The progress of embryo cryopreservation, particularly in vitrification, has made freeze-all strategy more acceptable. However, the freeze all strategy is still controversial due to unclear advantages or disadvantages. In this study, we analyzed whether patients benefited from freeze all strategy in comparison with fresh ET cycles in GnRH-a long protocol. The reason we chosen the first ET cycle was that the first ET usually selected the best-quality embryo, whereas the embryo quality of the second FET cycle may differ from the fresh ET. Simultaneously, patients whose age > 34 years, endometrium thickness < 0.7 cm, blastocyst transfer and PGT cycles were excluded, due to these confounding factors were extremely unbalanced between the two groups. The characteristics of the patients including age, infertility duration, AMH level, basal FSH level, primary infertility and primary cause of infertility were still significantly different between two groups (Table 1). Especially, the younger age and higher AMH level in FET group, which might indicate that the function of ovarian reserve of the FET group was better than the fresh ET group. As expected, the outcomes of COS of the FET group were better, including less gonadotropin dose, more oocytes retrieved and more available embryos (Table 2).
It is still controversial about the efficacy of GnRH-a and GnRH-ant protocols with fresh ET. Several studies suggested that the pregnancy rate, ongoing pregnancy rate and live birth rate of fresh transfer cycles were lower in the GnRH-ant protocol than in the GnRH-a protocol (3, 18), whereas other studies showed no significant difference (2, 19). Furthermore, implantation is one of the most important steps to achieve live birth, therefore it is considered as an important indicator to the efficacy of the treatment. Implantation relies on embryo quality and endometrial receptivity (20). Hershko et al have conducted a randomized trial showed there was no difference in embryo quality between GnRH-a and GnRH-ant group (21). Hernandez et al have reported GnRH-ant may disrupt an auto/paracrine loop, that is essential for the mitotic programme of the endometrial epithelial cells, leading to decrease of pregnancy rates and an increase of abortion rates (22). Rackow et al found HOXA10 (an essential regulator of endometrial receptivity) expression was significantly decreased in endometrial stromal cells in GnRH-ant-treated cycles compared with GnRH-a-treated cycles or natural cycle (23). Ruan et al found GnRH agonist, may partially restore the endometrial physiological secretion and improve uterine receptivity in mice (24). A comparative proteomic analysis demonstrated endometrial receptivity was more strongly impaired by GnRH-ant than GnRH-a treatments (25). The results of the above studies (22–25) indicated that the endometrial receptivity of GnRH-a protocol might be better than GnRH-ant protocol in fresh ET cycles. As we know, FET has become increasingly common in many countries (8). It has been hypothesized that FET may provide a more physiologic uterine environment for embryo implantation than fresh ET (26). Furthermore, the elective freezing embryos also can reduce the risk of OHSS, which is an iatrogenic, serious, and potentially life-threatening complication in COS treatment (27, 28). However, it should be noted to take care the damage of embryo by freezing and thawing, which was associated with ice crystal formation, increased of salt concentrations and cryoprotectant agents toxicity caused by cryopreservation (29–31). Tachataki et al demonstrated that cryopreservation affected the normal pattern of gene expression during human pre-implantation development (32). Therefore, when the uterine environment benefits from FET are less than the damages of freezing and thawing to embryos, the live birth rate will be finally lower for the FET compared to fresh ET. Moreover, freeze all strategy and additional frozen cycles will increase time to live birth and treatment costs for infertile patients (33).
There are controversial opinions regarding the ectopic pregnancy rate and pregnancy loss rate between fresh ET and FET cycles in different studies. Most researchers thought the supra physiologic hormonal levels could confer a higher ectopic pregnancy rate with fresh ET cycles (34, 35). However, Xiao et al found no significant difference in ectopic pregnancy rate between fresh ET and FET (36). Chen et al found there was higher pregnancy loss rate in the fresh ET group compared to FET group in ovulatory women (13). However, Heather et al found a higher first trimester pregnancy loss risk after FET compared with fresh ET among women younger than 38 years old (37). In this cohort study, the ectopic pregnancy rate and pregnancy loss rate were higher in the FET group, but after adjusting for potential confounders, multivariate logistic regression analysis showed no significant difference between two groups, while that implantation rate and live birth rate in the fresh ET group was significantly higher than FET group although the younger age and higher AMH level in FET group.
This study has its inherent limitation as a retrospective analysis. The characteristics of patients were unbalanced. Although we adjusted the confounders and used multivariate logistic regression analysis, some potential confounders still might be ignored. In conclusion, compared to FET, fresh ET following GnRH-a long protocol tended to increase live birth rate in patients undergoing their first ART cycle. This study suggest that freeze all strategies should be individualized and made with caution especially for GnRH-a long protocol in clinical practice. A well-designed, multicenter, prospective RCT is still required to further support these results.