Timing of human preimplantation embryonic development is confounded by embryo origin

Abstract

STUDY QUESTIONTo what extent do patient- and treatment-related factors explain the variation in morphokinetic parameters proposed as embryo viability markers?SUMMARY ANSWERUp to 31% of the observed variation in timing of embryo development can be explained by embryo origin, but no single factor elicits a systematic influence.WHAT IS KNOWN ALREADYSeveral studies report that culture conditions, patient characteristics and treatment influence timing of embryo development, which have promoted the perception that each clinic must develop individual models. Most of the studies have, however, treated embryos from one patient as independent observations, and only very few studies that evaluate the influence from patient- and treatment-related factors on timing of development or time-lapse parameters as predictors of viability have controlled for confounding, which implies a high risk of overestimating the statistical significance of potential correlations.STUDY DESIGN, SIZE, DURATIONInfertile patients were prospectively recruited to a cohort study at a hospital fertility clinic from February 2011 to May 2013. Patients aged <38 years without endometriosis were eligible if ≥8 oocytes were retrieved. Patients were included only once. All embryos were monitored for 6 days in a time-lapse incubator.PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 1507 embryos from 243 patients were included. The influence of fertilization method, BMI, maternal age, FSH dose and number of previous cycles on timing of t2-t5, duration of the 2- and 3-cell stage, and development of a blastocoel (tEB) and full blastocoel (tFB) was tested in multivariate, multilevel linear regression analysis. Predictive parameters for live birth were tested in a logistic regression analysis for 223 single transferred blastocysts, where time-lapse parameters were investigated along with patient and embryo characteristics.MAIN RESULTS AND THE ROLE OF CHANCEModerate intra-class correlation coefficients (0.16–0.31) were observed for all parameters except duration of the 3-cell stage, which demonstrates that embryos from one patient elicit clustering at a patient level. No single patient- and treatment-related factor was found to systematically influence the timing from cleavage to blastocyst stage, which indicates that no individual patient-related factor can be identified that separately explains the clustering throughout the entire developmental stages. The blastocyst parameters were more affected by patient-related factors than cleavage stage parameters, as tEB occurred significantly later with older age (0.29 h/year (95% confidence interval: CI 0.03; 0.56)), while both tEB and tFB occurred significantly later with increasing dose of FSH (tEB: 0.12 h/100 IU FSH (95% CI 0.01;0.24); tFB 0.14 h/100 IU FSH (95% CI 0.03;0.27)) and with more previous attempts (tEB: 1.2 h/attempt (95% CI 0.01;2.5); tFB 1.4 h/attempt (0.10;2.7)). Fertilization method affected timing of the first division, with ICSI embryos cleaving significantly faster than IVF embryos (−3.6% (95% CI −6....

Synchrony of the first division as an index of the blastocyst formation rate during embryonic development

“…Previous reports have shown that early‐cleavage embryos had strong developmental potential . Some studies classified all embryos into “early‐cleavage” and “non‐early‐cleavage” groups and compared them .…”

“…Some studies classified all embryos into “early‐cleavage” and “non‐early‐cleavage” groups and compared them . Other studies also grouped the embryos into those that ultimately resulted in pregnancy and those that did not . In contrast, this study compared the embryos that were retrieved from a single oocyte retrieval cycle and measured the synchrony of the first division, thereby predicting the subsequent embryo development more accurately than the retardation time until first division.…”

“…Various studies attempting to identify the indicators of the blastocyst formation rate have found: correlations between the time from fertilization to the first division and the number of blastomeres and embryo implantation potential on day 2; an association between the times of first and second division and embryo implantation potential on day 3; relationships between synchrony of the second and third divisions and the rate of formation of good‐quality blastocysts; and correlations between synchrony of the second division and the potential of embryos to develop into blastocysts . Several other studies also have found that the time until the first division is an important factor for blastocyst formation rates . From this perspective, it was examined whether synchrony and the average time until the first division were indicators of blastocyst formation rates in order to determine the characteristics of the embryos that developed into transferable blastocysts during the early culture period.…”

Morphokinetic Characteristics and Developmental Potential of In Vitro Cultured Embryos from Natural Cycles in Patients with Poor Ovarian Response

“…They depend on many factors that influence embryo development. Kirkegaard et al demonstrated that up to 31% of variation in timing of the events in embryo development can be explained by the origin of the embryo, including the patient-related and treatment-related factors [39]. Because of these limitations, as well as the small study size, timing of the events was not the primary study focus, but, rather, the occurrence of the cleavage abnormalities was.…”

Embryo Morphokinetics Based on Time-Lapse Observation

“…Patients' age and dose of FSH have a positive correlation with delayed blastocyst development. It is also shown that embryos fertilized by ICSI have a signiicant faster irst cleavage division than IVF originate embryos [49].…”