Beyond appearance: Can morphologically low‐grade euploid blastocysts yield successful pregnancies?
Abstract: PurposeThe primary objective of this investigation is to evaluate how morphological quality affects the pregnancy outcomes in euploid embryos determined by preimplantation genetic testing for aneuploidies (PGT‐A). Concurrently, as a secondary objective, we aim to identify which specific aspects of morphological evaluation exert the most significant impact on these outcomes.MethodsA retrospective analysis of 451 single euploid embryo transfer cycles at our clinic was conducted. Embryos were evaluated based on t… Show more
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Steady morphokinetic progression is an independent predictor of live birth: a descriptive reference for euploid embryos
STUDY QUESTION Can modeling the longitudinal morphokinetic pattern of euploid embryos during time-lapse monitoring (TLM) be helpful for selecting embryos with the highest live birth potential? SUMMARY ANSWER Longitudinal reference ranges of morphokinetic development of euploid embryos have been identified, and embryos with steadier progression during TLM are associated with higher chances of live birth. WHAT IS KNOWN ALREADY Time-lapse monitoring (TLM) imaging is increasingly adopted by fertility clinics as an attempt to improve the ability of selecting embryos with the highest potential for implantation. Many markers of embryonic morphokinetics have been incorporated into decision algorithms for embryo (de)selection. However, longitudinal changes during this temporal process, and the impact of such changes on embryonic competence remains unknown. Aiming to model the reference ranges of morphokinetic development of euploid embryos and using it as a single longitudinal trajectory might provide an additive value to the blastocyst morphological grade in identifying highly competent embryos. STUDY DESIGN, SIZE, DURATION This observational, retrospective cohort study was performed in a single IVF clinic between October 2017 and June 2021 and included only autologous single euploid frozen embryo transfers (seFET). PARTICIPANTS/MATERIALS, SETTING, METHODS Reference ranges were developed from [hours post insemination (hpi)] of the standard morphokinetic parameters of euploid embryos assessed as tPB2, tPNa, tPNf, t2-t9, tSC, tM, tSB and tB. Variance in morphokinetic patterns was measured and reported as morphokinetic variance score (MVS). Nuclear errors (micronucleation, binucleation and multinucleation) were annotated when present in at least one blastomere at the two- or four-cell stages. The blastocyst grade of expansion, trophectoderm (TE) and inner cell mass (ICM) were assessed immediately before biopsy using Gardner’s criteria. Pre-implantation genetic diagnosis for aneuploidy (PGT-A) was performed by next generation sequencing (NGS). All euploid embryos were singly transferred in a frozen transferred cycle and outcomes were assessed as live birth, pregnancy loss or not pregnant. Association of MVS with live birth was investigated with regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE TLM data from 340 seFET blastocysts were included in the study, of which 189 (55.6%) resulted in a live birth. The median time for euploid embryos to reach blastulation was 109.9 hpi (95% CI: 98.8-121.0 hpi). The MVS was calculated from the variance in time taken for the embryo to reach all morphokinetic points and reflects the total morphokinetic variability it exhibits during its development. Embryos with more erratic kinetics, ie, higher morphokinetic variance, had higher rates of pregnancy loss (p < 0.004) and no pregnancy (p < 0.001) compared to embryos with steadier morphokinetic patterns. In the multivariable analysis adjusting for ICM, TE grade, presence of nuclear errors and time of blastulation, MVS was independently associated with live birth (OR : 0.62, 95% CI: 0.46-0.84, p = 0.002) along with ICM quality. Live birth rate of embryos with the same ICM grading but different morphokinetic variance patterns differed significantly. Live birth rates of embryos exhibiting low MVS with ICM grade A, B, and C were 85%, 76% and 67%, respectively. However, ICM grade A, B, and C embryos with high MVS had live birth rates of 65%, 48% and 21% (P < 0.001). The addition of the MVS to embryo morphology score (ICM and TE grading) significantly improved the model’s area under the curve value (0.67 vs. 0.62, P = 0.015) and this finding persisted through repeat cross-validation (0.64 ± 0.08 vs. 0.60 ± 0.07, P < 0.001). LIMITATIONS, REASONS FOR CAUTION The exclusion of IVF cases limits, for now, the utility of the model to only ICSI-derived embryos. Utility of these reference ranges and association of MVS with various clinical outcomes should be further investigated. WIDER IMPLICATIONS OF THE FINDINGS We have developed reference ranges for morphokinetic development of euploid embryos and a marker for measuring total morphokinetic variability exhibited by developed blastocysts. Longitudinal assessment of embryonic morphokinetics rather than static time-points may provide more insight about which embryos have higher live birth potential. The developed reference ranges and MVS show an association with live birth that is independent of known morphological factors and could emerge as a valuable tool in prioritizing PGT-A tested embryos for transfer. STUDY FUNDING/COMPETING INTEREST(S) This study received no external funding. The authors declare no conflicting interests. TRIAL REGISTRATION NUMBER N/A
Steady morphokinetic progression is an independent predictor of live birth: a descriptive reference for euploid embryos
STUDY QUESTION Can modeling the longitudinal morphokinetic pattern of euploid embryos during time-lapse monitoring (TLM) be helpful for selecting embryos with the highest live birth potential? SUMMARY ANSWER Longitudinal reference ranges of morphokinetic development of euploid embryos have been identified, and embryos with steadier progression during TLM are associated with higher chances of live birth. WHAT IS KNOWN ALREADY Time-lapse monitoring (TLM) imaging is increasingly adopted by fertility clinics as an attempt to improve the ability of selecting embryos with the highest potential for implantation. Many markers of embryonic morphokinetics have been incorporated into decision algorithms for embryo (de)selection. However, longitudinal changes during this temporal process, and the impact of such changes on embryonic competence remains unknown. Aiming to model the reference ranges of morphokinetic development of euploid embryos and using it as a single longitudinal trajectory might provide an additive value to the blastocyst morphological grade in identifying highly competent embryos. STUDY DESIGN, SIZE, DURATION This observational, retrospective cohort study was performed in a single IVF clinic between October 2017 and June 2021 and included only autologous single euploid frozen embryo transfers (seFET). PARTICIPANTS/MATERIALS, SETTING, METHODS Reference ranges were developed from [hours post insemination (hpi)] of the standard morphokinetic parameters of euploid embryos assessed as tPB2, tPNa, tPNf, t2-t9, tSC, tM, tSB and tB. Variance in morphokinetic patterns was measured and reported as morphokinetic variance score (MVS). Nuclear errors (micronucleation, binucleation and multinucleation) were annotated when present in at least one blastomere at the two- or four-cell stages. The blastocyst grade of expansion, trophectoderm (TE) and inner cell mass (ICM) were assessed immediately before biopsy using Gardner’s criteria. Pre-implantation genetic diagnosis for aneuploidy (PGT-A) was performed by next generation sequencing (NGS). All euploid embryos were singly transferred in a frozen transferred cycle and outcomes were assessed as live birth, pregnancy loss or not pregnant. Association of MVS with live birth was investigated with regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE TLM data from 340 seFET blastocysts were included in the study, of which 189 (55.6%) resulted in a live birth. The median time for euploid embryos to reach blastulation was 109.9 hpi (95% CI: 98.8-121.0 hpi). The MVS was calculated from the variance in time taken for the embryo to reach all morphokinetic points and reflects the total morphokinetic variability it exhibits during its development. Embryos with more erratic kinetics, ie, higher morphokinetic variance, had higher rates of pregnancy loss (p < 0.004) and no pregnancy (p < 0.001) compared to embryos with steadier morphokinetic patterns. In the multivariable analysis adjusting for ICM, TE grade, presence of nuclear errors and time of blastulation, MVS was independently associated with live birth (OR : 0.62, 95% CI: 0.46-0.84, p = 0.002) along with ICM quality. Live birth rate of embryos with the same ICM grading but different morphokinetic variance patterns differed significantly. Live birth rates of embryos exhibiting low MVS with ICM grade A, B, and C were 85%, 76% and 67%, respectively. However, ICM grade A, B, and C embryos with high MVS had live birth rates of 65%, 48% and 21% (P < 0.001). The addition of the MVS to embryo morphology score (ICM and TE grading) significantly improved the model’s area under the curve value (0.67 vs. 0.62, P = 0.015) and this finding persisted through repeat cross-validation (0.64 ± 0.08 vs. 0.60 ± 0.07, P < 0.001). LIMITATIONS, REASONS FOR CAUTION The exclusion of IVF cases limits, for now, the utility of the model to only ICSI-derived embryos. Utility of these reference ranges and association of MVS with various clinical outcomes should be further investigated. WIDER IMPLICATIONS OF THE FINDINGS We have developed reference ranges for morphokinetic development of euploid embryos and a marker for measuring total morphokinetic variability exhibited by developed blastocysts. Longitudinal assessment of embryonic morphokinetics rather than static time-points may provide more insight about which embryos have higher live birth potential. The developed reference ranges and MVS show an association with live birth that is independent of known morphological factors and could emerge as a valuable tool in prioritizing PGT-A tested embryos for transfer. STUDY FUNDING/COMPETING INTEREST(S) This study received no external funding. The authors declare no conflicting interests. TRIAL REGISTRATION NUMBER N/A
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