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.

Effect of postthaw change in embryo score on single euploid embryo transfer success rates.

OBJECTIVE: To assess whether the change in embryo morphology from precryopreservation to postthaw is associated with the embryo transfer success rates in single euploid embryo transfer cycles. DESIGN: Retrospective cohort study. SETTING: Academic affiliated fertility clinic. PATIENT(S): Patients who underwent a single euploid embryo transfer cycle from September 2016 to April 2022 were included. A decision support tool was used to assign each embryo a reproductive potential score on the basis of the day of biopsy, expansion, and grade of trophectoderm and inner cell mass at the time of cryopreservation and after thaw. Embryos were divided into 4 groups: group 1 included embryos with the same score after thaw (reference); group 2 included those with a higher score; group 3 included those with a lower score; and group 4 included those that did not re-expand after thaw. INTERVENTION(S): No interventions administered. MAIN OUTCOME MEASURE(S): The primary outcome was the live birth rates (LBRs) per embryo transfer. The secondary outcomes included the chemical pregnancy, clinical pregnancy, and clinical pregnancy loss rates. Comparative statistics and univariate analyses were performed using the Kruskal-Wallis and χ2tests. Multivariate logistic regression fitted with generalized estimating equation was performed to compare the odds of live birth between groups. RESULT(S): A total of 7,750 embryo transfers performed for 4,613 patients met inclusion criteria: 5,331 in group 1; 486 in group 2; 1,726 in group 3; and 207 in group 4. In the univariate analysis, there was a statistically significant difference in the LBR between groups 1, 2, 3, and 4 (55.8% vs. 51.4%, 47.5%, and 26.6%). Logistic regression controlling for oocyte age, antimüllerian hormone, body mass index, endometrial thickness, year of embryo transfer, time from thaw to final grading, and embryo score before cryopreservation showed significantly lower odds of live birth when the embryo was downgraded (odds ratio [OR], 0.70; confidence interval [CI], 0.62-0.79) or did not re-expand (OR, 0.36; CI, 0.26-0.51) than those with no change in score. When controlling for all variables, there was a significant increase in the odds of live birth between embryos that had a higher score after thaw and those without a change (OR, 1.42; CI, 1.14-1.76). There was no significant difference in the clinical pregnancy loss rate among the 4 groups. CONCLUSION(S): The change in the quality of the embryo after thaw is an important factor in embryo transfer success. In an adjusted analysis, the chemical and clinical pregnancy rates and LBR per embryo transfer all significantly decrease in embryos that were downgraded or did not expand on the day of single euploid embryo transfer. Embryos that re-expand and have improved quality after thaw have the highest odds of live birth.

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.

Family Building in Transgender Patients: Modern Strategies with Assisted Reproductive Technology Treatment.

Purpose: Transgender and gender diverse (TGD) individuals continue to face adversity, stigma, and inequality, especially in health care. This study aimed to characterize the experience of TGD people and partners of TGD people with regard to fertility treatment. Methods: All TGD patients presenting to a single academic center between 2013 and 2021 were included. Baseline demographics collected included patient age, body mass index, anti-Mullerian hormone, basal antral follicle count, history of gender-affirming surgery, and/or gender-affirming hormone therapy. Outcomes included total patients who progressed to treatment, cycle type(s), and clinical outcomes. Results: In total, 82 patients who identified as TGD or had a partner who identified as TGD presented to care seeking fertility treatment. Of the 141 planned cycles, 106 (75.2%) progressed to treatment. Of the 15 in vitro fertilization (IVF) and co-IVF cycles, 12 achieved live birth. Of the 76 intrauterine inseminations 7 patients were discharged with ongoing pregnancies and one achieved live birth. Conclusion: These findings reaffirm that TGD individuals utilize the entire array of fertility services. With recent advances in access to care and modern medicine, assisted reproductive technology treatment has the power to support TGD patients in building contemporary family structures.

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.

Association of Myomectomy With Anti-Müllerian Hormone Levels and Ovarian Reserve.

OBJECTIVE: To assess whether open and minimally invasive myomectomy are associated with changes in postoperative ovarian reserve as measured by serum anti-müllerian hormone (AMH) level. METHODS: This prospective cohort study included patients who were undergoing open abdominal myomectomy that used a tourniquet or minimally invasive (robot-assisted or laparoscopic) myomectomy that used vasopressin. Serum AMH levels were collected before the procedure and at 2 weeks, 3 months, and 6 months after surgery. The mean change in AMH level at each postsurgery timepoint was compared with baseline. The effect of surgical route on the change in AMH level at each timepoint was assessed by using multivariable linear regression. A subanalysis evaluated postoperative changes in AMH levels among the open myomectomy and minimally invasive myomectomy groups individually. RESULTS: The study included 111 patients (mean age 37.9±4.7 years), of whom 65 underwent open myomectomy and 46 underwent minimally invasive myomectomy. Eighty-seven patients contributed follow-up data. Serum AMH levels declined significantly at 2 weeks postsurgery (mean change -0.30 ng/mL, 95% CI -0.48 to -0.120 ng/mL, P=.002). No difference was observed at 3 months or 6 months postsurgery. On multiple linear regression, open myomectomy was significantly associated with a decline in AMH level at 2 weeks postsurgery (open myomectomy vs minimally invasive myomectomy: ß=-0.63±0.22 ng/mL, P=.007) but not at 3 months or 6 months. Subanalysis revealed a significant decline in mean serum AMH levels in the open myomectomy group at 2 weeks (mean change -0.46 ng/mL, 95% CI -0.69 to -0.25 ng/mL, P<.001) postsurgery but not at three or 6 months. In the minimally invasive myomectomy group, no significant differences in mean AMH levels were detected between baseline and any postoperative timepoint. CONCLUSION: Myomectomy is associated with a transient decline in AMH levels in the immediate postoperative period, particularly after open surgery in which a tourniquet is used. Anti-müllerian hormone levels returned to baseline by 3 months after surgery, indicating that myomectomy is not associated with a long-term effect on ovarian reserve, even with the use of a tourniquet to decrease blood loss. FUNDING SOURCE: This study was funded in part by a Roche Diagnostics Investigator-Initiated Study Grant.

Rate of Post-Fertilization Mitotic Activity Predicts Embryonic Competence via Next Generation Sequencing: An Analysis of 39,301 Cleavage Stage Embryos.

OBJECTIVE: To investigate the association between cleavage stage development, embryonic competence, and euploidy in patients undergoing in vitro fertilization (IVF) with subsequent next generation sequencing. METHODS: The retrospective cohort study included patients at an academic fertility center who underwent IVF with at least one cleavage stage embryo from 2016 to 2019. Embryos were analyzed as slow (<6 cells), intermediate (6-8 cells), or fast (>8 cells); day 3 cell count was also analyzed as a continuous variable. Primary outcomes were blastulation rate, biopsied blastocyst rate, and euploid rate. Odds of blastulation, biopsy, and euploidy were also calculated. Additionally, we modeled the predicted probability of an embryo reaching blastulation, biopsy, and euploidy based on cleavage stage development. RESULTS: When compared with intermediate and slow cohorts, fast cleaving embryos had significantly higher rates of blastulation (82.70% vs. 75.13 vs. 42.48%), biopsy (55.04% vs. 44.00% vs. 14.98%), and euploidy (50.65% vs. 47.93% vs. 48.05%). After adjustment for covariates, there was a significant association between cleavage stage development and odds of blastulation (OR 1.38, 95% CI 1.29-1.48), biopsy (OR 1.42, 95% CI 1.34-1.51), and euploidy (OR 1.08, 95% CI 1.01-1.17). Finally, we observed significant associations between cleavage stage development and predicted probability of reaching blastulation (OR 1.29, 95% CI 1.27-1.32), biopsy (OR 1.24, 95% CI 1.22-1.26), and euploidy (OR 1.02, 95% CI 1.01-1.04). CONCLUSIONS: Cleavage stage embryos with greater mitotic activity perform as well as or better than intermediate or slower cleaving embryos. Rapidly cleaving embryos have high rates of euploidy and significant clinical potential.

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.

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.

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.

Conservative treatment versus surgical excision of ovarian dermoid cysts: Impact on ovarian stimulation and IVF cycle success.

OBJECTIVE: To analyze outcomes of IVF treatment among women diagnosed with an ovarian dermoid cyst (DC). METHODS: Retrospective analysis of women with an ovarian DC who underwent IVF with fresh blastocyst transfer at a single center in New York from January 2010 to March 2018. Outcomes were compared between women with conservative treatment and those with surgical excision of the DC. Multivariate logistic regression was used to assess associations between variables and the presence of a DC during treatment. RESULTS: Overall, 119 women with a DC were included. No differences were found in demographic characteristics, controlled ovarian hyperstimulation parameters, and IVF outcomes between women with an intact DC (n=65, 54.6%) and those who underwent cystectomy (n=54, 45.4%) (all P<0.05). Similarly, there was no difference in anti-Mϋllerian hormone and basal antral follicle count among women with a DC (respectively, ß=-0.1, P=0.8, and ß=-1.0, P=0.28) or resected DC (respectively, ß=0.9, P=0.07, and ß=1.5, P=0.08) as compared with control women with no DC (n=352). CONCLUSION: Ovarian reserve, embryo implantation and IVF success rates were not lower in the presence of an ovarian DC. Surgical therapy, if indicated, can be safely postponed until family planning goals have been achieved.

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).

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.

Endometrial preparation before the transfer of single, vitrified-warmed, euploid blastocysts: does the duration of estradiol treatment influence clinical outcome?

OBJECTIVE: To investigate whether the duration of estrogen administration before euploid embryo transfer affects clinical outcome. DESIGN: Retrospective cohort study. SETTING: Private, academic fertility center. PATIENT(S): Patients (n = 1,439) undergoing autologous freeze-only in vitro fertilization with preimplantation genetic testing (PGT) followed by endometrial preparation with estrogen and progesterone in a frozen, euploid blastocyst transfer cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome was live birth, and secondary outcomes included implantation, clinical pregnancy, early pregnancy loss, live birth, infant birthweight, low birth weight, infant gestational age at delivery, and preterm birth. RESULT(S): The duration of estrogen administration (mean: 17.5 ± 2.9 days; range: 10-36 days) before frozen embryo transfer did not impact implantation (odds ratio [OR] 0.99; 95% confidence interval [CI], 0.95-1.03), clinical pregnancy (OR 0.98; 95% CI, 0.94-1.01), early pregnancy loss (OR 1.03; 95% CI, 0.95-1.12), or live birth (OR 0.99; 95% CI, 0.95-1.03). The duration of estrogen exposure did not affect infant birthweight (in grams) (ß= -10.65 ± 8.91) or the odds of low birth weight (OR 0.87; 95% CI, 0.68-1.13). For every additional day of estrogen administration, we observed a reduction in gestational age at delivery (in weeks) (ß= -0.07 ± 0.03), but the odds of preterm delivery were not affected (OR 1.05; 95% CI, 0.95-1.17). CONCLUSION(S): Variation in the duration of estradiol supplementation before progesterone initiation does not impact frozen, euploid blastocyst transfer outcome. The duration of estrogen administration was inversely correlated with gestational age at delivery, but this did not translate into an increase in preterm delivery. Further studies are required on the downstream effects of endometrial preparation on the placental-endometrium interface.

Understanding the Reproductive Experience and Pregnancy Outcomes of Lesbian Women Undergoing Donor Intrauterine Insemination.

PURPOSE: The study purpose was to evaluate the reproductive experience, specifically cycle characteristics and treatment outcomes, of lesbian women. In addition, we aimed to determine whether there are differences in pregnancy outcomes when comparing lesbian women undergoing ovulation induction (OI) versus natural cycles with donor intrauterine insemination (IUI), as well as lesbian and heterosexual women undergoing the same assisted reproductive technology treatment. METHODS: This was a retrospective cohort study including women who underwent an IUI with cryopreserved sperm between 2006 and 2018. The primary outcome of interest was clinical pregnancy (CP) rate. RESULTS: A total of 216 lesbian women (451 natural cycles and 441 OI cycles) and 584 heterosexual women (1177 natural cycles and 1238 OI cycles) were included in the study. Thirty percent of lesbian women had a hysterosalpingogram as part of their initial workup. Approximately 40% of lesbian women who underwent OI/IUI had previously undergone at least one natural cycle/IUI. There was no significant difference in CP rate when comparing lesbian women and heterosexual women undergoing natural or OI/IUI, or when comparing lesbian women who underwent natural versus OI/IUI cycles. However, there was a significantly higher multiple gestation rate among lesbian women undergoing OI compared with those undergoing natural cycles (11.8% vs. 0%, p = 0.01). CONCLUSION: This large study showed that while pregnancy outcomes were similar between groups, the multiple gestation rate was higher in lesbian women undergoing OI compared with lesbian women undergoing natural cycles.

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.

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.

Embryo aneuploidy is not impacted by selective serotonin reuptake inhibitor exposure.

OBJECTIVE: To study whether maternal exposure to selective serotonin reuptake inhibitors (SSRIs) has any influence on rates of blastocyst aneuploidy and/or in vitro fertilization (IVF) cycle outcomes. DESIGN: Retrospective cohort analysis. SETTING: Private and academic IVF center. PATIENT(S): Patients who underwent IVF with preimplantation genetic treatment with trophectoderm biopsy (n = 4,355 cycles) and patients who underwent a single-embryo transfer (SET) between January-2012 and June-2017 (n = 2,132 cycles). INTERVENTION(S): Comprehensive chromosome screening and euploid SET. MAIN OUTCOME MEASURE(S): Odds of embryo aneuploidy. RESULT(S): Of 19,464 embryos analyzed, 3.9% (n = 743) were exposed to a SSRI, and the remaining 96.1% (n = 18,721) were not. The embryo euploid rate was 52.1%, and the aneuploid rate was 42.5%; 5.4% of the reports were inconclusive. No differences were found in clinical and IVF characteristics among the cohorts. After controlling for cofounders, there was no statistically significant associations between exposure to SSRIs and the odds of aneuploidy (adjusted odds ratio [OR] 0.04; 95% confidence interval [CI], -0.04-0.09). In a subanalysis including 2,132 thawed SET cycles, no differences were observed in implantation rate (71.3% vs. 70.1%; OR 0.60; 95% CI, 0.60-1.47), clinical pregnancy rate (58.2% vs. 59.7%; OR 0.70; 95% CI, 0.70-1.61), loss rate (18.5% vs. 11.49%; OR 1.54; 95% CI, 0.94-2.54), or multiple pregnancy rate (0.6% vs. 0; OR 0.7; 95% CI, 0.02-7.32) between cohorts. CONCLUSION(S): Patients exposed to SSRIs in vivo are not susceptible to an increased rate of embryo aneuploidy in IVF. The IVF outcomes of patients exposed to SSRIs do not differ from those of unexposed patients.

Freeze-only versus fresh embryo transfer in a multicenter matched cohort study: contribution of progesterone and maternal age to success rates.

OBJECTIVE: To compare implantation and ongoing pregnancy rates in freeze-only versus fresh transfer cycles. DESIGN: Retrospective matched cohort study. SETTING: Not applicable. PATIENT(S): Women selected using a matching algorithm for similar distributions of clinical characteristics for a total of 2,910 cycles (1,455 fresh cohort and 1,455 freeze-only cohort). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation and ongoing pregnancy rates. RESULT(S): Implantation and ongoing pregnancy rates were statistically significantly higher in the freeze-only transfer cohort than in the matched fresh transfer cohort: ongoing pregnancy rate for freeze-only was 52.0% (95% confidence interval [CI], 49.4-54.6) and for fresh was 45.3% (95% CI, 42.7-47.9), odds ratio (OR) 1.31 (95% CI, 1.13-1.51). In a stratified analysis, the odds of ongoing pregnancy after freeze-only transfer were statistically significantly higher for women both above and below age 35 with progesterone concentration >1.0 ng/mL (age ≤35: OR 1.38 [1.11-1.71]; age >35: OR 1.73 [1.34-2.24]). For women with progesterone concentration ≤1.0 ng/mL, no statistically significant difference in freeze-only odds of ongoing pregnancy was observed in either age group. The sensitivity analysis revealed that increasing maternal age alone (regardless of progesterone) trended toward a more beneficial effect of freeze-only cycles. A lower progesterone concentration was associated with statistically significantly higher ongoing pregnancy odds for fresh but not freeze-only cycles. CONCLUSION(S): Freeze-only transfer protocols are associated with statistically significantly higher ongoing implantation and pregnancy rates compared with fresh transfer cycles. This effect is most pronounced for cycles with progesterone >1.0 ng/mL at trigger and may also be stronger for older patients.