The time interval between oocyte retrieval and frozen embryo transfer does not impact reproductive outcomes

Abstract

Research question

Does the time interval between oocyte retrieval and frozen embryo transfer (FET) affect pregnancy outcomes after a freeze-all strategy?

Design

Retrospective study including a total of 5995 patients who underwent their first FET following a freeze-all cycle between 1 January 2017 and 31 December 2020. Patients were divided into immediate (the interval between oocyte retrieval and the day of first FET ≤40 days), delayed (>40 days but ≤180 days) and overdue groups (>180 days). Pregnancy and neonatal outcomes were analysed, and multivariable regression analysis was used to study the effect of FET timing on the live birth rate (LBR) in the entire cohort and the different subgroups.

Results

The LBR was significantly lower in the overdue group than in the delayed group (34.9% versus 42.8%, P = 0.002); however, after adjusting for confounding factors, the difference was not statistically significant. The immediate group had a comparable LBR (36.9%) to the other two groups in both the crude and adjusted analyses. Multivariable regression analysis showed no impact of FET timing on LBR in the whole cohort or in the subgroups according to ovarian stimulation protocol, trigger type, insemination method, reason for freezing all, FET protocol or transferred embryo stage.

Conclusions

The time interval between oocyte retrieval and FET does not impact reproductive outcomes. Unnecessary delays in FET should be avoided to shorten the time to live birth.

Introduction

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.