Assessment of Artificial FET Reproductive Outcomes: Transfer of Blastocysts on Progesterone + 4 Versus Progesterone + 5

During the first 20 years of IVF embryo transfers were performed on days 1 to 3, even though evidence suggested that embryos dispelled into the uterus from fallopian tubes were at a post-compaction stage. This meant that initially all embryo transfers were asynchronous transfers. This strategy was imposed upon IVF by the vitro culture conditions of the time, which were sub-optimal for normal rates of blastocyst development. Transferred asynchronously cleavage stage embryos have to adapt to "alien" non- physio-metabolic conditions that may result in embryonic stress and compromised embryo development. In fresh embryo transfer this is further exacerbated by the supraphysiological hormone effects of controlled ovarian stimulation. In addition, there are mechanical factors (i.e. uterine contractility) and time factors, related to the endometrium (i.e., window of implantation) and embryo (i.e., time to hatching), that may reduce the chances of implantation. In contrast, to most other mammalian species the transfer of cleavage stage embryos to human uteruses led to acceptable levels of pregnancy and live birth.

The regulation of synchrony between embryo and endometrium has not been fully addressed clinically in the human. This limitation affects IVF significantly in that up to 30% of embryo transfers may be affected by endometrial receptivity factors. The endometrium is a highly specialized, hormonally regulated tissue which is only receptive to embryo communication/interaction for a self-limiting period referred to as the window of implantation. Currently, there is no way to non-invasively determine the time of optimal receptivity, with IVF transfers performed on the assumption that the WOI was sufficiently wide enough to accommodate implantation in most patients and most treatments. During this period, the endometrial epithelium acquires optimal receptivity by progressing through specific structural, functional, and morphological changes induced by pre-ovulatory estrogen and progesterone and post-ovulatory progesterone, LH, and hCG.

During the last three decades, there has been a major increase in the understanding of embryo physiology and correspondingly major improvements in the in vitro culture technologies used, in particular culture media and incubator technologies. These improvements have resulted in the culture of more good quality cleavage stage embryos and consequently blastocysts after extended culture, increasing embryo utility and the pregnancy capacity of an cycle. The increased implantation rates obtained with blastocyst transfers may be as much to do with embryo quality and stage, i.e., blastocysts have the required bi-directional communication competency needed for implantation, as with the WOI, i.e., the time of blastocyst formation and transfer coincides with the WOI of endometria. Moreover, the presently improved culture conditions may also be changing traditional embryo developmental milestones, in particular, the time to blastulation may be decreasing. An increasing number of blastocysts are being formed on day 4 of culture - ±100 hours post-insemination. Traditionally, day 4 embryos were only assessed for evidence of compaction, which is the developmental stage leading to blastulation and cell differentiation.

Zygotes or embryos that reach developmental milestones first (i.e., syngamy, early cleavage, early compaction and early blastulation) are generally believed to have increased chances of normal developmental potential. In recent artificial frozen embryo transfers (FET) in which blastocysts vitrified on day 4 of culture and transferred on P+4, with blastocysts traditionally transferred on P+5, a high rate of implantation has been observed. In addition, a greater number of these implantations resulted in clinical pregnancies (i.e., a conceptus with normal fetal heart activity). In this prospective randomised control study, the investigators will investigate whether this increased viability, is due either to embryo quality, endometrial receptivity, or a combination of the two factors by randomizing the transfer of day 5 blastocysts to P+4 or P+5.