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Planned oocyte cryopreservation-10-15-year follow-up: return rates and cycle outcomes

Blakemore, Jennifer K; Grifo, James A; DeVore, Shannon M; Hodes-Wertz, Brooke; Berkeley, Alan S
OBJECTIVE:To evaluate the outcomes of planned oocyte cryopreservation patients most likely to have a final disposition. DESIGN/METHODS:Retrospective cohort study of all patients who underwent at least 1 cycle of planned oocyte cryopreservation between Jan 2005 and December 2009. SETTING/METHODS:Large urban University-affiliated fertility center PATIENT(S): All patients who underwent ≥1 cycle of planned oocyte cryopreservation in the study period. INTERVENTION(S)/METHODS:None MAIN OUTCOME MEASURE(S): Primary outcome was the disposition of oocytes at 10-15 years. Secondary outcomes included thaw/warming types, laboratory outcomes, and live birth rates. Outcomes and variables treated per patient. RESULT(S)/RESULTS:A total of 231 patients with 280 cycles were included. The mean age at the first retrieval was 38.2 years (range 23-45). A total of 3,250 oocytes were retrieved, with an average of 10 metaphase II frozen/retrieval. To date, the oocytes of 88 patients (38.1%) have been thawed/warmed, 109 (47.2%) remain in storage, 27 (11.7%) have been discarded, and 7 (3.0%) have been transported elsewhere. The return rate (patients who thawed/warmed oocytes) was similar by Society for Assisted Reproductive Technology age group. The mean age of patients discarding oocytes was 47.4 years (range, 40-57). Of the 88 patients who thawed/warmed oocytes, the mean age at the time of thaw/warming was 43.9 years (range, 38-50) with a mean of 5.9 years frozen (range, 1-12). Nine patients (10.2%) thawed/warmed for secondary infertility. A total of 62.5% of patients created embryos with a partner, and 37.5% used donor sperm. On average, 14.3 oocytes were thawed/warmed per patient, with 74.2% survival (range, 0%-100%) and a mean fertilization rate of 68.8% of surviving oocytes. Of 88 patients, 39 (44.3%) planned a fresh embryo transfer (ET); 36 of 39 patients had at least 1 embryo for fresh ET, and 11 had a total of 14 infants. Forty-nine of 88 patients (55.7%) planned for preimplantation genetic testing for aneuploidy, with a mean of 4.2 embryos biopsied (range, 0-14) and a euploidy rate of 28.9%. Of the 49 patients, 17 (34.7%) had all aneuploidy or no embryos biopsied. Twenty-four patients underwent a total of 36 single euploid ET with 18 live births from 16 patients. Notably, 8 PGT-A patients had a euploid embryo but no ET, affecting the future cumulative pregnancy rate. Overall, 80 patients with thaw/warming embryos had a final outcome. Of these, 20 had nothing for ET (arrested/aneuploid), and of the 60 who had ≥1 ET, 27 had a total of 32 infants, with a live birth rate of 33.8% (27/80). CONCLUSION(S)/CONCLUSIONS:We report the final outcomes of patients most likely to have returned, which is useful for patient counseling: a utilization rate of 38.1% and a no-use rate of 58.9%, similar across age groups. Further studies with larger cohorts as well as epidemiologic comparisons to patients currently cryopreserving are needed.
PMID: 33712289
ISSN: 1556-5653
CID: 4817192

Clinical application of sequencing-based methods for parallel preimplantation genetic testing for mitochondrial DNA disease and aneuploidy

Spath, Katharina; Babariya, Dhruti; Konstantinidis, Michalis; Lowndes, Jo; Child, Tim; Grifo, James A; Poulton, Joanna; Wells, Dagan
OBJECTIVE:To validate and apply a strategy permitting parallel preimplantation genetic testing (PGT) for mitochondrial DNA (mtDNA) disease and aneuploidy (PGT-A). DESIGN/METHODS:Preclinical test validation and case reports. SETTING/METHODS:Fertility centers. Diagnostics laboratory. PATIENTS/METHODS:Four patients at risk of transmitting mtDNA disease caused by m.8993T>G (Patients A and B), m.10191T>G (Patient C), and m.3243A>G (Patient D). Patients A, B, and C had affected children. Patients A and D displayed somatic heteroplasmy for mtDNA mutations. INTERVENTIONS/METHODS:Embryo biopsy, genetic testing, and uterine transfer of embryos predicted to be euploid and mutation-free. MAIN OUTCOME MEASURES/METHODS:Test accuracy, treatment outcomes, and mutation segregation. RESULTS:Accuracy of mtDNA mutation quantification was confirmed. The test was compatible with PGT-A, and half of the embryos tested were shown to be aneuploid (16/33). Mutations were detected in approximately 40% of embryo biopsies from Patients A and D (10/24) but in none from Patients B and C (n = 29). Patients B and C had healthy children following PGT and natural conception, respectively. The m.8993T>G mutation displayed skewed segregation, whereas m.3243A>G mutation levels were relatively low and potentially impacted embryo development. CONCLUSIONS:Considering the high aneuploidy rate, strategies providing a combination of PGT for mtDNA disease and aneuploidy may be advantageous compared with approaches that consider only mtDNA. Heteroplasmic women had a higher incidence of affected embryos than those with undetectable somatic mutant mtDNA but were still able to produce mutation-free embryos. While not conclusive, the results are consistent with the existence of mutation-specific segregation mechanisms occurring during oogenesis and possibly embryogenesis.
PMID: 33745725
ISSN: 1556-5653
CID: 4822192

The effect of endometrial thickness on live birth outcomes in women undergoing hormone-replaced frozen embryo transfer

Martel, Rachel A; Blakemore, Jennifer K; Grifo, James A
Objective/UNASSIGNED:To determine the impact of endometrial thickness on live birth outcomes and obstetric complication rate after hormone-replaced frozen embryo transfer. Design/UNASSIGNED:Retrospective cohort study. Setting/UNASSIGNED:Large, urban, academic fertility center. Patients/UNASSIGNED:All patients with a singleton live birth after single euploid embryo transfer (by array comparative genomic hybridization or next-generation sequencing) in a hormone-replaced frozen embryo transfer cycle between January 2017 and December 2018 were reviewed. Interventions/UNASSIGNED:None. Main Outcome measures/UNASSIGNED:The primary outcomes were birth weight and obstetric complication rate. Results/UNASSIGNED:A total of 492 patients were included. The median endometrial thickness was 8.60 mm (range, 6.0-20.0). The median gestational age at live birth was 39.4 weeks with a median birth weight of 3,345.2 g. Endometrial thickness was significantly correlated with birth weight. When patients were dichotomized into groups (those with an endometrial thickness of <7 mm and those with an endometrial thickness of >7 mm), neonates born from endometria with a thickness of <7 mm were born earlier (37.3 vs. 39.4 weeks and born with lower birth weights (2,749.9 vs. 3,345.2 g). It should be noted that only seven patients had an endometrium measuring <7 mm. Moreover, 7.1% (n = 35) of patients had an obstetric complication. Endometrial thickness was not significantly associated with obstetric complications, even with adjustments for age and medical history. Conclusions/UNASSIGNED:Endometrial thickness may be a valuable predictor of placental health and birth weight. Further study is required to examine the relationship with individual obstetric complications, as our study may not have been powered to observe differences in obstetric complication rate, as well as the relationship between endometrial thickness and outcomes in natural frozen embryo transfer cycles.
PMID: 34278346
ISSN: 2666-3341
CID: 4947852

Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use

Viotti, Manuel; Victor, Andrea R; Barnes, Frank L; Zouves, Christo G; Besser, Andria G; Grifo, James A; Cheng, En-Hui; Lee, Maw-Sheng; Horcajadas, Jose A; Corti, Laura; Fiorentino, Francesco; Spinella, Francesca; Minasi, Maria Giulia; Greco, Ermanno; Munné, Santiago
OBJECTIVE:To study how the attributes of mosaicism identified during preimplantation genetic testing for aneuploidy relate to clinical outcomes, in order to formulate a ranking system of mosaic embryos for intrauterine transfer. DESIGN/METHODS:Compiled analysis. SETTING/METHODS:Multi-center. PATIENT(S)/METHODS:A total of 5,561 euploid blastocysts and 1,000 mosaic blastocysts used in clinical transfers in patients undergoing fertility treatment. INTERVENTION(S)/METHODS:None. MAIN OUTCOME MEASURE(S)/METHODS:Implantation (gestational sac), ongoing pregnancy, birth, and spontaneous abortion (miscarriage before 20 weeks of gestation). RESULT(S)/RESULTS:The euploid group had significantly more favorable rates of implantation and ongoing pregnancy/birth (OP/B) compared with the combined mosaic group or the mosaic group affecting only whole chromosomes (implantation: 57.2% vs. 46.5% vs. 41.8%; OP/B: 52.3% vs. 37.0% vs. 31.3%), as well as lower likelihood of spontaneous abortion (8.6% vs. 20.4% vs. 25%). Whole-chromosome mosaic embryos with level (percent aneuploid cells) <50% had significantly more favorable outcomes than the ≥50% group (implantation: 44.5% vs. 30.4%; OP/B: 36.1% vs. 19.3%). Mosaic type (nature of the aneuploidy implicated in mosaicism) affected outcomes, with a significant correlation between number of affected chromosomes and unfavorable outcomes. This ranged from mosaicism involving segmental abnormalities to complex aneuploidies affecting three or more chromosomes (implantation: 51.6% vs. 30.4%; OP/B: 43.1% vs. 20.8%). Combining mosaic level, type, and embryo morphology revealed the order of subcategories regarding likelihood of positive outcome. CONCLUSION(S)/CONCLUSIONS:This compiled analysis revealed traits of mosaicism identified with preimplantation genetic testing for aneuploidy that affected outcomes in a statistically significant manner, enabling the formulation of an evidence-based prioritization scheme for mosaic embryos in the clinic.
PMID: 33685629
ISSN: 1556-5653
CID: 4809162

Prospective analysis of progesterone exposure in programmed single thawed euploid embryo transfer cycles and outcomes

Hirschberg, Carly I; Blakemore, Jennifer K; Fino, Elizabeth; Grifo, Jamie A
PURPOSE/OBJECTIVE:In the era of personalized medicine and the increased use of frozen embryo transfer (FET), assay of the endometrium's receptivity prior to transfer has gained popularity, especially among patients. However, the optimal timing for single thawed euploid embryo transfers (STEET) in a programmed FET has yet to be determined Mackens et al. (Hum Reprod. 32(11):2234-42, 2017). We sought to examine the outcomes of euploid FETs by length of progesterone (P4) exposure. METHODS:Prospective cohort study of programmed FETs of single euploid embryos between June 1, 2018, and December, 18, 2018, at our center. Subjects reported the exact start time for initiating progesterone. The transfer time was noted to calculate the primary independent variable, duration of progesterone exposure. Statistical analysis included ANOVA and Spearman's rho correlation, with p < 0.05 considered significant. RESULTS:Inclusion criteria were met for 253 programmed STEET cycles in the analysis. There was no significant difference in P4 duration when comparing outcome groups (112.8 ± 3.1 ongoing pregnancy (OP), 112.4 ± 4.4 spontaneous abortion (SAB), 111.6 ± 1.7 biochemical pregnancy (BP), 113.9 ± 5.7 no pregnancy (NP), F 1.76, df 3, p = 0.16). An ROC curve assessing the ability of P4 duration to predict ongoing pregnancy (OP) had an area under the curve of 0.467 (p = 0.38). CONCLUSION/CONCLUSIONS:Duration of P4 was not associated with outcome. Of the cycles, 65.6% resulted in ongoing pregnancy with our center's instructions resulting in an average progesterone exposure of 112.8 h, with a range of 98.3-123.7 h. With growing popularity for individualized testing, these results provide evidence for patient counseling of the high likelihood of ongoing pregnancy without personalized testing.
PMID: 33566261
ISSN: 1573-7330
CID: 4836322

Comparison of subchorionic hematoma in medicated or natural single euploid frozen embryo transfer cycles

Reich, Jenna; Blakemore, Jennifer K; Grifo, James A
OBJECTIVE:To study the effect of frozen embryo transfer (FET) preparation protocol on incidence of subchorionic hematoma (SCH) and serum hormone levels. DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:University-affiliated fertility center. PATIENT(S)/METHODS:Patients who underwent FET at the New York University Langone Fertility Center. INTERVENTION(S)/METHODS:None. MAIN OUTCOME MEASURE(S)/METHODS:The primary outcome was incidence of SCH by protocol in FET cycles. RESULT(S)/RESULTS:There were 1,273 FET cycles that met criteria for inclusion. The frequency of SCH was lower in natural compared with programmed cycles (P<.05; relative risk = 0.4 [0.27-0.78]; odds ratio = 0.4 [0.23-0.75]). Serum estrogen level was higher in programmed compared with natural cycles on day of progesterone initiation (P<.001) and cycle day 28 (P<.001). However, serum estrogen levels at the same time points were not associated with formation of SCH in programmed or natural cycles. CONCLUSION(S)/CONCLUSIONS:This is the first study to evaluate the formation of SCHs by FET protocol type. Our results highlight that high serum estradiol levels do not independently lead to an increase in rate of SCH. Further research must be done to understand other clinical, or perhaps molecular, differences between natural and programmed FET cycle preparations that can be better associated with SCH formation.
PMID: 32709380
ISSN: 1556-5653
CID: 4539872

Infertility influencers: an analysis of information and influence in the fertility webspace

Blakemore, Jennifer K; Bayer, Arielle H; Smith, Meghan B; Grifo, James A
PURPOSE/OBJECTIVE:To examine fertility-related social media accounts and influencers on two social media platforms. METHODS:The search function of Twitter (TW) and Instagram (IG) was used to generate a list of accounts with the terms: fertility, infertility, ttc, egg freezing, ivf, endometriosis, and reproductive. Accounts not in English, in private, with no posts in > 1 year, or with content unrelated to search terms were excluded. Accounts were assessed for author type; REI board certification (REI-BC); influencer (INF) status (> 10 K followers on IG; verified check mark on TW); account demographics; and content in last 5 posts. Statistical analysis included unpaired t tests, a classification and regression tree (CART) analysis, and stepwise multiple logistic regression. RESULTS:Seven hundred ten accounts were identified and 537 (278 TW, 259 IG) were included. Account types included societies, clinics, physicians, patients, groups, and "other." Instagram content (1290 posts reviewed) was primarily personal stories (31.7%) or inspiration/support (23.7%). Twitter content (1390 posts reviewed) was mostly promotion (28.2%) and research/education (20.2%). Thirty-nine accounts (12.5%) were influencers. Fertility influencers were most often awareness/support accounts (59.8% TW, 25.0% IG), patients (12.8% TW, 25% IG), or other (17.9% TW, 21.0% IG). Only 7.7% TW and 7.1% IG INFs were board-certified REI physicians. The best predictor for classification as an influencer was high activity (> 50 posts/month TW, > 10 posts/month IG). CONCLUSION/CONCLUSIONS:As patients increasingly utilize social media to obtain and engage with health information, it is critical to understand the fertility-related SM landscape. This understanding may help to successfully enhance relationships with patients and ensure dissemination of accurate information.
PMID: 32382959
ISSN: 1573-7330
CID: 4430592

The reproducibility of trophectoderm biopsies in euploid, aneuploid, and mosaic embryos using independently verified next-generation sequencing (NGS): a pilot study

Sachdev, Nidhee M; McCulloh, David H; Kramer, Yael; Keefe, David; Grifo, James A
PURPOSE/OBJECTIVE:To assess the accuracy and reliability of comprehensive chromosome screening by next-generation sequencing (NGS) of human trophectoderm (TE) biopsy specimens. METHODS:The reliability and accuracy of diagnoses made by preimplantation genetic testing for aneuploidy (PGT-A) from TE biopsy were tested. Repeat biopsies of TE and inner cell mass (ICM) samples were obtained from thawed blastocysts previously tested by NGS. To test for the reliability of the NGS assay, biopsy samples were compared with the original PGT-A results. Prior NGS testing classified the TE samples as euploid, aneuploid, or aneuploid-mosaic. The resulting re-biopsied samples underwent SurePlex whole genome amplification followed by NGS via the MiSeq platform, with copy number value (CNV) determined using BlueFuse Multi Software. The primary outcome measure was reliability, defined as concordance between initial TE result and the repeat biopsies. Accuracy was determined by concordance between the TE and ICM samples, and compared between three chromosome types (disomic, aneuploid, and mosaic). RESULTS:Re-biopsies were performed on 32 embryos with prior PGT-A showing euploidy (10 embryos), aneuploidy of one or two chromosomes (4 embryos), or aneuploid-mosaic with one aneuploid chromosome and one mosaic chromosome (18 embryos). One hundred twenty-nine biopsy samples completed NGS (90 TE and 39 ICM biopsies) and 105 biopsy results were included in the analysis. TE biopsies provide a highly accurate test of the future fetus, with the ICM disomic concordance rate of 97.6%. Clinical concordance rates indicate that TE biopsies provide a reliable test when the result is euploid (99.5%) or aneuploid (97.3%), but less reliable when the result is mosaic (35.2%). CONCLUSION/CONCLUSIONS:TE biopsies predict euploidy or aneuploidy in the ICM with a high degree of accuracy. PGT-A with NGS of TE biopsies is shown to be highly reliable, with clinically relevant concordance rates for aneuploidy and euploidy over 95%. TE biopsies indicating mosaicism were less reliable (35.2%), presumably because mitotic non-disjunction events are not uniformly distributed throughout the blastocyst. However, classification of TE biopsy of PGT-A with NGS results as either aneuploid or euploid provides a highly reliable test.
PMID: 32112203
ISSN: 1573-7330
CID: 4324512

Prognostic role of preimplantation genetic testing for aneuploidy in medically indicated fertility preservation

Blakemore, Jennifer K; Trawick, Emma C; Grifo, James A; Goldman, Kara N
OBJECTIVE:To investigate the use of preimplantation genetic testing for aneuploidy (PGT-A) among patients pursuing embryo banking (EB) for medically indicated fertility preservation (FP). DESIGN/METHODS:Retrospective cohort. SETTING/METHODS:University-affiliated fertility center. PATIENTS/METHODS:All patients who underwent in vitro fertilization with or without PGT-A for medically indicated FP between January 2014 and April 2018. INTERVENTIONS/METHODS:None MAIN OUTCOME MEASURES: EB cycle characteristics, subsequent cycle pursuit/outcomes, and frozen embryo transfer (FET) outcomes. RESULTS:A total of 58 medical EB cycles were compared; 34 cycles used PGT-A. Of the EB patients with breast cancer, 67% used PGT-A; other indications were evenly divided between PGT-A (FP/PGT-A) and no PGT-A (FP). PGT-A use increased over the study period. Groups were similar in age, days of stimulation, and days from initial FP consultation to treatment initiation. Number of oocytes (14.5 [2-63] FP vs. 17.5 [1-64] FP/PGT-A), 2PN zygotes (7 [1-38] FP vs. 9 [0-36] FP/PGT-A), and blastocysts (5.5 [0-22] FP vs. 5 [0-18] FP/PGT-A) cryopreserved were similar between groups. Equal numbers cryopreserved both oocytes and embryos (5 vs. 3). Five FP/PGT-A patients underwent a second EB cycle. Among FP/PGT-A patients, an average of 6.7 ± 5 blastocysts underwent PGT-A, with 3.5 ± 3 (48.2%) euploid embryos cryopreserved for future FET compared to an average of 7.2 ± 7 untested embryos in the FP group. CONCLUSION/CONCLUSIONS:PGT-A in medical EB cycles increased over time and did not limit the use of other FP methods such as oocyte cryopreservation. In some cases, poor PGT-A results informed patients to pursue a second EB cycle. When counseling patients, the prognostic benefits of PGT-A must be weighed against the financial costs and potential for "terminal" fertility diagnosis.
PMID: 31973902
ISSN: 1556-5653
CID: 4273382

Clinical error rates of next generation sequencing and array comparative genomic hybridization with single thawed euploid embryo transfer

Friedenthal, Jenna; Maxwell, Susan M; Tiegs, Ashley W; Besser, Andria G; McCaffrey, Caroline; Munné, Santiago; Noyes, Nicole; Grifo, James A
We investigated clinical error rates with single thawed euploid embryo transfer (STEET) diagnosed by next generation sequencing (NGS) and array comparative genomic hybridization (aCGH). A total of 1,997 STEET cycles after IVF with preimplantation genetic testing for aneuploidy (PGT-A) from 2010 to 2017 were identified; 1,151 STEET cycles utilized NGS, and 846 STEET cycles utilized aCGH. Any abortions, spontaneous or elective, in which products of conception (POCs) were collected were reviewed. Discrepancies between chorionic villus sampling, amniocentesis, or live birth results and PGT-A diagnosis were also included. Primary outcomes were clinical error rate per: ET, pregnancy with gestational sac, live birth, and spontaneous abortion with POCs available for analysis. Secondary outcomes included implantation rate (IR), spontaneous abortion rate (SABR), and ongoing pregnancy/live birth rate (OPR/LBR). The clinical error rates in the NGS cohort were: 0.7% per embryo, 1% per pregnancy with gestational sac, and 0.1% rate per OP/LB. The error rate per SAB with POCs was 13.3%. The IR was 69.1%, the OPR/LBR was 61.6%, and the spontaneous abortion rate was 10.2%. The clinical error rates in the aCGH cohort were: 1.3% per embryo, 2% per pregnancy with gestational sac, and 0.4% rate per OP/LB. The error rate per SAB with POCs was 23.3%. The IR was 63.8%, the OPR/LBR was 54.6%, and the SAB rate was 12.4%. Our findings demonstrate that, although NGS and aCGH are sensitive platforms for PGT-A, errors still occur. Appropriate patient counseling and routine prenatal screening are recommended for all patients undergoing IVF/PGT-A.
PMID: 31972371
ISSN: 1878-0849
CID: 4273342