Faculty Bibliography

PURPOSE/OBJECTIVE:To explore whether letrozole improved outcomes in subsequent controlled ovarian hyperstimulation (COH) cycles. METHODS:This was a retrospective repeated measures cohort study examining COH cycles. Patients were included if they underwent two cycles for unexplained infertility, male factor infertility, or planned oocyte/embryo cryopreservation. The first cycles for all patients implemented a non-letrozole, conventional gonadotropin protocol. Second cycles for the study group included letrozole (2.5-7.5 mg for 5 days) with no medication change to second cycles amongst controls. Our primary objective was to compare oocyte yield. Cohorts were then subdivided by pursuit of oocyte (OC) or embryo (IVF) cryopreservation. Secondary outcome amongst the OC subgroup was oocyte maturation index (metaphase II (MII)/total oocytes). Secondary outcomes amongst the IVF subgroup were normal fertilization rate (2-pronuclear zygotes (2PN)/oocytes exposed to sperm), blastocyst formation rate (blastocysts/2PNs), and embryo ploidy (%euploid and aneuploid). RESULTS:Fifty-four cycles (n = 27) were included in letrozole and 108 cycles (n = 54) were included in control. Oocyte yield was higher in second cycles (p < 0.008) in the letrozole group but similar in second cycles (p = 0.26) amongst controls. Addition of letrozole did not impact MII index (p = 0.90); however, MII index improved in second cycles amongst controls (p < 0.001). Both groups had similar rates of normal fertilization (letrozole: p = 0.52; control: p = 0.61), blast formation (letrozole: p = 0.61; control: p = 0.84), euploid (letrozole: p = 0.29; control: p = 0.47), and aneuploid embryos (letrozole: p = 0.17; control: p = 0.78) between cycles. CONCLUSIONS:Despite improved oocyte yield, letrozole did not yield any difference in oocyte maturation or embryo outcomes.

OBJECTIVE:To assess the association between coronavirus disease 2019 (COVID-19) vaccination and female assisted reproduction outcomes through a systematic review and meta-analysis. DATA SOURCES/METHODS:We searched Medline (OVID), EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov on January 11, 2023, for original articles on assisted reproduction outcomes after COVID-19 vaccination. The primary outcome was rates of clinical pregnancy; secondary outcomes included number of oocytes retrieved, number of mature oocytes retrieved, fertilization rate, implantation rate, ongoing pregnancy rate, and live-birth rate. METHODS OF STUDY SELECTION/METHODS:Two reviewers independently screened citations for relevance, extracted pertinent data, and rated study quality. Only peer-reviewed published studies were included. TABULATION, INTEGRATION, AND RESULTS/RESULTS:Our query retrieved 216 citations, of which 25 were studies with original, relevant data. Nineteen studies reported embryo transfer outcomes, with a total of 4,899 vaccinated and 13,491 unvaccinated patients. Eighteen studies reported data on ovarian stimulation outcomes, with a total of 1,878 vaccinated and 3,174 unvaccinated patients. There were no statistically significant results among our pooled data for any of the primary or secondary outcomes: clinical pregnancy rate (odds ratio [OR] 0.94, 95% CI 0.88-1.01, P=.10), number of oocytes retrieved (mean difference -0.26, 95% CI -0.68 to 0.15, P=.21), number of mature oocytes retrieved (mean difference 0.31, 95% CI -0.14 to 0.75, P=.18), fertilization rate (OR 0.99, 95% CI 0.87-1.11, P=.83), implantation rate (OR 0.92, 95% CI 0.84-1.00, P=.06), ongoing pregnancy rate (OR 0.95, 95% CI 0.86-1.06, P=.40), or live-birth rate (OR 0.95, 95% CI 0.78-1.17, P=.63). A subanalysis based on country of origin and vaccine type was also performed for the primary and secondary outcomes and did not change the study results. CONCLUSION/CONCLUSIONS:Vaccination against COVID-19 is not associated with different fertility outcomes in patients undergoing assisted reproductive technologies. SYSTEMATIC REVIEW REGISTRATION/BACKGROUND:PROSPERO, CRD42023400023.

PURPOSE/OBJECTIVE:To evaluate live birth rates (LBRs) for in vitro fertilization (IVF) cycles with ≤5 follicles at trigger, with the goal of helping patients with low follicle counts decide whether to proceed to retrieval. METHODS:This is a retrospective cohort study from an urban, university-affiliated fertility center. All IVF cycles that yielded <10 oocytes between 2016 and 2020 were reviewed. Cycles were included if <5 follicles measuring >14 mm were verified on trigger day. The primary outcome was LBR per retrieval after fresh or frozen transfer. Secondary outcomes were number of oocytes, mature oocytes, 2-pronuclear zygotes (2-PNs), blastocysts for transfer/biopsy, and euploid blastocysts (if preimplantation genetic testing for aneuploidy (PGT-A) was used). RESULTS:1502 cycles (900 with PGT-A) from 972 patients were included. Mean number of oocytes, mature oocytes, 2-PNs, blastocysts for transfer/biopsy, and euploid blastocysts differed by follicle number (p < 0.001). Across all age groups, there were differences in LBR associated with follicle number (p < 0.001). However, within age groups, not all results were significant. For example, for patients <35 years, LBR did not differ by follicle number and among patients 35-37 years; LBR with two or three follicles was lower than with five (p < 0.02). LBR for patients 35-40 years was <20% with 1-3 follicles and 25-40% with 4-5 follicles. LBR for patients >41 years was <5% with 1-3 follicles and <15% with 4-5 follicles. CONCLUSION/CONCLUSIONS:As expected, LBR is higher with more follicles. Providing patients with <5 follicles with specific data can help them weigh the emotional, physical, and financial costs of retrieval.

The telomere length of human blastocysts exceeds that of oocytes and telomerase activity increases after zygotic activation, peaking at the blastocyst stage. Yet, it is unknown whether aneuploid human embryos at the blastocyst stage exhibit a different profile of telomere length, telomerase gene expression, and telomerase activity compared to euploid embryos. In present study, 154 cryopreserved human blastocysts, donated by consenting patients, were thawed and assayed for telomere length, telomerase gene expression, and telomerase activity using real-time PCR (qPCR) and immunofluorescence (IF) staining. Aneuploid blastocysts showed longer telomeres, higher telomerase reverse transcriptase (TERT) mRNA expression, and lower telomerase activity compared to euploid blastocysts. The TERT protein was found in all tested embryos via IF staining with anti-hTERT antibody, regardless of ploidy status. Moreover, telomere length or telomerase gene expression did not differ in aneuploid blastocysts between chromosomal gain or loss. Our data demonstrate that telomerase is activated and telomeres are maintained in all human blastocyst stage embryos. The robust telomerase gene expression and telomere maintenance, even in aneuploid human blastocysts, may explain why extended in vitro culture alone is insufficient to cull out aneuploid embryos during in vitro fertilization.

The goal of fertility-sparing treatment (FST) for patients desiring future fertility with EMCA, and its precursor EH, is to clear the affected tissue and revert to normal endometrial function. Approximately 15% of patients treated with FST will have a live birth without the need for assisted reproductive technology (ART). Despite this low number, little information exists on the pregnancy outcomes of patients who utilize ART. The purpose of this study was to evaluate pregnancy outcomes following embryo transfer in patients with EMCA or EH who elected for FST. This retrospective cohort study at a large urban university-affiliated fertility center included all patients who underwent embryo transfer after fertility-sparing treatment for EMCA or EH between January 2003 and December 2018. Primary outcomes included embryo transfer results and a live birth rate (defined as the number of live births per number of transfers). There were 14 patients, three with EMCA and 11 with EH, who met the criteria for inclusion with a combined total of 40 embryo transfers. An analysis of observed outcomes by sub-group, compared to the expected outcomes at our center (patients without EMCA/EH matched for age, embryo transfer type and number, and utilization of PGT-A) showed that patients with EMCA/EH after FST had a significantly lower live birth rate than expected (Z = −5.04, df = 39, p < 0.01). A sub-group analysis of the 14 euploid embryo transfers resulted in a live birth rate of 21.4% compared to an expected rate of 62.8% (Z = −3.32, df = 13, p < 0.001). Among patients with EMCA/EH who required assisted reproductive technology, live birth rates were lower than expected following embryo transfer when compared to patients without EMCA/EH at our center. Further evaluation of the impact of the diagnosis, treatment, and repeated cavity instrumentation for FST is necessary to create an individualized and optimized approach for this unique patient population.

The objective of this study was to investigate the utility of using serum gonadotropin levels to predict optimal luteinizing hormone (LH) response to gonadotropin releasing hormone agonist (GnRHa) trigger. A retrospective cohort study was performed of all GnRH-antagonist controlled ovarian hyperstimulation (COH) cycles at an academic fertility center from 2017-2020. Cycles that utilized GnRHa alone or in combination with human chorionic gonadotropin (hCG) for trigger were included. Patient and cycle characteristics were collected from the electronic medical record. Optimal LH response was defined as a serum LH ≥ 40 mIU/mL on the morning after trigger. Total sample size was 3865 antagonist COH cycles, of which 91% had an optimal response to GnRHa trigger. Baseline FSH (B-FSH) and earliest in-cycle LH (EIC-LH) were significantly higher in those with optimal response. Multivariable logistic regression affirmed association of optimal response with EIC-LH, total gonadotropin dosage, age, BMI and Asian race. There was no difference in the number of oocytes retrieved (p = 0.14), maturity rate (p = 0.40) or fertilization rates (p = 0.49) based on LH response. There was no difference in LH response based on use of combination vs. GnRHa alone trigger (p = 0.21) or GnRHa trigger dose (p = 0.46). The EIC-LH was more predictive of LH trigger response than B-FSH (p < 0.005).The optimal B-FSH and EIC-LH values to yield an optimal LH response was ≥ 5.5 mIU/mL and ≥ 1.62 mIU/mL, respectively. In an era of personalized medicine, utilizing cycle and patient characteristics, such as early gonadotropin levels, may improve cycle outcomes and provide further individualized care.

PURPOSE/OBJECTIVE:To investigate the role of standardized preimplantation genetic testing for aneuploidy (PGT-A) using artificial intelligence (AI) in patients undergoing single thawed euploid embryo transfer (STEET) cycles. METHODS:Technology Platform, AI 1.0). The second group included embryos analyzed by AI 1.0 and SNP analysis (PGTai2.0, AI 2.0). Primary outcomes included rates of euploidy, aneuploidy and simple mosaicism. Secondary outcomes included rates of implantation (IR), clinical pregnancy (CPR), biochemical pregnancy (BPR), spontaneous abortion (SABR) and ongoing pregnancy and/or live birth (OP/LBR). RESULTS:A total of 24,908 embryos were analyzed, and classification rates using AI platforms were compared to subjective NGS. Overall, those tested via AI 1.0 showed a significantly increased euploidy rate (36.6% vs. 28.9%), decreased simple mosaicism rate (11.3% vs. 14.0%) and decreased aneuploidy rate (52.1% vs. 57.0%). Overall, those tested via AI 2.0 showed a significantly increased euploidy rate (35.0% vs. 28.9%) and decreased simple mosaicism rate (10.1% vs. 14.0%). Aneuploidy rate was insignificantly decreased when comparing AI 2.0 to NGS (54.8% vs. 57.0%). A total of 1,174 euploid embryos were transferred. The OP/LBR was significantly higher in the AI 2.0 group (70.3% vs. 61.7%). The BPR was significantly lower in the AI 2.0 group (4.6% vs. 11.8%). CONCLUSION/CONCLUSIONS:Standardized PGT-A via AI significantly increases euploidy classification rates and OP/LBR, and decreases BPR when compared to standard NGS.

Objective: Historically, PGT-A results were applied in a binary fashion: embryos categorized as normal were transferred, and those categorized as abnormal were not. While embryos with euploid results have consistent reproductive outcomes, it has now become evident that "abnormal" results can be subcategorized, depending on whether an intermediate copy number is observed ("mosaic"), range of intermediate copy number (estimated percentage of biopsied cells with the abnormality), and type of abnormality (segmental or full monosomy/trisomy).
Material(s) and Method(s): Frozen embryo transfers at our clinic in which PGT-A was performed by next-generation sequencing (NGS) were reviewed. Biopsies from embryos transferred were categorized as either euploid (<20% undetectable abnormal cells), low level segmental mosaic (LL-SM; 20-40% abnormal), high level segmental mosaic (HL-SM; 40-80% abnormal), low level whole chromosome mosaic (LL-WCM), high level whole chromosome mosaic (HL-WCM), or aneuploid (80-100% abnormal). Primary outcomes were implantation rate (IR; defined as presence of gestational sac), ongoing pregnancy rate at 7 weeks gestation (OPR), and spontaneous abortion rate (SABR; defined as loss of gestational sac). Contingency Chi-square (X²; 6x2) analysis with post hoc (2x2)'s were used for comparisons.
Result(s): Table 1 lists the primary outcomes for each PGT-A category. For IR and OPR, euploid and LL-SM embryos were indistinguishable; however, HL-SM, LL-WCM, HL-WCM, and aneuploid embryos were significantly different (p<0.001). While the limited sample size of spontaneous abortions was too small to make accurate comparisons between all 6 groups, a significantly higher SABR was observed for non-euploid embryos (p<0.001). There were no cases in which a non-euploid PGT-A result was confirmed by amniocentesis or in the newborn. [Formula presented]
Conclusion(s): Embryos with euploid and LL-SM results have the highest chance of producing a viable pregnancy. Those with other types of mosaic results can produce viable pregnancies, but at lower rates, and aneuploid embryos are least likely to be viable. Therefore, a spectrum of PGT-A results can help to predict reproductive potential. These data can be used to guide patient counseling about embryo transfer after PGT-A. Impact Statement: The amount and type of mosaicism in embryos correlates with OPR and SABR. Trophectoderm biopsy with NGS is a powerful tool in predicting reproductive outcomes. Support: None
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Objective: Planned OC is increasing; yet, there is a lack of thaw data to provide an accurate estimate of CLBR.¹ We reviewed our AO thaws to determine CLBR by age and #AOs.
Material(s) and Method(s): We reviewed AO thaws at our academic center from 2004-2021. Inclusion criteria: 1) >=1 live birth (LB)/ongoing pregnancy (OP) >12 weeks, or 2) all AOs + embryos from OC consumed. Exclusion criteria: 1) OC for a medical reason, as research, due to lack of sperm or a natural disaster, combined with embryos or for gestational carrier use, or 2) AOs/embryos from OC transported out before a LB. Primary outcome was CLBR (LB + OP). Patients (pts) were stratified by age and #AOs or metaphase II oocytes (M2s) thawed. If pts had >=1 OC cycle, we calculated a weighted age: [SIGMA (#AOs thawed x age at OC)] / [#AOs thawed]. Statistics included multiple logistic regression (MLR), Fischer's exact test, and chi-squared test (p<0.05 significant).
Result(s): 548 pts (median age at OC 38y, range 28-45y; 151 weighted ages used) underwent 767 OC (location: 90% our center, 9% elsewhere, 2% both; method: 77% vitrification, 4% slow cooling, 19% both), 604 thaw and 465 transfer cycles. 40% (n=218) of pts had >=1 LB/OP, resulting in 221 babies + 30 OPs. See table for CLBRs. In pts of all ages and <38y, CLBR increased as #AO/M2s thawed increased from 0-10 to 11-20 to >20 (p<0.03). In pts 38-39y, CLBR was lower if 0-10 vs. 11-20 or >20 AOs were thawed (p<0.01), but was similar if 11-20 vs. >20 AOs (p=0.34) or M2s (p=0.13) were thawed. In pts >=40y, CLBR did not differ based on #AOs (p=0.81) or M2s thawed (p=0.17). For pts with any # or >20 AO/M2s thawed, CLBR was higher in pts <38y and 38-39y vs. pts >=40y (p<0.04). In a MLR model adjusting for effect of age on #AOs, age and age-independent #AOs were predictive of LB.
Conclusion(s): CLBR increases as more AO/M2s are thawed. OC at <38y has a CLBR of ~50%, a reasonable rate in younger pts at an ideal age for OC. Impact Statement: Pts who freeze >20 AOs at <38y can expect >=70% CLBR based on actual outcomes. This is the largest report to date of AO thaw outcomes from a single U.S. center. [Formula presented] REFERENCES:: 1 Practice Committee of the American Society for Reproductive Medicine. Evidence-based outcomes after oocyte cryopreservation for donor oocyte in vitro fertilization and planned oocyte cryopreservation: a guideline. Fertil Steril. 2021 Jul;116(1):36-47.
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