Key message
This retrospective study explored the optimal timing of frozen embryo transfer
IVF has evolved rapidly since its inception 40 years ago. Ovarian stimulation is a critical step in IVF; it can help in the retrieval of more oocytes and embryos, but is also a double-edged sword, as multiple follicle development leads to a supraphysiological oestrogen concentration and premature progesterone elevation, which have adverse effects on endometrial receptivity and perinatal outcomes (Boomsma et al., 2010; Chaouat, 2013; Horcajadas et al., 2008; Junovich et al., 2011; Maheshwari et al., 2012,2016).
To avoid this detrimental effect of ovarian stimulation, and with improvements in embryo cryopreservation technology, the use of frozen embryo transfer (FET) has steadily increased in recent years. An increasing number of studies have demonstrated that FET cycles have comparable or even better clinical pregnancy outcomes than fresh embryo transfer cycles (Chen et al., 2016; Roque et al., 2013,2019; Shapiro et al., 2013; Shi et al., 2018) and a lower risk of ovarian hyperstimulation syndrome (OHSS), especially in hyper-responders (Chen et al., 2016).
Although the detrimental effect of superovulation on reproductive and perinatal outcomes seems clear, the best time to perform FET following ovarian stimulation is still controversial in clinical work, as no studies have reported how long it takes for the endometrial and hormone environment to return to their pre-stimulation functionality. Traditionally, the standard clinical practice is to postpone FET for at least one menstrual cycle to minimize the possible residual negative effect of ovarian stimulation. However, this selection is an empirical strategy based on suggestion and lacks sufficient scientific evidence. In the past few years, some studies regarding the timing of FET have been published, most of which were retrospective studies that were largely heterogeneous, varying in terms of the reason for FET, ovarian stimulation and FET protocol (artificial and/or natural cycle), embryo stage at transfer and number of embryos transferred. In these studies, most researchers reported similar clinical pregnancy and live birth rates (LBR) between immediate and delayed FET (Bortoletto et al., 2021; Bourdon et al., 2018; Chen et al., 2020; He et al., 2020; Horowitz et al., 2019; Hu et al., 2020; Kaye et al., 2018; Lattes et al., 2017; Ozgur et al., 2018; Santos-Ribeiro et al., 2016a,2016b; Song et al., 2019; Zuo et al., 2021), while two studies demonstrated a statistically significant difference in LBR in favour of immediate compared with postponed FET (Higgins et al., 2018; Huang et al., 2019). However, only one study with an extremely small sample size reported an advantage of postponed FET (Volodarsky-Perel et al., 2017). In addition, two randomized controlled trials studying when to perform FET have been published recently (Li et al., 2021; Song et al., 2021), and both demonstrated that immediate FET following a stimulated IVF cycle produced significantly higher ongoing pregnancy and live birth rates than delayed FET. Higher levels of anxiety and stress in delayed FET patients might be involved in these results (Song et al., 2021).
However, in the published literature, regardless of retrospective research or randomized controlled trials, there were stringent inclusion criteria for patients, such as certain ovarian stimulation or FET protocols. Therefore, the conclusions drawn can only represent the group that meets the inclusion criteria. However, the individual situations of patients in the clinic are unique, and it is obviously impractical to consider whether they meet the inclusion criteria of these published studies before deciding the FET timing. The current study included almost all first FET cycles after a freeze-all ovarian stimulation protocol in the study centre from 2017 to 2020, with extremely low inclusion criteria, expecting to obtain conclusions that can represent the majority of patients.
This was a retrospective cohort study including the first FET cycle of all women who underwent their first freeze-all ovarian stimulation protocol between 1 January 2017 and 31 December 2020 at Peking University Third Hospital.
Studies involving human participants are reviewed and approved by the Ethics Committee of Peking University Third Hospital (no: 2018SZ-002, 12 January 2018).
Only conventional ovarian stimulation protocols were included, while in-vitro maturation, mild stimulation
A total of 5995 patients who underwent their first FET following a freeze-all IVF/ICSI cycle were included in this study. The immediate, delayed and overdue FET groups consisted of 252, 5356 and 387 patients, respectively (Figure 1). Due to the conventional opinion about the adverse effect of ovarian stimulation, the overwhelming majority of FET cycles were initiated after more than one menstrual cycle in the study centre (95.8%).
This retrospective study found that the patients in the immediate FET group had comparable pregnancy and prenatal outcomes to the patients in the delayed FET group. The independent risk factors for live birth were maternal age, number of good-quality embryos, endometrial thickness on FET and FET protocol, while the time interval of FET was not associated with pregnancy or neonatal outcomes.
The advancement of ovarian stimulation, which multiplies the number of oocytes obtained, and embryo
Ying Wang and Rong Li supervised the entire study and participated in the interpretation of study data and revisions to the article. Ying Huang collected the data and drafted the manuscript. Jiangman Gao and Yan Yang participated in drafting the article. Hua Zhang, Yuanyuan Wang and Lixue Chen conducted the statistical analysis. All authors contributed to the article and approved the submitted version.
The authors thank all the staff of the reproductive centre in PUTH for their work on this study. This work was supported by grants from the National Science Foundation for Young Scientists of China [no. 81701408] and the National Natural Science Foundation [81873833].
Ying Wang, MD, PhD, is Chief Physician at the Department of Obstetrics and Gynecology at Peking University Third Hospital. She is a member of the American Society for Reproductive Medicine, the European Society of Human Reproduction and Embryology and the Chinese Eugenics Science Association; she has hosted and participated in several National Natural Science Foundation of China meetings. Key message This retrospective study explored the optimal timing of frozen embryo transfer
Ying Wang, MD, PhD, is Chief Physician at the Department of Obstetrics and Gynecology at Peking University Third Hospital. She is a member of the American Society for Reproductive Medicine, the European Society of Human Reproduction and Embryology and the Chinese Eugenics Science Association; she has hosted and participated in several National Natural Science Foundation of China meetings. Key message This retrospective study explored the optimal timing of frozen embryo transfer (FET) after a freeze-all cycle. No significant benefit in pregnancy outcomes was observed when FET was delayed for at least one menstrual cycle in either the whole cohort or in subgroups according to demographic characteristics.