mosaic embryos from transfer despite the literature demonstrating the significant reproductive potential for these embryos. When accounting for the lost deliveries induced by this non-evidence-based decision, the expected delivery rates in the two groups become virtually identical. That is an important issue because the data from the study actually demonstrate the safety of PGT-A without diminution in outcomes from the impact of trophectoderm biopsy or the discarding of competent embryos which had wrongfully been considered aneuploid. A final serious flaw in the experimental design and interpretation of the data surrounding the issue of the miscarriage rate. The investigators noted that the miscarriage rate was lower in the PGT-A group but stated that its impact was insufficient to alter the CLBR. Of course, by design, the CLBRs were limited to being equivalent. There was no potential for enhanced outcomes in the PGT-A group and thus no possibility that the lower risk of miscarriage in the PGT-A group would raise the CLBR. The benefit of a lower miscarriage rate is real and significant. Its relevance should not be diminished based on the lack of a change in the CLBR since that was never possible in this study. The investigators of the study concluded that the CLBR with conventional ART is equivalent to that with PGT-A, but a simple review of the experiment reassigns their genuine findings to those of a safety study. Significantly, the data in the study demonstrate that the intervention of PGT-A is safe. This study neither supports nor refutes the efficacy of clinical PGT-A.

Investigation of the reliability of semi-automatic annotation by the Geri time-lapse system.

RESEARCH QUESTION: 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? DESIGN: 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. RESULTS: 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%. CONCLUSIONS: 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.

Validation of the French IVF guidelines during the COVID-19 pandemic.

RESEARCH QUESTION: Is a symptom questionnaire as per the French IVF guidelines adequate for screening patients during the COVID-19 pandemic? DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Recurrent implantation failure: how common is it?

PURPOSE OF REVIEW: To clarify a lingering issue, the true incidence of repeated implantation failures (RIF) in women undergoing successive frozen euploid single embryo transfers (FE-SET). RECENT FINDINGS: As not all Assisted reproductive techinique (ART) attempts are crowned by success, it has been questioned since incept of ART whether failures resulted from an embryonic or endometrial cause. RIF has received no precise definition but a trend has existed toward setting a more stringent definition, as reproductive biology has become more effective and ART success rates improved. No scientific society has yet convened on a universally accepted definition. The advent of effective and well tolerated pregestational testing of embryos for aneuploidy (PGT-A) has allowed to not transfer aneuploid embryos, which are bound not to succeed. This, therefore, justify revisiting the concept of RIF when only euploid embryos are transferred. SUMMARY: Contrary to lingering beliefs, the results of our study indicate that RIF following three successive euploid embryo transfers in a morphologically normal endometrium is a rare occurrence (<5%). This supports the concept that ART failures mainly result from embryonic causes. Our data also propose a new - functional - definition of RIF being an ART failure following 3 successive FE-SET attempts. Our findings, therefore seriously question the soundness of prescribing the often complex and expensive endometrial testing procedures that largely publicized for treating RIF.

Is there a link between plasma progesterone 1-2 days before frozen embryo transfers (FET) and ART outcomes in frozen blastocyst transfers?

OBJECTIVE: To study the efficacy of combined administration of subcutaneous and vaginal progesterone for priming frozen blastocysts transfers, looking at progesterone levels and ART outcome. DESIGN: Retrospective study. SETTING PATIENTS: Three hundred and twenty frozen blastocyst transfer cycles conducted in 213 women aged up to 42 years, BMI between 18 and 30 kg/m2, with anatomically normal uterus who underwent frozen embryo transfers (FETs) from February 2019 to December 2019 with a combined luteal-phase support (LPS) associating subcutaneous and vaginal progesterone. Patients with recurrent pregnancy loss (RPL) were excluded. RESULTS: When using combined vaginal and subcutaneous LPS, SPL >10.50 ng/mL in 95% of cases, with a minimum value of 7.02 ng/mL. CPR, OPR, and global miscarriage rates were 38.4%, 30.9%, and 19.5%, respectively. Analyzing results per quartiles, revealed that miscarriage rates were significantly inferior, and IR were higher in the upper two quartiles of serum progesterone (>21.95 ng/mL) on the day before FET, while there was no difference in CPR and OPR. CONCLUSIONS: We report ART outcome of frozen blastocyst transfers performed using a combination of vaginal and subcutaneous progesterone for LPS. ART results were honorable and SPL favorable 1-2 days before FET in 99% of cases.

Utilization of in vitro maturation in cases with a FSH receptor mutation.

PURPOSE: To identify the FSH receptor (FSHR) variant and efficacy of in vitro maturation (IVM) in a 28-year-old woman with secondary amenorrhea, primary infertility, and ovarian resistance to FSH, and to analyze the genotype-to-phenotype relationship in cases of FSHR mutation for the development of an IVM algorithm for use in patients with gonadotropin resistance syndrome (GRS). METHODS: Oocytes retrieved after menstruation induction with norethisterone, followed by daily estrogen and an ovulatory trigger, underwent IVM, ICSI, and culture in a time-lapse (TL) incubator. Embryo transfers were performed on day 2, and after thawing on day 5. Genes associated with disorders of sex development were sequenced for both the patient and her parents. All reported cases of FSHR mutation were analyzed to investigate genotype/phenotypic relationships. RESULTS: After ovum pickup, seven of 16 oocytes matured and all fertilized. After unsuccessful day 2 transfer, our patient delivered with a thawed day 5 blastocyst, the sole embryo without abnormal TL phenotypes. Genetic analysis revealed a new composite heterozygous FSHR variant. Analysis of our patient case with published cases of GRS revealed associations among FSHR variant genotype, location on the FSHR, functionality of tested variants, and type of amenorrhea. An algorithm for application of IVM for GRS patients was developed. CONCLUSIONS: We report two novel variants of the FSHR. Although IVM successfully matured some oocytes, only one resulted in an embryo with normal TL phenotypes. We recommend FSHR genetic testing in GRS patients, which will help guide their suitability for IVM.

Three-dimensional ultrasound diagnosis of T-shaped uterus is associated with adverse pregnancy outcomes after embryo transfer.

RESEARCH QUESTION: Is T-shaped uterine cavity morphology associated with adverse pregnancy outcomes after transfer of a single thawed euploid blastocyst? DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Simulation and professional development: added value of 3D modelization in reproductive endocrinology and infertility and assisted reproductive technologies teamwork.

As in other specialties of medicine, there is more to clinical performance in reproductive endocrinology, infertility, and assisted reproductive technologies (REI-ART) than simply the individual knowledge and technical skills. Simulation is commonly used during fellowship training in REI-ART, aiming to produce a virtual cycle of professional development in order to improve patient outcome. With scientific certification and the joint development of evaluation tools, the contribution of digitalization, such as 3 D printing and digital simulators, will facilitate teamwork in REI-ART and enable a better transmission of knowledge in the specialty.

[The menopausal hormone therapy in 2016]. / Traitement hormonal de la ménopause en 2016.

The menopausal hormone therapy (MHT) is the first line treatment for climacteric symptoms related to estrogen deficiency. A personalized evaluation of the benefit-risk ratio should precede a MHT prescription, and take into consideration cardiovascular, thromboembolic, oncological and osteoporosis risks. MHT should be prescribed at the lowest effective dose and for the shortest duration, respecting the window of opportunity in the 10 years following menopause or before the age of 60 years. The choice of the MHT type depends on the patient's profile, her medical history and personal preferences, with the aim of improving quality of life from a physical, psychological and sexual point of view.

Le traitement hormonal de la ménopause (THM) est recommandé en première intention pour les symptômes climatériques liés à la carence œstrogénique. Une évaluation individuelle de la balance bénéfice/risque devrait être effectuée avant la prescription d'un THM, en prenant en compte des facteurs de risque cardiovasculaires, thromboemboliques, oncologiques et ostéoporotiques. Le THM devrait être prescrit à la dose minimale efficace pour une durée la plus courte possible, en respectant la « fenêtre d'opportunité thérapeutique ¼ de 10 ans après la ménopause ou avant l'âge de 60 ans. Le choix du type de THM se fait en fonction du profil, des antécédents et des préférences de la patiente, dans le but d'améliorer sa qualité de vie du point de vue physique, psychologique et sexuel.

Dual ovarian stimulation is a new viable option for enhancing the oocyte yield when the time for assisted reproductive technnology is limited.

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.

Telomere length: a marker for reproductive aging?

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.

The Impact of Conservative Surgical Treatment of Adenomyosis on Fertility and Perinatal Outcomes.

Adenomyosis is a benign condition commonly encountered in patients with infertility. While the definitive surgical management is hysterectomy, conservative surgical management is gaining attention in patients desiring future fertility. This review explores whether the surgical treatment of adenomyosis affects fertility outcomes for patients trying to conceive. The PubMed and Medline databases were searched using the keywords: "adenomyosis", "surgery", "radiofrequency", "infertility", "pregnancy", "sterility", "conception", "miscarriage", and "endometrial receptivity". Abstracts were screened, and relevant articles were selected for review. This review reveals that surgery appears to improve fertility outcomes with or without medical therapy; however, the risk of uterine rupture remains high and the best technique to reduce this risk is still not known. More studies are needed to formulate the best surgical approach for preserving fertility in treating adenomyosis and to establish standardized guidelines.

Endometrial receptivity in adenomyosis and/or endometriosis.

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.

The impact of paternal age on cumulative assisted reproductive technology outcomes.

Objective: To investigate the impact of paternal age on cumulative live birth rate in ART. Design: Retrospective single-center cohort study. Patients: All female patients aged 18-43 years and male patients aged 18-60 years, who performed their first ART cycle between January 2018 and December 2020, were included. Main outcome measures: The primary outcome, cumulative live birth rate (cLBR), was estimated following fresh or frozen embryo transfers issued from an ART cycle. Secondary outcomes included the cumulative pregnancy rate (cPR) and miscarriage rate. Subgroup analyzes were performed as follows: men <45 and ≥ 45; female <35, 35-38, and > 38 years. Results: A total of 2,358 couples were included in this study. The sperm quantity of male patients within both age groups was divided in two groups: normal and abnormal, which were found to be in significantly equal proportions. There were significantly fewer current smokers in the male group ≥45. The cPR was 0.5301 in the group <45 and 0.3111 in the group ≥45, with a p-value <0.001. Analysis according to the female age revealed that, in the female group >38, the cLBR rate was 0.26 for men <45 and 0.19 for men ≥45, with a p-value of 0.061. Additionally, the cPR was 0.34 in the male group <45 and 0.21 in the group ≥45, with a p-value <0.001. In the female group between 35 and 38 years of age, the cLBR was 0.44 in the male group <45 and 0.3 in the male group ≥45, with a p-value of 0.031. The cPR was 0.49 in the male group <45 and 0.34 in the group ≥45, p = 0.036. Within the female group <35, we observed non-significant results. The miscarriage rate results were not significantly different for women ≤38. Conclusion: According to the results from our study, male age ≥ 45 has a significant impact on cumulative ART outcomes.

Recurrent implantation failure: reality or a statistical mirage?: Consensus statement from the July 1, 2022 Lugano Workshop on recurrent implantation failure.

IMPORTANCE: 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. OBJECTIVE: 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. EVIDENCE REVIEW: A systematic review without meta-analysis of studies published in English from January 2015 to May 2022. FINDINGS: 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. CONCLUSION: 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). RELEVANCE: Given the number of internationally recognized experts in the field present at the Lugano meeting 2022, our publication constitutes a consensus statement.