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.

Spironolactone use and oocyte maturation in patients undergoing controlled ovarian hyperstimulation.

PURPOSE: To evaluate the association between spironolactone use and controlled ovarian hyperstimulation (COH) outcomes. METHODS: Retrospective study, including patients who underwent COH. Oocyte yield and maturation rates were compared by categories of spironolactone use at the start of their cycle. RESULTS: 402 patients were included. 83 patients continued spironolactone, 44 patients discontinued spironolactone, and 275 matched control patients were spironolactone-naïve. No difference was observed in the number of oocytes retrieved (17 ± 14 vs. 15 ± 13, p = 0.4) or mature oocytes vitrified (15 ± 9.5 vs. 12 ± 11, p = 0.4) in patients who continued spironolactone use and spironolactone naïve patients, respectively. When comparing patients who continued spironolactone use and patients who discontinued spironolactone use, no difference was seen in the number of oocytes retrieved (17 ± 14 vs. 17.5 ± 7.8, p = 0.9) or mature oocytes vitrified (15 ± 9.5 vs. 13.5 ± 6.5, p = 0.5), respectively. There was no observed relationship between total daily spironolactone dose (< 100mg/day, 100mg/day, 150mg/day and > 200 mg/day) and the total number of mature oocytes vitrified (respectively, 14.0 ± 13.0, 16.0 ± 7.8, 14.0 ± 4.5, 11.0 ± 7.0 oocytes, p = 0.4). CONCLUSIONS: This is the first study to evaluate the association between spironolactone and oocyte yield and maturation rates during COH cycles. These findings can assist in counseling patients on the implications of continuing spironolactone during COH cycle.

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.

Assisted Reproductive Technology Treatment Outcomes in Women With Liver Disease.

INTRODUCTION: There is a need for evidence-based counseling for women with chronic liver disease (LD) who may experience impaired fertility. Currently, the literature on assisted reproductive technology (ART) treatment in women with LD has been limited to a single European case series. We evaluated ART treatment outcomes in patients with LD and compared with controls. METHODS: The retrospective study evaluated women with and without LD who had normal ovarian reserve and underwent ART treatment in a high-volume fertility practice from 2002 to 2021. RESULTS: We identified 295 women with LD (mean age 37.8 ± 5.2 years) who underwent 1,033 ART treatment cycles; of these women, 115 underwent 186 in vitro fertilization (IVF) cycles. Six women (2.0%) had cirrhosis, 8 (2.7%) were postliver transplantation, and 281 (95.3%) had chronic LD, with viral hepatitis (B and C) being the most prevalent. In the subgroup who underwent IVF and embryo biopsy, the median fibrosis-4 score was 0.81 (0.58-1.03), and there were no statistically significant differences in response to controlled ovarian stimulation, embryo fertilization rate, or ploidy outcome in patients with LD compared with controls. In those who subsequently underwent a single thawed euploid embryo transfer to achieve pregnancy, there were no statistically significant differences in rates of clinical pregnancy, clinical pregnancy loss, or live birth in patients with LD compared with controls. DISCUSSION: To the best of our knowledge, this study is the largest to date to evaluate IVF efficacy in women with LD. Our study demonstrates that patients with LD have similar ART treatment outcomes compared with those without LD.

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.

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.

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.

Optimal Interval of Time from Operative Hysteroscopy to Embryo Transfer in an In Vitro Fertilization Cycle.

STUDY OBJECTIVE: Data are limited regarding optimal timing between operative hysteroscopy and embryo transfer (ET). This study aimed to assess whether the time interval from operative hysteroscopy to ET affects implantation and clinical pregnancy rates. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Private academic center. PATIENTS: All patients who had operative hysteroscopy followed by a day 5 ET from 2012 to 2017. INTERVENTION: Interval of time from operative hysteroscopy to ET. MEASUREMENTS AND MAIN RESULTS: The interval of time from hysteroscopy to ET was calculated, and linear regression analyses were performed to assess the impact on clinical outcome. A subanalysis of patients who underwent subsequent single, euploid, frozen ET(s) was performed. A total of 318 patients were included. Indications for hysteroscopy included polypectomy (n = 205), myomectomy (n = 36), lysis of adhesions (n = 46), septum resection (n = 19), and retained products of conception (n = 12). The mean interval of time from hysteroscopy to ET was 138.4 ± 162.7 days (range, 20-1390). There was no significant difference in mean interval of time between procedure and subsequent ET when comparing patients who achieved and did not achieve implantation. Patients stratified by interval of time from operative hysteroscopy to ET had similar clinical outcomes. The time interval from hysteroscopy had no impact on odds of implantation (odds ratio [OR], 1.001; 95% confidence interval [CI], .999-1.002; p = .49), ongoing pregnancy (OR, 1.001; 95% CI, .999-1.002; p = .42), or early pregnancy loss (OR, .997; 95% CI, .994-1.000; p = .07) (adjusted for oocyte age, recipient age, endometrial thickness, use of preimplantation genetic testing, use of donor egg, fresh vs frozen ET, ET count). Similar results were observed in the subanalysis restricted to euploid single frozen ETs from autologous cycles. CONCLUSION: The time interval from operative hysteroscopy to subsequent ET does not impact the likelihood of successful clinical outcome. Patients who have undergone operative hysteroscopy do not need to delay fertility treatment.

Blastocyst vitrification, cryostorage and warming does not affect live birth rate, infant birth weight or timing of delivery.

RESEARCH QUESTION: Does vitrification and warming affect live birth rate, infant birth weight and timing of delivery? DESIGN: Retrospective, cohort study comparing outcomes of donor oocyte recipient fresh (n = 25) versus vitrified (n = 86) euploid blastocyst transfers; donor oocyte recipient singleton live births from fresh (n = 100) versus vitrified (n = 102) single embryo transfers (SET); and autologous vitrified euploid SET (n = 1760) (cryostored 21-1671 days). RESULTS: Group 1: fresh and vitrified-warmed blastocysts had similar live birth (OR 1.7; 95% CI 0.5 to 5.9), implantation (OR 0.9; 95% CI 0.2 to 3.9), clinical pregnancy (OR 3.4; 95% CI 0.9 to 13.0) and pregnancy loss (OR 1.2; 95% CI 0.98 to 1.4); group 2: low birth weight (OR 0.44; 95% CI 0.1 to 1.6) and preterm delivery (0.99; 95% CI 0.4 to 2.3) rates were similar in fresh and vitrified-warmed blastocyst transfers; group 3: cryostorage duration did not affect live birth (OR 1.0; 95% CI 1.0 to 1.0), implantation (OR 1.0; 95% CI 0.99 to 1.01), clinical pregnancy (OR 1.0; 95% CI 1.0 to 1.0]), pregnancy loss (OR 0.99; 95% CI 1.0 to 1.0), birth weight (ß = -15.7) or gestational age at delivery (ß = -0.996). CONCLUSIONS: Vitrification and cryostorage (up to 4 years) are safe and effective practices that do not significantly affect clinical outcome after embryo transfer.

The effect of female body mass index on in vitro fertilization cycle outcomes: a multi-center analysis.

PURPOSE: The aim of this study is to examine the impact of female body mass index (BMI) on IVF cycle outcomes. METHODS: This is a retrospective cohort study including 51,198 women who initiated their first autologous IVF cycle in 13 fertility centers in the USA between 2009 and 2015. The effect of underweight, overweight, and obese BMI on four different IVF cycle outcomes (cycle cancellation, oocyte and embryo counts, and ongoing clinical pregnancy [OCP]) was evaluated in logistic or Poisson regression analyses with confounders adjusted. RESULTS: Women with an overweight or obese BMI experienced worse outcomes than those with a normal BMI. These differences included (1) greater odds of cycle cancellation (aOR [95%CI] 1.17 [1.08, 1.26] for overweight, 1.28 [1.15, 1.41] for class-I obesity, and 1.50 [1.33, 1.68] for class-II/III obesity, P < .001 for all); (2) fewer oocytes retrieved (aIRR [95%CI] 0.98 [0.98,0.99] for class-I obesity, 0.93 [0.92,0.94] for class-II/III obesity, P < .001 for both); (3) fewer usable embryos (aIRR [95%CI] 0.98 [0.97,0.99] for overweight, 0.97 [0.96,0.99] for class-I obesity, 0.95 [0.93,0.97] for class-II/III obesity, P < .01 for all); and (4) lower odds of OCP (aOR [95%CI] 0.89 [0.83,0.95] for class-I obesity, 0.86 [0.79,0.93] for class-II/III obesity, P < .001 for both). In a subgroup analysis based on primary infertility diagnosis, these trends persisted in those with male or uterine factor and were especially pronounced in women with ovulatory dysfunction or PCOS. CONCLUSIONS: A BMI above the normal range was an independent negative prognostic factor for multiple outcomes, including cycle cancellation, oocyte and embryo counts, and OCP. These negative outcomes were most profound in women with class-II/III obesity, ovulatory dysfunction, or PCOS.

The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response.

OBJECTIVE: Controlled ovarian hyperstimulation (COH) promotes multifollicular growth, increasing the chance of obtaining euploid embryos that will successfully implant. Whether aneuploidy is increased from COH with exogenous gonadotropins interfering with natural selection of dominant follicles is a concern. This study evaluates the association between gonadotropin exposure and aneuploidy. METHODS: This is a retrospective cohort study of 828 patients that underwent 1122 IVF cycles involving controlled ovarian stimulation and trophectoderm biopsy for preimplantation genetic screening (PGS), from 2010 to 2015. Polymerase chain reaction (PCR) was used to assess aneuploidy. Kruskal-Wallis tests and logistic regression with generalized estimating equations (GEEs) were used for data analysis. RESULTS: Overall, after controlling for patient age, ovarian reserve, stimulation protocol, days of stimulation, and diagnoses, there was no significant association between cumulative gonadotropin (GND) dose and the odds of aneuploidy (adjusted OR = 1.049, p = 0.232). Similarly, in cycles where patients did not require COH beyond cycle day 12, there was no significant association between cumulative gonadotropin dose and the odds of aneuploidy (adjusted OR = 0.909, p = 0.148). However, in cases where patients were stimulated past cycle day 12, there was a significant increase in the odds of aneuploidy (adjusted OR = 1.20, 95% CI 1.125-1.282, p < 0.0001) with increasing cumulative gonadotropin dose, with a small effect size (Cohen's d = 0.10, 95% CI 0.08-0.12). In this cohort, there was a 16.4% increase in the odds of aneuploidy for each 1000-u increase in cumulative GND exposure (adjusted OR = 1.164, p = 0.002). When the analysis was restricted to low responders (peak estradiol <500 pg/mL or <4 mature follicles achieved; there was no significant association between gonadotropin dose and aneuploidy (adjusted OR = 1.12, 95% CI 0.982-1.28, p = 0.09), regardless of the duration of COH required to reach vaginal oocyte retrieval. CONCLUSION: The degree of exposure to exogenous gonadotropins did not significantly modify the likelihood of aneuploidy in patients with a normal ovarian response to stimulation (not requiring COH beyond cycle day 12). Patients requiring prolonged COH were demonstrated to have elevated odds of aneuploidy with increasing cumulative gonadotropin dose. This finding may reflect an increased tendency towards oocyte and embryonic aneuploidy in patients with a diminished response to gonadotropin stimulation.

Do elevated TSH levels predict early pregnancy loss in ART patients?

INTRODUCTION: The upper limit of normal TSH has been revised from 5 mIU/L to 2.5 mIU/L. We sought to evaluate IVF patients and the association between abnormal TSH and early pregnancy loss. METHODS: A retrospective study of patients who had TSH levels measured within the 2 weeks prior to their fresh autologous IVF cycles (2002-2014). Cohorts were stratified by oocyte age (<35, [35-38), [38-41), [41-43) and ≥43 years), and TSH level [(0-0.5], (0.5-2.5], (2.5-5], and (5-23) mIU/L]. Patients were followed until pregnancy loss or delivery. Model was assessed by chi-square of ANOVA with significance at p < 0.05. RESULTS: TSH was abnormally elevated (>5 mIU/L), mildly elevated ((2.5-5] mIU/L) or suppressed (≤0.5 mIU/L) in 46, 317 and 65 of the 1201 total cycles, respectively. Treatment resulted in 630 pregnancies, 524 clinical pregnancies and 409 deliveries. Pregnancy loss rates were increased in patients ≥38 yo (p < 0.001) but not [35-38) yo (p = 0.40) compared with those <35 yo. Early pregnancy loss rate was not associated with TSH level (p > 0.30) compared with euthyroid patients after adjusting for oocyte age. CONCLUSION: Early pregnancy loss rate in IVF patients appears to have no relation to recent TSH levels.

Maximum basal FSH predicts reproductive outcome better than cycle-specific basal FSH levels: waiting for a "better" month conveys limited retrieval benefits.

BACKGROUND: Elevated follicle stimulating hormone (FSH) is associated with poor vaginal oocyte retrieval (VOR) outcomes and cycle cancellations but intercycle variability in basal FSH reportedly does not predict ovarian response. METHODS: We conducted a retrospective cohort study of basal FSH (n = 15573 cycles) in couples (n = 9132) who initiated IVF cycle(s) with basal estradiol (E2) <100 pg/mL between 2002 and 2014 to reevaluate this hypothesis. The most recent (current) FSH, maximum FSH (Max FSH) and prior cycle maximum basal FSH (PMax FSH) were computed for each cycle. Metaphase II (MII) oocyte counts were modeled by age, stimulation type, prior peak E2 level, prior MII count, Max FSH, PMax FSH and current FSH. Antral follicle counts, pregnancy, clinical pregnancy and live birth rates were modeled as secondary outcomes. RESULTS: Max FSH level distinguished completed cycles from cancelled cycles better than PMax FSH or current FSH (AUC of 0.72, 0.71 and 0.61, respectively, p < 0.001). Fewer MIIs were retrieved (5.7 ± 3.8) in cycles with Max FSH >13 mIU/mL (n = 1475) than those with ≤13 mIU/mL (n = 11978) (11.6 ± 7.1) (p < 0.001). Max FSH was a better predictor of MII count than PMax FSH or current FSH after controlling for age, stimulation type, prior peak E2 level and prior MII count. Additional MIIs were retrieved on average in cycles with PMax FSH >13 mIU/mL (n = 1930) whose current FSH was ≤13 mIU/ml rather than >13 mIU/ml (p < 0.01) after controlling for age, cycle number and stimulation type. However, no improvement in pregnancy or live birth rate was detected. CONCLUSIONS: Max FSH is the best FSH-based predictor of ovarian reserve. Retrieval benefits from waiting for a "better" month appear to exist but are limited.