Walking the tightrope: Fertility preservation among hereditary breast and ovarian Cancer syndrome Previvors.

INTRODUCTION: Fertility-related concerns cause significant anxiety among patients with Hereditary Breast and Ovarian Cancer Syndrome (HBOC). The Society of Gynecologic Oncology and the American Society for Reproductive Medicine recommend patients diagnosed with HBOC receive early referral to a reproductive endocrinologist. However, evidence about fertility trends in this patient population are limited and guidelines are scarce. The aim of this study is to compare fertility preservation among patients with HBOC to control patients undergoing fertility treatment without a diagnosis of infertility. METHODS: This retrospective study included patients who presented to a single academic institution for fertility preservation in the setting of diagnosis of HBOC. In this study, HBOC patients are referred to as those who had tested positive for pathogenic mutations in BRCA1, BRCA2 or were at high-risk for HBOC based on a strong family history (defined as >3 family members diagnosed with HBOC) without a genetic mutation. HBOC patients were matched in a 1:1 fashion to a control group undergoing fertility preservation without a diagnosis of infertility or HBOC. All analysis was done using SPSS version 9.4 (SAS Institute, Cary, NC). RESULTS: Between August 1st, 2016 and August 1st, 2022, 81 patients presented to the study center for consultation in the setting of HBOC. Of those who presented, 48 (59.2%) ultimately underwent oocyte cryopreservation and 33 (40.7%) underwent embryo cryopreservation. Patients who underwent oocyte cryopreservation due to BRCA1 status were more likely to present for fertility consultation at a younger age compared to control patients (32.6 vs. 34.7 years, p = 0.03) and were more likely to undergo oocyte cryopreservation at a younger age (32.1 vs. 34.6 years, p = 0.007). There was no difference in age at initial consultation or age at procedure for patients with BRCA2 or patients with a strong family history compared to control patients (p > 0.05). There was no difference in the mean age of patients with HBOC at presentation for consultation for embryo cryopreservation or the mean age the patient with HBOC underwent embryo cryopreservation compared to control patients (p > 0.05). Patients with BRCA1 or BRCA2 did not have expedited time from consultation to first cycle start (p > 0.05). After adjusting for factors including anti-Müllerian hormone (AMH) level and age, patients considered in the HBOC group due to family history had less time between consultation and oocyte cryopreservation cycle compared to control patients. (179 vs. 317 days, p = 0.045). There was no difference in time from consultation to starting cycle for embryo cryopreservation for patients with HBOC compared to controls (p > 0.05). CONCLUSION: Patients with HBOC did not undergo expedited fertility treatment compared to control patients undergoing oocyte and embryo cryopreservation for non-infertility reasons. Patients diagnosed with BRCA1 had more oocytes retrieved compared to the control population which is possibly due to earlier age of presentation in the setting of recommended age of risk reducing surgery being age 35-40. When age matched, cycle outcomes did not differ between HBOC and control patients. Given the known cancer prevention benefit and recommendations for risk-reducing surgery, future studies should focus on guidelines for fertility preservation for patients with HBOC.

Obstetric outcomes of nulliparous women with pelvic pain undergoing fertility treatment.

RESEARCH QUESTION: Is there any association between pelvic pain and primary caesarean delivery for patients undergoing assisted reproductive technology (ART) treatment? DESIGN: Retrospective cohort study of nulliparous patients with singleton pregnancies who underwent ART treatment and achieved a live birth between 2012 and 2020. Cases included patients diagnosed with pelvic pain. A 3:1 ratio propensity-score-matched population of patients without a history of pelvic pain was included as the control group. Comparative statistics were performed using chi-squared test and Student's t-test. A multivariate regression analysis was conducted to evaluate the association between pelvic pain and mode of delivery. RESULTS: One hundred and seventy-four patients with pelvic pain were compared with 575 controls. Patients with pelvic pain reported a significantly longer duration of infertility compared with controls (18.98 ± 20.2 months versus 14.06 ± 14.06 months; P = 0.003). Patients with pelvic pain had a significantly higher rate of anxiety disorders (115 ± 21.9 versus 55 ± 31.6; P = 0.009) and use of anxiolytics at embryo transfer (17 ± 3.2 versus 12 ± 6.9; P = 0.03) compared with controls. In addition, patients with pelvic pain had a higher rate of primary caesarean delivery compared with controls (59.8% versus 49.0%; P = 0.01). After adjusting for multiple variables, a significant association was found between pelvic pain and increased odds of primary caesarean delivery (adjusted OR 1.48, 95% CI 1.02-2.1). CONCLUSION: Patients with pelvic pain have significantly higher odds of primary caesarean delivery compared with patients without a history of pelvic pain. The infertility outpatient setting may be uniquely positioned to identify patients at risk for undergoing primary caesarean delivery, and could facilitate earlier intervention for pelvic floor physical therapy during the preconception and antepartum periods.

Single Euploid Embryo Transfer Outcomes After Uterine Septum Resection.

STUDY OBJECTIVE: To study pregnancy outcomes after single euploid embryo transfer (SEET) in patients who underwent prior uterine septum resection to those with uteri of normal contour, without Müllerian anomalies or uterine abnormalities including polyps or fibroids, and without a history of prior uterine surgeries. DESIGN: Retrospective cohort study. SETTING: Single academic affiliated center. PATIENTS: 60 cycles of patients with prior hysteroscopic uterine septum resection who underwent an autologous SEET between 2012 and 2020 were used as the investigational cohort. A 3:1 ratio propensity score matched control cohort of 180 single euploid embryo transfer cycles from patients without a history of uterine septa were used as the control group. INTERVENTIONS: No interventions administered. MEASUREMENTS AND MAIN RESULTS: Pregnancy, clinical pregnancy loss, ongoing clinical pregnancy, and live birth rates in patients with a history of uterine septum resection compared with matched patients without Müllerian anomalies or uterine surgeries. Patients with a prior uterine septum had significantly lower rates of chemical pregnancy (58.33% vs 77.2%, p = .004), implantation (41.67% vs 65.6%, p = .001), and live birth (33.33% vs 57.8%, p = .001) per transfer. No statistical difference in clinical pregnancy loss rates was found when comparing septum patients with controls (8.33% vs 7.8%, p = .89). CONCLUSION: Patients with a history of hysteroscopic resection who undergo in vitro fertilization are more susceptible to suboptimal clinical outcomes compared with patients with normal uteri. Early pregnancy loss rates in patients with a uterine septum are higher than in those without; however, after resection, the rates are comparable. Patients born with septate uteri require assessment of surgical intervention prior to SEET, and to optimize their reproductive outcomes.

Correlation of self-reported racial background to euploidy status and live birth rates in assisted reproductive technology cycles.

PURPOSE: To determine whether the embryonic euploidy rate and live birth outcomes following single, euploid embryo transfer (SEET) differ among women of self-reported racial and ethnic backgrounds. METHODS: This retrospective cohort study included all infertile patients of different self-reported racial backgrounds who underwent In vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy (PGT-A) and an autologous single euploid embryo transfer (SEET) from December 2015 to December 2019 at a single private and academic assisted reproduction technology center. Primary outcome measures included ploidy rates among different racial groups. Secondary outcomes included clinical pregnancy, clinical pregnancy loss, and live birth rates. RESULTS: Five thousand five hundred sixty-two patients who underwent an IVF cycle with ICSI-PGT-A were included. A total of 24,491 blastocysts were analyzed. White participants had on average more euploid embryos and higher euploidy rates when compared to their counterparts (p ≤ 0.0001). However, after controlling for confounding factors, there was no association between race and the odds of having  a higher euploidy rate (aOR 1.31; 95% CI 0.63-2.17, p = 0.42). A total of 4949 patients underwent SEET. Pregnancy outcomes did not differ among patients of varying self-reported races. CONCLUSIONS: Euploidy rates and pregnancy outcomes were comparable among patients of different racial backgrounds who underwent a SEET.

Rescue in vitro maturation using ovarian support cells of human oocytes from conventional stimulation cycles yields oocytes with improved nuclear maturation and transcriptomic resemblance to in vivo matured oocytes.

PURPOSE: Determine if the gene expression profiles of ovarian support cells (OSCs) and cumulus-free oocytes are bidirectionally influenced by co-culture during in vitro maturation (IVM). METHODS: Fertility patients aged 25 to 45 years old undergoing conventional ovarian stimulation donated denuded immature oocytes for research. Oocytes were randomly allocated to either OSC-IVM culture (intervention) or Media-IVM culture (control) for 24-28 h. The OSC-IVM culture condition was composed of 100,000 OSCs in suspension culture with human chorionic gonadotropin (hCG), recombinant follicle stimulating hormone (rFSH), androstenedione, and doxycycline supplementation. The Media-IVM control lacked OSCs and contained the same supplementation. A limited set of in vivo matured MII oocytes were donated for comparative evaluation. Endpoints consisted of MII formation rate, morphological and spindle quality assessment, and gene expression analysis compared to in vitro and in vivo controls. RESULTS: OSC-IVM resulted in a statistically significant improvement in MII formation rate compared to the Media-IVM control, with no apparent effect on morphology or spindle assembly. OSC-IVM MII oocytes displayed a closer transcriptomic maturity signature to IVF-MII controls than Media-IVM control MII oocytes. The gene expression profile of OSCs was modulated in the presence of oocytes, displaying culture- and time-dependent differential gene expression during IVM. CONCLUSION: The OSC-IVM platform is a novel tool for rescue maturation of human oocytes, yielding oocytes with improved nuclear maturation and a closer transcriptomic resemblance to in vivo matured oocytes, indicating a potential enhancement in oocyte cytoplasmic maturation. These improvements on oocyte quality after OSC-IVM are possibly occurring through bidirectional crosstalk of cumulus-free oocytes and ovarian support cells.

Recent clomiphene citrate exposure does not impact subsequent clinical outcomes in single euploid frozen embryo transfer cycles.

STUDY QUESTION: Do infertile couples who recently utilized clomiphene citrate (CC) for ovulation induction or ovarian stimulation (<90 days previously) followed by a single euploid embryo transfer (SEET) have lower implantation potential compared with patients who were not exposed to CC within 90 days before embryo transfer (ET)? SUMMARY ANSWER: There does not appear to be an association between recent CC exposure and lower implantation potential in patients who undergo a frozen embryo transfer (FET) of euploid embryos. WHAT IS KNOWN ALREADY: Clomiphene has been found to be associated with lower pregnancy rates when compared against other ovarian stimulation medications. The majority of published research about the effects of CC on implantation potential suggest an anti-estrogenic effect on the endometrium. Quality evidence and information about utilization of CC and its effect on implantation potential after euploid ETs is lacking in the literature. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study with propensity score matching was carried out. We included all patients that underwent an autologous SEET from September 2016 to September 2022 at a single academic-private ART center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study group included patients that had utilized CC during either ovulation induction cycles and/or controlled ovarian stimulation at least 90 days before FET. A propensity score-matched control group of patients that were unexposed to CC within 90 days prior to SEET was used for comparisons. The primary outcome was positive pregnancy test (defined as a positive serum ß-hCG measured 9 days after ET), with other outcomes including clinical pregnancy, ongoing pregnancy, biochemical pregnancy loss, and clinical pregnancy loss rates per SEET. Multivariate regression analyses fitted with generalized estimating equations were utilized to analyze if there was an association between CC utilization and IVF outcomes. Furthermore, the study evaluated the cumulative effect of CC and endometrial receptivity in vivo and subsequent IVF outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 593 patients with utilization of CC in <90 days before ET were compared with 1779 matched controls. Positive pregnancy test rates were comparable among the control group and the CC exposed groups, respectively (74.3% versus 75.7%, P = 0.79), as were clinical pregnancy (64.0% versus 65.0%, P = 0.60), ongoing pregnancy (51.8% versus 53.2%, P = 0.74), biochemical pregnancy loss (15.7% versus 14.03%, P = 0.45), and clinical pregnancy loss rates were also comparable among cohorts (17.1% versus 18.1%, P = 0.71). No association was found between utilization of clomiphene and lower implantation rates (adjusted odds ratio 0.95, 95% CI 0.76-1.18). Also, no differences were observed in sub-analyses based on multiple CC utilization periods. Finally, no association was found between the number of consecutive cumulative clomiphene cycles and sub-optimal IVF outcomes. LIMITATIONS, REASONS FOR CAUTION: The study has inherent bias that originated from its retrospective design. Serum levels of CC were not measured and sample size for the sub-analyses was small. WIDER IMPLICATIONS OF THE FINDINGS: There does not appear to be an association between recent CC exposure and lower implantation potential in patients who undergo a FET of euploid embryos. This finding remains consistent, even in patients who undergo multiple, consecutive clomiphene cycles prior to ET. There were no long-term effects of CC on endometrial development and clinical characteristics examined in this study. Patients that utilized CC medication prior to a SEET cycle for either ovarian stimulation or ovulation induction, can be assured that there is no evidence of a residual effect of recent CC administration that could jeopardize their pregnancy probability. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the realization of this study. A.C. is advisor and/or board member of Sema4 (stakeholder in data) and Progyny. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Assessing the clinical viability of micro 3 pronuclei zygotes.

PURPOSE: What is the rate of euploidy and clinical viability of embryos resulting from micro 3 pronuclei zygotes? METHODS: Retrospective cohort analysis in a single, academic in vitro fertilization (IVF) center from March 2018 to June 2021. Cohorts were separated by fertilization as either a 2 pronuclear zygote (2PN) or micro 3 pronuclear zygote (micro 3PN). PGT-A was performed to identify embryonic ploidy rates in embryos created from micro 3PN zygotes. The clinical outcomes of all transferred euploid micro 3PN zygotes were evaluated from frozen embryo transfer (FET) cycles. RESULTS: During the designated study period, 75,903 mature oocytes were retrieved and underwent ICSI. Of these, 60,161 were fertilized as 2PN zygotes (79.3%) and 183 fertilized as micro 3PN zygotes (0.24%). Of the micro 3PN-derived embryos that underwent biopsy, 27.5% (n=11/42) were deemed euploid by PGT-A, compared to 51.4% (n=12,301/23,923) of 2PN-derived embryos, p=0.06. Four micro 3PN-derived embryos were transferred in subsequent single euploid FET cycles, which includes one live birth and one ongoing pregnancy. CONCLUSION: Micro 3PN zygotes that develop to the blastocyst stage and meet the criteria for embryo biopsy have the potential to be euploid by preimplantation genetic testing for aneuploidy (PGT-A) and if selected for transfer can achieve a live birth. Although there are a significantly lower number of micro 3PN embryos that make it to blastocyst biopsy, the potential to continue to culture abnormally fertilized oocytes may give these patients a chance at pregnancy that they previously did not have.

An interpretable machine learning model for individualized gonadotrophin starting dose selection during ovarian stimulation.

RESEARCH QUESTION: Can we develop an interpretable machine learning model that optimizes starting gonadotrophin dose selection in terms of mature oocytes (metaphase II [MII]), fertilized oocytes (2 pronuclear [2PN]) and usable blastocysts? DESIGN: This was a retrospective study of patients undergoing autologous IVF cycles from 2014 to 2020 (n = 18,591) in three assisted reproductive technology centres in the USA. For each patient cycle, an individual dose-response curve was generated from the 100 most similar patients identified using a K-nearest neighbours model. Patients were labelled as dose-responsive if their dose-response curve showed a region that maximized MII oocytes, and flat-responsive otherwise. RESULTS: Analysis of the dose-response curves showed that 30% of cycles were dose-responsive and 64% were flat-responsive. After propensity score matching, patients in the dose-responsive group who received an optimal starting dose of FSH had on average 1.5 more MII oocytes, 1.2 more 2PN embryos and 0.6 more usable blastocysts using 10 IU less of starting FSH and 195 IU less of total FSH compared with patients given non-optimal doses. In the flat-responsive group, patients who received a low starting dose of FSH had on average 0.3 more MII oocytes, 0.3 more 2PN embryos and 0.2 more usable blastocysts using 149 IU less of starting FSH and 1375 IU less of total FSH compared with patients with a high starting dose. CONCLUSIONS: This study demonstrates retrospectively that using a machine learning model for selecting starting FSH can achieve optimal laboratory outcomes while reducing the amount of starting and total FSH used.

Biological relevance of trophectoderm morphology: initial ß-hCG measurements correlate with trophectoderm grading on euploid frozen embryo transfers.

OBJECTIVE: To analyze the correlation between TE grading and initial ß-hCG serum level after single euploid embryo transfer. Secondarily, to explore the association between TE grading with subsequent IVF outcomes. DESIGN: Retrospective cohort analysis. SETTING: Single, academic, private infertility and assisted reproductive care institute. PATIENTS OR OTHER PARTICIPANTS: Infertility patients who underwent a single euploid embryo transfer that resulted in a positive pregnancy test. INTERVENTION(S): ß-hCG measurements. MAIN OUTCOME MEASURE(S): Correlation between TE grade with first ß-hCG measurement. Second outcome measurements included ongoing pregnancy, biochemical pregnancy loss, and clinical pregnancy loss rates. RESULTS: 2,798 cases were analyzed. A significant difference in initial ß-hCG measurement among groups (TE A: median 143.4 mIU/mL IQR 79.2-211.2; TE B: 119 mIU/mL IQR 57.1-177.8; TE C: 82.4 mIU/mL IQR 36.3-136.4, p ≤ 0.0001) was observed. There was a significant correlation found between the TE grade and ß-hCG measurements (p ≤ 0.0001, r2 = 0.10). TE grade was not associated with higher odds of biochemical pregnancy loss (TE A vs. TE B: aOR 1.01 CI95% 0.97-1.05; TE A vs. TE C: aOR 1.03 CI95% 0.98-1.08), or higher odds of clinical pregnancy loss (TE A vs. TE B: aOR 1.02 CI95% 0.98-1.05; TE A vs. TE C: aOR 1.03 CI95% 0.98-1.07). CONCLUSIONS: In patients with euploid embryos, TE grade correlates with the first pregnancy test measurement of ß-hCG. We propose this finding helps to appoint a relevant link between morphology assessment and early embryo development in vivo.

A multi-centre international study of salivary hormone oestradiol and progesterone measurements in ART monitoring.

RESEARCH QUESTION: Ovarian stimulation during IVF cycles involves close monitoring of oestradiol, progesterone and ultrasound measurements of follicle growth. In contrast to blood draws, sampling saliva is less invasive. Here, a blind validation is presented of a novel saliva-based oestradiol and progesterone assay carried out in samples collected in independent IVF clinics. DESIGN: Concurrent serum and saliva samples were collected from 324 patients at six large independent IVF laboratories. Saliva samples were frozen and run blinded. A further 18 patients had samples collected more frequently around the time of HCG trigger. Saliva samples were analysed using an immunoassay developed with Salimetrics LLC. RESULTS: In total, 652 pairs of saliva and serum oestradiol were evaluated, with correlation coefficients ranging from 0.68 to 0.91. In the European clinics, a further 237 of saliva and serum progesterone samples were evaluated; however, the correlations were generally poorer, ranging from -0.02 to 0.22. In the patients collected more frequently, five out of 18 patients (27.8%) showed an immediate decrease in oestradiol after trigger. When progesterone samples were assessed after trigger, eight out of 18 (44.4%) showed a continued rise. CONCLUSIONS: Salivary oestradiol hormone testing correlates well to serum-based assessment, whereas progesterone values, around the time of trigger, are not consistent from patient to patient.

The association between prior cesarean delivery and subsequent in vitro fertilization outcomes in women undergoing autologous, frozen-thawed single euploid embryo transfer.

BACKGROUND: The rates of cesarean deliveries continue to increase worldwide. Previous work suggests an association between a previous cesarean delivery and reduced fertility in natural conception and in vitro fertilization treatment cycles. To our knowledge, there is no published research that explored the relationship between a previous cesarean delivery and the clinical outcomes after in vitro fertilization and the subsequent transfer of a single frozen-thawed euploid embryo. OBJECTIVE: This study aimed to investigate the relationship between the previous mode of delivery and subsequent pregnancy outcomes in patients undergoing a single frozen-thawed euploid embryo transfer after in vitro fertilization. STUDY DESIGN: A retrospective cohort study was performed at a single academic fertility center from January 2012 to April 2020. All women with a history of a live birth undergoing autologous, frozen-thawed single euploid embryo transfers were identified. Cases included patients with a single previous cesarean delivery; controls included patients with a single previous vaginal delivery. Only the first embryo transfer cycle was included. The primary outcome was the implantation rate. Secondary outcomes included ongoing pregnancy and live birth rates, biochemical pregnancy rate, and clinical miscarriage rate. RESULTS: A total of 525 patients met the inclusion criteria and were included in the analysis. Patients with a previous cesarean delivery had a higher body mass index (24.5±4.5 vs 23.4±4.1; P=.004) than those in the vaginal delivery cohort; the rest of the demographic data were otherwise similar. In a univariate analysis, the implantation rate was significantly lower in patients with a previous cesarean delivery (111/200 [55.5%] vs 221/325 [68.0%]; P=.004). After adjusting for the relevant covariates, a previous cesarean delivery was associated with a 48% reduction in the odds of implantation (adjusted odds ratio, 0.52; 95% confidence interval, 0.34-0.78; P=.002). In addition, after adjusting for the same covariates, a previous cesarean delivery was significantly associated with a 39% reduction in the odds of an ongoing pregnancy and live birth (adjusted odds ratio, 0.61; 95% confidence interval, 0.41-0.90; P=.01). There were no differences in the biochemical pregnancy rates or clinical miscarriage rates. CONCLUSION: This study demonstrated a marked reduction in implantation and ongoing pregnancy and live birth associated with a previous cesarean delivery in patients undergoing a single euploid embryo transfer. Our work stresses the importance of reducing the primary cesarean delivery rates at a national level and elucidating the mechanisms behind the substantially lower implantation rates after a cesarean delivery.

Factors associated with vitrification-warming survival in 6167 euploid blastocysts.

PURPOSE: To understand the clinical factors associated with embryo survival after vitrification in a cohort of human blastocysts screened by preimplantation genetic testing for aneuploidy (PGT-A). METHODS: Patient demographic, embryo, and cycle characteristics associated with failed euploid blastocyst survival were compared in a cohort of women (n = 6167) who underwent IVF-PGT-A. RESULTS: Compared to those that survived warming, vitrified euploid embryos that failed to survive after warming came from IVF cycles with significantly higher estradiol levels at time of surge (2754.8 ± 1390.2 vs. 2523.1 ± 1190.6 pg/mL, p = 0.03), number of oocytes retrieved (19.6 ± 10.7 vs. 17.5 ± 9.8, p = 0.005), and basal antral follicle count (BAFC) (15.3 ± 8.5 vs. 13.9 ± 7.2, p = 0.05). Euploid embryos were less likely to survive warming if they came from cycles before 2015 (24.6% vs. 13.2%, p < 0.001), were cryopreserved on day 7 versus day 5 or 6 (9.1% vs. 3.0%, p < 0.001), underwent two trophectoderm biopsies (6.9% vs. 2.3%, p < 0.001), had a grade C inner cell mass (15.4% vs. 7.7%, p < 0.001), or were fully hatched (41.1% vs. 12.2%, p < 0.001). In the multivariate model, which controlled for relevant confounders, the association between decreased survival and increased BAFC, year of IVF cycle, double trophectoderm biopsy, and fully hatched blastocysts remained statistically significant. CONCLUSION: Euploid embryos that are fully hatched at time of vitrification, come from patients with high ovarian reserve, or require repeat trophectoderm biopsy are less likely to survive vitrification-warming. Our results provide a framework for reproductive counseling and offer realistic expectations to patients about the number of embryos needed to achieve family building goals.

Clinical implementation of algorithm-based embryo selection is associated with improved pregnancy outcomes in single vitrified warmed euploid embryo transfers.

PURPOSE: To assess whether utilization of a mathematical ranking algorithm for assistance with embryo selection improves clinical outcomes compared with traditional embryo selection via morphologic grading in single vitrified warmed euploid embryo transfers (euploid SETs). METHODS: A retrospective cohort study in a single, academic center from September 2016 to February 2020 was performed. A total of 4320 euploid SETs met inclusion criteria and were included in the study. Controls included all euploid SETs in which embryo selection was performed by a senior embryologist based on modified Gardner grading (traditional approach). Cases included euploid SETs in which embryo selection was performed using an automated algorithm-based approach (algorithm-based approach). Our primary outcome was implantation rate. Secondary outcomes included ongoing pregnancy/live birth rate and clinical loss rate. RESULTS: The implantation rate and ongoing pregnancy/live birth rate were significantly higher when using the algorithm-based approach compared with the traditional approach (65.3% vs 57.8%, p<0.0001 and 54.7% vs 48.1%, p=0.0001, respectively). After adjusting for potential confounding variables, utilization of the algorithm remained significantly associated with improved odds of implantation (aOR 1.51, 95% CI 1.04, 2.18, p=0.03) ongoing pregnancy/live birth (aOR 1.99, 95% CI 1.38, 2.86, p=0.0002), and decreased odds of clinical loss (aOR 0.42, 95% CI 0.21, 0.84, p=0.01). CONCLUSIONS: Clinical implementation of an automated mathematical algorithm for embryo ranking and selection is significantly associated with improved implantation and ongoing pregnancy/live birth as compared with traditional embryo selection in euploid SETs.

Late follicular phase progesterone elevation during ovarian stimulation is not associated with decreased implantation of chromosomally screened embryos in thaw cycles.

STUDY QUESTION: What is the impact of a late follicular phase progesterone elevation (LFPE) during controlled ovarian hyperstimulation (COH) on embryonic competence and reproductive potential in thaw cycles of preimplantation genetic testing for aneuploidy (PGT-A) screened embryos? SUMMARY ANSWER: Our study findings suggest that LFPE, utilizing a progesterone cutoff value of 2.0 ng/ml, is neither associated with impaired embryonic development, increased rate of embryonic aneuploidy, nor compromised implantation and pregnancy outcomes following a euploid frozen embryo transfer (FET) cycle. WHAT IS KNOWN ALREADY: Premature progesterone elevation during COH has been associated with lower pregnancy rates due to altered endometrial receptivity in fresh IVF cycles. Also, increased levels of progesterone (P) have been suggested to be a marker for ovarian dysfunction, with some evidence to show an association between LFPE and suboptimal embryonic development. However, the effect of LFPE on embryonic competence is still controversial. STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis in a single, academic ART center from September 2016 to March 2020. In total, 5244 COH cycles for IVF/PGT-A were analyzed, of those 5141 were included in the analysis. A total of 23 991 blastocysts underwent trophectoderm biopsy and PGT analysis. Additionally, the clinical IVF outcomes of 5806 single euploid FET cycles were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohorts were separated in two groups: Group 1: oocytes retrieved from cycles with normal P levels during ovulation trigger (P ≤ 2.0 ng/ml); Group 2: oocytes retrieved after cycles in which LFPE was noted (P > 2.0 ng/ml). Extended culture and PGT-A was performed. Secondly, IVF outcomes after a single euploid FET were evaluated for each cohort. MAIN RESULTS AND THE ROLE OF CHANCE: Four thousand nine hundred and twenty-five cycles in Group 1 were compared with 216 cycles on Group 2. Oocyte maturity rates, fertilization rates and blastulation rates were comparable among groups. A 65.3% (n = 22 654) rate of utilizable blastocysts was found in patients with normal P levels and were comparable to the 62.4% (n = 1337) observed in those with LFPE (P = 0.19). The euploidy rates were 52.8% (n = 11 964) and 53.4% (n = 714), respectively, albeit this difference was not statistically significant (P = 0.81). Our multivariate analysis was fitted with a generalized estimating equation (GEE) and no association was found with LFPE and an increased odds of embryo aneuploidy (adjusted odds ratio 1.04 95% CI 0.86-1.27, P = 0.62). A sub-analysis of subsequent 5806 euploid FET cycles (normal P: n = 5617 cycles and elevated P: n = 189 cycles) showed no differences among groups in patient's BMI, Anti-Müllerian hormone (AMH), endometrial thickness at FET and number of prior IVF cycles. However, a significant difference was found in patient's age and oocyte age. The number of good quality embryos transferred, implantation rate, clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate and clinical pregnancy loss rates were comparable among groups. Of the registered live births (normal P group: n = 2198; elevated P group: n = 52), there were no significant differences in gestational age weeks (39.0 ± 1.89 versus 39.24 ± 1.53, P = 0.25) and birth weight (3317 ± 571.9 versus 3 266 ± 455.8 g, P = 0.26) at delivery, respectively. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and probable variability in the study center's laboratory protocol(s), selected progesterone cutoff value and progesterone assay techniques compared to other ART centers may limit the external validity of our findings. WIDER IMPLICATIONS OF THE FINDINGS: Based on robust sequencing data from a large cohort of embryos, we conclude that premature P elevation during IVF stimulation does not predict embryonic competence. Our study results show that LFPE is neither associated with impaired embryonic development nor increased rates of aneuploidy. Embryos obtained from cycles with LFPE can be selected for transfer, and patients can be reassured that the odds of achieving a healthy pregnancy are similar to the embryos exposed during COH cycles to physiologically normal P levels. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the realization of this study. Dr A.B.C. is advisor and/or board member of Sema 4 (Stakeholder in data), Progyny and Celmatix. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NA.

Expanded carrier screening for preconception reproductive risk assessment: Prevalence of carrier status in a Mexican population.

OBJECTIVE: Genetic carrier screening has the potential to identify couples at risk of having a child affected with an autosomal recessive or X-linked disorder. However, the current prevalence of carrier status for these conditions in developing countries is not well defined. This study assesses the prevalence of carrier status of selected genetic conditions utilizing an expanded, pan-ethnic genetic carrier screening panel (ECS) in a large population of Mexican patients. METHODS: Retrospective chart review of all patients tested with a single ECS panel at an international infertility center from 2012 to 2018 were included, and the prevalence of positive carrier status in a Mexican population was evaluated. RESULTS: Eight hundred five individuals were analyzed with ECS testing for 283 genetic conditions. Three hundred fifty-two carriers (43.7%) were identified with 503 pathogenic variants in 145 different genes. Seventeen of the 391 participating couples (4.34%) were identified as being at-risk couples. The most prevalent alleles found were associated with alpha thalassemia, cystic fibrosis, GJB2 nonsyndromic hearing loss, biotinidase deficiency, and familial Mediterranean fever. CONCLUSION: Based on the prevalence and severity of Mendelian disorders, we recommend that couples who wish to conceive regardless of their ethnicity background explore carrier screening and genetic counseling prior to reproductive medical treatment.

Infertile patients with inflammatory bowel disease have comparable in vitro fertilization clinical outcomes to the general infertile population.

To assess clinical outcomes of females diagnosed with Inflammatory Bowel Disease (IBD) and infertility, which underwent in vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy. (PGT-A). Retrospective cohort study comparing clinical outcomes of patients with Inflammatory bowel disease who underwent IVF with PGT-A with a subsequent euploid single embryo transfer (SET) against a matched control group. Thirty-eight patients with an IBD diagnosis were compared to 114 controls. There was no significant difference in cycle outcomes among IBD and Control cohorts [implantation rate (71.0% vs. 78.0% (p = .68)], clinical pregnancy rate [50.0% vs. 60.5% (p = .68)], live birth [62.9% vs. 73.0% (p = .06)] multiple pregnancy rate [0% vs. 1.1% (p = .25)] and clinical pregnancy loss rate [10.5% vs. 5.7% (p = .54)]. An IBD diagnosis was not found to significantly modify the odds of implantation [adjusted OR = 0.6 (95% CI -1.2 to 0.8)]. Additionally, the odds of implantation in patients with IBD were not altered by having ulcerative colitis or Crohn's disease diagnosis. (OR = 0.4 95% CI 0.1-1.9). Patients diagnosed with IBD who undergo a SET have clinical outcomes comparable to the general infertile population. Patients and physicians can be reassured that an IBD diagnosis does not impair IVF treatment outcomes.SYNOPSISInfertile patients with inflammatory bowel disease who utilized a single, euploid blastocyst transfer had IVF success rates comparable to the general infertile population.

What is the reproductive potential of day 7 euploid embryos?

STUDY QUESTION: What is the rate of euploidy and the reproductive potential of embryos biopsied after 6 days of development? SUMMARY ANSWER: Embryos biopsied after 6 days of development have higher rates of aneuploidy; however, day 7 euploid embryos selected at transfer can achieve acceptable pregnancy rates and live birth (LB) outcomes. WHAT IS KNOWN ALREADY: Recent publications have shown promising treatment results after euploid day 7 embryo transfers (ETs), albeit these studies were limited by small sample sizes. Whereas the current clinical standard has been to discard embryos that do not reach expansion by day 6 of development, the lack of robust data surrounding the clinical utility of day 7 embryos warrants further evaluation. STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis in a single, academic in vitro fertilization (IVF) center from January 2012 to March 2018. A total of 25 775 embryos underwent trophectoderm (TE) biopsy and preimplantation genetic testing for aneuploidy (PGT-A). Additionally, the clinical IVF outcomes of 3824 single, euploid frozen embryo transfer (FET) cycles were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohorts were segregated by day of TE biopsy following oocyte retrieval (day 5, day 6 or day 7). PGT-A was performed to identify embryonic ploidy rates. Secondly, IVF and LB outcomes after single, euploid FET were evaluated for each cohort. MAIN RESULTS AND THE ROLE OF CHANCE: A total of day 5 (n = 12 535), day 6 (n = 11 939) and day 7 (n = 1298) embryos were included in the study analysis. The rate of embryo euploidy was significantly lower in day 7 blastocysts compared to day 5 or day 6 cohorts (day 7 = 40.5%; day 5 = 54.7%; day 6 = 52.9%; (P < 0.0001)). After adjusting for age, anti-Müllerian hormone, BMI, embryo quality and number of embryos biopsied, there was a significant association between aneuploidy and embryos biopsied on day 7 when compared to day 5 biopsied embryos (OR = 1.34, CI 95% 1.09-1.45, P = 0.001) and day 6 biopsied embryos (OR = 1.26, CI95% 1.07-1.16, P < 0.001).A sub-analysis of subsequent 3824 single, euploid FET cycles (day 5: n = 2321 cycles; day 6: n = 1381 cycles; and day 7: n = 116 cycles) showed significant differences among cohorts in implantation, clinical pregnancy, LB and clinical loss rates. There was a significant decrease in the odds of implantation, clinical pregnancy and LB, but no association with clinical loss or multiple pregnancy rates in patients who utilized day 7-biopsied embryos during treatment. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and potential variability in the study center's laboratory protocol(s) compared to other reproductive treatment centers may limit the external validity of our findings. Additionally, patients who transferred euploid embryos, biopsied on day 7 of development due to an absence of day 5 or day 6 counterparts, may have introduced selection bias in this study. WIDER IMPLICATIONS OF THE FINDINGS: Embryonic developmental stage, morphological grade and ploidy status are paramount factors affecting ET selection and implantation potential. This study reveals that embryos ineligible for TE biopsy on day 5 or day 6 of development may benefit from extended culture to day 7. Our study demonstrates patient benefit when extended culture to day 7 of development is routinely performed for embryos failing to meet biopsy criteria by day 5 or 6. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the realization of this manuscript. Dr Alan Copperman is Advisor or Board Member of Sema 4 (Stake holder in Data), Progyny and Celmatix. TRIAL REGISTRATION NUMBER: This retrospective analysis was approved by an Institutional Review Board (WIRB PRO NUM: 20161791; Study Number: 1167398).

The correlation between morphology and implantation of euploid human blastocysts.

RESEARCH QUESTION: Does the composite morphology score or a particular developmental component (expansion stage, inner cell mass [ICM] or trophectoderm [TE]) of euploid blastocysts undergoing single frozen embryo transfer (FET) impact ongoing pregnancy/live birth (OP/LB) rates? DESIGN: Retrospective cohort study including a total of 2236 embryos from 1629 patients who underwent single euploid FET between 2012 and 2017. RESULTS: Embryos with an ICM grade of A compared with C had a higher OP/LB rate (55.6% versus 32.3%, P < 0.001). Blastocysts with a TE grade of A or B compared with C had a higher likelihood of OP/LB (A versus C: odds ratio [OR] 1.6, 99% confidence interval [CI] 1.1-2.3, B versus C: OR 1.5, 99% CI 1.1-2.1), and blastocysts with a developmental stage of 4 or 5 compared with 6 had higher odds of OP/LB (4 versus 6: OR 1.6, 99% CI 1.2-2.2, 5 versus 6: OR 1.6, 99% CI 1.2-2.3). CONCLUSIONS: Among euploid embryos, ICM morphology is the best predictor of sustained implantation; however, a composite score may provide additional guidance. While there is a known benefit in genomic screening prior to embryo selection, morphology provides individualized, prognostic information about implantation potential.

How time to healthy singleton delivery could affect decision-making during infertility treatment: a Delphi consensus.

RESEARCH QUESTION: How might time to healthy singleton delivery affect decision-making during infertility treatment? DESIGN: This was a Delphi consensus investigating expert opinion that comprised three steps. In Step 1, 12 experts developed statements. In Step 2, 27 experts (including 12 from Step 1) voted (online survey) on their agreement/disagreement with each statement (providing reasons). Consensus was reached if ≥66% of participants agreed/disagreed. Statements not reaching consensus were revised and the process repeated until consensus was achieved. In Step 3 details of the final agreed statements were communicated. RESULTS: Twelve statements were developed, and consensus (agreement) was reached on all after one round of voting. CONCLUSIONS: Time to healthy singleton delivery should be taken into consideration when making decisions related to infertility treatment, and it is important that fertility treatment is provided in a timely manner, avoiding over- or under-treatment. In all subfertile women <40 years old, IVF outcomes could be optimized by performing up to six single-embryo transfers and certain procedures might reduce time to healthy singleton delivery. These procedures include preimplantation genetic testing for aneuploidies, frozen replacement cycles immediately after failed fresh cycles and use of gonadotrophin-releasing hormone antagonists. Finally, the number of oocytes retrieved should be maximized to increase cumulative live birth rate.

New insights into human prolactin pathophysiology: genomics and beyond.

PURPOSE OF REVIEW: To briefly summarize what is known regarding hyperprolactinemia and prolactin-secreting tumors, and review recent findings. RECENT FINDINGS: Prolactin was previously thought to inhibit secretion of gonadotropin-releasing hormone (GnRH) by directly inhibiting the firing of GnRH neurons, resulting in hypogonadotropic hypogonadism and infertility. However, kisspeptin has recently been implicated as the mediator of hyperprolactinemia-induced infertility, by acting upstream of the GnRH neurons as an integrator of endocrine signals.Macroprolactin is generally considered to be inactive and clinically insignificant, but new studies have suggested that patients with macroprolactinemia may have reproductive manifestations as well as sexual dysfunction.Several mutations and polymorphisms in the prolactin receptor have been described, which could describe a genetic cause for prolactinomas and characterize cases of isolated familial hyperprolactinemia.Kisspeptin and tyrosine kinase inhibitors have emerged as potential new therapeutic targets for the treatment of hyperprolactinemia and dopamine-resistant prolactinomas. SUMMARY: Molecular studies are shedding light on the pathophysiology of hyperprolactinemia and the effects of excess prolactin production on the reproductive system. Similarly, genetic studies have begun to reveal how differences in prolactin receptor function may account for some of the previously 'idiopathic' cases of hyperprolactinemia and bring to light new causes of prolactinomas. Further elucidation of the transcriptional pathways affected by these genetic changes may help to create new therapeutic targets.