A time to look back: analysis of morphokinetic characteristics of human embryo development.

OBJECTIVE To describe the times associated with the morphological changes that occur in the embryo during preimplantation development based on the largest sample size described with time lapse. DESIGN Cohort study. SETTING University-affiliated private center. PATIENT(S) A total of 9,530 embryos from 1,806 intracytoplasmic sperm injection (ICSI) cycles. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Using a time-lapse system, embryo images were acquired for at least 68 hours, in some cases reaching 120-130 hours. Embryo cleavage time points up to 8-cell-stage (t2-t8) as well as morulae (tM) and blastocyst formation (tB) were registered in hours after ICSI. Additionally, duration of the cell cycle (cc) and synchrony (s) of the second and third cell cycles were defined. Finally, four subgroups of embryos were considered: the "regular divisions" group excluded embryos with a direct cleavage from 1 to 3 or 2 to 5 cells, and the "viable 8-cell," the "viable blastocyst," and "implanted embryos" groups included only embryos viable to the 8-cell stage, blastocyst stage, or transferred and successfully implanted, respectively. RESULT(S) Averages of times in the general population were: t2 = 27.9 hours, t3 = 38.2 hours, t4 = 40.7 hours, t5 = 51.0 hours, t6 = 54.1 hours, t7 = 56.7 hours, t8 = 59.1 hours, tM = 86.6 hours, tB = 104.1 hours, cc2 = 10.3 hours, cc3 = 12.8 hours, s2 = 2.7 hours, and s3 = 9.9 hours. Comparison between groups showed significant differences between regular divisions and viable 8 cells for t2, t3, t5, cc2, cc3, s2, and s3; between 8 cells and blastocyst for t5, t8, tM, cc3, and s2; and between blastocyst and implanted embryos for t8, tM, tB, and s2. Differences in timing related to morphology of cleavage- and blastocyst-stage embryos were detected. CONCLUSION(S) A time-lapse monitoring system applied to embryology allows accuracy and objectivity when defining the basis of embryo development within a clinic. The sample size is the largest ever described that provides consistent information about the normal distribution of embryo developmental timings.

[1]  A. Pinborg.  IVF/ICSI twin pregnancies: risks and prevention. , 2005, Human reproduction update.

[2]  M. Meseguer,et al.  The use of morphokinetics as a predictor of embryo implantation. , 2011, Human reproduction.

[3]  M. Meseguer,et al.  Sperm and oocyte donor selection and management: experience of a 10 year follow-up of more than 2100 candidates. , 2002, Human reproduction.

[4]  Yasuyuki Mio,et al.  Time-lapse cinematography of dynamic changes occurring during in vitro development of human embryos. , 2008, American journal of obstetrics and gynecology.

[5]  V. Goossens,et al.  Assisted reproductive technology in Europe, 2008: results generated from European registers by ESHRE , 2012 .

[6]  M. Meseguer,et al.  Type of culture media does not affect embryo kinetics: a time-lapse analysis of sibling oocytes. , 2013, Human reproduction.

[7]  Marcos Meseguer,et al.  Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study. , 2012, Fertility and sterility.

[8]  María Cruz,et al.  Timing of cell division in human cleavage-stage embryos is linked with blastocyst formation and quality. , 2012, Reproductive biomedicine online.

[9]  C. Racowsky,et al.  The number of eight-cell embryos is a key determinant for selecting day 3 or day 5 transfer. , 2000, Fertility and sterility.

[10]  S. Wen,et al.  SHORT COMMUNICATION: Adverse maternal outcomes in multifetal pregnancies , 2004 .

[11]  M. Meseguer,et al.  A prospective, randomized, controlled trial comparing three different gonadotropin regimens in oocyte donors: ovarian response, in vitro fertilization outcome, and analysis of cost minimization. , 2010, Fertility and sterility.

[12]  V. Goossens,et al.  Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). , 2009, Human reproduction.

[13]  M. Meseguer,et al.  Dose of recombinant FSH and oestradiol concentration on day of HCG affect embryo development kinetics. , 2012, Reproductive biomedicine online.

[14]  M. Meseguer,et al.  Limited implantation success of direct-cleaved human zygotes: a time-lapse study. , 2012, Fertility and sterility.

[15]  Lynette Scott,et al.  Pronuclear scoring as a predictor of embryo development. , 2003, Reproductive biomedicine online.

[16]  T. Baer,et al.  Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage , 2010, Nature Biotechnology.

[17]  K. Kirkegaard,et al.  Effect of oxygen concentration on human embryo development evaluated by time-lapse monitoring. , 2013, Fertility and sterility.

[18]  O. Heikinheimo,et al.  The molecular mechanisms of oocyte maturation and early embryonic development are unveiling new insights into reproductive medicine. , 1998, Molecular human reproduction.

[19]  J. Lemmen,et al.  Kinetic markers of human embryo quality using time-lapse recordings of IVF/ICSI-fertilized oocytes. , 2008, Reproductive biomedicine online.

[20]  Lisa Cowan,et al.  The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. , 2011, Human reproduction.

[21]  Elena De Ponti,et al.  Cleavage kinetics analysis of human embryos predicts development to blastocyst and implantation. , 2012, Reproductive biomedicine online.

[22]  Markus Montag,et al.  Which morphological scoring system is relevant in human embryo development? , 2011, Placenta.

[23]  M. J. de los Santos,et al.  Reduced oxygen tension improves embryo quality but not clinical pregnancy rates: a randomized clinical study into ovum donation cycles. , 2013, Fertility and sterility.

[24]  Yoshiharu Morimoto,et al.  Selection of high-potential embryos by culture in poly(dimethylsiloxane) microwells and time-lapse imaging. , 2012, Fertility and sterility.

[25]  M. Meseguer,et al.  Effect of sperm DNA fragmentation on pregnancy outcome depends on oocyte quality. , 2011, Fertility and sterility.

[26]  M. Meseguer,et al.  Differential transcriptomic profile in spermatozoa achieving pregnancy or not via ICSI. , 2011, Reproductive biomedicine online.

[27]  Hans Jakob Ingerslev,et al.  Time-lapse monitoring as a tool for clinical embryo assessment. , 2012, Human reproduction.

[28]  J. Shaw,et al.  A formula for scoring human embryo growth rates in in vitro fertilization: Its value in predicting pregnancy and in comparison with visual estimates of embryo quality , 1986, Journal of in Vitro Fertilization and Embryo Transfer.

[29]  A L Mikkelsen,et al.  The impact of pronuclei morphology and dynamicity on live birth outcome after time-lapse culture. , 2012, Human reproduction.

[30]  Neurological sequelae in children born after in-vitro fertilisation: a population-based study , 2002, The Lancet.

[31]  D. Payne,et al.  Preliminary observations on polar body extrusion and pronuclear formation in human oocytes using time-lapse video cinematography. , 1997, Human reproduction.