Investigating the Impact of the Timing of Blastulation on Implantation: Management of Embryo-endometrial Synchrony Improves Outcomes

Study Question: Do embryos with delayed blastulation have inferior reproductive potential or poorer outcomes due in part to embryo and endometrial synchrony?

Summary Answer: Diminished outcomes in embryos with delayed blastulation undergoing fresh embryo transfer (ET) may be attributed to a loss of embryonic-endometrial synchrony.

What Is Known Already: Embryos that blastulate slowly have lower sustained implantation rates (SIR) than those which blastulate normally on Day 5 (D5). Traditionally this has been attributed to reduced embryo quality; however, dyssynchrony with the endometrium is also a possibility and has not been fully described. This convenient cohort composed of groups that resulted from a practice wide change in laboratory protocol allows for evaluation of embryo and endometrial synchrony as it related to blastocyst expansion.

Study Design Size Duration: A retrospective cohort analysis was carried out from January 2009 to February 2013. Three cohorts were identified: D5 ET, D6 ET and frozen ET that comprised 822 patients, 763 patients and 718 patients, respectively. Each of these cohorts had slowly blastulating and normally blastulating embryos identified.

Participants/materials Setting Methods: The study setting was academic affiliated private practice. All first fresh or cryopreserved ETs from 2010 to 2013 were studied. Non-biopsied embryos were classified into two groups on D5: slowly blastulating (Morula-Gardner 1) or normally blastulating (Gardner 2-6). Only single ETs or transfer of two embryos within the same classification group were included. Outcomes were compared between classification groups in embryos undergoing transfer on D5, D6, or after cryopreservation. This assesses the impact of transfer timing in fresh cycles as well as isolating a pure embryonic factor in frozen ET cycles. Sustained implantation was defined as heart beat detection at discharge sonogram at 8 weeks gestation. SIR was defined as the number of embryos transferred meeting criteria for sustained implantation divided by the total number of embryos transferred.

Main Results And The Role Of Chance: In total, 3391 embryos were transferred to 1966 patients. On D5, SIRs were significantly lower with slowly blastulating embryos (44% versus 64% in women <35 years of age ( < 0.001) and 18% versus 56% in women ≥35 years of age ( < 0.001)). Fresh D6 ETs also had significantly lower SIRs for embryos that were slowly blastulating on D5 (52% versus 63% in <35 years of age ( < 0.05) and 32% versus 48% in ≥35 years of age ( < 0.005)) despite continued development to full blastocysts and being morphologically equivalent at the time of ET, suggesting dyssynchrony. However, when slowly blastulating embryos underwent vitrification and then ET, they had SIRs which were equivalent to their normally blastulating counterparts (57% versus 60% in <35 years of age ( = 0.5) and 37% versus 42% in ≥35 years of age ( = 0.3)). An intraclass correlation and a generalized estimating equation corrected for patient age was performed which confirmed these findings. The normalization in cryopreserved ETs indicates that dyssynchrony may be a major adverse factor limiting outcomes with late blastulating embryos in fresh cycles.

Limitations Reasons For Caution: This is a retrospective study comprising cohorts from a convenient sample chosen due to a uniform change in embryology laboratory protocol regarding ET day, however, this was done independent of the management of embryo and endometrial synchrony. Although strict ultrasound and serum progesterone criteria were utilized to make endometrial receptivity uniform, pathologic states of pre-receptive and post-receptive endometrium cannot be ruled out.

Wider Implications Of The Findings: The data surrounding embryo and endometrial synchrony should be considered in patients undergoing IVF and attention to the variations in blastulation rates can be applied to any patient undergoing extended embryo culture.

Study Funding/competing Interests: None.