Department of Obstetrics, Gynaecology and Reproductive Medicine, Dexeus Mujer - Dexeus University Hospital, 08028 Barcelona, Spain.
Hum Reprod. 2021 May 17;36(6):1552-1560. doi: 10.1093/humrep/deab031.
Does an individualised luteal phase support (iLPS), according to serum progesterone (P4) level the day prior to euploid frozen embryo transfer (FET), improve pregnancy outcomes when started on the day previous to embryo transfer?
Patients with low serum P4 the day prior to euploid FET can benefit from the addition of daily subcutaneous P4 injections (Psc), when started the day prior to FET, and achieve similar reproductive outcomes compared to those with initial adequate P4 levels.
The ratio between FET/IVF has spectacularly increased in the last years mainly thanks to the pursuit of an ovarian hyperstimulation syndrome free clinic and the development of preimplantation genetic testing (PGT). There is currently a big concern regarding the endometrial preparation for FET, especially in relation to serum P4 levels around the time of embryo transfer. Several studies have described impaired pregnancy outcomes in those patients with low P4 levels around the time of FET, considering 10 ng/ml as one of the most accepted reference values. To date, no prospective study has been designed to compare the reproductive outcomes between patients with adequate P4 the day previous to euploid FET and those with low, but restored P4 levels on the transfer day after iLPS through daily Psc started on the day previous to FET.
STUDY DESIGN, SIZE, DURATION: A prospective observational study was conducted at a university-affiliated fertility centre between November 2018 and January 2020 in patients undergoing PGT for aneuploidies (PGT-A) IVF cycles and a subsequent FET under hormone replacement treatment (HRT). A total of 574 cycles (453 patients) were analysed: 348 cycles (leading to 342 euploid FET) with adequate P4 on the day previous to FET, and 226 cycles (leading to 220 euploid FET) under iLPS after low P4 on the previous day to FET, but restored P4 levels on the transfer day.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall we included 574 HRT FET cycles (453 patients). Standard HRT was used for endometrial preparation. P4 levels were measured the day previous to euploid FET. P4 > 10.6 ng/ml was considered as adequate and euploid FET was performed on the following day (FET Group 1). P4 < 10.6 ng/ml was considered as low, iLPS was added in the form of daily Psc injections, and a new P4 analysis was performed on the following day. FET was only performed on the same day when a restored P4 > 10.6 ng/ml was achieved (98.2% of cases) (FET Group 2).
Patient's demographics and cycle parameters were comparable between both euploid FET groups (FET Group 1 and FET Group 2) in terms of age, weight, oestradiol and P4 levels and number of embryos transferred. No statistically significant differences were found in terms of clinical pregnancy rate (56.4% vs 59.1%: rate difference (RD) -2.7%, 95% CI [-11.4; 6.0]), ongoing pregnancy rate (49.4% vs 53.6%: RD -4.2%, 95% CI [-13.1; 4.7]) or live birth rate (49.1% vs 52.3%: RD -3.2%, 95% CI [-12; 5.7]). No significant differences were also found according to miscarriage rate (12.4% vs 9.2%: RD 3.2%, 95% CI [-4.3; 10.7]).
LIMITATIONS, REASONS FOR CAUTION: Only iLPS through daily Psc was evaluated. The time for Psc injection was not stated and no serum P4 determinations were performed once the pregnancy was achieved.
Our study provides information regarding an 'opportunity window' for improved ongoing pregnancy rates and miscarriage rates through a daily Psc injection in cases of inadequate P4 levels the day previous to FET (P4 < 10.6 ng/ml) and restored values the day of FET (P4 > 10.6 ng/ml). Only euploid FET under HRT were considered, avoiding one of the main reasons of miscarriage and implantation failure and overcoming confounding factors such as female age, embryo quality or ovarian stimulation protocols.
STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. B.C. reports personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, IBSA and Gedeon Richter outside the submitted work. N.P. reports grants and personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, Theramex and Besins International and personal fees from IBSA and Gedeon Richter outside the submitted work. The remaining authors have no conflicts of interest to declare.
NCT03740568.
在进行整倍体冷冻胚胎移植（FET）之前一天，根据血清孕激素（P4）水平确定黄体期支持（iLPS）是否可以在胚胎移植前一天开始每日皮下注射 P4（Psc），从而改善妊娠结局？
在前一天 P4 水平低的整倍体 FET 患者中，通过每日 Psc 注射添加 iLPS 可以使 P4 水平恢复正常，与初始 P4 水平足够的患者相比，可获得相似的生殖结局。
在过去几年中，由于对卵巢过度刺激综合征（OHSS）免费诊所的追求以及对植入前遗传检测（PGT）的发展，FET/IVF 的比例惊人地增加了。目前，人们对 FET 的子宫内膜准备特别关注，尤其是在胚胎移植时血清 P4 水平方面。多项研究表明，在 FET 时 P4 水平低的患者中，妊娠结局受损，考虑到 10ng/ml 是最可接受的参考值之一。迄今为止，还没有前瞻性研究设计来比较在 FET 前一天 P4 水平充足的患者与在 FET 前一天 P4 水平低但通过 iLPS 恢复的患者（通过在 FET 前一天开始每日 Psc 注射使 P4 水平恢复正常）之间的生殖结局。
研究设计、规模、持续时间：2018 年 11 月至 2020 年 1 月期间，在大学附属生育中心进行了一项前瞻性观察性研究，研究对象为接受整倍体非整倍体（PGT-A）体外受精（IVF）周期和随后的激素替代治疗（HRT）下 FET 的患者。共分析了 574 个周期（453 例患者）：348 个周期（导致 342 个整倍体 FET）在 FET 前一天 P4 水平充足，226 个周期（导致 220 个整倍体 FET）在 FET 前一天 P4 水平低，但在 FET 当天恢复正常。
参与者/材料、设置、方法：我们总共纳入了 574 个 HRT FET 周期（453 例患者）。标准 HRT 用于子宫内膜准备。在进行整倍体 FET 前一天测量 P4 水平。P4>10.6ng/ml 被认为是充足的，并且在第二天进行 FET（FET 组 1）。P4<10.6ng/ml 被认为是低的，添加每日 Psc 注射形式的 iLPS，并且在第二天进行新的 P4 分析。只有当恢复的 P4>10.6ng/ml 时才进行 FET（98.2%的情况下）（FET 组 2）。
在 FET 组 1 和 FET 组 2 中，整倍体 FET 组患者的年龄、体重、雌二醇和 P4 水平以及转移胚胎数量等方面的患者特征和周期参数无统计学差异。在临床妊娠率（56.4%vs59.1%：差异率（RD）-2.7%，95%CI[-11.4；6.0]）、持续妊娠率（49.4%vs53.6%：RD-4.2%，95%CI[-13.1；4.7]）或活产率（49.1%vs52.3%：RD-3.2%，95%CI[-12；5.7]）方面均未发现统计学差异。根据流产率（12.4%vs9.2%：RD 3.2%，95%CI[-4.3；10.7]）也未发现统计学差异。
局限性、谨慎原因：仅评估了 iLPS 通过每日 Psc。没有说明 Psc 注射的时间，并且一旦妊娠成功，就没有进行血清 P4 测定。
我们的研究提供了有关通过每日 Psc 注射提高持续妊娠率和流产率的“机会窗口”的信息，适用于 FET 前一天（P4<10.6ng/ml）P4 水平不足且 FET 当天恢复（P4>10.6ng/ml）的情况。仅考虑整倍体 FET 在 HRT 下进行，避免了导致妊娠丢失和植入失败的主要原因之一，克服了女性年龄、胚胎质量或卵巢刺激方案等混杂因素。
研究资金/利益冲突：没有外部资金支持。B.C. 报告了与 Merck Serono、Ferring Pharmaceuticals、IBSA 和 Gedeon Richter 公司有关的个人酬金，这些酬金来自于 MSD，不在本研究范围内。N.P. 报告了来自 MSD、Merck Serono、Ferring Pharmaceuticals、Theramex 和 Besins International 的拨款和个人酬金，以及来自 IBSA 和 Gedeon Richter 的个人酬金，这些酬金均来自于 MSD，不在本研究范围内。其他作者没有利益冲突需要申报。
NCT03740568。
