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Schmidt, Joana. "Ovarielle Stimulation beeinflusst nicht Euploidie- und Lebendgeburtrate." gynäkologie + geburtshilfe 25, no. 5 (October 2020): 18. http://dx.doi.org/10.1007/s15013-020-3141-7.
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Gazzo, Eduardo, Fernando Peña, Federico Valdez, Arturo Chung, Claudio Bonomini, Mario Ascenzo B., Marcelo Velit, and Ernesto Escudero. "El uso de la tecnología Time-Lapse y algoritmo predictivo KIDScore 5 ayudan a mejorar la selección de embriones euploides para la transferencia." Revista Peruana de Ginecología y Obstetricia 65, no. 2 (May 9, 2019): 189–95. http://dx.doi.org/10.31403/rpgo.v65i2173.
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Objetivos. Evaluar si el uso del algoritmo KIDScore 5 (known implantation data) puede ayudar a seleccionar entre los embriones euploides, para mejorar las tasas de embarazo e implantación en pacientes sometidas a procedimientos de reproducción asistida. Métodos. Estudio de cohorte retrospectivo en una clínica de fertilidad, desde octubre 2016 a diciembre 2018. Se estudió 1 049 embriones provenientes de 328 pacientes. Todos los embriones fueron cultivados en la incubadora Time-Lapse, Embryoscope® (Vitrolife®, Canadá) durante 5 a 6 días. De estos, 896 embriones (85,4%) fueron biopsiados y analizados mediante NGS y recibieron una valoración otorgada por el algoritmo predictivo KIDScore 5 (Vitrolife®, Canadá). Los 153 embriones restantes (14,6%) únicamente recibieron la valoración mediante el algoritmo predictivo KIDScore 5. Se realizó 256 transferencias únicas de embriones euploides en parejas sometidas a tratamientos de FIV en el laboratorio de reproducción asistida de la Clínica Inmater, Lima – Perú. Resultados. La tasa de implantación de los embriones euploides transferidos con valores de KIDScore = 6 versus los transferidos con valores de KIDScore = 1 tuvo diferencia estadísticamente signficativa (73,5% vs. 50,8%; p=0,030). Al evaluar la relación entre la tasa de euploidia embrionaria versus el resultado del valor de KIDScore 5, se obtuvo diferencias altamente significativas en las tasas de euploidia en los embriones con resultados de KIDScore 6 y 5 versus los de KIDScore 0 y 1 (60,5% vs. 45,7%; p=0,0004). Conclusiones. La selección embrionaria con ayuda del algoritmo KIDScore 5 ofrece ventaja en las tasas de implantación y embarazo únicamente cuando se transfieren embriones euploides. Su uso como criterio adicional a la selección embrionaria debiera ser considerado siempre que se acompañe estudio genético a los embriones a transferir. Los embriones euploides con valor más alto en la escala del algoritmo KIDScore 5, tienen mejores tasas de implantación y euploidía que los embriones con el valor mínimo de dicho algoritmo.
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Irani, M., C. Canon, A. Robles, B. Maddy, V. Gunnala, X. Qin, C. Zhang, K. Xu, and Z. Rosenwaks. "No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies." Human Reproduction 35, no. 5 (April 29, 2020): 1082–89. http://dx.doi.org/10.1093/humrep/deaa028.
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STUDY QUESTION Does ovarian stimulation affect embryo euploidy rates or live birth rates (LBRs) after transfer of euploid embryos? SUMMARY ANSWER Euploidy rates and LBRs after transfer of euploid embryos are not significantly influenced by gonadotropin dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger or number of oocytes retrieved, regardless of a woman’s age. WHAT IS KNOWN ALREADY Aneuploidy rates increase steadily with age, reaching >80% in women >42 years old. The goal of ovarian stimulation is to overcome this high aneuploidy rate through the recruitment of several follicles, which increases the likelihood of obtaining a euploid embryo that results in a healthy conceptus. However, several studies have suggested that a high response to stimulation might be embryotoxic and/or increase aneuploidy rates by enhancing abnormal segregation of chromosomes during meiosis. Furthermore, a recent study demonstrated a remarkable difference in euploidy rates, ranging from 39.5 to 82.5%, among young oocyte donors in 42 fertility centres, potentially suggesting an iatrogenic etiology resulting from different stimulation methods. STUDY DESIGN, SIZE, DURATION This is a retrospective cohort study that included 2230 in vitro fertilisation (IVF) with preimplantation genetic testing for aneuploidy (PGT-A) cycles and 930 frozen-thawed single euploid embryo transfer (FET) cycles, performed in our centre between 2013 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 12 298 embryos were analysed for ploidy status. Women were divided into five age groups (<35, 35–37, 38–40, 41–42 and >42 years old). Outcomes were compared between different durations of stimulation (<10, 10–12 and ≥13 days), total gonadotropin dosages (<4000, 4000–6000 and >6000 IU), numbers of oocytes retrieved (<10, 10–19 and ≥20 oocytes), peak estradiol levels (<2000, 2000–3000 and >3000 pg/mL), and sizes of the largest follicle on the day of trigger (<20 and ≥20 mm). MAIN RESULTS AND THE ROLE OF CHANCE Within the same age group, both euploidy rates and LBRs were comparable between cycles regardless of their differences in total gonadotropin dosage, duration of stimulation, number of oocytes harvested, size of the largest follicles or peak estradiol levels. In the youngest group, (<35 years, n = 3469 embryos), euploidy rates were comparable between cycles with various total gonadotropin dosages (55.6% for <4000 IU, 52.9% for 4000–6000 IU and 62.3% for >6000 IU; P = 0.3), durations of stimulation (54.4% for <10 days, 55.2% for 10–12 days and 60.9% for >12 days; P = 0.2), number of oocytes harvested (59.4% for <10 oocytes, 55.2% for 10–19 oocytes and 53.4% for ≥20 oocytes; P = 0.2), peak estradiol levels (55.7% for E2 < 2000 pg/mL, 55.4% for E2 2000–3000 pg/mL and 54.8% for E2 > 3000 pg/mL; P = 0.9) and sizes of the largest follicle (55.6% for follicles <20 mm and 55.1% for follicles ≥20 mm; P = 0.8). Similarly, in the oldest group (>42 years, n = 1157 embryos), euploidy rates ranged from 8.7% for gonadotropins <4000 IU to 5.1% for gonadotropins >6000 IU (P = 0.3), from 10.8% for <10 days of stimulation to 8.5% for >12 days of stimulation (P = 0.3), from 7.3% for <10 oocytes to 7.4% for ≥20 oocytes (P = 0.4), from 8.8% for E2 < 2000 pg/mL to 7.5% for E2 > 3000 pg/mL (P = 0.8) and from 8.2% for the largest follicle <20 mm to 8.9% for ≥20 mm (P = 0.7). LBRs after single FET were also comparable between these groups. LIMITATIONS, REASONS FOR CAUTION Although this large study (2230 IVF/PGT-A cycles, 12 298 embryos and 930 single FET cycles) demonstrates the safety of ovarian stimulation in terms of aneuploidy and implantation potential of euploid embryos, a multi-centre study may help to prove the generalisability of our single-centre data. WIDER IMPLICATIONS OF THE FINDINGS These findings reassure providers and patients that gonadotropin dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger and number of oocytes retrieved, within certain ranges, do not appear to significantly influence euploidy rates or LBRs, regardless of the woman’s age. STUDY FUNDING/COMPETING INTEREST(S) No external funding was received and there are no competing interests to declare. TRIAL REGISTRATION NUMBER N/A
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Rao, Durga Gedela, Krishna Chaitanya Mantravadi, and Vijay Kumar Sharanappa. "Euploid Day-5 Blastocysts Versus Euploid Day-6 Blastocysts — Will the Reproductive Outcomes Differ? An Observational Study." Fertility & Reproduction 03, no. 02 (June 2021): 42–48. http://dx.doi.org/10.1142/s2661318221500055.
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Background and objective: Day-5 blastocyst embryos are usually chosen for assisted reproductive therapy. We compared the reproductive outcomes of the euploid blastocysts developed on Day 5 versus Day 6. Methods: This single-center, retrospective observational study analyzed patients aged 25–45 years, who underwent intracytoplasmic sperm injection from December 2014 to November 2018. Depending on the day of trophectoderm biopsy, patients were categorized into Day-5 and Day-6 groups. Percentages of euploid embryos were calculated for both groups, and elective single euploid blastocysts were transferred in a frozen embryo transfer (FET) cycles. The study endpoints were the comparisons of the reproductive outcomes including clinical pregnancy rate (CPR), implantation rate (IR), miscarriage rate (MR), and live birth rate (LBR) between Day-5 and Day-6 euploid FET groups. Results: A total of 801 embryos from 184 patients were evaluated [Day 5 ([Formula: see text]=769); Day 6 ([Formula: see text]=32); 42.45% were euploid] with the rate of euploidy in Day-5 and Day-6 groups at 42.52% and 40.62%, respectively. A total of 126 patients underwent FET with 126 elective single euploid embryos (Day 5: 117; Day 6: 9). For Day-5 versus Day-6 groups, a significantly higher IR (61.54% vs. 44.44%; [Formula: see text] = 0.0531), CPR (61.54% vs. 44.44%; [Formula: see text] = 0.0531), and LBR (61.54% vs. 33.33%; [Formula: see text] = 0.0014) were reported. Multivariate analysis on ANOVA suggested, comparable pregnancy rates at Day 5 and Day 6 ([Formula: see text] = 0.728). Conclusions: Day-5 euploid blastocysts seem to offer better reproductive outcomes than Day-6 euploid blastocysts. Further research is recommended to evaluate the reproductive outcomes of Day-6 blastocysts.
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Merhi, Zaher, Serin Seckin, and Marco Mouanness. "Intraovarian platelet-rich plasma administration could improve blastocyst euploidy rates in women undergoing in vitro fertilization." Clinical and Experimental Reproductive Medicine 49, no. 3 (September 1, 2022): 210–14. http://dx.doi.org/10.5653/cerm.2021.05057.
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Objective: Platelet-rich plasma (PRP) therapy has received a considerable attention as an adjunct to fertility treatments, especially in women with very low ovarian reserve and premature ovarian insufficiency. Although recent studies have demonstrated that PRP led to improvements in folliculogenesis and biomarkers of ovarian reserve, the effect of intraovarian PRP administration on embryo genetics has not been studied.Methods: We report a pilot study of patients who had preimplantation genetic testing for aneuploidy (PGT-A) before and then within 3 months following PRP administration. Twelve infertile women with at least one prior failed in vitro fertilization (IVF) cycle underwent ovarian stimulation (cycle 1) with a gentle stimulation protocol and PGT-A performed at the blastocyst stage. Following cycle 1, autologous intraovarian PRP administration was performed. Within 3 months following PRP administration, the patients underwent cycle 2 and produced blastocysts for PGT-A. The percentage of euploid embryos between both cycles was compared.Results: The mean age of all participants was 40.08±1.46 years, and their mean body mass index was 26.18±1.18 kg/m2. The number of good-quality embryos formed at the blastocyst stage was similar between cycle 1 and cycle 2 (3.08±0.88 vs. 2.17±0.49, respectively; p=0.11). Among all patients in cycle 1, 3 of 37 embryos were euploid (8.11%) while in cycle 2, 11 out of 28 embryos were euploid (39.28%, p=0.002). Three clinical pregnancies were noted among this patient group.Conclusion: This novel study is the first to present an improvement in the embryo euploidy rate following intraovarian PRP application in infertile women with prior failed IVF cycles. The growth factors present in PRP may exhibit a local paracrine effect that could improve meiotic aberrations in human oocytes and thus improve euploidy rates. Whether PRP improves live birth rates and lowers miscarriage rates remains to be determined in large trials.
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Bayram, A., I. Elkhatib, A. Arnanz, A. Linan, F. Ruiz, B. Lawrenz, and H. M. Fatemi. "What Drives Embryo Development? Chromosomal Normality or Mitochondria?" Case Reports in Genetics 2017 (2017): 1–4. http://dx.doi.org/10.1155/2017/4397434.
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Objective. To report the arrest of euploid embryos with high mtDNA content. Design. A report of 2 cases. Setting. Private fertility clinic. Patients. 2 patients, 45 and 40 years old undergoing IVF treatment. Interventions. Mature oocytes were collected and vitrified from two ovarian stimulations. Postthaw, survived mature oocytes underwent fertilization by intracytoplasmic sperm injection (ICSI). Preimplantation genetic screening (PGS) and mitochondrial DNA (mtDNA) copy number were done using next generation sequencing (NGS). The only normal embryo among the all-biopsied embryos had the highest “Mitoscore” value and was the only arrested embryo in both cases. Therefore, the embryo transfer was cancelled. Main Outcome Measures. Postthaw survival and fertilization rate, embryo euploidy, mtDNA copy number, and embryo development. Results. In both patients, after PGS only 1 embryo was euploid. Both embryos had the highest mtDNA copy number from all tested embryos and both embryos were arrested on further development. Conclusions. These cases clearly demonstrate the lack of correlation between mtDNA value (Mitoscore) and chromosomal status of embryo.
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Kusaba, Yuki, Akira Otsuka, Huanghuang Dai, Shigeki Inaba, and Hiroshi Kitagaki. "Induction of Chromosomal Aneuploids from Brewery Shochu Yeast with Novel Brewery Characteristics." Fermentation 8, no. 2 (January 30, 2022): 62. http://dx.doi.org/10.3390/fermentation8020062.
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The first development method of brewery shochu yeast focusing on chromosomal aneuploidy is reported in this study. Euploidy diploid shochu yeast S-3 was treated with a microtubule inhibitor, nocodazole, for the purpose of inducing aneuploidy. Next, 2,3,5-triphenyl tetrazolium chloride (TTC) staining and the growth rate were investigated to select aneuploids. Aneuploids were selected at a frequency of 8.2 × 10−4, which was significantly higher than that of the control group, mainly at chromosomes I, II, III, IX, XII, XIII, and XVI. The acquired aneuploids were evaluated for their metabolic and brewing characteristics. A hierarchical cluster analysis based on endogenous metabolite data discriminated euploid S-3 and aneuploids. In addition, principal-component analysis of the constituents of the broth brewed with the strains discriminated between euploid S-3 and aneuploids. Sensory evaluation of the broth brewed with euploid S-3 and aneuploids showed that it tended to differ in aroma and taste. Specific ethanol production rates of the aneuploids were not deteriorated. The method of this selection made it possible to efficiently obtain aneuploids with various brewing characteristics from brewer’s yeast, which do not correspond to genetically modified organisms. This novel breeding method focusing on chromosomal aneuploidy will facilitate the development of novel shochu yeast strains.
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Gultom, Tumiur. "PENGARUH PEMBERIAN KOLKISIN TERHADAP JUMLAH KROMOSOM BAWANG PUTIH (Allium sativum) LOKAL KULTIVAR DOULU." JURNAL BIOSAINS 2, no. 3 (December 1, 2016): 165. http://dx.doi.org/10.24114/jbio.v2i3.4959.
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Bawang putih lokal kultivar Doulu berasal dari Desa Doulu Kabupaten Karo Sumatera Utara. Bawang putih lokal Doulu dikenal luas oleh masyarakat di Sumatera Utara karena rasa yang pedas dan aromanya yang tajam. Jumlah kromosom bawang putih lokal ini sebanyak 16 =2n. Penelitian ini bertujuan untuk mengetahui pengaruh kolkisin terhadap jumlah kromosom bawang putih (Allium sativum) pada konsentrasi dan lama waktu perendaman yang berbeda. Metode yang digunakan dalam penelitian ini adalah metode eksperimen dengan menggunakan metode squash. Rancangan percobaan yang digunakan adalah percobaan faktorial dengan dua faktor perlakuan. Faktor pertama adalah dosis pemberian larutan konsentrasi kolkisin (D) dengan 3 taraf yaitu : 0,1% (D1), 0,2% (D2), dan 0,3% (D3). Faktor kedua adalah lama waktu perendaman (T) dengan 4 taraf perlakuan yaitu 6 jam (T1), 12 jam (T2), 18 jam (T3), dan 24 jam (T4). Hasil penelitian menunjukkan bahwa kromosom bertambah secara euploid dan aneuploidi yang menyebabkan terbentuknya sel-sel poliploidi. Tipe-tipe poliploidi yang terbentuk yang ditemukan yaitu euploidi yang tetraploid (4n) pada perlakuan D1T2, D2T3 dan D3T4. Kromosom yang bertambah secara aneuploid yaitu 2n + 4 pada perlakuan D2T2, 2n + 6 pada perlakuan D1T1; 3n + 6 pada perlakuan D1T3 dan D1T4 ; 4n + 1 pada perlakuan D2T1 dan T3D3; 4n +8 pada perlakuan D3T2; 5n +8 pada perlakuan D3T1 dan 6n +4 pada perlakuan D2T4. Kata kunci: Kolkisin, metode squash, poliploid, aneuploid, euploidi.
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Cimadomo, Danilo, Antonio Capalbo, Lisa Dovere, Luisa Tacconi, Daria Soscia, Adriano Giancani, Emiliano Scepi, et al. "Leave the past behind: women’s reproductive history shows no association with blastocysts’ euploidy and limited association with live birth rates after euploid embryo transfers." Human Reproduction 36, no. 4 (February 20, 2021): 929–40. http://dx.doi.org/10.1093/humrep/deab014.
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Abstract STUDY QUESTION Is there an association between patients’ reproductive history and the mean euploidy rates per biopsied blastocysts (m-ER) or the live birth rates (LBRs) per first single vitrified-warmed euploid blastocyst transfers? SUMMARY ANSWER Patients’ reproductive history (as annotated during counselling) showed no association with the m-ER, but a lower LBR was reported after euploid blastocyst transfer in women with a history of repeated implantation failure (RIF). WHAT IS KNOWN ALREADY Several studies have investigated the association between the m-ER and (i) patients’ basal characteristics, (ii) ovarian stimulation strategy and dosage, (iii) culture media and conditions, and (iv) embryo morphology and day of full blastocyst development. Conversely, the expected m-ER due to women’s reproductive history (previous live births (LBs), miscarriages, failed IVF cycles and transfers, and lack of euploid blastocysts among prior cohorts of biopsied embryos) still needs investigations. Yet, this information is critical to counsel new patients about a first cycle with preimplantation genetic testing for aneuploidy (PGT-A), but even more so after former adverse outcomes to prevent treatment drop-out. STUDY DESIGN, SIZE, DURATION This observational study included all patients undergoing a comprehensive chromosome testing (CCT)-based PGT-A cycle with at least one biopsied blastocyst in the period April 2013-December 2019 at a private IVF clinic (n = 2676 patients undergoing 2676 treatments and producing and 8151 blastocysts). m-ER were investigated according to women’s reproductive history of LBs: no/≥1, miscarriages: no/1/>1; failed IVF cycles: no/1/2/>2, and implantation failures after previous transfers: no/1/2/>2. Among the 2676 patients included in this study, 440 (16%) had already undergone PGT-A before the study period; the data from these patients were further clustered according to the presence or absence of euploid embryo(s) in their previous cohort of biopsied blastocysts. The clinical outcomes per first single vitrified-warmed euploid blastocyst transfers (n =1580) were investigated according to the number of patients’ previous miscarriages and implantation failures. PARTICIPANTS/MATERIALS, SETTING, METHODS The procedures involved in this study included ICSI, blastocyst culture, trophectoderm biopsy without hatching in Day 3, CCT-based PGT-A without reporting segmental and/or putative mitotic (or mosaic) aneuploidies and single vitrified-warmed euploid blastocyst transfer. For statistical analysis, Mann–Whitney U or Kruskal–Wallis tests, as well as linear regressions and generalised linear models among ranges of maternal age at oocyte retrieval were performed to identify significant differences for continuous variables. Fisher’s exact tests and multivariate logistic regression analyses were instead used for categorical variables. MAIN RESULTS AND THE ROLE OF CHANCE Maternal age at oocyte retrieval was the only variable significantly associated with the m-ER. We defined five clusters (<35 years: 66 ± 31%; 35–37 years: 58 ± 33%; 38–40 years: 43 ± 35%; 40–42 years: 28 ± 34%; and >42 years: 17 ± 31%) and all analyses were conducted among them. The m-ER did not show any association with the number of previous LBs, miscarriages, failed IVF cycles or implantation failures. Among patients who had already undergone PGT-A before the study period, the m-ER did not associate with the absence (or presence) of euploid blastocysts in their former cohort of biopsied embryos. Regarding clinical outcomes of the first single vitrified-warmed euploid blastocyst transfer, the implantation rate was 51%, the miscarriage rate was 14% and the LBR was 44%. This LBR was independent of the number of previous miscarriages, but showed a decreasing trend depending on the number of previous implantation failures, reaching statistical significance when comparing patients with >2 failures and patients with no prior failure (36% versus 47%, P < 0.01; multivariate-OR adjusted for embryo quality and day of full blastocyst development: 0.64, 95% CI 0.48–0.86, P < 0.01). No such differences were shown for previous miscarriage rates. LIMITATIONS, REASONS FOR CAUTION The sample size for treatments following a former completed PGT-A cycle should be larger in future studies. The data should be confirmed from a multicentre perspective. The analysis should be performed also in non-PGT cycles and/or including patients who did not produce blastocysts, in order to investigate a putative association between women’s reproductive history with outcomes other than euploidy and LBRs. WIDER IMPLICATIONS OF THE FINDINGS These data are critical to counsel infertile couples before, during and after a PGT-A cycle, especially to prevent treatment discontinuation due to previous adverse reproductive events. Beyond the ‘maternal age effect’, the causes of idiopathic recurrent pregnancy loss (RPL) and RIF are likely to be endometrial receptivity and selectivity issues; transferring euploid blastocysts might reduce the risk of a further miscarriage, but more information beyond euploidy are required to improve the prognosis in case of RIF. STUDY FUNDING/COMPETING INTEREST(S) No funding was received and there are no competing interests. TRIAL REGISTRATION NUMBER N/A.
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Coll, Lluc, Mònica Parriego, Montserrat Boada, Marta Devesa, Gemma Arroyo, Ignacio Rodríguez, Bonaventura Coroleu, Francesca Vidal, and Anna Veiga. "Transition from blastomere to trophectoderm biopsy: comparing two preimplantation genetic testing for aneuploidies strategies." Zygote 26, no. 3 (May 25, 2018): 191–98. http://dx.doi.org/10.1017/s0967199418000084.
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SummaryShortly after the implementation of comprehensive chromosome screening (CCS) techniques for preimplantation genetic testing for aneuploidies (PGT-A), the discussion about the transition from day 3 to blastocyst stage biopsy was initiated. Trophectoderm biopsy with CCS is meant to overcome the limitations of cleavage-stage biopsy and single-cell analysis. The aim of this study was to assess the results obtained in our PGT-A programme after the implementation of this new strategy. Comparisons between the results obtained in 179 PGT-A cycles with day 3 biopsy (D+3) and fresh embryo transfer, and 204 cycles with trophectoderm biopsy and deferred (frozen–thawed) embryo transfer were established. Fewer embryos were biopsied and a higher euploidy rate was observed in the trophectoderm biopsy group. No differences in implantation (50.3% vs. 61.4%) and clinical pregnancy rate per transfer (56.1% vs. 65.3%) were found. Although the mean number of euploid embryos per cycle did not differ between groups (1.5 ± 1.7 vs. 1.7 ± 1.8), the final number of euploid blastocysts available for transfer per cycle was significantly higher in the trophectoderm biopsy group (1.1 ± 1.3 vs. 1.7 ± 1.8). This factor led to an increased cumulative live birth rate in this last group (34.1% vs. 44.6%). Although both strategies can offer good results, trophectoderm biopsy offers a more robust diagnosis and the intervention is less harmful for the embryos so more euploid blastocysts are finally available for transfer and/or vitrification.
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KELLEY, Rebecca L., Fleur CATTRALL, Sharyn STOCK-MYER, Lisa Y. S. LEE, and David K. GARDNER. "Is Cleavage Stage Multinucleation Indicative of Lower Pregnancy Potential in Euploid Blastocysts?" Fertility & Reproduction 04, no. 03n04 (September 2022): 188. http://dx.doi.org/10.1142/s2661318222740991.
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Background: Cleavage stage multinucleation is a morphological assessment IVF labs may use to rank embryos for transfer, as blastocysts that were multinucleated at the 2-cell or 4-cell stage have a lower live birth rate (LBR) compared to blastocysts that were mononucleated 1 . However, when these blastocysts are PGT-A tested, the euploidy rate is similar 2 , indicating that the poorer pregnancy outcomes may not be due to aneuploidy. It is unknown if multinucleation is indicative of a lower likelihood of pregnancy for euploid blastocysts. Aim: To determine if LBR following transfer of euploid blastocysts is lower when blastocysts were multinucleated at the 2-cell or 4-cell stages. Method: Retrospective study on 360 euploid blastocysts cultured in the EmbryoScope or EmbryoScope+ between March 2018 and October 2019, and individually transferred. Time-lapse images were retrospectively assessed for multinucleation at the 2-cell and 4-cell stage. A multinucleated embryo was defined as having [Formula: see text] 1 cell with [Formula: see text] 2 nuclei. Results: Blastocysts that were multinucleated at the 2-cell stage (n=139) had a similar LBR to mononucleated embryos (40.3% vs 41.6%). Multinucleation at the 4-cell stage (n=43) also did not significantly affect LBR (37.2% vs 43.6%). Multivariate logistic regression analysis found no significant effect of multinucleation on LBR. Biochemical pregnancy, clinical pregnancy (fetal heart), and miscarriage rates were also similar between multinucleated and mononucleated embryos. Conclusion: This study found no evidence that multinucleation at the 2-cell or 4-cell stage influences pregnancy rate in euploid blastocysts. As such, the assessment of cleavage stage multinucleation for PGT-A tested embryos may not be useful in ranking PGT-A tested embryos for transfer. Further work is required with larger numbers of embryos to confirm how the degree of multinucleation may influence LBR.
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Kavoussi, Shahryar K., Shu-Hung Chen, John David Wininger, Arnav Lal, William E. Roudebush, Hayes C. Lanford, Amy S. Esqueda, et al. "The expression of pregnancy-associated plasma protein-A (PAPP-A) in human blastocoel fluid–conditioned media: a proof of concept study." Journal of Assisted Reproduction and Genetics 39, no. 2 (January 11, 2022): 389–94. http://dx.doi.org/10.1007/s10815-022-02393-4.
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Abstract Purpose The aim of this study was to determine if pregnancy-associated plasma protein-A (PAPP-A), typically measured in maternal serum and a potential predictor of adverse maternal and fetal outcomes such as spontaneous miscarriage, pre-eclampsia, and stillbirth, is expressed in blastocoel fluid–conditioned media (BFCM) at the embryonic blastocyst stage. Design This is an in vitro study. Methods BFCM samples from trophectoderm-tested euploid blastocysts (n = 80) from in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) patients were analyzed for PAPP-A mRNA. BFCM was obtained from blastocyst stage embryos in 20 uL drops. Blastocysts underwent trophectoderm biopsy for preimplantation genetic testing for aneuploidy prior to blastocyst vitrification and BFCM collection for snap freezing. cfDNA was synthesized using BFCM collected from 80 individual euploid blastocysts. Next, real-time qPCR was performed to detect expression of PAPP-A with GAPDH for normalization of expression in each sample. Results PAPP-A mRNA was detected in 45 of 80 BFCM samples (56.3%), with varying levels of expression across samples. Conclusion Our study demonstrates the expression of PAPP-A in BFCM. To our knowledge, this is the first study to report detection of PAPP-A mRNA in BFCM. Further studies are required and underway to investigate a greater number of BFCM samples as well as the possible correlation of PAPP-A expression with pregnancy outcomes of transferred euploid blastocysts. If found to predict IVF and obstetric outcomes, PAPP-A may provide additional information along with embryonic euploidy for the selection of the optimal blastocyst for embryo transfer.
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LAZZARO, Leah, Martin HEALEY, and Tiki OSIANLIS. "Multinucleation in the Two-Cell Stage Embryo Matters." Fertility & Reproduction 04, no. 03n04 (September 2022): 167. http://dx.doi.org/10.1142/s2661318222740796.
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Background: Blastomere multinucleation (MN), defined as the presence of more than one nucleus per cell, in the cleavage-stage embryo, is a well-documented phenomenon 1 . This nuclear anomaly has become more visible with the introduction of time-lapse incubation and an understanding of the potential outcomes of these embryos is necessary to inform decision-making and manage patient expectations. Aim: To determine rates of blastocyst utilisation and euploidy for embryos with MN at the two-cell stage (MN2) in comparison to mononucleated and binucleated embryos. Method: A retrospective analysis was performed at a single IVF unit, of embryos with known two-cell nucleation status from October 2019 to March 2021. Blastomere nucleation was assessed, via time-lapse monitoring (EmbryoScope; UnisenseFertiliTech), and categorised as mononucleate, binucleate or MN in all fertilised oocytes. Blastocyst utilisation rates (number of embryos frozen+transferred/number of oocytes fertilised) were compared together with euploidy rates in embryos that had preimplantation genetic testing for aneuploidy. Outcomes were modelled using multilevel logistic regression to allow for lack of independence between embryos when grouped by patient and cycle, and adjusted for patient age. Results: Of the 4388 embryos included in this study, 68% were mononucleated, 14% binucleated and 18% MN. The likelihood of embryos becoming usable blastocysts based on nucleation status at the two-cell stage for mononucleated, binucleated and MN were 63%, 55%(p<0.001) and 35%(p<0.001) respectively. The euploidy rates for mono-, bi- and MN were 45%, 38%(p=0.09) and 31%(p=0.004) respectively. Predictive modeling, with adjusting for age, showed that a mononucleate two-cell embryo has 44% likelihood of becoming a euploid blastocyst, binucleate 36% and MN 28%. Conclusion: There was a clear reduction in rate of blastocyst utilisation and euploidy in binucleate and a further reduction in MN two-cell stage embryos, in comparison to mononucleate embryos, which should preferentially be prioritised for transfer.
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Greco, Ermanno, Katarzyna Litwicka, Maria Giulia Minasi, Elisabetta Cursio, Pier Francesco Greco, and Paolo Barillari. "Preimplantation Genetic Testing: Where We Are Today." International Journal of Molecular Sciences 21, no. 12 (June 19, 2020): 4381. http://dx.doi.org/10.3390/ijms21124381.
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Background: Preimplantation genetic testing (PGT) is widely used today in in-vitro fertilization (IVF) centers over the world for selecting euploid embryos for transfer and to improve clinical outcomes in terms of embryo implantation, clinical pregnancy, and live birth rates. Methods: We report the current knowledge concerning these procedures and the results from different clinical indications in which PGT is commonly applied. Results: This paper illustrates different molecular techniques used for this purpose and the clinical significance of the different oocyte and embryo stage (polar bodies, cleavage embryo, and blastocyst) at which it is possible to perform sampling biopsies for PGT. Finally, genetic origin and clinical significance of embryo mosaicism are illustrated. Conclusions: The preimplantation genetic testing is a valid technique to evaluated embryo euploidy and mosaicism before transfer.
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Hernandez-Nieto, Carlos, Joseph A. Lee, Richard Slifkin, Benjamin Sandler, Alan B. Copperman, and Eric Flisser. "What is the reproductive potential of day 7 euploid embryos?" Human Reproduction 34, no. 9 (August 9, 2019): 1697–706. http://dx.doi.org/10.1093/humrep/dez129.
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Abstract STUDY QUESTION What is the rate of euploidy and the reproductive potential of embryos biopsied after 6 days of development? SUMMARY ANSWER Embryos biopsied after 6 days of development have higher rates of aneuploidy; however, day 7 euploid embryos selected at transfer can achieve acceptable pregnancy rates and live birth (LB) outcomes. WHAT IS KNOWN ALREADY Recent publications have shown promising treatment results after euploid day 7 embryo transfers (ETs), albeit these studies were limited by small sample sizes. Whereas the current clinical standard has been to discard embryos that do not reach expansion by day 6 of development, the lack of robust data surrounding the clinical utility of day 7 embryos warrants further evaluation. STUDY DESIGN, SIZE, DURATION Retrospective cohort analysis in a single, academic in vitro fertilization (IVF) center from January 2012 to March 2018. A total of 25 775 embryos underwent trophectoderm (TE) biopsy and preimplantation genetic testing for aneuploidy (PGT-A). Additionally, the clinical IVF outcomes of 3824 single, euploid frozen embryo transfer (FET) cycles were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS Cohorts were segregated by day of TE biopsy following oocyte retrieval (day 5, day 6 or day 7). PGT-A was performed to identify embryonic ploidy rates. Secondly, IVF and LB outcomes after single, euploid FET were evaluated for each cohort. MAIN RESULTS AND THE ROLE OF CHANCE A total of day 5 (n = 12 535), day 6 (n = 11 939) and day 7 (n = 1298) embryos were included in the study analysis. The rate of embryo euploidy was significantly lower in day 7 blastocysts compared to day 5 or day 6 cohorts (day 7 = 40.5%; day 5 = 54.7%; day 6 = 52.9%; (P < 0.0001)). After adjusting for age, anti-Müllerian hormone, BMI, embryo quality and number of embryos biopsied, there was a significant association between aneuploidy and embryos biopsied on day 7 when compared to day 5 biopsied embryos (OR = 1.34, CI 95% 1.09–1.45, P = 0.001) and day 6 biopsied embryos (OR = 1.26, CI95% 1.07–1.16, P < 0.001). A sub-analysis of subsequent 3824 single, euploid FET cycles (day 5: n = 2321 cycles; day 6: n = 1381 cycles; and day 7: n = 116 cycles) showed significant differences among cohorts in implantation, clinical pregnancy, LB and clinical loss rates. There was a significant decrease in the odds of implantation, clinical pregnancy and LB, but no association with clinical loss or multiple pregnancy rates in patients who utilized day 7-biopsied embryos during treatment. LIMITATIONS, REASONS FOR CAUTION The retrospective nature of the study and potential variability in the study center’s laboratory protocol(s) compared to other reproductive treatment centers may limit the external validity of our findings. Additionally, patients who transferred euploid embryos, biopsied on day 7 of development due to an absence of day 5 or day 6 counterparts, may have introduced selection bias in this study. WIDER IMPLICATIONS OF THE FINDINGS Embryonic developmental stage, morphological grade and ploidy status are paramount factors affecting ET selection and implantation potential. This study reveals that embryos ineligible for TE biopsy on day 5 or day 6 of development may benefit from extended culture to day 7. Our study demonstrates patient benefit when extended culture to day 7 of development is routinely performed for embryos failing to meet biopsy criteria by day 5 or 6. STUDY FUNDING/COMPETING INTEREST(S) No funding was received for the realization of this manuscript. Dr Alan Copperman is Advisor or Board Member of Sema 4 (Stake holder in Data), Progyny and Celmatix. TRIAL REGISTRATION NUMBER This retrospective analysis was approved by an Institutional Review Board (WIRB PRO NUM: 20161791; Study Number: 1167398).
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Murray, JD, CD Nancarrow, RJ Scaramuzzi, and Y. Cognie. "Polyploid Abnormalities in Day 3 and Day 5 Merino Sheep Embryos." Australian Journal of Biological Sciences 41, no. 2 (1988): 157. http://dx.doi.org/10.1071/bi9880157.
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The chromosome complement was assessed in Merino sheep embryos collected at 3 and 5 days after the onset of oestrus. Donor ewe treatments were: untreated, or immunized against androstenedione (day 3); and untreated, or treated with follicle-stimulating hormone (FSH), or treated with FSH plus immunization against androstenedione (day 5). No significant differences in the frequency of chromosomally abnormal embryos between treatment groups within each age group were observed, so the data have been combined. Euploid abnormalities were observed in 10�8070 of the day-3 embryos (4/37), with the abnormalities being one In, one 3n and two 5n. Embryos with euploidy (10%) were also observed at day 5, with three 1n12n mosaics and a 3n embryo present in a sample of 40. These data suggest that chromosomally aberrant embryos are not lost before day 5 of development.
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Cimadomo, Danilo, Daria Soscia, Alberto Vaiarelli, Roberta Maggiulli, Antonio Capalbo, Filippo Maria Ubaldi, and Laura Rienzi. "Looking past the appearance: a comprehensive description of the clinical contribution of poor-quality blastocysts to increase live birth rates during cycles with aneuploidy testing." Human Reproduction 34, no. 7 (June 27, 2019): 1206–14. http://dx.doi.org/10.1093/humrep/dez078.
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Abstract STUDY QUESTION Which are the clinical benefits and risks of including poor-quality blastocysts (PQBs) in the cohort of biopsied embryos during a cycle with preimplantation genetic testing for aneuploidies (PGT-A)? SUMMARY ANSWER PQBs show a worse prognosis with respect to sibling non-PQBs, but their clinical use allows an overall 2.6% increase in the number of live births (LBs) achievable after PGT-A. WHAT IS KNOWN ALREADY PQBs (<BB according to Gardner and Schoolcraft’s classification) are generally disregarded for clinical use and/or research purposes. Therefore, limited data exist in literature to estimate the benefits and risks deriving from the transfer of a PQB. In Italy, the law imposes the transfer or cryopreservation of all embryos, unless proven not viable. This regulation has allowed the production of a large amount of data regarding poor-quality embryos. Previous reports outlined a lower chance of euploidy and implantation for PQBs. Yet, a comprehensive picture of their real clinical contribution is missing. STUDY DESIGN, SIZE, DURATION This observational cohort study including 2757 oocyte retrievals for PGT-A (mean maternal age, 39.6 ± 3.3 years) conducted at a private IVF centre between April 2013 and May 2018. A total of 1497 PQBs were obtained and their embryological, chromosomal and clinical features were compared to 5250 non-PQBs (≥BB according to Gardner and Schoolcraft’s classification) and adjusted for all significant confounders. After defining the overall increase in LBs due to PQBs, we outlined the population of patients who might benefit the most from their clinical use. PARTICIPANTS/MATERIALS, SETTING, METHODS ICSI cycles, involving ovarian stimulation, blastocyst culture, trophectoderm biopsy, vitrification, comprehensive chromosome testing and vitrified-warmed euploid single embryo transfers (SETs), were conducted. Overall analyses and sub-analyses in populations of patients clustered according to maternal age at retrieval and size of the cohort of sibling non-PQBs were performed. Finally, the risk of miscarriage and the chance of LB per biopsied PQB and non-PQB were estimated. MAIN RESULTS AND THE ROLE OF CHANCE PQBs allowed a 12.4% increase in the cycles where ≥1 blastocyst was biopsied. To date, we report a concurrent 2.6% increase in the cycles resulting in ≥1 LB. On average 0.7 ± 0.9 (range, 0–9) PQBs were obtained per cycle for biopsy, including 0.2 ± 0.4 (range, 0–5) euploid PQBs. Maternal age solely correlates with the prevalence of PQBs from both overall and cycle-based analyses. Indeed, the patients who benefit the most from these embryos (i.e. 18 women achieving their only LBs thanks to PQBs) cluster among women older than 42 years and/or those with no or few sibling non-PQBs (1.1 ± 1.1; range, 0–3). The 1497 PQBs compared to the 5250 non-PQBs showed slower development (Day 5, 10.1% versus 43.9%; Day 6, 60.5% versus 50.8%; Day 7, 29.4% versus 5.2%) and lower euploidy rates (23.5% versus 51%; adjusted OR, 0.36). Among the 195 and 1697 transferred euploid PQBs and non-PQBs, the former involved a lower implantation rate (16.9% versus 52.3%) and a higher miscarriage rate per clinical pregnancy (36.4% versus 13.9%), therefore resulting in a lower LB rate (LBR, 10.8% versus 44.6%; adjusted OR, 0.22). Based on these rates, we estimated an overall 1.5% risk of miscarriage and 2.6% chance of LB after euploid vitrified-warmed SET per each biopsied PQB. The same estimates for non-PQBs were 3.7% and 22.8%. LIMITATIONS, REASONS FOR CAUTION The clinical benefit of PQBs is underestimated since they are the last option for transfer and this analysis entailed only the first LB. The higher miscarriage rate per clinical pregnancy here reported might be the consequence of a population of patients of poorer prognosis undergoing the SET of euploid PQBs, an option that requires further investigation. Finally, a cost-benefit analysis is needed in a prospective non-selection fashion. WIDER IMPLICATIONS OF THE FINDINGS PQBs show higher aneuploidy rates. If to be included, PGT-A is recommended. When selected against aneuploid-PQBs, euploid ones could still involve a worse prognosis, yet, their LBR is not negligible. Women should be informed that a poor morphology does not define a non-viable embryo per se, although PQBs show a reduced chance of resulting in an LB. STUDY FUNDING/COMPETING INTEREST(S) No external funding was used for this study. The authors have no conflict of interest related to this study. TRIAL REGISTRATION NUMBER N/A
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Tiegs, A. W., L. Sun, G. Patounakis, and R. T. Scott. "Worth the wait? Day 7 blastocysts have lower euploidy rates but similar sustained implantation rates as Day 5 and Day 6 blastocysts." Human Reproduction 34, no. 9 (August 12, 2019): 1632–39. http://dx.doi.org/10.1093/humrep/dez138.
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Abstract STUDY QUESTION Does the reproductive potential of embryos change when blastocyst development takes longer than the traditionally accepted 5 days when accounting for aneuploidy and endometrial-embryo asynchrony? SUMMARY ANSWER Aneuploidy increases with increasing duration of blastulation, but if blastocyst morphologic quality and endometrial-embryo asynchrony are controlled for, euploid Day 7 embryos have similar sustained implantation as compared to Days 5 and 6 euploid blastocysts. WHAT IS KNOWN ALREADY The relative contributions of diminished embryo quality versus endometrial and embryo asynchrony to poor outcomes associated with embryos cultured past Day 6 are not clear. Asynchrony can be eliminated by embryo vitrification with transfer in a subsequent month after retrieval. STUDY DESIGN, SIZE, DURATION Retrospective cohort study of patients from a single center attempting conception through ICSI and utilizing preimplantation genetic testing for aneuploidy screening (PGT-A) from January 2017 to September 2018. Cycles were excluded if they utilized surgical sperm or preimplantation genetic testing for monogenetic/single gene defects. ICSI cycle outcomes from 2586 patients were evaluated for ploidy status of embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS Only patients undergoing single, euploid frozen embryo transfer were included when analyzing cycle outcomes by day of blastocyst expansion of the transferred embryo (n = 2130). Ploidy rates by the day upon which an embryo was considered to be usable (denoted, ‘usable blastulation day’) were determined so as to assess the contribution of aneuploidy to slow embryo development. Outcomes of euploid frozen single embryo transfers (SET) of Day 7 embryos were evaluated to assess the reproductive potential associated with embryos that were slowly developing for reasons other than aneuploidy. Analyses were adjusted by maternal age and blastocyst morphology. MAIN RESULTS AND THE ROLE OF CHANCE Overall, 67.7% (n = 3508) of usable Day 5 blastocysts were euploid, 52.1% (n = 5560) of usable Day 6 blastocysts were euploid and 43.1% (n = 229) of usable Day 7 embryos were euploid (Day 5 versus Day 6: odds ratio (OR) 0.7 (95% CI, 0.64–0.76), P < 0.001; Day 5 versus Day 7: OR 0.56 (95% CI, 0.46–0.69), P < 0.001; Day 6 versus Day 7: OR 0.81 (95% CI, 0.67–0.99), P = 0.036). Stratified by Society for Assisted Reproductive Technology maternal age groups, a reduction in the prevalence of euploidy by increasing time to embryo blastulation was still seen. The sustained implantation rate (SIR) was similar after euploid SET of Days 5 and 6 embryos (overall, 68.9% (95% CI, 66.0–71.6) and 66.8% (95% CI, 63.8–69.7), respectively; P = 0.81). SIR after euploid Day 7 SET appeared slightly lower than that of Days 5 and 6 embryos (52.6% (95% CI, 35.8–69.0); (Day 5 versus Day 7: OR, 0.67 (95% CI, 0.32–1.41), P = 0.29; Day 6 versus Day 7: OR 0.58 (95% CI, 0.28–1.2), P = 0.14)) but did not achieve statistical significance. LIMITATIONS, REASONS FOR CAUTION The primary limitation is the low number of Day 7 blastocyst transfers that limits statistical power. Additionally, the retrospective nature of this study may prevent full elucidation of potential biases with respect to culture, morphologic assessment and selection of Day 7 embryos for transfer. WIDER IMPLICATIONS OF THE FINDINGS Routine culture through Day 7 may successfully increase the pool of transferrable embryos for patients who would otherwise have no usable embryos if culture terminated on Day 6. This is particularly true for older patients (i.e. greater than 35 years of age), whose embryos take longer to blastulate and, therefore, are more susceptible to cycle cancelation. Additionally, as evidenced by an adequate overall SIR of 52.6% after euploid SET of Day 7 blastocysts, embryos developing to a usable blastocyst on Day 7 are likely within the ‘window of blastulation.’ STUDY FUNDING/COMPETING INTEREST(S) None.
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Shah, Jaimin S., Marta Venturas, Tim H. Sanchez, Alan S. Penzias, Daniel J. Needleman, and Denny Sakkas. "Fluorescence lifetime imaging microscopy (FLIM) detects differences in metabolic signatures between euploid and aneuploid human blastocysts." Human Reproduction 37, no. 3 (February 1, 2022): 400–410. http://dx.doi.org/10.1093/humrep/deac016.
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Abstract STUDY QUESTION Can non-invasive imaging with fluorescence lifetime imaging microscopy (FLIM) detect metabolic differences in euploid versus aneuploid human blastocysts? SUMMARY ANSWER FLIM has identified significant metabolic differences between euploid and aneuploid blastocysts. WHAT IS KNOWN ALREADY Prior studies have demonstrated that FLIM can detect metabolic differences in mouse oocytes and embryos and in discarded human blastocysts. STUDY DESIGN, SIZE, DURATION This was a prospective observational study from August 2019 to February 2020. Embryo metabolic state was assessed using FLIM to measure the autofluorescence metabolic factors nicotinamide adenine dinucleotide dehydrogenase together with nicotinamide adenine phosphate dinucleotide dehydrogenase (NAD(P)H) and flavin adenine dinucleotide (FAD). Eight metabolic FLIM parameters were obtained from each blastocyst (four for NAD(P)H and four for FAD): short (T1) and long (T2) fluorescence lifetime, fluorescence intensity (I) and fraction of the molecules engaged with enzymes (F). The redox ratio (NAD(P)H-I)/(FAD-I) was also calculated for each image. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was performed at a single academically affiliated centre where there were 156 discarded frozen blastocysts (n = 17 euploids; 139 aneuploids) included. Ploidy status was determined by pre-implantation genetic testing for aneuploidy (PGT-A). Discarded human blastocysts were compared using single FLIM parameters. Additionally, inner cell mass (ICM) and trophectoderm (TE) were also evaluated. Multilevel models were used for analysis. A post-hoc correction used Benjamini–Hochberg’s false discovery rate, at a q-value of 0.05. MAIN RESULTS AND THE ROLE OF CHANCE Comparing euploid (n = 17) versus aneuploid (n = 139) embryos, a significant difference was seen in NAD(P)H-F (P < 0.04), FAD-I (P < 0.04) and redox ratio (P < 0.05). Euploid ICM (n = 15) versus aneuploid ICM (n = 119) also demonstrated significantly different signatures in NAD(P)H-F (P < 0.009), FAD-I (P < 0.03) and redox ratio (P < 0.03). Similarly, euploid TE (n = 15) versus aneuploid TE (n = 119) had significant differences in NAD(P)H-F (P < 0.0001) and FAD-I (P < 0.04). LIMITATIONS, REASONS FOR CAUTION This study utilized discarded human blastocysts, and these embryos may differ metabolically from non-discarded human embryos. The blastocysts analysed were vitrified after PGT-A biopsy and it is unclear how the vitrification process may affect the metabolic profile of blastocysts. Our study was also limited by the small number of rare donated euploid embryos available for analysis. Euploid embryos are very rarely discarded due to their value to patients trying to conceive, which limits their use for research purposes. However, we controlled for the imbalance with the bootstrap resampling analysis. WIDER IMPLICATIONS OF THE FINDINGS These findings provide preliminary evidence that FLIM may be a useful non-invasive clinical tool to assist in identifying the ploidy status of embryos. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Blavatnik Biomedical Accelerator Grant at Harvard University. Becker and Hickl GmbH and Boston Electronics sponsored research with the loaning of equipment for FLIM. D.J.N. is an inventor on patent US20170039415A1. There are no other conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A
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Yamaguchi, Katsumi, Alisha O. Soares, Loyal A. Goff, Anjali Talasila, Jungbin A. Choi, Daria Ivenitsky, Sadik Karma, et al. "Striking heterogeneity of somatic L1 retrotransposition in single normal and cancerous gastrointestinal cells." Proceedings of the National Academy of Sciences 117, no. 51 (December 4, 2020): 32215–22. http://dx.doi.org/10.1073/pnas.2019450117.
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Somatic LINE-1 (L1) retrotransposition has been detected in early embryos, adult brains, and the gastrointestinal (GI) tract, and many cancers, including epithelial GI tumors. We previously found numerous somatic L1 insertions in paired normal and GI cancerous tissues. Here, using a modified method of single-cell analysis for somatic L1 insertions, we studied adenocarcinomas of colon, pancreas, and stomach, and found a variable number of somatic L1 insertions in tumors of the same type from patient to patient. We detected no somatic L1 insertions in single cells of 5 of 10 tumors studied. In three tumors, aneuploid cells were detected by FACS. In one pancreatic tumor, there were many more L1 insertions in aneuploid than in euploid tumor cells. In one gastric cancer, both aneuploid and euploid cells contained large numbers of likely clonal insertions. However, in a second gastric cancer with aneuploid cells, no somatic L1 insertions were found. We suggest that when the cellular environment is favorable to retrotransposition, aneuploidy predisposes tumor cells to L1 insertions, and retrotransposition may occur at the transition from euploidy to aneuploidy. Seventeen percent of insertions were also present in normal cells, similar to findings in genomic DNA from normal tissues of GI tumor patients. We provide evidence that: 1) The number of L1 insertions in tumors of the same type is highly variable, 2) most somatic L1 insertions in GI cancer tissues are absent from normal tissues, and 3) under certain conditions, somatic L1 retrotransposition exhibits a propensity for occurring in aneuploid cells.
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Ting, Ning-Shiuan, Ying-Hsi Chen, Shih-Fen Chen, and Pao-Chu Chen. "Successful Live Twin Birth through IVF/ICSI from a Couple with an Infertile Father with Pericentric Inversion of Chromosome 9 (p12q13): A Case with a High Aneuploidy Rate." Medicina 58, no. 11 (November 14, 2022): 1646. http://dx.doi.org/10.3390/medicina58111646.
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Evidence suggests that the pericentric inversion of chromosome 9 (inv(9)) does not affect the aneuploidy rate (38.5%) after IVF. Herein, we report a successful live female twin birth through IVF/ICSI with a high aneuploidy rate from a couple within which the infertile father has inv(9)(p12q13). A couple (a 34-year-old male and a 35-year-old female) was referred to our clinic due to infertility. The wife has a child with her previous husband. Results from the infertility workup of both parents were normal. Karyotyping revealed that the inv(9)(p12q13) of the father was the only cytogenetic abnormality. Preimplantation genetic testing for aneuploidies (PGT-A) after IVF/ICSI revealed a high aneuploidy rate (77%; 10/13). Two euploid blastocysts were transferred, resulting in a successful live female twin birth. The presented case highlights the possibility that inv(9)(p12q13) in males may impact the fertility and euploidy rate. PGT-A facilitates the selection of qualified blastocysts for the optimization of live-birth outcomes.
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Lim, Adelle Yun Xin, and Colin Soon Soo Lee. "Embryos Arising from Apronuclear (0PN) and Unipronuclear (1PN) Have Similar Euploidy Rates with Those from 2PN and Should be Considered for Transfer." Fertility & Reproduction 01, no. 02 (June 2019): 73–77. http://dx.doi.org/10.1142/s266131821930006x.
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Background: Fertilisation assessment is routinely made at 16–18 hours post-ICSI and 18–20 hours post-insemination. However, the absence of pronuclei (PN) during standard fertilisation assessment does not necessarily indicate fertilisation failure. The aim of this study is to assess the chromosomal status of blastocysts derived from 0PN and 1PN zygotes as well as to assess the clinical outcome after transfer of such embryos. Methods: In this study, we use microarray comparative genomic hybridisation (MaCGH) or next generation sequencing (NGS) to analyse the chromosomal status of 271 blastocysts (204 from 2PN, 41 from 0PN, 26 from 1PN) obtained from 42 patients who underwent conventional IVF (cIVF) and ICSI cycles with preimplantation genetic testing for aneuploidy (PGT-A). Results: Euploidy was confirmed in 126 (126/204; 61.8%), 31 (31/41; 75.6%) and 18 (18/26; 69.2%) 2PN-, 0PN- and 1PN-derived blastocysts respectively while the remaining 96 blastocysts displayed various chromosomal abnormalities. A Y-chromosome was observed in 0PN-derived blastocysts (19/41; 46.3%) and 1PN-derived blastocysts (13/26; 50%), indicating that sperm had penetrated the oocyte and not due to parthenogenetic activation. Four euploid 0PN-derived blastocysts were transferred to 4 patients and 3 healthy live births were achieved. Four euploid 1PN-derived blastocysts were transferred to 4 patients and 1 on-going pregnancy was achieved. Conclusion(s): 0PN- and 1PN-derived zygotes can be chromosomally normal and result in healthy live births. Such zygotes should not be discarded but instead be subjected to extended culture with PGT-A to ascertain the chromosomal and ploidy status and be considered for transfer.
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McDonough, Paul G. "Recurrent Aneuploidic and Euploidic Abortion." Obstetrics and Gynecology Clinics of North America 14, no. 4 (December 1987): 1099–113. http://dx.doi.org/10.1016/s0889-8545(21)00604-5.
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Vaiarelli, Alberto, Danilo Cimadomo, Erminia Alviggi, Anna Sansone, Elisabetta Trabucco, Ludovica Dusi, Laura Buffo, et al. "The euploid blastocysts obtained after luteal phase stimulation show the same clinical, obstetric and perinatal outcomes as follicular phase stimulation-derived ones: a multicenter study." Human Reproduction 35, no. 11 (September 20, 2020): 2598–608. http://dx.doi.org/10.1093/humrep/deaa203.
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Abstract STUDY QUESTION Are the reproductive outcomes (clinical, obstetric and perinatal) different between follicular phase stimulation (FPS)- and luteal phase stimulation (LPS)-derived euploid blastocysts? SUMMARY ANSWER No difference was observed between FPS- and LPS-derived euploid blastocysts after vitrified-warmed single embryo transfer (SET). WHAT IS KNOWN ALREADY Technical improvements in IVF allow the implementation non-conventional controlled ovarian stimulation (COS) protocols for oncologic and poor prognosis patients. One of these protocols begins LPS 5 days after FPS is ended (DuoStim). Although, several studies have reported similar embryological outcomes (e.g. fertilization, blastulation, euploidy) between FPS- and LPS-derived cohort of oocytes, information on the reproductive (clinical, obstetric and perinatal) outcomes of LPS-derived blastocysts is limited to small and retrospective studies. STUDY DESIGN, SIZE, DURATION Multicenter study conducted between October 2015 and March 2019 including all vitrified-warmed euploid single blastocyst transfers after DuoStim. Only first transfers of good quality blastocysts (≥BB according to Gardner and Schoolcraft’s classification) were included. If euploid blastocysts obtained after both FPS and LPS were available the embryo to transfer was chosen blindly. The primary outcome was the live birth rate (LBR) per vitrified-warmed single euploid blastocyst transfer in the two groups. To achieve 80% power (α = 0.05) to rule-out a 15% difference in the LBR, a total of 366 first transfers were required. Every other clinical, as well as obstetric and perinatal outcomes, were recorded. PARTICIPANTS/MATERIALS, SETTING, METHODS Throughout the study period, 827 patients concluded a DuoStim cycle and among them, 339 did not identify any transferable blastocyst, 145 had an euploid blastocyst after FPS, 186 after LPS and 157 after both FPS and LPS. Fifty transfers of poor quality euploid blastocysts were excluded and 49 patients did not undergo an embryo transfer during the study period. Thus, 389 patients had a vitrified-warmed SET of a good quality euploid blastocyst (182 after FPS and 207 after LPS). For 126 cases (32%) where both FPS- and LPS-derived good quality blastocysts were available, the embryo transferred was chosen blindly with a ‘True Random Number Generator’ function where ‘0’ stood for FPS-derived euploid blastocysts and ‘1’ for LPS-derived ones (n = 70 and 56, respectively) on the website random.org. All embryos were obtained with the same ovarian stimulation protocol in FPS and LPS (GnRH antagonist protocol with fixed dose of rec-FSH plus rec-LH and GnRH-agonist trigger), culture conditions (continuous culture in a humidified atmosphere with 37°C, 6% CO2 and 5% O2) and laboratory protocols (ICSI, trophectoderm biopsy in Day 5–7 without assisted hatching in Day 3, vitrification and comprehensive chromosome testing). The women whose embryos were included had similar age (FPS: 38.5 ± 3.1 and LPS: 38.5 ± 3.2 years), prevalence of male factor, antral follicle count, basal hormonal characteristics, main cause of infertility and previous reproductive history (i.e. previous live births, miscarriages and implantation failures) whether the embryo came from FPS or LPS. All transfers were conducted after warming in an artificial cycle. The blastocysts transferred after FPS and LPS were similar in terms of day of full-development and morphological quality. MAIN RESULTS AND THE ROLE OF CHANCE The positive pregnancy test rates for FPS- and LPS-derived euploid blastocysts were 57% and 62%, biochemical pregnancy loss rates were 10% and 8%, miscarriage rates were 15% and 14% and LBRs were 44% (n = 80/182, 95% CI 37–51%) and 49% (n = 102/207, 95% CI 42–56%; P = 0.3), respectively. The overall odds ratio for live birth (LPS vs FPS (reference)) adjusted for day of blastocyst development and quality, was 1.3, 95% CI 0.8–2.0, P = 0.2. Among patients with euploid blastocysts obtained following both FPS and LPS, the LBRs were also similar (53% (n = 37/70, 95% CI 41–65%) and 48% (n = 27/56, 95% CI 35–62%) respectively; P = 0.7). Gestational issues were experienced by 7.5% of pregnant women after FPS- and 10% of women following LPS-derived euploid single blastocyst transfer. Perinatal issues were reported in 5% and 0% of the FPS- and LPS-derived newborns, respectively. The gestational weeks and birthweight were similar in the two groups. A 5% pre-term delivery rate was reported in both groups. A low birthweight was registered in 2.5% and 5% of the newborns, while 4% and 7% showed high birthweight, in FPS- and LPS-derived euploid blastocyst, respectively. Encompassing the 81 FPS-derived newborns, a total of 9% were small and 11% large for gestational age. Among the 102 LPS-derived newborns, 8% were small and 6% large for gestational age. No significant difference was reported for all these comparisons. LIMITATIONS, REASONS FOR CAUTION The LPS-derived blastocysts were all obtained after FPS in a DuoStim protocol. Therefore, studies are required with LPS-only, late-FPS and random start approaches. The study is powered to assess differences in the LBR per embryo transfer, therefore obstetric and perinatal outcomes should be considered observational. Although prospective, the study was not registered. WIDER IMPLICATIONS OF THE FINDINGS This study represents a further backing of the safety of non-conventional COS protocols. Therefore, LPS after FPS (DuoStim protocol) is confirmed a feasible and efficient approach also from clinical, obstetric and perinatal perspectives, targeted at patients who need to reach the transfer of an euploid blastocyst in the shortest timeframe possible due to reasons such as cancer, advanced maternal age and/or reduced ovarian reserve and poor ovarian response. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER N/A.
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Le, Phuong Thi Bich, Anh Hoang Le, Loc Minh Tai Nguyen, and Vinh Quang Dang. "Morphokinetic parameters comparison between euploid and aneuploid blastocysts." Biomedical Research and Therapy 8, no. 5 (May 30, 2021): 4325–32. http://dx.doi.org/10.15419/bmrat.v8i5.671.
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Background: Pre-implantation genetic testing for aneuploidy (PGT-A) has been using for years in embryoselection. However, this is an invasive method and may cause harm to the embryos. Therefore, time-lapse monitoring has been thought to be an alternative approach for embryo selection due to its efficiency. Up to now, several studies were investigating the relationship between the morphokinetic parameters and the embryo ploidy. However, the results are not consistent. This study aims to evaluate the correlation between morphokinetic parameters and PGT-A results.
Methods: This retrospective cohort study was conducted at IVFMD Phu Nhuan, My Duc Phu Nhuan Hospital, between September 2018 and June 2019. Patients undergoing PGT-A due to advanced maternal age, repeated implantation failure or recurrent miscarriage and having embryo cultured under time-lapse monitoring were included. Patients with the re-thawing embryo for PGT-A were not eligible. The time from insemination to the pronuclear appearing (tPN), the onset of two to eight-cell divisions (t2 to t8) and the duration of the second cell cycle (cc2, t3-t2) were observed.
Results: There were 39 patients included in the study, with mean age of 36.4 +/- 5.7 years. A total of 110 blastocysts were biopsied. Amongst them, 63 embryos (57.3%) were euploidy (group 1), and 47 embryos (42.7%) were aneuploidy (group 2). There was no significant difference between euploid, and aneuploid embryos regarding all morphokinetic parameters, including tPN, t2, t3, t4, t5, cc2, and t8 (7.2 +/- 1.5 hours vs. 7.4 +/- 1.6 hours; 25.0 +/- 2.8 hours vs. 25.6 +/- 3.2 hours; 35.8 +/- 3.6 hours vs. 36.9 +/- 3.3 hours; 37.5 +/- 4.4 hours vs. 38.3 +/- 4.3 hours; 49.2 +/- 5.52 hours vs. 49.9 +/- 6.2 hours; 10.7 +/- 2.6 hours vs. 11.2 +/- 1.7 hours; and 55.7 +/- 6.4 hours vs. 58.1 +/- 7.4 hours, respectively).
Conclusion: In this study, we found no difference in the morphokinetic parameters between euploid and aneuploid embryos.
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De Munck, Neelke, Ibrahim El Khatib, Andrea Abdala, Ahmed El-Damen, Aşina Bayram, Ana Arnanz, Laura Melado, Barbara Lawrenz, and Human M. Fatemi. "Intracytoplasmic sperm injection is not superior to conventional IVF in couples with non-male factor infertility and preimplantation genetic testing for aneuploidies (PGT-A)." Human Reproduction 35, no. 2 (February 2020): 317–27. http://dx.doi.org/10.1093/humrep/deaa002.
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Abstract STUDY QUESTION Does the insemination method impact the euploidy outcome in couples with non-male factor infertility? SUMMARY ANSWER Conventional IVF can be applied in cycles with preimplantation genetic testing for aneuploidies (PGT-A), as both IVF and ICSI generate equal numbers of euploid blastocysts. WHAT IS KNOWN ALREADY Ever since its introduction, the popularity of ICSI has increased tremendously, even in couples with non-male factor infertility. The use of conventional IVF is a contraindication for couples undergoing PGT to ensure monospermic fertilisation and to eliminate potential paternal contamination from extraneous sperm attached to the zona pellucida. Despite this, it has recently been shown that sperm DNA fails to amplify under the conditions used for trophectoderm biopsy samples. STUDY DESIGN, SIZE, DURATION This single-centre prospective pilot study included 30 couples between November 2018 and April 2019. PARTICIPANTS/MATERIALS, SETTING, METHOD Arab couples, with a female age between 18–40 years, body mass index ≤30 kg/m2, at least 10 cumulus oocyte complexes (COCs) following oocyte retrieval (OR) and normal semen concentration and motility (WHO) in the fresh ejaculate on the day of OR, were eligible for the study. Half of the sibling oocytes were assigned to conventional IVF, and the other half were assigned to ICSI. All embryos were cultured in a time-lapse imaging system in Global Total LP media. Blastocysts were subjected to trophectoderm biopsy on Day 5, 6 or 7 and next-generation sequencing (NGS) to determine blastocyst ploidy status. The primary objective was to determine the euploid rate in blastocysts from sibling oocytes. MAIN RESULTS AND THE ROLE OF CHANCE A total of 568 COCs were randomly allocated between IVF (n = 283; 9.4 ± 4.0) and ICSI (n = 285; 9.5 ± 4.1). While the incidence of normal fertilisation per cycle (6.1 ± 3.8 (64.0%) vs 6.3 ± 3.5 (65.4%); P = 0.609) was distributed equally between IVF and ICSI, the degeneration rate (0.1 ± 0.3 vs 0.7 ± 0.8; P = 0.0003) was significantly higher after ICSI and the incidence of abnormal fertilisation (≥3 pronuclei) was significantly higher after IVF (0.9 ± 1.2 vs 0.2 ± 0.4; P = 0.005). For all fertilised oocytes, there were no differences in the number of good-quality embryos on Day 3 (74% vs 78%; P = 0.467), nor in the blastulation rate on Day 5 (80.4% vs 70.8%; P = 0.076). The total number of blastocysts biopsied per cycle on Days 5, 6 and 7 was not significantly different between IVF or ICSI (4.0 ± 2.8 vs 3.9 ± 2.5; P = 0.774). With euploid rates of 49.8 and 44.1% (P = 0.755; OR: 1.05664 [0.75188–1.48494), respectively, there was no significant difference identified between IVF and ICSI (2.0 ± 1.8 vs 1.9 ± 1.7; P = 0.808) and all couples had at least one euploid blastocyst available for transfer. When considering only euploid blastocysts, the male/female ratio was 61/39 in IVF and 43/57 in ICSI (P = 0.063). LIMITATIONS, REASON FOR CAUTION This is a pilot study with a limited patient population of 30 couples (and 568 COCs) with a normal ovarian response. The results of our study should not be extrapolated to other patient populations. WIDER IMPLICATIONS OF THE FINDINGS It is safe to apply conventional IVF in couples with non-male factor infertility undergoing PGT-A. STUDY FUNDING/COMPETING INTEREST(S) No funding was obtained. There are no competing interests. TRIAL REGISTRATION NUMBER NCT03708991.
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Tain, Diana Chieh Xing, Michelle Sheng Rong Lim, Bee Lian Ng, Elizabeth Hammond, and Pak Seng Wong. "The Influence of Day 2 Blastomere Symmetry on Blastocyst Grade and Ploidy Status." Fertility & Reproduction 01, no. 02 (June 2019): 115–18. http://dx.doi.org/10.1142/s2661318219500117.
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Previous studies have suggested that aneuploidy rates are co-related with cell asymmetry at the cleavage stage. A retrospective study was carried out to determine the significance of blastomere symmetry at the 4-cell stage on blastocyst grade and ploidy status. 732 Day 5/6 blastocysts from 191 patients undergoing Pre-implantation Genetic Testing for Aneuploidy were analysed with time-lapse imaging (Embryoscope, Vitrolife) during 2017. Blastomere symmetry was measured at the first image of 4-cells on Day 2 by tabulating the mean diameter of 2 lines drawn perpendicularly on each blastomere. Symmetry was defined as the blastomere diameter difference of [Formula: see text] 25%. Trophectoderm (TE) biopsy was performed on Day 5/6 followed by chromosomal evaluation using Next Generation Sequencing (VeriSeq Protocol, Illumina). Blastocyst grade was classified as either “Good” (inner cell mass (ICM) and TE, AA respectively), “Fair/Good” (AB, BA), “Fair” (BB) and “Poor” (early blastocyst grade 2 or TE grading of C). The significance of blastomere symmetry on blastocyst grade and ploidy status was measured using chi-square tests. There was no significance difference in resulting blastocyst quality for symmetrical and asymmetrical embryos (Table 1: p [Formula: see text] 0.10). Furthermore, there was no significance difference in the euploid rate (42.5% vs. 45.3%) or mosaic rate (22.1% vs. 16.2%) between symmetrical and asymmetrical embryos (p [Formula: see text] 0.24). In conclusion, the presence of asymmetrical blastomeres at the 4-cell stage do not impact the good quality blastocyst formation rate and euploidy rate for embryos that progress into blastocysts. However, this study excludes embryos that do not develop to the blastocyst stage and those with erratic division patterns, direct cleavage and reverse cleavage on Day 2, both of which have potential to influence ploidy result. Asymmetrical 4-cell embryos have the potential for high quality euploid blastocyst progression and can be considered for day 2 embryo transfer in the absence of symmetrical 4-cell embryos.
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Salasin, Rian N., Robin Skory, Nathanael C. Koelper, and Dara Berger. "ARTIFICIAL INTELLIGENCE INCREASES EUPLOIDY RATE AND CLINICAL PREGNANCY RATE IN SINGLE THAWED EUPLOID EMBRYO TRANSFER AND DECREASES THE RATE OF MOSAIC Results." Fertility and Sterility 116, no. 3 (September 2021): e392-e393. http://dx.doi.org/10.1016/j.fertnstert.2021.07.1050.
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Lee, Chun-I., Hsiu-Hui Chen, Chun-Chia Huang, Chien-Hong Chen, En-Hui Cheng, Jing Yang Huang, Maw-Sheng Lee, and Tsung-Hsien Lee. "Effect of Interval between Human Chorionic Gonadotropin Priming and Ovum Pick-up on the Euploid Probabilities of Blastocyst." Journal of Clinical Medicine 9, no. 6 (June 2, 2020): 1685. http://dx.doi.org/10.3390/jcm9061685.
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This retrospective study attempts to elucidate the relevance of the interval between human chorionic gonadotropin priming and oocyte pick-up (hCG-OPU) to the euploidy probability of biopsied blastocysts in preimplantation genetic tests for aneuploidy (PGT-A) cycles. A total of 1889 blastocysts from 511 patients undergoing PGT- A cycles were used. An analysis of generalized estimating equations (GEE) was used to identify whether the hCG–OPU interval is associated with euploidy probabilities of blastocysts. Accordingly, maternal age (OR: 0.925, 95% CI: 0.903–0.948, p < 0.001) and the hCG–OPU interval (OR: 1.138, 95% CI: 1.028–1.260, p = 0.013) were the two significant factors associated with the euploidy probabilities. The Cochran-Armitage trend test demonstrated that the blastocyst euploidy percentage increased progressively with the increasing hCG-OPU interval in normal responders (p = 0.006) and advanced maternal age (age ≥38 years; p = 0.020) groups. In normal responders, the euploidy rate was highest in the 38–39 h interval (43.1%, 47/109). In contrast, the euploidy rate was lowest in the 34–35 h interval (28.7%, 29/105). In conclusion, the present study demonstrated that at an hCG-OPU interval between 34–39 h, the longer the hCG-OPU interval, the higher the probability of euploidy for blastocysts.
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Labarta, Elena, Ernesto Bosch, Amparo Mercader, Pilar Alamá, Emilia Mateu, and Antonio Pellicer. "A Higher Ovarian Response after Stimulation for IVF Is Related to a Higher Number of Euploid Embryos." BioMed Research International 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/5637923.
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This study has analysed the relationship between ovarian response and the number of euploid embryos. This is a post hoc analysis of a subset of data generated during a prospective cohort study previously published. Forty-six oocyte donors were subjected to ovarian stimulation with 150 IU of rFSH and 75 IU of hp-hMG in a GnRH agonist long protocol. Preimplantation genetic screening was performed in all viable embryos. We observed a positive relationship between ovarian response and the number of euploid embryos. When ovarian response was above the median (≥17 oocytes), the mean number of euploid embryos per donor was 5.0 ± 2.4, while when <17 oocytes were obtained the mean number of euploid embryos was 2.7 ± 1.4 (p=0.000). Aneuploidy rate did not increase with ovarian response or gonadotropin doses. Also, the number of euploid embryos was inversely related to the amount of gonadotropins needed per oocyte obtained (ovarian sensitivity index). These results suggest that the number of euploid embryos available for embryo transfer increases as the number of oocytes obtained does. Considering the total number of euploid embryos seems more relevant than the aneuploidy rate.
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McDonough, Paul. "The Role of Molecular Mutation in Recurrent Euploidic Abortion." Seminars in Reproductive Medicine 6, no. 02 (May 1988): 155–61. http://dx.doi.org/10.1055/s-2007-1021351.
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Stumpff, Jason, and Charles L. Asbury. "Chromosome Bi-Orientation: Euclidian Euploidy." Current Biology 18, no. 2 (January 2008): R81—R83. http://dx.doi.org/10.1016/j.cub.2007.11.036.
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KEEFE, David. "Why Euploid Blastocysts Fail." Fertility & Reproduction 04, no. 03n04 (September 2022): 104. http://dx.doi.org/10.1142/s2661318222740164.
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Preimplantation genetic testing for aneuploidy improves implantation and reduces miscarriage rates, but still about 30 to 35% of euploid blastocysts fail to implant and 10 to 13% of pregnancies following euploid blastocyst transfer miscarry. Both endometrial and embryo factors may contribute to failed euploid embryo transfers. Endometrial factors include uterine structural abnormalities, altered timing of endometrial receptivity, glandular-stromal disynchrony, and inflammatory states. Recent studies question the clinical benefit of some recent assays for endometrial receptivity. Other recent studies question the value of surgical correction of uterine septae and fibroids to prevent further pregnancy loss. Embryo factors include aneuploidy, either undetected by PGT-A performed on the blastocyst trophectoderm (i.e. false negative test) or de novo non-disjunction. Sub chromosomal genetic variation, e.g. copy number variants and de novo retrotransposon insertions, may impair embryo viability. We employ a “genetics first” approach, which relies on genetic analysis of products of conception, obtained by uterine evacuation, to evaluate miscarriage after euploid blastocyst transfer. Non-invasive genetic analysis of first trimester pregnancies also may help characterize the cause of embryo loss after euploid embryo transfer. Early results suggest that analysis of cfDNA and trophoblast retrieval and isolation from the cervix (TRIC) may allow women experiencing early pregnancy loss to learn about the genetic state of their miscarriage, without an invasive surgical procedure to obtain products of conception.
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Diblík, Jan, Milan Macek, Maria-Cristina Magli, Roman Krejčí, and Luca Gianaroli. "Topology of Chromosomes 18 and X in Human Blastomeres from 3- to 4-Day-old Embryos." Journal of Histochemistry & Cytochemistry 53, no. 3 (March 2005): 273–76. http://dx.doi.org/10.1369/jhc.4b6509.2005.
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The positions of chromosomes 18 and X fluorescence in situ hybridization signals were analyzed in blastomeres generated from human in vitro fertilization 3- to 4-day-old embryos after preimplantation screening of aneuploidy of chromosomes 13, 16, 18, 21, 22, X, and Y. Fluorescent signal localization compared with a three-dimensional sphere model of random signal distribution revealed significant differences, providing evidence of peripheral localization of chromosome 18 in aneuploid ( p=0.0013) and aneuploid/euploid blastomeres ( p=0.0011). No differences were found in localization of chromosome 18 in euploid and in chromosome X in euploid and aneuploid blastomeres.
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Kahraman, Semra, Aylin Pelin Çil, Çağrı Oğur, Altug Semiz, and Cihangir Yilanlioglu. "Probability of finding at least one euploid embryo and the euploidy rate according to the number of retrieved oocytes and female age using FISH and array CGH." Journal of Reproductive Biotechnology and Fertility 5 (June 24, 2016): 205891581665327. http://dx.doi.org/10.1177/2058915816653277.
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Cimadomo, Danilo, Laura Rienzi, Adriano Giancani, Erminia Alviggi, Ludovica Dusi, Rita Canipari, Laila Noli, et al. "Definition and validation of a custom protocol to detect miRNAs in the spent media after blastocyst culture: searching for biomarkers of implantation." Human Reproduction 34, no. 9 (August 16, 2019): 1746–61. http://dx.doi.org/10.1093/humrep/dez119.
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Abstract STUDY QUESTION Can miRNAs be reliably detected in the spent blastocyst media (SBM) after IVF as putative biomarkers of the implantation potential of euploid embryos? SUMMARY ANSWER Adjustment of the data for blastocyst quality and the day of full-expansion hinders the predictive power of a fast, inexpensive, reproducible and user-friendly protocol based on the detection of 10 selected miRNAs from SBM. WHAT IS KNOWN ALREADY Euploidy represents so far the strongest predictor of blastocyst competence. Nevertheless, ~50% of the euploid blastocysts fail to implant. Several studies across the years have suggested that a dialogue exists between the embryo and the endometrium aimed at the establishment of a pregnancy. MicroRNAs have been proposed as mediators of such a dialogue and investigated in this respect. Several expensive, time-consuming and complex protocols have been adopted and promising results have been produced, but conclusive evidence from large clinical studies is missing. STUDY DESIGN, SIZE, DURATION This study was conducted in two phases from September 2015 to December 2017. In Phase 1, the human blastocyst miRNome profile was defined from the inner cell mass (ICM) and the corresponding whole-trophectoderm (TE) of six donated blastocysts. Two different protocols were adopted to this end. In parallel, 6 pools of 10 SBM each were run (3 from only implanted euploid blastocysts, IEBs; and 3 from only not-implanted euploid blastocysts, not-IEBs). A fast, inexpensive and user-friendly custom protocol for miRNA SBM profiling was designed. In Phase 2, 239 SBM from IEB and not-IEB were collected at three IVF centres. After 18 SBM from poor-quality blastocysts were excluded from the analysis, data from 107 SBM from not-IEB and 114 from IEB were produced through the previously developed custom protocol and compared. The data were corrected through logistic regressions. PARTICIPANT/MATERIALS, SETTINGS, METHODS Donated blastocysts underwent ICM and whole-TE isolation. SBM were collected during IVF cycles characterized by ICSI, blastocyst culture in a continuous media, TE biopsy without zona pellucida opening in Day 3, quantitative PCR (qPCR)-based aneuploidy testing and vitrified-warmed single euploid embryo transfer. Not-IEB and IEB were clustered following a negative pregnancy test and a live birth, respectively. The Taqman Low Density Array (TLDA) cards and the Exiqon microRNA human panel I+II qPCR analysis protocols were adopted to analyse the ICM and whole-TE. The latter was used also for SBM pools. A custom protocol and plate was then designed based on the Exiqon workflow, validated and finally adopted for SBM analysis in study Phase 2. This custom protocol allows the analysis of 10 miRNAs from 10 SBM in 3 hours from sample collection to data inspection. MAIN RESULTS AND ROLE OF THE CHANCE The TLDA cards protocol involved a higher rate of false positive results (5.6% versus 2.8% with Exiqon). There were 44 miRNAs detected in the ICM and TE from both the protocols. One and 24 miRNAs were instead detected solely in the ICM and the TE, respectively. Overall, 29 miRNAs were detected in the pooled SBM: 8 only from not-IEB, 8 only from IEB and 13 from both. Most of them (N = 24/29, 82.7%) were also detected previously in both the ICM and TE with the Exiqon protocol; two miRNAs (N = 2/29, 6.9%) were previously detected only in the TE, and three (N = 3/29, 10.3%) were never detected previously. In study Phase 2, significant differences were shown between not-IEB and IEB in terms of both miRNA detection and relative quantitation. However, when the data were corrected for embryo morphology and day of full development (i.e. SBM collection), no significant association was confirmed. LIMITATIONS, REASONS FOR CAUTION This study did not evaluate specifically exosomal miRNAs, thereby reducing the chance of identifying the functional miRNAs. Ex-vivo experiments are required to confirm the role of miRNAs in mediating the dialogue with endometrial cells, and higher throughput technologies need to be further evaluated for miRNA profiling from clinical SBM samples. WIDER IMPLICATIONS OF THE FINDINGS Although no clinical predictive power was reported in this study, the absence of invasiveness related with SBM analysis and the evidence that embryonic genetic material can be reliably detected and analysed from SBM make this waste product of IVF an important source for further investigations aimed at improving embryo selection. STUDY FUNDING/COMPETING INTEREST(S) This project has been financially supported by Merck KgaA (Darmstadt, Germany) with a Grant for Fertility Innovation (GFI) 2015. The authors have no conflict of interest to declare related with this study. TRIAL REGISTRATION NUMBER None.
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Azambuja, R., F. Wingert, L. A. Proença, M. R. Hentschke, I. Badalotti-Teloken, V. C. Dornelles, Á. Petracco, and M. Badalotti. "P-289 KIDscore and PGT-A: Is there a relationship between the findings?" Human Reproduction 37, Supplement_1 (June 29, 2022). http://dx.doi.org/10.1093/humrep/deac107.277.
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Abstract Study question Is there a correlation between Preimplantation Genetic Tests (PGT) results and Embryoscope’s KIDscore? Summary answer It seems that the higher the KIDscore, the higher the percentage of euploid embryos. What is known already Time lapse technology is bringing new perspectives in the relationship of embryos' morphokinetics and implantation rates after assisted reproduction techniques. However, it seems that only the embryo morphokinetics could be insufficient to predict euploidy. The KIDscoreTM D5 (KS5) algorithm, thus, is used for improving the implantation rates after a single euploid embryo transfer in its blastocyst stage and is related to higher rates of euploid embryos the higher the KS5, which could lead to higher implantation rates. Study design, size, duration Retrospective, observational study performed at a reproductive medicine center, using data collected between 2019 and 2021. A total of 802 embryos were included for analysis. Participants/materials, setting, methods All the embryos were biopsied for PGT (A, SR, and M), after being cultured for five or six days in an Embryoscope® time-lapse incubator (Vitrolife®, Canada). The embryos were then divided into three groups according to the KS5 evaluation: G1 (1-4), G2 (4.1-7), G3 (7.1-9.9) and the percentage of euploidy was evaluated in each group. For statistical analysis, Chi-square, and ANOVA tests, and Pearson correlation were used, considering p < 0.05. Main results and the role of chance The women’s mean age among groups G1 vs. G2 vs. G3 was, respectively: 39.1±3.5 vs. 38.7±3.3 vs. 37.6±3.8, p < 0.001; the mean KS5 of each group was: 2.9±0.7 vs. 5.4±0.8 vs. 8.0±0.7, p < 0.001 and finally, the euploidy rates comparing the G1 vs. G2 vs. G3 were, respectively: 98/341, 28.7% vs. 124/340, 36.5% vs. 63/121, 52.1%, p < 0.001. A weak correlation between women's age and KIDScore was also observed (-0.173, p < 0.001). Limitations, reasons for caution Although there is a positive correlation between embryomorphokinetics and euploidy, and the euploidy rate increases with higher KIDscore, only 50% of the high score embryos are euploids. Therefore, it is still important to perform embryo biopsy. Wider implications of the findings The findings suggest that better embryo morphokinetics provide greater chances of euploidy. Moreover, a weak negative correlation between women's age and KIDScore, possibly due to age-related aneuploidy, was observed. These results highlight time-lapse technology’s importance and the future perspective of morphokinetics evaluation improving implantation rates through euploidy identification. Trial registration number Not Applicable
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Li, Na, Yichun Guan, Bingnan Ren, Yuchao Zhang, Yulin Du, Hongjiao Kong, Yongjie Zhang, and Hua Lou. "Effect of Blastocyst Morphology and Developmental Rate on Euploidy and Live Birth Rates in Preimplantation Genetic Testing for Aneuploidy Cycles With Single-Embryo Transfer." Frontiers in Endocrinology 13 (April 13, 2022). http://dx.doi.org/10.3389/fendo.2022.858042.
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ObjectiveThe aim of this study was to investigate whether blastocyst morphology and developmental rate are associated with euploidy and live birth rates (LBRs) in single euploid frozen–thawed embryo transfer (FET) cycles.DesignRetrospective cohort study.MethodsThis study included 431 preimplantation genetic testing for aneuploidy (PGT-A) cycles followed by 393 FET cycles performed at our center from June 2017 to March 2021. All cycles were analyzed for euploidy based on blastocyst morphology (good, average and poor), developmental stage (day 5 and 6) and maternal age (< 35 and ≥ 35 years old). Multivariate logistic analysis models were used to identify the independent effects of conventional blastocyst morphology, developmental rate and morphological parameters (degree of blastocoele expansion, and grade of inner cell mass and trophectoderm (TE)) on LBRs.ResultsIn the group of women aged < 35 years, compared with poor-quality blastocysts, good-quality blastocysts (62.90% vs. 32.46%; odds ratio (OR) 3.163, 95% confidence interval (CI) 2.247–4.451; P < 0.001) and average-quality blastocysts (46.70% vs. 32.46%; OR 1.665, 95% CI 1.287–2.154; P < 0.001) had significantly higher euploidy rates. Additionally, day 5 blastocysts were associated with higher euploidy rates than day 6 blastocysts (49.28% vs. 35.02%; OR 1.506, 95% CI 1.191–1.903; P= 0.001). In the group of women aged ≥ 35 years, euploidy rates were also associated with blastocyst morphology, with 41.86%, 45.65% and 24.39% of good, average and poor-quality embryos, respectively, exhibiting euploidy. However, no relationship was seen between euploidy and blastocyst developmental rate. Multiple logistic regression analysis show that overall blastocyst morphology of euploid embryos was not associated with LBR, only embryos with A-grade TE had significantly higher LBRs than those with C-grade TE (62.71% vs. 45.40%; OR 2.189, 95% CI 1.166–4.109; P=0.015). Similarly, LBRs were significantly higher when day 5 blastocysts were transferred than when day 6 blastocysts were transferred (57.75% vs. 41.67%; OR 2.132, 95% CI 1.370–3.318; P = 0.001).ConclusionPoor-quality embryos have reduced rates of euploidy. However, blastocyst developmental rate only significantly associates with euploidy rates in women aged younger than 35. Furthermore, only TE grade and blastocyst developmental rate are significantly associated with LBRs following FET cycles.
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Casciani, V., D. Cimadomo, S. Trio, V. Chiappetta, F. Innocenti, B. Iussig, E. Alviggi, et al. "P-189 Association between iDAScore v1.0, senior embryologists’ grading and euploidy in 546 blastocysts obtained during 189 PGT-A cycles." Human Reproduction 37, Supplement_1 (June 29, 2022). http://dx.doi.org/10.1093/humrep/deac107.182.
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Abstract Study question Is (intelligent data analysis) iDAScore v1.0 associated with euploidy at the blastocyst stage? Summary answer iDAScore v1.0 significantly correlated with euploidy (maternal age-adjusted OR:1.3 and AUC:0.72). Euploid blastocysts were ranked highest in ca.70% of the cohorts with both diagnoses. What is known already With machine learning and artificial intelligence (AI) implementation in IVF, several studies have been published mostly aimed at providing standardized and reproducible tools for gamete/embryo assessment and selection. Several of the proposed models might not be generally applicable due to their development on only a single center, small sample size and poor representation of the numerous clinical scenarios. Furthermore, the evidence has been rarely confirmed prospectively and/or in multicenter studies. Lately, the EmbryoScope+ has incorporated the iDAScore v1.0. This algorithm scores the chance of embryo implantation based on the video of blastocyst development and with no need for timing annotations. Study design, size, duration Interim analysis of a prospective study. Between April-December 2021, 189 preimplantation-genetic-testing (PGT) cycles (maternal age:38.4±4yr) with ≥1 blastocyst (N = 546 blastocysts, mean±SD:2.9±1.8, range:1-13) were included. We aimed at blindly analyzing the correlation between iDAScore v1.0 and (i) blastocyst quality estimated by senior embryologists, (ii) day of blastocyst full-expansion, (iii) chromosomal constitution diagnosed by NGS on a trophectoderm biopsy, (iv) the blastocyst to prioritize for transfer within cohorts with ≥2 blastocysts. Participants/materials, setting, methods Undisturbed culture was conducted in the EmbryoScope+. Assisted hatching was not performed and only fully-expanded blastocysts were biopsied. Morphology was assessed by 2 senior embryologists based on Gardner criteria. Average iDAScores were reported for the following groups: (i)excellent (AA)/good (AB,BA)/average (BB,AC,CA)/poor-quality (CC,BC,CB) blastocysts, (ii)day5/6/7 blastocysts, (iii)euploid/aneuploid/complex aneuploid blastocysts. Lastly, we reported how often the highest iDAScore corresponded to the highest ranked morphology (N = 143 cycles with ≥2 blastocysts) and/or euploid blastocysts (N = 79 cycles with both diagnoses). Main results and the role of chance In the study period, 546 blastocysts (iDAScore: 6.9±2.0, 2-9.7) were biopsied. The iDAScore was significantly different (Kruskal-Wallis<0.01) across blastocysts graded excellent (N = 256,46.9%; 8.1±1.3, 2.5-9.7), good (N = 97,17.7%; 6.9±1.6, 2.3-9.5), average (N = 75,13.9%; 5.8±1.4, 2.9-8.7) and poor (N = 118,21.5%; 4.8±1.6, 2-8.8). A significant difference (Kruskal-Wallis<0.01) was also found for the day of full-expansion (day5: N = 184,33.9%, 8.8±0.8, 4.3-9.7; day6: N = 324,59.1%, 6.0±1.6, 2.2-9.1; day7: N = 38,6.9%, 4.6±1.6, 2-7.8). Euploid blastocysts (N = 178,32.6%) had a significantly higher (Kruskal-Wallis<0.01) iDAScore (7.5±1.7, 2.4-9.6) than both simple (N = 209,38.3%, 6.7±2.1, 2.1-9.7) and complex aneuploid blastocysts (N = 159,29.1%, 6.3±2.0, 2-9.4). The logistic regression adjusted for maternal age highlighted a multivariate-OR 1.3, 95%CI 1.18-1.45, adjusted-p<0.01 for the association between iDAScore v1.0 and euploidy. The Receiver-Operating-Characteristic (ROC) curves outlined similar performance in predicting euploidy among the models encompassing iDAScore v1.0 adjusted for maternal age (AUC: 0.72, 95%CI 0.67-0.76, p < 0.01) or blastocyst quality (defined by senior embryologists) plus day of biopsy also adjusted for maternal age (AUC: 0.73, 95%CI 0.69-0.78, p < 0.01). iDAScore v1.0 and embryologists ranked the same blastocyst highest in 123 of 143 cycles with ≥2 blastocysts (86%). The highest ranked blastocyst according to iDAScore was a euploid blastocyst in 54 of the 79 cycles (68%) containing both euploid and aneuploid blastocysts. Limitations, reasons for caution The main purpose of iDAScore v1.0, for which the algorithm was trained, is implantation prediction of untested blastocysts. Thus, once the sample size of this blinded prospective study will be large enough, we will also examine the association between iDAScore v1.0 and the implantation of euploid blastocysts. Wider implications of the findings The similar predictivity on euploidy reported between subjective senior embryologists’ grading and objective AI-powered iDAscores is promising in view of IVF automation and standardization. This is especially relevant since iDAScore v1.0 has not been trained yet to specifically predict euploidy, and its future versions could be fine-tuned accordingly. Trial registration number Not Applicable
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Timotheou, E., T. Chartomatsidou, K. Kostoglou, E. Papa, C. Ioakeimidou, R. Najdecki, and E. Papanikolaou. "P–252 The correlation of first cleavage and blastulation timing to the euploid status of embryos after PGT-A." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.251.
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Abstract Study question To examine the correlation of first cleavage and blastulation timing on euploidy rates in IVF cycles after PGT-A. Summary answer The timing of blastulation is observed earlier in the euploid embryos. What is known already Embryo evaluation is one of the most critical processes that affect the clinical outcome in IVF cycles. Conventional morphologic assessment and morphokinetic assessment using time lapse technology are performed in order to select the embryo with the higher implantation potential to be transferred. It is stated that embryos with faster developmental potential, especially early forming blastocysts, show increased euploidy rate and higher implantation potential. Study design, size, duration This study includes ICSI/PGT-A treatments completed between May 2018 and December 2019. 117 blastocysts were biopsied and their euploidy status was analyzed by NGS. These embryos resulted from 32 different ICSI treatments. PGT-A was performed due to: a) repeated IVF failure, b) advanced maternal age, c) recurrent pregnancy loss.ICSI was implemented in all cases and blastocysts were vitrified awaiting the genetic results. Single euploid blastocyst transfer followed and clinical pregnancy rate was monitored. Participants/materials, setting, methods Based on the genetic results, the biopsied embryos were divided into two categories; group A representing the euploid embryos and group B the aneuploid embryos. The timing of 1st cleavage and the timing of blastulation, by means of forming a blastocoel, were investigated and compared between the two groups. The rate of early blastocysts in the two groups was also analysed. Early blastocysts are considered those formed at 96h ±2 of embryo culture post ICSI. Main results and the role of chance After the genetic analysis of the biopsied embryos, 37 blastocysts were included in group A-Euploid embryos and 80 blastocysts in group B-Aneuploid embryos. The mean time of the 1st cleavage division was similar between the two groups, with marginally no statistical significance (group A-euploid:25.9h, group B-aneuploid: 26.9h ,p>0.05). Regarding the blastulation time, it was achieved earlier in group A-Euploid, at a mean time of 102.6h, compared to the mean time of 106h in group B-Aneuploid (p < 0.05). Between the cohort of the Euploid embryos (group A), there was a higher rate of early blastulating embryos, compared to the cohort of aneuploid embryos (Group B) (24% VS 17.5%), although it was not statistically significant (p > 0.05). After transferring 1 euploid blastocyst, the ongoing pregnancy rate was monitored in 76.5%, independently of the 1stcleavage and blastulation time of the transferred embryo. Limitations, reasons for caution Further investigation in larger randomized studies is required, as only a limited number of cases were included in this study. Further analysis of the ongoing pregnancy rate between the euploid blastocysts, depending on other morphokinetic parameters would be of paramount significance, as well. Wider implications of the findings: High clinical pregnancy rates observed independently of the analyzed time points, indicate high success rates obtained after PGT-A/NGS. Additionally, success rates show that trophectoderm biopsy is not hazardous for the embryo viability, if performed properly. Concluding, genetic testing combined with time-lapse microscopy may provide further information to improve IVF outcomes. Trial registration number N/A
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Neves, A. R., S. Santos-Ribeiro, S. Garcí. Martínez, S. Soares, J. A. García-Velasco, N. Garrido, and N. P. Polyzos. "P–615 The effect of late-follicular phase progesterone rise on embryo ploidy, embryo quality and cumulative live birth rates following a freeze-only strategy." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.614.
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Abstract Study question Is late-follicular phase progesterone elevation (PE) associated with a deleterious effect on embryo euploidy, embryo blastulation and cumulative live birth rates (CLBRs)? Summary answer Late-follicular phase PE has no impact on impact on embryo euploidy rate, embryo blastulation rate nor on the CLBR. What is known already The effect of PE in ART outcomes has been extensively studied, yielding so far conflicting results. While some authors claim it is only detrimental to endometrial receptivity, others have suggested that it may also impair oocyte/embryo quality. Moreover, little is known regarding the potential effect PE may have on embryo ploidy and, consequently, CLBR. Study design, size, duration A multicenter retrospective cross-sectional study was performed between August 2017 and December 2019. A total of 1495 ICSI cycles coupled with preimplantation genetic diagnosis for aneuploidies (PGT-A) and deferred frozen embryo transfer (FET) were analyzed. Participants/materials, setting, methods All patients underwent ovarian stimulation with GnRH antagonist protocol and performed a serum progesterone measurement at one of the participating private fertility clinics on the day of trigger. The sample was stratified according to the progesterone levels: normal (≤1.50 ng/ml) and high (>1.50 ng/ml). The primary outcome was the embryo euploidy rate. Secondary outcomes were the number of euploid blastocysts, the blastulation rate and CLBR. Main results and the role of chance Late-follicular phase PE was associated with higher late-follicular estradiol levels (2847.56±1091.10 pg/ml vs. 2240.94± 996.37 pg/ml, p < 0.001) and more oocytes retrieved (17.67±8.86 vs. 12.70±7.00, p < 0.001). The number of euploid embryos was higher in the PE group (2.32±1.74 vs. 1.86±1.42, p < 0.001), whereas the embryo euploidy rate (48.3% [44.9%–51.7%] vs. 49.1% [47.7%–50.6%] and blastulation rate (47.1% [43.7%–50.5%] vs. 51.0% [49.7%–52.4%]) were comparable between the two groups. Likewise, no significant differences were found regarding the live birth rate (LBR) after the first FET (34.1% vs. 31.1%, p = 0.427) nor the CLBRs (38.9% vs. 37.0%, p = 0.637). Mixed-model analysis was performed in order to account for the clustering of cycles in the same patient. Adjusting for patients’ age, PE and BMI, PE failed to demonstrate any effect on the embryo euploidy rate (OR 1.03 [95% CI 0.89–1.20]). Mixed-model analysis for the number of euploid embryos was also performed. After adjusting for PE, age, BMI and ovarian response, PE did not affect the number of euploid embryos (0.02 [95%CI –0.21;0.25]. Multivariate logistic regression adjusted for PE, age, BMI and ovarian response revealed that PE was not associated with the CLBR (adjOR 0.96 [95% CI 0.66–1.38]). Limitations, reasons for caution Limitations of the study include its retrospective nature. Moreover, including only GnRH antagonist protocol and ICSI does not allow the extrapolation of these results to other populations. Wider implications of the findings: Our findings question results from previous studies claiming a detrimental effect of PE on embryo implantation potential. According to our results, PE has no impact on embryo euploidy rate, blastulation rate nor on CLBRs. Trial registration number Not applicable
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Buldo-Licciardi, Julia, Michael J. Large, David H. McCulloh, Caroline McCaffrey, and James A. Grifo. "Utilization of standardized preimplantation genetic testing for aneuploidy (PGT-A) via artificial intelligence (AI) technology is correlated with improved pregnancy outcomes in single thawed euploid embryo transfer (STEET) cycles." Journal of Assisted Reproduction and Genetics, January 7, 2023. http://dx.doi.org/10.1007/s10815-022-02695-7.
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Abstract Purpose 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 Retrospective cohort study at a single, large university-based fertility center with patients undergoing in vitro fertilization (IVF) utilizing PGT-A from February 2015 to April 2020. Controls included embryos tested using subjective NGS. The first experimental group included embryos analyzed by NGS utilizing AI and machine learning (PGTaiSM 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 Standardized PGT-A via AI significantly increases euploidy classification rates and OP/LBR, and decreases BPR when compared to standard NGS.
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Buerger, Jonathan D., Jitesh Datla, Shahab Minassian, Sarah Dreibelbis, Michael J. Glassner, John J. Orris, Nicolle Clements, Alyssa Sheffy, and Sharon H. Anderson. "Relationship Between Number of Oocytes Retrieved and Embryo Euploidy Rate in Controlled Ovarian Stimulation Cycles." Reproductive Sciences, August 23, 2022. http://dx.doi.org/10.1007/s43032-022-01017-7.
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AbstractThis cohort study is aimed to determine if higher number of oocytes retrieved affects the rate of euploidy in the embryos of women undergoing controlled ovarian stimulation (COS) for in vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy (PGT-A). A negative trend between the number of oocytes retrieved and embryo euploidy rate was observed using Visual Analytics software, especially when a higher number of oocytes were retrieved. After regression analysis, patient age was the only variable found to have a statistically significant negative effect (p < 0.0001) on euploidy rate in all regression models. Number of oocytes retrieved was not found to have a statistically significant effect on euploidy rate when analyzed per number of biopsied blastocysts (p = 0.5356), per number of oocytes retrieved (p = 0.1025), and per number of fertilized oocytes (p = 0.7241). The parameter estimates in the linear regression models were negative for number of oocytes retrieved. This study shows a statistically significant effect between patient age and embryo euploidy rate, which is already known. There is some evidence to suggest that higher number of oocytes retrieved may negatively impact the number of euploid embryos per number of oocytes retrieved based on the visual analytic graphs, p value approaching significance, and the negative parameter estimates in the regression models.
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Rabi, Odia, Vinals-Gonzalez Xavier, Health Carleen, Saab Wael, Ozturk Ozkan, Seshadri Srividya, and Serhal Paul. "Does Embryonic Culture Environment Affect Ploidy Rates in ART Cycles: A Single Center Study in UK." Journal of Reproduction & Infertility, July 11, 2022. http://dx.doi.org/10.18502/jri.v23i3.10007.
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Background: The purpose of the current study was to assess whether embryonic culture conditions has an impact on embryo ploidy in a preimplantation genetic testing for aneuploidy (PGT-A) cycle.
Methods: In this retrospective single center cohort study, a total of 1099 blastocysts from 278 PGT-A cycles were analyzed. The generated blastocysts were biopsied on days 5 and 6. Inseminated oocytes were allocated in different incubators (benchtop and time lapse) and assisted zona hatching was performed on day 3 of embryo development to facilitate the biopsy process which was performed on days 5 and 6 (blastocyst stage).
Results: The average age across the groups was 38.7±3.6 years and the total number of mature eggs was 2912 which were randomly distributed across both incubators. The euploidy rate obtained from both groups showed a higher proportion of euploid embryos in the TLM incubator (37.03%, 95% CI 31.9-42.1) compared to those cultured in the BT incubator (30.4%, 95% CI 23.1-37.7). Regression analysis showed that female age remains to be the key variable driving euploidy rates (0.85, 95% CI 0.82-0.88) although incubator type could be an important covariable (0.54, 95% CI 0.45-0.59). A subgroup analysis of 74 single euploid embryo transfers showed comparable pregnancy and live birth rates.
Conclusion: This large cohort study demonstrates that uninterrupted controlled culture environment provides increased probability to develop euploid embryo in a PGT-A cycle. However, further evaluation is required to assess how environmental culture conditions at a cellular level could affect epigenetic mechanisms in embryo development and higher aneuploidy rate.
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Cetinkaya, M., M. A. Tufekci, C. Cina. Yapan, and S. Kahraman. "P–526 Incidence of mosaic embryos in day–6 blastocysts, may late blastulation predispose to mosaicism?" Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.525.
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Abstract Study question May the mosaicism ratio be influenced by the time of blastulation in preimplantation genetic testing for aneuploidies (PGT-A)? Summary answer The mosaicism ratio is significantly higher in day–6 blastocysts when compared to day–5 when transferable embryos are considered only (euploids and mosaics). What is known already Conventionally, PGT-A has classified preimplantation embryos as either euploid or aneuploid. Yet, a major improvement in PGT-A methodology, with the introduction of high sensitivity diagnostic Next Generation Sequencing (NGS) technology, has allowed the identification of a third embryo category: the mosaic (Coll et al., 2021). Embryonic mosaicism can be defined as the presence of karyotypically distinct cell lines within an embryo and can be detected by NGS at a rate between 20–80%. In the absence of euploid embryos, mosaic embryos, when transferred, have been shown to deliver healthy live births (PGDIS, 2019). Study design, size, duration This retrospective study was based on 9828 trophectoderm biopsies performed in a single ART clinic between January 2017 and October 2020 for PGT-A cycles with more than one blastocyst. PGT-A cycles with only one blastocyst were excluded because in these cycles’ day–5/day–6 biopsy percentage cannot be calculated. A total number of 8398 and 1430 blastocysts were biopsied on day–5 and day–6, respectively for PGT-A by ReproSeq on Ion Torrent S5 (Thermo Fisher Scientific). Participants/materials, setting, methods Three categories were defined in the PGT-A group with >1 blastocyst biopsied to compare the rate of mosaicism: C1:cycles in which blastocysts were only biopsied on day–5 (n = 1872), C2:99–60% of blastocysts were biopsied on day–5 (n = 483) and C3:0–60% of blastocysts biopsied on day–5 (n = 411). The mean female age (C1:36.0±5.2; C2:35.7±4.8; C3:37.1±4.9) and metaphase II oocytes punctured (C1:9.8±6.5; C2:10.4±5.2; C3:8.4±5.4) were similar and statistically non-significant in all groups. T-test and Chi-square tests were used where appropriate. Main results and the role of chance Overall, from the blastocysts biopsied on day–5 and 6, 35.4% and 25.5% were euploid, 13.7% and 14.7% were mosaic, 50.9% and 59.8% were aneuploid, respectively (p < 0.0001, p = 0.32, p < 0.0001), the mosaicism rate being not statistically different. However, when only transferable blastocysts (euploids and mosaics) were considered (aneuploids being discarded), the rate of mosaic embryos was significantly higher in day–6 when compared to day–5 blastocysts (36.6% vs. 28.0%; p < 0.0001). Morphological blastocyst grading was then investigated: from the day–5 and 6 blastocysts biopsied, 51.5% and 30.8% were of top-quality and 48.5% and 69.2% were of good-quality, respectively. Looking deeper into the categories defined, the euploidy rate was found to be higher in C1 (35.1%) when compared to C2 (34.9%) and C3 (27.7%) (p < 0.0001). The mosaic embryo rate was found to be non-significant when all blastocysts (euploids, aneuploids, mosaics) were considered (C1: 13.7%; C2: 14.1%; C3: 14.2%; p = 0.6492). However, when transferable blastocysts were considered (euploids and mosaics only), the mosaic embryo rate was significantly higher in C3 (33.9%) when compared to C1 (28.1%) and C2 (28.8%) (p = 0.02). For morphological blastocyst grading, regardless of blastulation day, mosaicism was higher for good-quality embryos both when all biopsies and only transferrable embryos were considered (p = 0.0018, p < 0.0001, respectively). Limitations, reasons for caution This study focused on blastocyst formation day and morphological blastocyst grading. Extrinsic factors have also been reported to induce mosaicism: ovarian stimulation, culture media, laboratory and culture conditions, technical issues during the biopsy and sample processing (Munné and Wells, 2017; Katz-Jaffe et al., 2018, Fragouli et al., 2010, 2019). Wider implications of the findings: Mitotic errors during cleavage stage causing mosaicism may lead to lower morphological grade and late blastulation as some cells in those embryos are not diploid thus leading to higher mosaicism for blastocysts that reach blastulation on day6 and/or yield only good-quality embryos. Trial registration number Not applicable
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Metwalley, A. M., A. Hellani, S. Esteves, A. El-Damen, A. Abde. Razik, A. A. Dawood, M. E. Hamshary, and O. Khamiss. "P–518 Assessment of mitochondrial DNA viability ratio in day–4 biopsied embryos as an add-in to select euploid embryos for single embryo transfer." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.517.
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Abstract Study question Is mitochondrial DNA viability ratio of day–4 biopsied embryos associated with embryo implantation potential? Summary answer The mitochondrial DNA viability ratio is significantly higher in embryos that implant. The score might help to select euploid embryos for single embryo transfer. What is known already Embryo euploidy is a critical factor for successful pregnancy outcomes. However, transfer of euploid embryos does not invariably result in implantation, thus indicating that other factors may play a role. Metabolic rates and adenosine triphosphate content vary significantly in oocytes and embryos and might affect embryo viability. Embryo function, indirectly measured by mitochondrial DNA viability ratio (mtV) has emerged as a potential quantitative biomarker for embryonic selection before the transfer, but clinical data remains limited. The purpose of this study is to characterize and compare mtV in euploidy day 4 embryos. Study design, size, duration Retrospective cohort study carried out between Jan. 2017 to Jan. 2020, involving 75 infertile couples undergoing IVF-ICSI with PGT-A and single embryo transfer (SET) of day 4 euploid embryos. Participants/materials, setting, methods We compared the mtV ratios of 34 non-pregnant patients with those of 41 patients who achieved clinical pregnancy after SET. The mtV ratio was obtained from a cohort of 75 euploidy embryos. The embryos were biopsied 80–85 hours post–ICSI and subjected to next-generation sequencing (NGS). The mtV was determined using Multiple of Mean (MoM) values, obtained by dividing the mtV ratio of individual embryos by the mean mtV value of all implanted embryos. Main results and the role of chance The mean mtV ratio (1.51; 95% confidence interval [CI] 1.25–1.77) of non-pregnant patients was significantly lower than those of pregnancy counterparts (2.5; 95% CI 1.82–2.68; p < 0.01). At a 0.5 MoM cutoff, the sensitivity and specificity of mtV ratio to discriminate between implanted embryos versus non-implanted embryos were 35.3% and 78.2%, respectively., with a positive predictive value (PPV) of 41.4%. Limitations, reasons for caution Our study is limited by the small sample size and lack of stratification by causes of female/male infertility. Endometrial receptivity issues, which could have contributed to implantation failure, was not evaluated. Wider implications of the findings: Assessment of mtV ratio could provide additional prognostic information for selecting euploid embryos for transfer in SET programs. Further research is warranted to establish the clinical utility of routine application of mtV evaluation in PGT programs. Trial registration number N/A
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Ross, T. "P–200 To transfer or to discard: A retrospective analysis of ploidy, implantation and birthweight outcomes of grade “C” blastocysts following preimplantation genetic testing for aneuploidy (PGT-A)." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.199.
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Abstract Study question What’s the ploidy status of grade “C” blastocysts and what are their implantation potential and birthweight outcomes when tested euploid? Summary answer Grade “C” blastocysts were less likely to be euploid compared to grades “A/B”. Euploid “C”s led to reduced but reasonable implantation potential with similar birthweights. What is known already In contrast to grade “A” or “B”, grade “C” blastocysts are generally considered borderline quality in most in vitro fertilization programs, with inconsistent policies between clinics. Little evidence has been reported regarding their euploidy rate, implantation potential, and birthweight outcomes. Study design, size, duration This retrospective cohort study included 426 consecutive autologous-oocyte patients undergoing PGT-A (biopsy at day 5/6) at two associated private clinics between January 2013 and August 2020. A total of 1418 resulting blastocysts (tested either euploid or aneuploid) were analysed. Implantation outcomes were assessed in a subset of 520 singly transferred euploid blastocysts. Birthweight outcomes were evaluated in 209 singleton newborns using a gestation-adjusted Z score taking into account gestational age and baby gender. Participants/materials, setting, methods Blastocysts were graded “A/B/C” according to a combination of inner cell mass and trophectoderm morphology. Endpoints included ploidy, implantation and birthweight outcomes. Multiple regression (logistic or linear) was performed to investigate relative prognosis of grade “C” blastocysts using different endpoints in reference to grade “A/B” blastocysts, expressed as either adjusted odds ratio (aOR) or coefficients (β) with 95% confidence intervals (CI). Maternal age and biopsy day (5/6) were included as potential confounders at regression analysis. Main results and the role of chance Grade “C” blastocysts (n = 466) were associated with a lower euploidy rate in reference to either grade “A” (n = 179, aOR=0.412, 95% CI: 0.278–0.611, P = 0.000) or “B” blastocysts (n = 773, aOR=0.535, 95% CI: 0.418–0.685, P = 0.000). Euploid “C” grade blastocysts (n = 128) led to significantly reduced chance to implant when compared to either grade “A” (n = 90, aOR=0.387, 95% CI: 0.215–0.696, P = 0.002) or “B” blastocysts (n = 302, aOR=0.617, 95% CI: 0.404–0.944, P = 0.026); although implantation rate was still considered at a reasonable level (44.5%) as opposed to grades “A” (66.7%) or “B” (57.6%). However, no significant difference was observed in the birthweight (g, mean ± standard deviation) following the transfer of a single euploid grade “C” blastocyst (n = 42, 3310.8±704.1) in comparison to a single euploid grade “A” (n = 48, 3367.8±519.3, P > 0.05) or “B” blastocyst (n = 119, 3284.5±535.5, P > 0.05). Taking into account maternal age, biopsy day, gestational age and baby gender; further multiple linear regression analysis also showed similar results using either birthweight itself (C vs A, β=–52.395, 95% CI: –148.83–43.893, P = 0.282; C vs B, β=–104.338, 95% CI: –272.653–63.977, P = 0.223), or the gestation-adjusted Z score as an endpoint (C vs A, β = 0.101, 95% CI: –0.001–0.164, P = 0.052; C vs B, β = 0.084, 95% CI: -–0.073 – 0.241, P = 0.290). Limitations, reasons for caution The retrospective design of this study does not allow control for unknown confounders. Inner cell mass or trophectoderm was not graded separately making it difficult to further break down the “C” grade blastocysts. Only blastocysts suitable for biopsy were included for analysis, so results may not extrapolate to untested blastocysts. Wider implications of the findings: Grade “C” blastocysts may still hold its clinical value despite reduced euploidy rate. PGT-A may be considered as a potential approach to utilize grade “C” blastocysts more effectively, without affecting birthweight outcomes. This is also potentially useful in patient counselling. Trial registration number Not applicable
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Martinez, F., E. Clua, M. Roca, S. Garcia, M. Parriego, and N. P. Polyzos. "P–631 Embryo euploidy rates following follicular or luteal start ovarian stimulation. A prospective study with repeated ovarian stimulation ovarian stimulation cycles." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.630.
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Abstract Study question Is there any difference in embryo euploidy rates following luteal phase phase (LS) and follicular phase (FS) start ovarian stimulation. Summary answer: The number of euploid blastocysts and embryo euploidy rate are comparable when comparing FS and LS. What is known already Random start ovarian stimulation (starting at any time of the cycle) has been traditionally used in women undergoing urgent fertility preservation for medical reason. Although there is accumulating evidence that in infertile women, LS can result in equivalent number of oocytes and embryos as compared with FS, no study has evaluated the effect of luteal phase start ovarian stimulation on embryo euploidy rates. The current study is the first prospective study designed to evaluate embryo euploidy rates in donors undergoing two identical consecutive ovarian stimulation protocols within a period of 6 months starting either in the (FS), or (LS). Study design, size, duration In a prospective study, conducted between May 2018 and January 2020, 40 oocyte donors underwent two consecutive ovarian stimulation protocols within a period of 6 months with an identical fixed GnRH antagonist protocol starting either in the early follicular (FS), or and luteal menstrual cycle phase (LS). Participants/materials, setting, methods All participants underwent two identical consecutive ovarian stimulation cycles with 150μg corifollitropin alfa followed by 200 IU rFSH in a fixed GnRH antagonist protocol either in the FS or LS. Six MII oocytes from the same oocyte donor, from each stimulation cycle, were allocated to the recipients and were inseminated with the same sperm sample (recipients partner sperm or donor sperm). Embryos were cultivated to blastocyst stage followed by preimplantation genetic testing for aneuploidies (PGT-A). Main results and the role of chance When comparing FP with LP, the duration of ovarian stimulation was significantly shorter (9.68± 2.09 vs 10.93± 1.55 days), 95% CI [–1.95; –0.55] and a higher total additional dose of daily recFSH was significantly lower (526.14± 338.94 IU vs 726.14± 366.27), 95% CI [–315,12; –84,88] when CPT was administered in the luteal phase. . There were no differences in the hormone values on the triggering day (Estradiol 2137.61±1198.25 pg/ml vs 2362.96±1472.89); 95% CI [–1160.45;709.76]. Overall no differences were observed in the number of oocytes (24.84± 11.200 vs 24.27± 9.08); 95% CI[–2,61; 3.75] and MII oocytes (21.41±10.19 vs 21.59± 8.81), 95%CI [–2.72; 2.35] retrieved between FP and LP cycles in the oocytes donors. Following oocyte allocation and fertilization to the recipients, a total of 245 blastocysts were biopsied (blastocyst formation rate 245/408, 60.05%), 117 in FP group and 128 in LP group. The overall blastocyst euploidy rate was 59.18% . There were no differences in the number of euploid embryos between FS (1.59±1.32) and LS (1.70±1.29), mean difference 0.11, 95%CI [–0.65; 0.46]. Finally, there were no differences in the percentage of euploid embryos per oocytes inseminated between FS [70/287 (24.4%)] and LP [75/278 (24.7%), mean difference –0.027, 95%CI [–0.11; 0.06]. Limitations, reasons for caution The study was performed in oocyte derived from potentially fertile young oocyte donors thus caution is needed when extrapolating the results in oocytes derived from infertile women of older age. Wider implications of the findings: Luteal phase stimulation does not alter embryo euploidy status as compared with follicular phase stimulation and thus it appears that it can be safely used not only in cases of urgent medical fertility preservation but also in patients undergoing ovarian stimulation for IVF/ICSI. Trial registration number Clinical Trials Gov (NCT03555942).
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Martinez, F., E. Clua, M. Roca, S. Garcia, M. Parriego, and N. P. Polyzos. "P-631 Embryo euploidy rates following follicular or luteal start ovarian stimulation. A prospective study with repeated ovarian stimulation ovarian stimulation cycles." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab125.049.
Full textAbstract:
Abstract Study question Is there any difference in embryo euploidy rates following luteal phase phase (LS) and follicular phase (FS) start ovarian stimulation. Summary answer The number of euploid blastocysts and embryo euploidy rate are comparable when comparing FS and LS. What is known already Random start ovarian stimulation (starting at any time of the cycle) has been traditionally used in women undergoing urgent fertility preservation for medical reason. Although there is accumulating evidence that in infertile women, LS can result in equivalent number of oocytes and embryos as compared with FS, no study has evaluated the effect of luteal phase start ovarian stimulation on embryo euploidy rates. The current study is the first prospective study designed to evaluate embryo euploidy rates in donors undergoing two identical consecutive ovarian stimulation protocols within a period of 6 months starting either in the (FS), or (LS). Study design, size, duration In a prospective study, conducted between May 2018 and January 2020, 40 oocyte donors underwent two consecutive ovarian stimulation protocols within a period of 6 months with an identical fixed GnRH antagonist protocol starting either in the early follicular (FS), or and luteal menstrual cycle phase (LS). Participants/materials, setting, methods All participants underwent two identical consecutive ovarian stimulation cycles with 150μg corifollitropin alfa followed by 200 IU rFSH in a fixed GnRH antagonist protocol either in the FS or LS. Six MII oocytes from the same oocyte donor, from each stimulation cycle, were allocated to the recipients and were inseminated with the same sperm sample (recipients partner sperm or donor sperm). Embryos were cultivated to blastocyst stage followed by preimplantation genetic testing for aneuploidies (PGT-A). Main results and the role of chance When comparing FP with LP, the duration of ovarian stimulation was significantly shorter (9.68± 2.09 vs 10.93± 1.55 days), 95% CI [-1.95; -0.55] and a higher total additional dose of daily recFSH was significantly lower (526.14± 338.94 IU vs 726.14± 366.27), 95% CI [-315,12; -84,88] when CPT was administered in the luteal phase. . There were no differences in the hormone values on the triggering day (Estradiol 2137.61±1198.25 pg/ml vs 2362.96±1472.89); 95% CI [-1160.45;709.76]. Overall no differences were observed in the number of oocytes (24.84± 11.200 vs 24.27± 9.08); 95% CI[-2,61; 3.75] and MII oocytes (21.41±10.19 vs 21.59± 8.81), 95%CI [-2.72; 2.35] retrieved between FP and LP cycles in the oocytes donors. Following oocyte allocation and fertilization to the recipients, a total of 245 blastocysts were biopsied (blastocyst formation rate 245/408, 60.05%), 117 in FP group and 128 in LP group. The overall blastocyst euploidy rate was 59.18% . There were no differences in the number of euploid embryos between FS (1.59±1.32) and LS (1.70±1.29), mean difference 0.11, 95%CI [-0.65; 0.46]. Finally, there were no differences in the percentage of euploid embryos per oocytes inseminated between FS [70/287 (24.4%)] and LP [75/278 (24.7%), mean difference -0.027, 95%CI [-0.11; 0.06]. Limitations, reasons for caution The study was performed in oocyte derived from potentially fertile young oocyte donors thus caution is needed when extrapolating the results in oocytes derived from infertile women of older age. Wider implications of the findings Luteal phase stimulation does not alter embryo euploidy status as compared with follicular phase stimulation and thus it appears that it can be safely used not only in cases of urgent medical fertility preservation but also in patients undergoing ovarian stimulation for IVF/ICSI. Trial registration number Clinical Trials Gov (NCT03555942).
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Garg, A., L. Bari, M. A. Valera, E. I. Fernandez, J. C. Rocha, A. Quiñonero, F. Domínguez, and M. Meseguer. "O-121 Exploring non-invasive methods to predict Ploidy Status: Combination of blastocyst morphology image analysis and proteomic profiles by using Artificial Neural Networks." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab126.046.
Full textAbstract:
Abstract Study question Is the blastocyst morphology image analysis combined with the protein content of spent embryo culture medium a suitable way to predict embryo ploidy? Summary answer Morphological variables from blastocyst image analysis combined with IL-6 or MMP-1 concentration in spent culture medium showed more than 80% of accuracy for euploidy prediction. What is known already An artificial intelligence model based on the proteomic profile of euploid embryos and morphological data from blastocyst time-lapse images has been recently published (Bori et al., 2020). The most promising artificial neural network (ANN) algorithm considered 20 morphological variables extracted from image analysis and two proteins detected in embryo culture medium (MMP-1 and IL-6). The overall success rate on blind test data was 72.7% for live birth prediction. The main aim of the present study was to check if the same morphological variables combined with MMP-1 or IL-6 with a cost-effective technique could discriminate between euploid and aneuploid embryos. Study design, size, duration This prospective study included 120 embryos from the preimplantation genetic testing for aneuploidies (PGT-A) program. A single blastocyst image was obtained for each embryo and their spent culture medium was collected on the day 5/6 of embryo development (day of trophectoderm biopsy). Morphological variables were extracted for all the blastocyst. On the other hand, we quantified IL-6 levels of 67 embryos and MMP-1 levels of 53 embryos. Resulting parameters were used to predict PGT-A results. Participants/materials, setting, methods Blastocyst images were imported into Matlab software and segmented into regions of interest. We obtained 20 mathematical variables related to measurements of areas, number of pixels and texture analysis. Chromosome analysis was performed using next-generation sequence technology. In parallel, 20 µL of spent culture medium from each blastocyst was analyzed with ELISA kits (IL-6 or MMP-1). Protein concentrations and morphological variables were used as input data for an ANN associated with genetic algorithms. Main results and the role of chance The euploid rate for the set of embryos included in the IL-6 group was 51.4%. The ANN was trained with 49 embryos and blind tested with 18 embryos. Following results correspond to euploidy prediction on the blind test. The sensitivity, specificity, accuracy and area under the ROC curve (AUC) were: 0.56, 0.78, 0.67 and 0.72 considering only IL-6 values; 0.88, 0.78, 0.83 and 0.61 considering IL-6 values and blastocyst morphological data extracted from the image analysis. The euploid rate for the set of embryos included in the MMP-1 group was 51.9%. The ANN was trained with 39 embryos and blind tested with 14 embryos. Following results correspond to euploidy prediction on the blind test. The sensitivity, specificity, accuracy and AUC were: 0.71, 0.57, 0.64 and 0.67 considering only MMP-1 values; 0.86, 0.86, 0.86 and 0.61 considering MMP-1 values and morphological data extracted from the image analysis. Limitations, reasons for caution The detection limit in protein quantification is the main limitation of our study. The small number of embryos and the specific culture medium used should be considered for the model application. Wider implications of the findings Our preliminary results showed that blastocyst morphology and embryo secretomics could be useful for euploidy prediction by using artificial intelligence techniques. These findings may contribute to the emerging era of non-invasive preimplantation genetic testing (ni-PGT-A). Trial registration number not applicable