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

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.