Faculty Bibliography

OBJECTIVE:To evaluate the clinical outcome potential of embryos classified by preimplantation genetic testing for aneuploidy (PGT-A) as non-mosaic whole chromosome aneuploid (WCA) or segmental aneuploid (SA) in a large multicenter consortium study. DESIGN/METHODS:Multicenter retrospective cohort study. SUBJECTS/METHODS:Data were obtained from eight of the 26 fertility centers participating in the International Registry of Mosaic Embryo Transfers (IRMET) network that contributed non-mosaic WCA and SA embryo transfers between 2016 and 2026. The study included 250 embryo transfers (168 WCA and 82 SA) with complete clinical outcome documentation. Transfers were performed either with knowledge of the PGT-A result at the time of transfer or as non-selective transfers performed without knowledge of the PGT-A result. EXPOSURE/METHODS:Trophectoderm biopsy at blastocyst stage followed by PGT-A using whole-genome amplification (WGA) and next-generation sequencing (NGS). MAIN OUTCOME MEASURES/METHODS:Pregnancy and neonatal outcomes. RESULTS:Among 168 WCA transfers, including 111 performed without knowledge of the PGT-A result at the time of transfer, no live births occurred. Most transfers resulted in no pregnancy (78.6%), with smaller proportions showing biochemical pregnancy (8.3%), ectopic pregnancy (1.8%), early spontaneous abortion (9.5%), late spontaneous abortion (1.2%), or therapeutic termination (0.6%). In contrast, SA transfers (n = 82) resulted in a 17.1% live birth rate. Neonatal data available for 10 SA live births showed no differences in gestational age or birthweight compared with live births following euploid embryo transfer at the same centers, and prenatal or neonatal genetic testing were normal in all tested cases. CONCLUSIONS:In this large multicenter dataset of non-mosaic whole chromosome and segmental aneuploid embryo transfers, embryos classified as uniformly whole chromosome aneuploid produced no live births, whereas segmental aneuploid embryos retained a modest yet clinically meaningful potential for live birth. These findings support the biological validity of PGT-A classification of whole chromosome aneuploid embryos and highlight the distinct clinical implications of whole chromosome and segmental aneuploidies.

To our knowledge, this is the first documented case of presumed recurrent monozygotic (MZT) dichorionic diamniotic (DCDA) twin gestations following programmed single thawed euploid embryo transfer (STEET) cycles in an individual who is herself a MZT twin. This report presents a 34-year-old nulligravid female patient and her 33-year-old male partner with unexplained infertility who underwent in vitro fertilization with preimplantation genetic testing for aneuploidy followed by subsequent embryo transfers, resulting in a presumed MZT DCDA twin gestation (STEET #1), a singleton gestation (STEET #2) and a confirmed MZT DCDA twin gestation (STEET#3). Monozygosity was confirmed for the second twin gestation (STEET #3) via single nucleotide polymorphism (SNP)-based cell-free DNA screening; the first twin gestation (STEET#1) is presumed to be MZT with high likelihood given that it resulted from a STEET performed in the setting of confirmed ovulation suppression. Chorionicity was confirmed via first-trimester ultrasound in both twin gestations (STEET #1 and #3). Nevertheless, this case shows that recurrent MZT DCDA twinning may be possible even after single blastocyst transfer and that observed chorionicity may not always conform to traditional twinning. Further research is needed to better understand the mechanisms and predisposing factors underlying MZT twinning as well as the development of DCDA twin gestations after single blastocyst transfers in assisted reproduction. Specific factors contributing to early embryo splitting may relate to the individual person, the embryo cohort or laboratory techniques. Informed consent counseling should include a discussion that MZT DCDA twinning remains a rare but real possibility despite single embryo transfer.

OBJECTIVE:To estimate the cumulative probability of achieving at least one live birth (LB) after up to six sequential single euploid embryo transfers (euploid SET) and characterize per-transfer outcomes to inform evidence-based counseling for patients undergoing in vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy (PGT-A). DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:University-affiliated fertility center. SUBJECTS/METHODS:Patients who underwent IVF with PGT-A followed by euploid SET between January 2014 and December 2024. EXPOSURE/METHODS:Up to six sequential euploid SETs until a live birth was achieved, or the patient discontinued additional transfers. MAIN OUTCOME MEASURES/METHODS:Estimated cumulative probability of achieving ≥1 LB and per-transfer rates of live birth, spontaneous abortion, biochemical pregnancy, and non-pregnant. RESULTS:Among 5811 patients undergoing 7763 euploid SETs attempts, the estimated cumulative probability of a LB increased from 63.1% after one SET to 92.0% after three, 98.3% after five, and 98.8% after six SETs. Per-transfer live birth rate declined from 63.1% at the first euploid SET to 54.0% at the second, then remained stable across subsequent attempts. Rates of spontaneous abortion, biochemical pregnancy, and non-pregnant followed a similar trend. Fewer than 5% of patients met criteria for recurrent implantation failure after three euploid SETs, and fewer than 2% remained without live birth after five SETs. CONCLUSION/CONCLUSIONS:Continued sequential transfer of euploid embryos is supported as the primary management strategy after early transfer failure. For patients able to generate an adequate euploid embryo inventory aligned with their individual risk tolerance, persistence with treatment is associated with a high likelihood of achieving a live birth.

RESEARCH QUESTION/OBJECTIVE:What are the overall, singleton and twin live birth rates (LBR) after a double embryo transfer (DET) involving mosaic embryos? DESIGN/METHODS:This was a retrospective cohort study of DET with at least one mosaic embryo between 1 December 2016 and 1 December 2024. Each DET was assigned a prognostic score (A-F) based on the ploidy of both embryos. The primary outcome was the overall, singleton and twin LBR of good-prognosis (A and B), moderate-prognosis (C and D) and poor-prognosis (E and F) DET. Secondary outcomes were the LBR for mosaic/mosaic compared with euploid/mosaic transfers. Comparisons were also made with previously published data on euploid/euploid transfers. RESULTS:In total, there were 38 DET: 22 mosaic/mosaic and 16 euploid/mosaic. Twenty-nine (76.3%) patients had prior failed euploid transfers, and 19 (86.4%) mosaic/mosaic patients did not have any euploid embryos. The differences in overall LBR between the prognostic groups did not reach significance [65.0% (13/20) good-prognosis group versus 71.4% (5/7) moderate-prognosis group versus 45.5% (5/11) poor-prognosis group; P = 0.5]. The twin LBR was higher in the good-prognosis group (46.2%) compared with the moderate- and poor-prognosis groups (0% for both; P = 0.04). Overall [72.7% (16/22) versus 43.8% (7/16); P = 0.07], singleton [54.5% (12/22) versus 31.3% (5/11); P = 0.20] and twin [18.2% (4/22) versus 12.5% (2/16); P = 0.6] LBR were similar between mosaic/mosaic and euploid/mosaic DET. While the multiple LBR was high in both groups, it was lower for mosaic/mosaic and euploid/mosaic DET compared with euploid/euploid DET [26.1% (6/23) versus 49.8% (113/227, previously published data); P = 0.04]. CONCLUSIONS:Caution must be exercised with mosaic embryos as they can behave like euploid embryos, and DET can result in twins. DET with moderate- or poor-prognosis mosaic embryos had lower twin rates and may be reasonably considered. Larger studies are needed.

The objective of this review is to determine whether planned oocyte cryopreservation is successfully providing women with reproductive autonomy and the opportunity to shape their families. Planned oocyte cryopreservation is an established means to expand the reproductive function of oocytes and is not associated with an increased risk of congenital anomalies or short-term health risks to the offspring. There is sufficient clinical evidence to support the success of planned oocyte cryopreservation; however, this technology does not guarantee live birth, and outcomes greatly depend on both the age at cryopreservation and the total number of cryopreserved oocytes. While reproducibility between centres must be improved, the results from the authors two large, experienced centres are consistent and provide useful data for patient counselling. Planned oocyte cryopreservation provides the highest cumulative live birth rates (>75%) when it is performed below the age of 35 years and 15-20 or more mature oocytes are cryopreserved. Live birth rates from planned oocyte cryopreservation at an ideal age are higher than live birth rates from women who delay childbearing past their reproductive prime and then attempt natural conception followed by IVF if they are unsuccessful.

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 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.

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.

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.