Time-lapse: the remaining questions to be answered
2015; Elsevier BV; Volume: 105; Issue: 2 Linguagem: Inglês
10.1016/j.fertnstert.2015.12.126
ISSN1556-5653
Autores Tópico(s)Pluripotent Stem Cells Research
ResumoIn 2009, the first automatic time-lapse devices became commercially available for the in vitro fertilization (IVF) units, moving from very primitive cinematography to a massive analysis of growing embryos in a few hours. From that point, embryologists started to question its utility and two major issues were raised:Are culture conditions improved by avoiding embryo manipulation outside the incubator?Are the variables related to timing of cleavages and dynamic changes in morphology useful markers of embryo viability (morphokinetics and morphology dynamics)? The first question was elegantly answered by Wong et al. (1Wong C.C. Loewke K.E. Bossert N.L. Behr B. De Jonge C.J. Baer T.M. et al.Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage.Nat Biotechnol. 2010; 28: 1115-1121Crossref PubMed Scopus (577) Google Scholar) and further detailed and clinically applied by our group (2Meseguer M. Herrero J. Tejera A. Hilligsoe K.M. Ramsing N.B. Remohi J. The use of morphokinetics as a predictor of embryo implantation.Hum Reprod. 2011; 26: 2658-2671Crossref PubMed Scopus (614) Google Scholar). Both papers defined selection and deselection parameters based on optimal time-ranges of the embryo cell cycle and abnormal cleavage patterns. Wong's algorithm is commercially available as a diagnostic test and ours has been widely applied in IVI clinics, actually we have the largest number of cycles reported by time-lapse. An attempt to answer the second question was initially made by Cruz et al. through a sibling oocytes study on recipients for oocyte donation. An additional investigation undertaken by Park et al. in a randomized controlled trial (RCT) attempted to calculate the effect of undisturbed culture conditions provided by the EmbryoScope in comparison with the standard incubator. Both studies were properly designed but failed to have adequate power (sample size) to demonstrate a non-inferiority or equivalent hypothesis and/or a subtle or moderate effect (that should be expected from an improved embryo culture environment) reviewed by Basile et al. (3Basile N. Caiazzo M. Meseguer M. What does morphokinetics add to embryo selection and in-vitro fertilization outcomes?.Curr Opin Obstet Gynecol. 2015; 27: 193-200Crossref PubMed Scopus (30) Google Scholar). The only properly powered RCT (focused on time-lapse) was achieved by Rubio et al. (4Rubio I. Galán A. Larreategui Z. Ayerdi F. Bellver J. Herrero J. et al.Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope.Fertil Steril. 2014; 102: 1287-1294Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar), in which more than 800 patients were enrolled to demonstrate that a time-lapse strategy (combined culture conditions and morphokinetic embryo selection) is better than box incubators combined with single point morphological observation. Although it was clearly reflected that time-lapse strategy is improving our clinical results, many questions remained unreturned, as the project was unable to demonstrate whether the improvement were from the unchanging culture conditions provided by the EmbryoScope or the morphokinetic embryo selection algorithm applied. In this issue of Fertility and Sterility, Goodman et al. (5Goodman L. Goldberg J. Falcone T. Austin C. Desai N. Does the addition of time-lapse morphokinetics in the selection of embryos for transfer improve pregnancy rates? A randomized controlled trial.Fertil Steril. 2016; 105: 275-285Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar) finally present a properly designed study to determine if the addition of continuous morphokinetic data improves reproductive outcomes when all embryos are cultured in a closed system. Although there are morphokinetic parameters already available for embryo selection, even by a commercial diagnostic test, authors developed their own selection method combining early and late parameters, which in my opinion, provided strengthen to their work. This study is the first randomized controlled trial in which all embryos are similarly cultured in the closed EmbryoScope system. Although they did not reach significance, there were increased clinical pregnancy and implantation rates with the use of the additional parameters. These facts are inspiring to us, since with a similar sample size as that used by Rubio et al. (4Rubio I. Galán A. Larreategui Z. Ayerdi F. Bellver J. Herrero J. et al.Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope.Fertil Steril. 2014; 102: 1287-1294Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar), results would be probably comparable. Unfortunately, resources and logistics needed for such a sample size are rarely available, and Cleveland Clinic performed a tremendous but insufficient effort to achieve that objective. In any case results are confident and I assume that Nina Desay and her team of embryologists will keep using time lapse technology as a routine clinical tool. In addition, the authors confirmed that the time of the start of blastulation, the absence of multinucleation and the use of a score based on morphology were significant predictors of implantation. These are very relevant findings to our scientific community. Apart from these two main questions raised in this editorial, many other related as blastocyst, euploidy or implantation prediction have been extensively analyzed by retrospective designed studies. The remaining questions are: is blastocyst prediction clinically useful; is there any morphokinetic algorithm available for all time-lapse devices and clinics; can it be sold as a diagnostic test; regarding embryo euploidy, can it be forecast by a non-invasive morphokinetic test; and is time-lapse useful for selecting euploid embryos? For all these questions, no prospective evidence is published yet, and may never be, as the logistics and resources needed would make it impossible to undergo such kind of research. Embryology is becoming more exciting every year, time-lapse is significantly contributing to increase our knowledge in the field, and I firmly believe that this technology is here to stay. Does the addition of time-lapse morphokinetics in the selection of embryos for transfer improve pregnancy rates? A randomized controlled trialFertility and SterilityVol. 105Issue 2PreviewTo determine if the addition of continuous morphokinetic data improves reproductive outcomes when all embryos are cultured in a closed system. Full-Text PDF
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