Faculty Bibliography

PURPOSE/OBJECTIVE:Our aim was to evaluate if maternal age at transfer following autologous oocyte cryopreservation is associated with live birth rate (LBR). METHODS:We performed a retrospective cohort study of all patients who thawed autologous oocytes and then underwent a single frozen euploid embryo transfer between 2011 and 2021 at a large urban university-affiliated fertility center. Each oocyte thaw patient was matched 2:1 to in vitro fertilization (IVF) patients who underwent single embryo transfer < 1 year after retrieval. Primary outcome was LBR. Secondary outcomes included implantation rates (IR) and spontaneous abortion rates (SABR). RESULTS:A total of 169 oocyte thaw patients were matched to 338 IVF patients. As expected, oocyte thaw patients were older (median age 42.5 vs. 37.6 years, p < 0.001) and waited longer between retrieval and transfer than in vitro fertilization patients (median time 59 vs. 1 month, p < 0.001). In univariate analysis, implantation and LBR differed among oocyte thaw and IVF patients (p < 0.05), but SABR did not (p = 0.57). Transfer outcomes in oocyte thaw patients did not differ based on transfer age group (IR: p = 0.18; SABR: p = 0.12; LBR: p = 0.24). In a multiple logistic regression model, age at transfer was not predictive of live birth when controlling for age at retrieval, embryo morphology, and day of blastulation. CONCLUSIONS:Maternal age at transfer after oocyte cryopreservation is not predictive of LBR; this suggests that "an aging womb" does not impair LBR after oocyte thaw and empowers patients to return for transfer when ready for childbearing.

OBJECTIVE:To understand the clinical risks associated with the transfer of embryos classified as a mosaic using preimplantation genetic testing for aneuploidy. DESIGN:Analysis of data collected between 2017 and 2023. SETTING:Multicenter. PATIENTS:Patients of infertility treatment. INTERVENTION:Comparison of pregnancies resulting from embryos classified as euploid or mosaic using the 20%-80% interval in chromosomal intermediate copy numbers to define a mosaic result. MAIN OUTCOME MEASURES:Rates of spontaneous abortion, birth weight, length of gestation, incidence of birth defects, and chromosomal status during gestation. RESULTS:Implanted euploid embryos had a significantly lower risk of spontaneous abortion compared with mosaic embryos (8.9% [n = 8,672; 95% confidence interval {CI95} 8.3, 9.5] vs. 22.2% [n = 914; CI95 19.6, 25.0]). Embryos with mosaicism affecting whole chromosomes (not segmental) had the highest risk of spontaneous abortion (27.6% [n = 395; CI95 23.2, 32.3]). Infants born from euploid, mosaic, and whole chromosome mosaic embryos had average birth weights and lengths of gestation that were not statistically different (3,118 g and 267 days [n = 488; CI95 3,067, 3,169, and 266, 268], 3052 g and 265 days [n = 488; CI95 2,993, 3,112, and 264,267], 3,159 g and 268 days [n = 194; CI95 3,070, 3,249, and 266,270], respectively). Out of 488 infants from mosaic embryo transfers (ETs), one had overt gross abnormalities as defined by the Centers for Disease Control and Prevention. Most prenatal tests performed on pregnancies from mosaic ETs had normal results, and only three pregnancies produced prenatal test results reflecting the mosaicism detected at the embryonic stage (3 out of 250, 1.2%; CI95 0.25, 3.5). CONCLUSION:Although embryos classified as mosaic experience higher rates of miscarriage than euploid embryos (with a particularly high frequency shortly after implantation), infants born of mosaic ETs are similar to infants of euploid ETs. Prenatal testing indicates that mosaicism resolves during most pregnancies, although this process is not perfectly efficient. In a small percentage of cases, the mosaicism persists through gestation. These findings can serve as risk-benefit considerations for mosaic ETs in the fertility clinic.

The objective of this review is to provide an update on planned oocyte cryopreservation. This fertility preservation method increases reproductive autonomy by allowing women to postpone childbearing whilst maintaining the option of having a biological child. Oocyte cryopreservation is no longer considered experimental, and its use has increased dramatically in recent years as more women delay childbearing for personal, professional and financial reasons. Despite increased usage, most patients who have undergone oocyte cryopreservation have not yet warmed their oocytes. Most women who cryopreserve oocytes wait years to use them, and many never use them. Studies have demonstrated that oocyte cryopreservation results in live birth rates comparable with IVF treatment using fresh oocytes, and does not pose additional safety risks to offspring. Based on current evidence, cryopreserving ≥20 mature oocytes at <38 years of age provides a 70% chance of one live birth. However, larger studies from a variety of geographic locations and centre types are needed to confirm these findings. Additional research is also needed to determine the recommended age for oocyte cryopreservation, recommended number of oocytes to cryopreserve, return and discard/non-use rates, cost-effectiveness, and how best to distribute accurate and up-to-date information to potential patients.

PURPOSE/OBJECTIVE:Our aim was to describe the reproductive decisions and outcomes of BRCA-positive patients who used preimplantation genetic testing for monogenic disorders (PGT-M). METHODS:We performed a retrospective case series of all PGT-M cycles for BRCA variants between 2010-2021 at a large urban academic fertility center. All patients who underwent ≥ 1 cycle of IVF with PGT-M for BRCA1 or BRCA2 were included. The primary outcome was total number of BRCA-negative euploid embryos per patient. RESULTS:Sixty four patients underwent PGT-M for BRCA variants. Forty-five percent (29/64) were BRCA1-positive females, 27% (17/64) were BRCA2-positive females, 16% (10/64) were BRCA1-positive males, 11% (7/64) were BRCA2-positive males, and one was a BRCA1 and BRCA2-positive male. There were 125 retrieval cycles with PGT-M, and all cycles included PGT for aneuploidy (PGT-A). Eighty-six percent (55/64) of patients obtained at least one BRCA- negative euploid embryo, with median of 1 (range 0-10) BRCA-negative euploid embryo resulted per cycle and median 3 (range 0-10) BRCA-negative euploid embryos accumulated per patient after a median of 2 (range 1-7) oocyte retrievals. Sixty-four percent (41/64) of patients attempted at least one frozen embryo transfer (FET) with a total of 68 FET cycles. Fifty-nine percent (40/68) of embryos transferred resulted in live births. Subgroup analysis revealed different reproductive pathways for BRCA1-positive females, BRCA2-positive females, and BRCA1/2-positive males (p < 0.05). CONCLUSION/CONCLUSIONS:PGT-M is a viable option for BRCA-positive patients to avoid transmission while building their families. Most patients in our cohort achieved pregnancy with BRCA-negative euploid embryos.

OBJECTIVE:To determine how often a noneuploid result from a single trophectoderm (TE) biopsy tested with the next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) is concordant with rebiopsies tested with a single-nucleotide polymorphism (SNP) array-based PGT-A platform. DESIGN/METHODS:Blinded prospective cohort study. SETTING/METHODS:University-affiliated fertility center. PATIENT(S)/METHODS:One hundred blastocysts were chosen from donated samples; on TE biopsy with NGS-based PGT-A, 40 had at least one whole chromosome full copy number aneuploidy alone, 20 had a single whole chromosome intermediate copy number ("whole chromosome mosaic"), 20 had a single full segmental aneuploidy (segA), and 20 had a single segmental intermediate copy number ("segmental mosaic"). INTERVENTIONS/METHODS:Four rebiopsies were collected from each embryo: 3 TE biopsies and the remaining embryo. Each rebiopsy was randomized, blinded, and assessed with an SNP array-based PGT-A platform that combines copy number and allele ratio analyses, without mosaicism reporting. MAIN OUTCOME MEASURE(S)/METHODS:Concordance between the NGS result and rebiopsy results and within each embryo's blinded rebiopsy results. RESULT(S)/RESULTS:Next-generation sequencing-diagnosed whole chromosome aneuploidy (WCA) was reconfirmed in 95% (95% confidence interval [CI], 83%-99%) of embryos; 2 embryos with NGS-diagnosed WCA were called euploid on all conclusive rebiopsies. Among embryos with NGS-diagnosed whole chromosome mosaicism, 35% (95% CI, 15%-59%) were called euploid and 15% (95% CI, 3%-38%) were called whole chromosome aneuploid on all conclusive rebiopsies. A total of 30% (95% CI, 12%-54%) of embryos with NGS-diagnosed segA and 65% (95% CI, 41%-85%) of embryos with NGS-diagnosed segmental mosaicism were called euploid on all conclusive rebiopsies. In total, 13% (95% CI, 6%-25%) of embryos with NGS-diagnosed full copy number aneuploidy and 50% (95% CI, 34%-66%) of embryos with NGS-diagnosed mosaicism had uniformly euploid SNP results. Conversely, all embryos with at least one noneuploid SNP result (n = 72) either had SNP-diagnosed aneuploidy on another rebiopsy from the same embryo or NGS-diagnosed aneuploidy/mosaicism involving the same chromosome. CONCLUSION(S)/CONCLUSIONS:Next-generation sequencing-diagnosed WCA is highly concordant with rebiopsies tested with an SNP array-based PGT-A; however, whole chromosome mosaicism, segA, and segmental mosaicism are less concordant, reinforcing that embryos with these results may have reproductive potential and be suitable for transfer.

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.

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.

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.