Sequential (two-step) day 3/day 5 frozen-thawed embryo transfer: does it improve the pregnancy rate of patients suffering recurrent implantation failure?

Abstract

The best time of endometrial receptivity is the missing part of the implantation puzzle in patients with recurrent in vitro fertilization (IVF) failure. There are various treatment plans and strategies to meet the best endometrial timing for implantation. However, the lack of synchronization of the good-quality embryo with the patient's individual “window of implantation” is the hypothesis for most IVF failures so far. Sequential embryo transfer (ET) theoretically extends the availability time of embryos on the window of implantation. The study aimed to evaluate the improvement of pregnancy rate in sequential (two-step) frozen-thawed embryo transfer (FET) on day 3/day 5 in individuals who suffer from repeated IVF failures. This randomized controlled trial study was done in a university-affiliated infertility center for women with repeated consecutive IVF failures. Two hundred women aged 20–39 years who met our inclusion criteria were included in the study between January 2020 and September 2021. Participants were allocated with a 1:1 ratio to either sequential (two-step) ET on day 3/day 5 (study group, n=100) and conventional day 5 FET (n=100, control group). The frozen-thawed embryos were transferred to hormone replacement therapy-prepared endometrium in both groups. The primary outcomes were clinical pregnancy and implantation rates. The secondary outcomes were early pregnancy loss and multiple pregnancies. The demographic and clinical characteristics of the two groups were comparable. Clinical pregnancy rates were significantly higher in the sequential (two-step) FET group (40%) compared to the day 5 group (19%) (P<0.001). The sequential transfer of frozen-thawed embryos on day 3/day 5 was more effective than regular day 5 for patients suffering from repeated IVF failure.

A Case Series Based on the Mixed Double-Embryo Transfer (MDET) Outcome in Patients With Recurrent Implantation Failure

“…These include a decrease in cumulative live birth rates per couple, an elevated risk of preterm birth, delivering larger-than-average infants for the gestational age, an increased likelihood of monozygotic twins, and a higher incidence of congenital anomalies when compared to embryo transfer during the cleavage stage [ 6 ]. Upon reviewing the literature, there has been research based on sequential embryo transfer in which one day 3 embryo is transferred on day 3 and one blastocyst is transferred on day 5/6 of progesterone in a single menstrual cycle [ 11 , 12 ]. Though initial reports suggested improved pregnancy outcomes using sequential embryo transfer, recent research points out that it has a comparable outcome over blastocyst transfer [ 11 - 13 ].…”

Sequential embryo transfer versus double cleavage-stage embryo or double blastocyst transfer in patients with recurrent implantation failure with frozen-thawed embryo transfer cycles: a cohort study

“…Since then, some clinicians have tried to use a sequential ET approach to help patients with RIF increase their chances of pregnancy. Some studies showed that sequential ET did not improve clinical outcomes for patients with RIF (18-20), while other studies suggested that it was more effective toward increasing the clinical pregnancy and live birth rates than day 3 or day 5 ET in these patients (11)(12)(13) randomized trial by Torky et al (13) showed that the implantation and clinical pregnancy rates were significantly higher in patients who underwent sequential embryo transfer than in those who underwent cleavage transfer on day 3 or blastocyst transfer on day 5 in IVF fresh cycles. Arefi et al (11) conducted a prospective study to evaluate the improvement of pregnancy rate in sequential FET on day 3/day 5 in individuals who suffered from RIF and suggested that sequential transfer was more effective than regular day 5.…”

“…Some studies showed that sequential ET did not improve clinical outcomes for patients with RIF (18-20), while other studies suggested that it was more effective toward increasing the clinical pregnancy and live birth rates than day 3 or day 5 ET in these patients (11)(12)(13) randomized trial by Torky et al (13) showed that the implantation and clinical pregnancy rates were significantly higher in patients who underwent sequential embryo transfer than in those who underwent cleavage transfer on day 3 or blastocyst transfer on day 5 in IVF fresh cycles. Arefi et al (11) conducted a prospective study to evaluate the improvement of pregnancy rate in sequential FET on day 3/day 5 in individuals who suffered from RIF and suggested that sequential transfer was more effective than regular day 5. A systematic review by Zhang et al demonstrated that the clinical pregnancy rate and live birth rate were higher in the sequential ET group than in the cleavage-stage ET group for women who experienced RIF, and there were no significant differences between sequential ET and blastocyst ET (21).…”

“…In recent years, scientists have proposed a sequential transfer procedure, a two-step interval transfer of a cleavage-stage embryo followed by a blastocyst in one transfer cycle to help RIF patients increase the chance of pregnancy. Several studies have suggested that sequential ET significantly improves the clinical outcomes of IVF-ET (11)(12)(13). However, the effect of sequential ET is still controversial, and its effectiveness and potential biological mechanisms have not been proven.…”