Investigating the Impact of Different Strategies for Endometrial Preparation in Frozen Cycles Considering Normal Responders Undergoing IVF/ICSI Cycles: a Multicenter Retrospective Cohort Study

Uncertainty exists concerning the type, adjunct, or dose of regimen to offer in frozen cycles in infertile women undergoing IVF/ICSI. Current systematic reviews have failed to identify one method of endometrial preparation as being more effective than another, whereas many IVF Units use variable and mixed protocols mainly based on their experience and convenience of use. Thus, we performed a four-center two-arm retrospective cohort study, encompassing 439 cycles in 311 women. The modalities analyzed were: Modified natural cycle without and with luteal support (Groups 1,2) and Hormone Replacement cycle (HRC) with and without GnRHa suppression (Groups 3,4). Various schemes of progesterone and estradiol were used and compared. χ tests for categorical data and t-tests for continuous data were employed, stratifying by exposure, along with univariate and multivariable Logistic Regression models and subgroup analyses, according to the number of embryos transferred (1 vs. ≥2) and day of transfer (d2 vs. d5). Group 3 presented with statistically significant higher live birth and miscarriage rates in comparison to Group 4 (RR = 5.87, 95%CI: 2.44-14.14 and RR = 0.19, 95%CI: 0.06-0.60, respectively), findings that persisted in subgroup analyses according to the day of transfer and the number of embryos transferred. Progesterone administration through the combination of vaginal tabs and gel was associated with lower clinical pregnancy rates when compared to tabs (RR = 0.19, 95%CI: 0.05-0.71). The stable estrogen protocol compared to increasing estrogen at day 5 was associated with a higher positive hCG test and clinical pregnancy rate, while the progesterone through vaginal tabs was linked with lower miscarriages compared either with gel or combinations. In conclusion, HRC with GnRHa appears to be superior to HRC without GnRHa, concerning live birth and miscarriage, especially when the number of embryos transferred are ≥2 and irrespective of day of transfer. The use of progesterone vaginal tabs compared to gel or combinations is associated with better outcomes. Age is a significant predictor of a negative hCG test and clinical pregnancy rates. A properly conducted RCT is needed to evaluate the optimal frozen embryo transfer preparation strategy.: SD: standard deviation; BMI: body mass index; PCOS: polycystic ovarian syndrome; IQR: interquartile range; FSH: follicle-stimulating hormone; LH: luteinizing hormone; TSH: thyroid-stimulating hormone.