Faculty Bibliography

PURPOSE/OBJECTIVE:Induction of meiotic competence is a major goal of the controlled ovarian stimulation used in ART. Do factors intrinsic to the oocyte contribute to oocyte maturation? Deletions in mtDNA accumulate in long-lived post mitotic tissues and are found in human oocytes. If oogenesis cleanses the germline of deleterious deletions in mtDNA, meiotically competent oocytes should contain lower levels of mtDNA deletions vs. meiotically arrested oocytes. We tested this hypothesis using a novel PCR assay for a deletion ratio in human oocytes derived from IVF. METHODS:among oocytes which matured to metaphase II (MII) vs. oocytes arrested at GV or metaphase I (MI). RESULTS:51.75% of oocytes reached MII, and 17% remained at MI. Mean mtDNADR in GV, MI and MII oocytes were 27.87%, 31.88% and 20.05%, respectively. The difference in deletion ratios between GV and MII and between MI and MII stages was statistically significant p < 0.001 and p = 0.034, respectively. Additionally, patient age was found to be positively correlated with time to Polar body extrusion (- 0.278 Pearson correlation). CONCLUSIONS:Oocytes with impaired meiotic maturation contain an increased load of mtDNA deletions. This is the first report of an association between the mtDNA deletion ratio and human oocyte maturation in vitro.

PURPOSE/OBJECTIVE:To investigate pregnancy outcomes resulting from transfer of embryos with non-mosaic (NM) segmental aneuploid (SA) results following preimplantation genetic testing for aneuploidy (PGT-A). METHODS:All patients who underwent frozen embryo transfer (FET) of at least one embryo with a NM-SA between March 2021 and April 2024 were retrospectively reviewed. Primary outcomes included live birth rate (LBR) and results of prenatal diagnosis. Embryos with NM-SA results were also compared to those with NM whole chromosome aneuploid (WCA) and mosaic SA results. RESULTS:Out of 25 NM-SA embryos transferred, the LBR was 24%. Prenatal diagnosis by amniocentesis and/or chorionic villus sampling was performed in 3/6 pregnancies, and results were normal. Embryos with duplications produced more live births compared to those with deletions. NM-SA embryos had a significantly higher ongoing pregnancy (OP)/LBR compared to embryos with NM-WCA results and a significantly lower OP/LBR compared to embryos with mosaic SA results; however, when compared to embryos with high-level SA mosaicism > 40%, the OP/LBR was not significantly different. CONCLUSION/CONCLUSIONS:Embryos with NM-SAs can result in euploid live births, albeit at reduced rates compared to those with mosaic SAs. These data can be used to aid in patient counseling about PGT-A results and embryo transfer decisions.

PURPOSE/OBJECTIVE:To examine the effects of age, mature oocyte number, and cycle number on cumulative live birth rates after planned oocyte cryopreservation (OC), with the goal of developing a patient counselling tool. METHODS:We performed a retrospective cohort study of all patients with ≥ 1 autologous oocyte thaw at our university-affiliated fertility center before 12/31/2023. Patients were included if they (1) had a live birth or ongoing pregnancy > 12 weeks from OC, or (2) used all oocytes and euploid/untested embryos from OC. Primary outcome was cumulative live birth / ongoing pregnancy rate (CLBR). RESULTS:527 patients with 1 OC cycle, 149 patients with 2 OC cycles, and 55 patients with ≥ 3 OC cycles were included. Overall CLBR was 43%. CLBR was > 70% among patients who thawed ≥ 20 mature oocytes that were cryopreserved at age < 38 years. Multiple logistic regression showed that age at first OC and total number of mature oocytes thawed independently predicted CLBR, but number of OC cycles did not. CONCLUSION/CONCLUSIONS:Patients must be counselled that younger age at OC and more mature oocytes improve CLBR. However, additional OC cycles do not independently improve CLBR. Our results can help patients decide whether to pursue additional OC cycles to obtain more oocytes.

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.

Automated live embryo imaging has transformed in vitro fertilization (IVF) into a data-intensive field. Unlike clinicians who rank embryos from the same IVF cycle cohort based on the embryos visual quality and determine how many embryos to transfer based on clinical factors, machine learning solutions usually combine these steps by optimizing for implantation prediction and using the same model for ranking the embryos within a cohort. Herein, it is established that this strategy can lead to suboptimal selection of embryos. It is revealed that despite enhancing implantation prediction, inclusion of clinical properties hampers ranking. Moreover, it is found that ambiguous labels of failed implantations, due to either low-quality embryos or poor clinical factors, confound both the optimal ranking and even implantation prediction. To overcome these limitations, conceptual and practical steps are proposed to enhance machine learning-driven IVF solutions. These consist of separating the optimizing of implantation from ranking by focusing on visual properties for ranking and reducing label ambiguity.

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 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.

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.

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.