Aristotle University of Thessaloniki, Medical School, Unit for Human Reproduction, 1st Department of Obstetrics and Gynecology, Thessaloniki, Greece.
University of New South Wales, Centre for Big Data Research in Health & School of Women's and Children's Health, UNSW Medicine, Sydney, Australia.
Hum Reprod. 2019 Mar 1;34(3):491-505. doi: 10.1093/humrep/dey388.
Does the outcome of the comparison of live birth rates between the first frozen embryo transfer (ET) (in a freeze-only cycles strategy, i.e. frozen ET group) and a fresh embryo transfer (fresh ET group) differ considering the type of ovarian response?
Α significantly higher probability of live birth is present in high, but not normal, responders, after the first frozen ET in a freeze-only cycle strategy as compared to a fresh ET.
It has been hypothesised that freezing all good embryos in a fresh in-vitro fertilisation (IVF) cycle and deferring embryo transfer in subsequent cycles may provide a more physiological endometrial environment for embryo implantation when compared to a fresh ET. However, currently, three relevant meta-analyses have been published with conflicting results, while none of them has taken into consideration the type of ovarian response. Recently, the publication of additional, large relevant randomised controlled trials (RCTs) in patients with different types of ovarian response makes possible the comparative evaluation of the first frozen ET (in a freeze-only cycle strategy) versus fresh ET, considering the type of ovarian response.
STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis was performed aiming to identify RCTs comparing the first frozen ET (in a freeze-only cycle strategy) to a fresh ET. The main outcome was live birth, while secondary outcomes included ongoing pregnancy, clinical pregnancy, moderate/severe ovarian hyperstimulation syndrome (OHSS) and miscarriage.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified eight eligible RCTs, including 5265 patients, which evaluated the first frozen ET in a freeze-only cycle strategy versus a fresh ET either in high responders (n = 4) or in normal responders (n = 4). No relevant RCTs were present in poor responders. Meta-analysis of weighted data using fixed and random effects model was performed. Results are reported as relative risk (RR) with 95% confidence interval (CI).
Eligible RCTs were published between 2011 and 2018. Four RCTs (n = 3255 patients) compared the first frozen ET (in a freeze-only cycle strategy) to a fresh ET in normal responders and four RCTs (n = 2010 patients) did the comparison in high responders. In high responders, a significantly higher probability of live birth was observed in the frozen ET group when compared with the fresh ET group (RR: 1.18, 95% CI: 1.06-1.31; fixed effects model; heterogeneity: I2 = 0%; three studies; n = 3398 patients). However the probability of live birth was not significantly different between the frozen ET group and the fresh ET group in normal responders (RR: 1.13, 95% CI: 0.90-1.41; random effects model; heterogeneity: I2 = 77%; three studies; n = 1608 patients). The risk of moderate/severe OHSS was significantly lower in the frozen ET group when compared with the fresh ET group both in high (RR: 0.19, 95% CI: 0.10-0.37; fixed effects model; heterogeneity: not applicable; a single study; n = 1508 patients) and normal responders (RR: 0.39, 95% CI: 0.19-0.80; fixed effects model; heterogeneity: I2 = 0%; two studies; n = 2939 patients).
LIMITATIONS, REASONS FOR CAUTION: Considerable heterogeneity was present among the studies, regarding ovarian stimulation protocols and the triggering signal used for inducing final oocyte maturation as well as the cryopreservation methods, while the quality of evidence was poor for the live birth rate in high responders. Moreover, the analysis did not apply a standard for determining 'high' or 'normal' responders since the type of ovarian response followed the characterisation of populations as reported by the authors of the eligible studies.
A freeze-only cycle strategy should be the preferred option in high responders since it enhances the probability of live birth, while reducing the chance of moderate/severe OHSS. In normal responders, the same strategy could be applied, in the interest of patient safety or clinic convenience, without compromising the chances of live birth.
STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and there were no competing interests.
PROSPERO registration number: CRD42018099389.
在仅冷冻周期策略（即冷冻胚胎移植组）中，第一次冷冻胚胎移植（FET）与新鲜胚胎移植（FET 组）之间的活产率比较结果是否因卵巢反应类型而异？
在高反应者中，与新鲜 ET 相比，在仅冷冻周期策略中进行第一次冷冻 FET 后，活产的可能性显著增加，但在正常反应者中则不然。
有人假设，与新鲜 IVF 周期中的新鲜 ET 相比，在随后的周期中冷冻所有优质胚胎并推迟胚胎移植可能为胚胎着床提供更生理的子宫内膜环境。然而，目前已经发表了三篇相关的荟萃分析，结果存在冲突，而且它们都没有考虑到卵巢反应的类型。最近，在不同卵巢反应类型的患者中发表了更多相关的大型随机对照试验（RCT），这使得有可能在考虑卵巢反应类型的情况下，对第一次冷冻 FET（仅冷冻周期策略）与新鲜 ET 进行比较评估。
研究设计、规模、持续时间：进行了一项系统评价和荟萃分析，旨在确定比较第一次冷冻 FET（仅冷冻周期策略）与新鲜 ET 的 RCT。主要结局是活产，次要结局包括持续妊娠、临床妊娠、中重度卵巢过度刺激综合征（OHSS）和流产。
参与者/材料、设置、方法：我们确定了八项符合条件的 RCT，其中包括 5265 名患者，这些 RCT 评估了仅冷冻周期策略中第一次冷冻 FET 与新鲜 ET 的比较，分别在高反应者（n = 4）或正常反应者（n = 4）中进行。在低反应者中没有相关的 RCT。使用固定和随机效应模型对加权数据进行荟萃分析。结果以相对风险（RR）和 95%置信区间（CI）表示。
合格的 RCT 发表于 2011 年至 2018 年之间。四项 RCT（n = 3255 名患者）比较了正常反应者中第一次冷冻 FET（仅冷冻周期策略）与新鲜 ET 的比较，四项 RCT（n = 2010 名患者）比较了高反应者中第一次冷冻 FET 与新鲜 ET 的比较。在高反应者中，与新鲜 ET 组相比，冷冻 ET 组活产的可能性显著增加（RR：1.18，95%CI：1.06-1.31；固定效应模型；异质性：I2 = 0%；三项研究；n = 3398 名患者）。然而，在正常反应者中，冷冻 ET 组与新鲜 ET 组的活产率无显著差异（RR：1.13，95%CI：0.90-1.41；随机效应模型；异质性：I2 = 77%；三项研究；n = 1608 名患者）。与新鲜 ET 组相比，冷冻 ET 组中中重度 OHSS 的风险显著降低，无论在高反应者（RR：0.19，95%CI：0.10-0.37；固定效应模型；异质性：不适用；一项研究；n = 1508 名患者）还是正常反应者（RR：0.39，95%CI：0.19-0.80；固定效应模型；异质性：I2 = 0%；两项研究；n = 2939 名患者）。
局限性、谨慎的原因：研究之间存在相当大的异质性，涉及卵巢刺激方案和用于诱导最后卵母细胞成熟的触发信号以及冷冻保存方法，而高反应者的活产率的证据质量较差。此外，由于卵巢反应的类型遵循合格研究作者报告的人群特征，因此该分析未应用确定“高”或“正常”反应者的标准。
在高反应者中，仅冷冻周期策略应该是首选，因为它可以提高活产率，同时降低中重度 OHSS 的机会。在正常反应者中，出于患者安全或临床方便的考虑，也可以应用相同的策略，而不会影响活产率的机会。
研究资金/利益冲突：没有外部资金使用，也没有利益冲突。
PROSPERO 注册号：PROSPERO 注册号：CRD42018099389。
