Assessing the Convenience of Natural Proliferative Phase Frozen Embryo Transfer

Frozen embryo transfer (FET) is increasingly used nowadays in Assisted Reproductive Techniques (ART) clinics. Several factors account for this uprising. Among them, the concept of ovarian hyperstimulation syndrome (OHSS)-free clinic, the increasing use of preimplantation genetic testing (PGT), the improved vitrification systems, and the growing evidence regarding similar, or even better, pregnancy rates when FET are compared to fresh embryo transfers.

In the last few years, research has focused on the selection of the best protocol for endometrial preparation in patients undergoing FET cycles. Despite the accumulating evidence suggesting similar reproductive outcomes following both artificial cycle (AC-FET) and natural cycle (NC-FET) protocols, AC-FET is frequently adopted in ART centers due to its convenience in terms of cycle scheduling. However, a role for the corpus luteum in the maternal vasodilatory changes of early pregnancy has recently been associated with a decreased risk of pre-eclampsia. In fact, several large cohort studies have reported a higher risk of hypertensive diseases of pregnancy, macrosomia, post-term delivery and cesarean section following AC-FET.

The NPP-FET protocol is a strategy that potentially allows for cycle scheduling while maintaining the benefits of the natural cycle in terms of pregnancy outcomes. The main goal of the present study is to analyze its convenience in terms of the number of appointments needed before FET scheduling by comparing it with the NC-FET protocol. Additionally, the investigators aim to compare the reproductive outcomes between the two strategies and to analyze whether NPP-FET patients undergo ovulation.

Briefly, the study group will prospectively recruit ovulatory patients who will perform vaginal ultrasound monitoring will be performed on cycle day 8-12, depending on the length of the patients' menstrual cycle. When the endometrial thickness is at least 7 mm and the dominant follicle is at least 13 mm, vaginal micronized progesterone will be initiated at 400mg every 12 hours. One embryo will be transferred on the fifth day of progesterone supplementation under ultrasound guidance. The control group will include a retrospective cohort of ovulatory patients who underwent NC-FET.

Inclusion criteria

• Endometrial thickness ≥ 7 mm on the day of starting progesterone-based luteal phase support (LPS)
• Serum progesterone levels <1.5 ng/ml on the day of starting progesterone-based LPS
• LPS with micronized progesterone 400mg b.i.d.
• Regular cycles (>24 days, ≤ 38 days)
• IVF/ICSI with donated oocytes
• Single blastocyst stage embryo transfer
• First or second embryo transfer from the same cohort

Exclusion criteria

• Use of exogenous ovarian stimulation during FET
• Untreated hydrosalpinx, polyp, submucous myomas or severe adenomyosis
• Recurrent pregnancy loss (≥ 3 previous pregnancy losses)
• Recurrent implantation failure with embryos from oocyte donation (≥ 3 previous failed embryo transfers)
• Personalized initiation of exogenous progesterone according to a previous endometrial receptivity assay test