Infertility  不孕不育

WIDER IMPLICATION OF THE FINDINGS: Implantation failure seems to be mainly due to embryonic factors. Given the stable and high live birth rates up to five euploid blastocysts, unexplained recurrent implantation failure should have a prevalence of . Proceeding with another embryo transfer can be the best next step once a known etiology for implantation failure is ruled out.
研究结果的广泛意义：植入失败似乎主要是由于胚胎因素造成的。鉴于5个优倍囊胚以内的活产率稳定且较高，原因不明的反复植入失败的发生率应为 。一旦排除了植入失败的已知病因，下一步最好的办法就是再次进行胚胎移植。
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Keywords: in vitro fertilization / assisted reproduction / implantation failure / preimplantation genetic testing / live birth
关键词：体外受精/辅助生殖/植入失败/植入前基因检测/活产

The term 'recurrent implantation failure' (RIF) aims to define a milestone during the course of multiple embryo transfers, all of which have failed to result in implantation. The recurrent nature of the failures presumably suggests a currently unknown etiology that may affect the success of subsequent transfers, perhaps requiring a different diagnostic and therapeutic approach to achieve a live birth (Ata et al., 2021). Until recently, the term has been used loosely with varying definitions based on female age, developmental stage and quality of embryos transferred, fresh or frozen embryo transfers, as well as number of embryos that failed to implant (Shaulov et al., 2020). The heterogeneity of definitions without an underpinning biological rationale has led to several challenges affecting patients and reproductive medicine professionals worldwide. First and foremost, using low thresholds to diagnose RIF has triggered multiple diagnostic and therapeutic interventions to be offered to couples in the absence of sound biological rationale or proper proof of effectiveness (reviewed in Franasiak et al., 2021). Such an approach does not only consume funds available for further treatment, but also puts couples at risk of unintended harm in the form of complications or lower success rates caused by the new intervention. Second, inclusion of women with too few failed transfers in RIF research leads to heterogenous study populations yielding unreliable and conflicting results and conclusions (Ata et al., 2021).
反复植入失败"（RIF）一词旨在定义多次胚胎移植过程中的一个里程碑，即所有胚胎移植均未成功植入。胚胎移植失败的复发性推测表明，目前未知的病因可能会影响后续移植的成功率，也许需要采用不同的诊断和治疗方法才能实现活产（Ata 等人，2021 年）。直到最近，这一术语的使用还很宽泛，根据女性年龄、发育阶段、移植胚胎的质量、新鲜或冷冻胚胎移植以及未能着床的胚胎数量等因素有不同的定义（Shaulov 等人，2020 年）。在没有生物学依据的情况下，定义的多样性导致了一些影响全球患者和生殖医学专业人员的挑战。首先，使用低阈值诊断 RIF 引发了向夫妇提供多种诊断和治疗干预，但却缺乏合理的生物学依据或适当的有效性证明（Franasiak 等人，2021 年综述）。这种做法不仅消耗了可用于进一步治疗的资金，还使夫妇们面临因新干预措施引起并发症或成功率降低而遭受意外伤害的风险。其次，在 RIF 研究中纳入转运失败次数过少的妇女，会导致研究人群的异质性，从而产生不可靠且相互矛盾的结果和结论（Ata 等人，2021 年）。

There have been recent efforts to define RIF with an underpinning biological rationale (Ata et al., 2021; Somigliana et al., 2022; ESHRE Working Group on Recurrent Implantation Failure, 2023; (The writing group) for the participants to the 2022 Lugano RIF Workshop, 2023). These new approaches recognize embryo aneuploidy as the most common reason for implantation failure, in the absence of other known factors, e.g. communicating hydrosalpinges or intracavitary lesions. Since the incidence of aneuploidy is strongly dependent on female age, recent definitions consider euploidy status of the embryos transferred, either as directly determined by preimplantation genetic testing for aneuploidy (PGT-A) or by using female age to calculate anticipated probability of euploidy. This information is used to estimate the expected cumulative probability of implantation or live birth to be achieved with the number of embryos transferred. If this figure is above a threshold, that is regarded high enough to rule out implantation failure due to randomly occurring aneuploidy, the patient can be diagnosed with RIF (Ata et al., 2021; ESHRE Working Group on Recurrent Implantation Failure, 2023; (The Writing Group) for the Participants to the 2022 Lugano RIF Workshop, 2023).
最近，人们一直在努力根据生物学原理来定义 RIF（Ata 等人，2021 年；Somigliana 等人，2022 年；ESHRE 复发性着床失败工作组，2023 年；2022 年卢加诺 RIF 研讨会与会者（编写小组），2023 年）。这些新方法认为，在没有其他已知因素（如交流性鞘膜积液或腔内病变）的情况下，胚胎非整倍体是植入失败的最常见原因。由于非整倍体的发生率与女性年龄密切相关，最近的定义考虑了移植胚胎的非整倍体状态，即通过植入前非整倍体基因检测（PGT-A）直接确定的非整倍体状态，或利用女性年龄计算预期的非整倍体概率。这些信息可用于估算移植胚胎数达到的植入或活产的预期累积概率。如果该数字高于一个阈值，即足以排除随机发生的非整倍体导致的植入失败，则患者可被诊断为 RIF（Ata 等人，2021 年；ESHRE 复发性植入失败工作组，2023 年；2022 年卢加诺 RIF 研讨会与会者（编写小组），2023 年）。
An initial landmark study reported the cumulative sustained implantation and live birth rates achieved with three consecutive single euploid blastocyst transfers (SETs) in the absence of other obvious factors (Pirtea et al., 2021). Euploid blastocysts had similar sustained implantation and live birth rates across the first three consecutive single embryo transfers, leading to a cumulative probability of implantation and a cumulative probability of live birth among the 4429 women included in the study. These figures were in agreement with the predictions of a mathematical model, which was informed by euploid blastocyst implantation and live birth rates reported in the literature (Ata et al., 2021). Based on these studies, the incidence of 'true' unexplained RIF would be in the IVF population, since a statistically significant progressive decline in either the implantation or live birth rate per euploid blastocyst transferred was not observed between the first three consecutive SETs.
一项具有里程碑意义的初步研究报告了在没有其他明显因素的情况下，连续三次单个极性囊胚移植（SET）所获得的累积持续植入率和活产率（Pirtea 等人，2021 年）。在前三次连续的单胚胎移植中，极性囊胚具有相似的持续植入率和活产率，因此，在参与研究的 4429 名妇女中，植入的累积概率为 ，活产的累积概率为 。这些数字与一个数学模型的预测结果一致，该数学模型参考了文献中报道的优倍囊胚植入率和活产率（Ata 等人，2021 年）。根据这些研究，试管婴儿人群中 "真正的 "不明原因 RIF 的发生率为 ，因为在前三次连续的 SET 之间，没有观察到每移植一个极性囊胚的植入率或活产率出现统计学意义上的显著下降。

Despite significant progress in our understanding of RIF based on these studies, the fate of the fourth and the fifth euploid blastocyst transfers following the failure of the first three remains unknown. If the fourth and the fifth euploid transfers result in implantation with a similar rate as the first three attempts, the true prevalence of RIF could be much . However, if there is a significant drop in the implantation potential of the embryo at the fourth and the fifth transfer, this finding could be used to identify a subgroup of patients with true RIF and possible biological mechanisms preventing implantation. In the current study, we addressed this question by examining clinical pregnancy and live birth rates in women who underwent at least one additional euploid blastocyst transfer after three failures in the absence of another known factor that affects implantation.
尽管基于这些研究，我们对 RIF 的理解有了很大的进步，但在前三次失败后，第四次和第五次极性囊胚移植的命运仍然未知。如果第四和第五次卵裂囊胚移植的着床率与前三次相似，那么 RIF 的真实发生率可能远低于 。但是，如果胚胎在第四次和第五次移植时的植入潜能显著下降，那么这一发现可用于确定真正的 RIF 患者亚群以及阻止植入的可能生物学机制。在当前的研究中，我们针对这一问题，在没有其他已知的影响植入因素的情况下，对三次失败后至少再进行一次优倍囊胚移植的妇女进行了临床妊娠率和活产率的研究。

This was an international multi-center retrospective study conducted at 26 individual clinics operating as part of Reproductive Medicine Associates (RMA) USA, IVI Spain, Genera, Italy, and ART Fertility Clinics, United Arab Emirates (Supplementary Table S1). Research ethics committee approvals were obtained in each participating institution (RMA Network in the USA: Advarra # 00064197; IVI Spain: PI 229/22; Genera Italy 0747/2023-7283; YALE IRB: 2000032741; and ART Fertility Clinics: REFA095-2304ABU-005-BA; DOH/ZHCD/2023/1226).
这是一项国际多中心回顾性研究，在美国生殖医学协会 (RMA)、西班牙 IVI、意大利 Genera 和阿联酋 ART 生育诊所旗下的 26 家诊所进行（补充表 S1）。各参与机构均获得了研究伦理委员会的批准（美国 RMA 网络：Advarra # 00064197；西班牙 IVI：美国 RMA 网络：Advarra # 00064197；西班牙 IVI：PI 229/22；意大利 Genera 0747/2023-7283；耶鲁大学 IRB：2000032741；ART 生育诊所：REFA095-2304ABU-005-BA; DOH/ZHCD/2023/1226).

The study period spanned between January 2012 and December 2022. All patients who failed to achieve a positive pregnancy test after the cumulative transfer of three consecutive euploid blastocysts (regardless of the number of transfer procedures) and who subsequently underwent at least one more euploid blastocyst transfers at participating centers were included. Patients were between the age of 18 and 45 years old and had a BMI . Exclusion criteria included history of any embryo transfer in another clinic, history of any unscreened embryo transfer in participating clinics, parental karyotype abnormalities, the use of donor oocytes or a gestational carrier, intracavity uterine pathology (e.g. polyp, leiomyoma), congenital uterine anomalies (e.g. septum), intramural fibroids distorting uterine cavity, adenomyosis, communicating hydrosalpinx, endometrial thickness prior to initiating of progesterone, use of testicular sperm due to non-obstructive azoospermia in the male partner, transfer of an embryo with a reported intermediate chromosome copy number (i.e. mosaic), PGT cycles for monogenic disorders, or structural chromosome
研究时间跨度为 2012 年 1 月至 2022 年 12 月。研究对象包括所有在参与中心连续移植三次（无论移植次数多少）优生囊胚后妊娠试验未呈阳性，且随后至少再进行一次优生囊胚移植的患者。患者年龄在 18 至 45 岁之间，体重指数 。排除标准包括曾在其他诊所进行过胚胎移植、曾在参与诊所进行过未经筛查的胚胎移植、父母核型异常、使用过供体卵母细胞或妊娠载体、腔内子宫病变（如息肉、子宫肌瘤）、先天性子宫异常（如子宫纵隔、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症、子宫内膜异位症等。子宫腔内病变（如息肉、子宫肌瘤）、先天性子宫异常（如子宫纵隔）、子宫腔内肌瘤扭曲、子宫腺肌病、沟通性输卵管积水、开始使用黄体酮前子宫内膜厚度 、因男方患有非梗阻性无精子症而使用睾丸精子、移植据报告染色体拷贝数为中间值（即马赛克）的胚胎、单基因疾病的 PGT 周期或染色体结构性异常。
rearrangements. Patients who received a double-euploid blastocyst transfer (DET) were excluded if only one of the embryos implanted.
重排。如果只有一个胚胎着床，则排除接受双倍性囊胚移植（DET）的患者。

Participants were stimulated with commonly used ovarian stimulation protocols. Embryology laboratory procedures followed the usual practice of each participating center. Fertilization was achieved with IVF or ICSI depending on sperm characteristics and each center's practice. Embryo culture and trophoectoderm biopsy followed each centers' own protocol.
参与者采用常用的卵巢刺激方案进行刺激。胚胎实验室程序遵循各参与中心的惯例。根据精子的特性和各中心的惯例，采用体外受精或卵胞浆内单精子显微注射进行受精。胚胎培养和滋养层活检按照各中心自己的方案进行。

The ploidy status of blastocysts was determined with comprehensive chromosome screening (CCS), using next-generation sequencing (NGS) (ART, RMA, IVI, Genera) or quantitative real-time polymerase chain reaction (qPCR) (RMA, Genera) (Forman et al., 2013; Scott et al., 2013; Capalbo et al., 2015, 2021; de Los Santos et al., 2018; Tiegs et al., 2021; Ata et al., 2023). CCS diagnoses included euploid, whole chromosome aneuploid, segmental aneuploid, or intermediate copy number (i.e. mosaic). Any transfers of blastocysts with a reported intermediate copy number, or segmental or whole chromosome aneuploid were excluded from the analyses.
囊胚的倍性状态是通过全面染色体筛查（CCS）确定的，采用的是新一代测序（NGS）（ART、RMA、IVI、Genera）或实时定量聚合酶链反应（qPCR）（RMA、Genera）（Forman 等，2013 年；Scott 等，2013 年；Capalbo 等，2015 年、2021 年；de Los Santos 等，2018 年；Tiegs 等，2021 年；Ata 等，2023 年）。CCS 诊断包括超整倍体、全染色体非整倍体、节段非整倍体或中间拷贝数（即马赛克）。任何报告为中间拷贝数、节段性或全染色体非整倍体的囊胚移植都不在分析之列。

Embryos were vitrified after biopsy until time of transfer. Endometrial preparation protocols followed the usual practice of participating centers and included programmed cycles with sequential exogenous estrogen and progesterone administration, natural or modified natural cycles (Vaiarelli et al., 2020; Rafael et al., 2022; Ata et al., 2023).
胚胎在活检后进行玻璃化处理，直至移植。子宫内膜制备方案遵循参与中心的惯例，包括连续使用外源性雌激素和孕激素的计划周期、自然周期或改良自然周期（Vaiarelli 等，2020 年；Rafael 等，2022 年；Ata 等，2023 年）。

The primary outcomes were clinical pregnancy rate and live birth rate after the fourth and the fifth consecutive euploid blastocyst transfer. Clinical pregnancy was defined as the presence of an intrauterine gestational sac and yolk sac. Live birth was defined as delivery of a fetus beyond 22 weeks gestational age (ZegersHochschild et al., 2017).
临床妊娠率和活产率是连续第四次和第五次优倍囊胚移植后的主要结果。临床妊娠的定义是宫内出现孕囊和卵黄囊。活产是指胎龄超过 22 周的胎儿娩出（ZegersHochschild 等人，2017 年）。

Continuous variables were defined with mean and standard deviation or median and quartiles and compared with KruskalWallis and ANOVA tests depending on distribution characteristics. Categorical variables were defined with numbers and percentages and compared with chi-squared test and its derivatives as appropriate. Unit of analysis was euploid blastocyst transferred. Clinical pregnancy and live birth rates were calculated for the fourth and fifth euploid blastocysts per participating center and in aggregate. Relative risks (RR) and 95% CIs were calculated for comparisons. Sensitivity analyses were done excluding blastocysts biopsied on Day 7 postfertilization, women with a BMI , cycles using non-ejaculate or donor sperm, doubleembryo transfer cycles, and cycles in which the day of embryo transfer was modified due to endometrial receptivity array (ERA) test result. A life table was prepared using the previously published data pertaining to first three consecutive euploid blastocyst transfers and the fourth and fifth euploid blastocyst transfers done in the same center (RMA, New Jersey) with the same CCS platform (Pirtea et al., 2021).
连续变量用均值和标准差或中位数和四分位数定义，并根据分布特征用 KruskalWallis 检验和方差分析检验进行比较。分类变量用数字和百分比定义，并根据情况使用卡方检验及其导数进行比较。分析单位为移植的单倍体囊胚。临床妊娠率和活产率是根据每个参与中心的第四个和第五个优倍囊胚计算得出的。计算比较的相对风险 (RR) 和 95% CI。敏感性分析排除了受精后第 7 天活检的囊胚、体重指数 的女性、使用非射精精子或供精精子的周期、双胚胎移植周期以及因子宫内膜受体阵列（ERA）检测结果而修改胚胎移植日的周期。利用之前公布的前三次连续极性囊胚移植以及在同一中心（RMA，新泽西州）使用相同的 CCS 平台进行的第四和第五次极性囊胚移植的相关数据编制了生命表（Pirtea 等人，2021 年）。

During the study period 123987 patients underwent an egg retrieval and 94401 had an embryo transfer, with a total of 64572 euploid blastocyst transfers performed in the 25 participating clinics. Of the 123987 patients, 105 ( of the total population) underwent at least one more euploid blastocyst transfer after failing to achieve a pregnancy with three euploid blastocyst transfers and met the other inclusion criteria to be included in the analyses.
在研究期间，有 123987 名患者进行了取卵，94401 名患者进行了胚胎移植，25 家参与研究的诊所共进行了 64572 次优倍囊胚移植。在这 123987 例患者中，有 105 例（占总人数的 ）在进行了 3 次优倍囊胚移植后未能成功妊娠，但至少又进行了 1 次优倍囊胚移植，并符合其他纳入分析的标准。

Among the 105 patients, female age was years, BMI was , median serum anti-Müllerian hormone (AMH) level was at the time of first egg retrieval. Male age was years. The origin of the sperm was ejaculate in 99 cycles, fine-needle aspiration due to obstructive azoospermia in one, testicular sperm extraction due to prior vasectomy in one, and donor sperm in four cycles. Thirty-one women had one, 55 women had two, 11 women had three, and 4 women had four oocyte retrieval procedures.
105名患者中，女性年龄为 岁，体重指数为 ，首次取卵时血清抗缪勒氏管激素（AMH）水平中位数为 。男性年龄为 岁。99个周期的精子来源于射精，1个周期的精子来源于梗阻性无精子症，1个周期的精子来源于输精管结扎术前的睾丸取精，4个周期的精子来源于捐精。31名妇女进行了一次取卵，55名妇女进行了两次取卵，11名妇女进行了三次取卵，4名妇女进行了四次取卵。

The median number of oocytes collected was 17 (12-24.5), metaphase two (MII) oocytes was 13 (10-18), fertilization rate per MII oocyte was (73.86-90.91%), blastulation rate per MII oocyte was (33.33-57.14%), and euploidy rate per biopsied blastocyst was (50-83.33%). There were euploid blastocysts per stimulation cycle. Table 1 shows baseline demographics and stimulation cycle outcomes per participating center.
采集到的卵母细胞中位数为 17 个（12-24.5），二分裂期（MII）卵母细胞为 13 个（10-18），每个 MII 卵母细胞的受精率为 (73.86-90.91%)，每个 MII 卵母细胞的囊胚形成率为 (33.33-57.14%)，每个活检囊胚的非整倍体率为 (50-83.33%)。每个刺激周期有 个非整倍体囊胚。表 1 显示了每个参与中心的基线人口统计学和刺激周期结果。

Participants received a total of 493 euploid blastocysts in 461 embryo transfer cycles. All 105 women had failed to achieve implantation after receiving three euploid blastocysts, in two or three embryo transfer procedures. There were 105 first (102 SETs, 3 DETs), 105 second ( 98 SETs, 7 DETs), 105 third ( 99 SETs, 6 DETs), 100 fourth ( 90 SETs, 10 DETs), 33 fifth ( 31 SETs, 2 DETs), 9 sixth ( 9 SETs), 4 seventh (4 SETs), 2 eighth (2 SETs), and 2 ninth (2 SETs) embryo transfer cycles. One-hundred and ninety-four blastocysts were biopsied on the fifth, 265 on the sixth, and 34 on the seventh day postfertilization; 373 blastocysts were tested with NGS and 120 with qPCR.
在 461 个胚胎移植周期中，参与者共接受了 493 个优倍囊胚。所有 105 名妇女都在两次或三次胚胎移植手术中接受了三个优倍囊胚，但都未能成功着床。共有 105 个第一次胚胎移植周期（102 个 SET，3 个 DET）、105 个第二次胚胎移植周期（98 个 SET，7 个 DET）、105 个第三次胚胎移植周期（99 个 SET，6 个 DET）、100 个第四次胚胎移植周期（90 个 SET，10 个 DET）、33 个第五次胚胎移植周期（31 个 SET，2 个 DET）、9 个第六次胚胎移植周期（9 个 SET）、4 个第七次胚胎移植周期（4 个 SET）、2 个第八次胚胎移植周期（2 个 SET）和 2 个第九次胚胎移植周期（2 个 SET）。受精后第五天对 194 个囊胚进行了活检，第六天对 265 个囊胚进行了活检，第七天对 34 个囊胚进行了活检；对 373 个囊胚进行了 NGS 检测，对 120 个囊胚进行了 qPCR 检测。

Endometrial thickness was on the day of progesterone commencement (in programmed cycles), hCG injection (in modified natural cycles), or the day of ovulation (in natural cycles). ERA was used prior to 57 embryo transfer cycles, and in 34, ET day was changed by 1 day based on ERA result.
子宫内膜厚度是在开始使用黄体酮（在程序周期中）、注射 hCG（在修改后的自然周期中）或排卵日（在自然周期中）的当天测量的。在 57 个胚胎移植周期前使用了ERA，其中 34 个周期的胚胎移植日根据ERA结果改变了一天。

The outcomes of the fourth and fifth euploid blastocyst transfers were similar across participating centers and are shown in Table 2. Overall, the live birth rate achieved with the fourth euploid blastocyst was and with the fifth (after four prior failures) was . hCG positivity, clinical pregnancy, and live birth rates were also similar with the fourth and fifth euploid blastocysts as shown in Table 3.
表 2 显示了各参与中心第四和第五次极性囊胚移植的结果。如表 3 所示，第四个和第五个极性囊胚的 hCG 阳性率、临床妊娠率和活产率也相似。

Sensitivity analyses excluding blastocysts biopsied on Day 7 postfertilization (Supplementary Tables S2, S3, and S4), women with a BMI (Supplementary Tables S5, S6, and S7), cycles using non-ejaculate or donor sperm (Supplementary Tables S8, S9, and S10), double-embryo transfer cycles (Supplementary Tables S11, S12, and S13), and cycles in which the day of embryo transfer was modified due to ERA test result (Supplementary Tables S14, S15, and S16) yielded similar results.
敏感性分析排除了受精后第 7 天活检的囊胚（补充表 S2、S3 和 S4）、BMI 的女性（补充表 S5、S6 和 S7）、使用非射精或供精的周期（补充表 S8、S9 和 S10）、双胚胎移植周期（补充表 S11、S12 和 S13）以及因 ERA 测试而更改胚胎移植日的周期（补充表 S11、S12 和 S13）、S9和S10）、双胚胎移植周期（补充表S11、S12和S13）以及因ERA检测结果而更改胚胎移植日的周期（补充表S14、S15和S16），结果相似。

The endometrial preparation protocol was changed for 11 patients ( ), however, without a systematic trend, i.e., from a natural to programmed cycle in one, from a modified natural to a programmed cycle in six, from a programmed to a modified natural cycle in four. Thirty-four ( ) patients underwent the fourth and the fifth euploid blastocyst transfer with same protocol. The distribution of endometrial preparation protocols was similar for fourth and fifth transfers (Supplementary Table S17). The number of patients who underwent six, seven, eight, or nine euploid embryo transfers without achieving a pregnancy was too low for hypothesis testing (Supplementary Table S18).
11例患者（ ）的子宫内膜准备方案发生了改变，但没有系统性趋势，即1例从自然周期改为程序周期，6例从改良自然周期改为程序周期，4例从程序周期改为改良自然周期。34例（ ）患者以相同的方案进行了第四和第五次优胚移植。第四次和第五次移植的子宫内膜准备方案分布相似（补充表 S17）。进行六次、七次、八次或九次极胚胎移植而未妊娠的患者人数太少，无法进行假设检验（补充表 S18）。

There were 24 fourth and 7 fifth euploid single blastocyst transfers from RMA New Jersey, which underwent CCS with NGS
来自新泽西州 RMA 的 24 个第四代和 7 个第五代优倍单囊胚移植接受了 NGS 的 CCS 处理

Table 1. Demographics and stimulation cycle characteristics per participating center.
表 1.各参与中心的人口统计学特征和刺激周期特征。

Numbers are mean (standard deviation) or median (quartiles).
数字为平均值（标准差）或中位数（四分位数）。
AMH: anti-Müllerian hormone
AMH： 抗缪勒氏管激素

Table 2. Outcomes of the fourth and fifth euploid blastocyst transfers subsequent to three prior failed euploid blastocyst transfers.
表 2.之前三次极性囊胚移植失败后，第四次和第五次极性囊胚移植的结果。

Table 3. Comparison of outcomes between the fourth and fifth euploid blastocysts.
表 3.第四个和第五个优倍囊胚的结果比较。

RR: relative risk. RR：相对风险。
or qPCR as in the prior study reporting the outcomes of the first three euploid single blastocyst transfers (Pirtea et al., 2021). When these were tabulated together, the fourth euploid blastocyst fared as well as the first euploid blastocyst (RR for livebirth 0.84 with CI between 0.58 and . The number of fifth SETs was too few to make a comparison, yet three out of seven reached live birth with a rate of . Overall cumulative live birth rate with five euploid blastocyst transfers reached CI = 96.5-99.6%) (Fig. 1).
或 qPCR，如之前报告前三次单倍性囊胚移植结果的研究（Pirtea 等人，2021 年）。当把这些结果放在一起统计时，第四个极性囊胚的情况与第一个极性囊胚一样好（活产率为 0.84， CI 在 0.58 和 之间。第五次 SET 的数量太少，无法进行比较，但七次 SET 中有三次达到活产，活产率为 。五次优倍囊胚移植的总体累积活产率达到 CI = 96.5-99.6%（图 1）。

Our results demonstrate that, following the failure with three consecutive euploid blastocyst transfers, the transfer of a fourth and fifth euploid blastocyst provides similar live birth rates at and , respectively. Moreover, when we built up on the prior study, which reported live birth rates with the first three euploid blastocysts conducted at RMA New Jersey (Pirtea et al., 2021) and assessed subsequent euploid blastocyst transfers of the same women at the same institution, the fourth euploid blastocyst achieved similar live birth rate as the first one. While the number of women who underwent a fifth euploid blastocyst transfer at the same institution was too small to make a reliable comparison, the live birth rate of after four prior failures is remarkably high and overall provides a cumulative live birth rate of ( CI ).
我们的研究结果表明，在连续三次极性囊胚移植失败后，第四次和第五次极性囊胚移植的活产率相似，分别为 和 。此外，我们在之前研究的基础上，报告了在新泽西州 RMA 进行的前三次极性囊胚移植的活产率（Pirtea 等人，2021 年），并评估了在同一机构对同一妇女进行的后续极性囊胚移植，第四个极性囊胚移植的活产率与第一个相似。虽然在同一机构进行第五次极性囊胚移植的妇女人数太少，无法进行可靠的比较，但之前四次失败后的 活产率非常高，总体上提供了 （ CI ）的累积活产率。

The term RIF intends to define implantation failure due to one or more abnormalities that would systematically prevent embryo implantation beyond random events in the absence of a known pathology. Implantation failure can be due to embryonic or uterine factors. In a group of patients undergoing consecutive embryo transfers, if a proportion of them had definitive uterine factor abnormalities, some of the patients without these abnormalities would achieve implantation with each consecutive embryo transfer and would not undergo the next one and drop from its denominator, while patients with these uterine abnormalities would continuously fail and proceed with subsequent transfers and remain in the denominator. This would increase the proportion of women with these abnormalities in each subsequent transfer cycle, and implantation and live birth rates per embryo transfer would progressively fall as the group becomes enriched with them ((The writing group) for the participants to the 2022 Lugano RIF Workshop, 2023). Such an enrichment was not observed in a prior study that excluded the most common random event preventing implantation, i.e. chromosome aneuploidy, by including euploid blastocyst transfers (Pirtea et al., 2021). Their results suggested that the prevalence of true unexplained RIF would be after three euploid blastocyst transfers in women without other known reasons for implantation failure (Pirtea et al., 2021). Our observations provide further evidence against such an enrichment even after the transfer of the fourth and the fifth euploid blastocyst, suggesting that, in the absence of an obvious factor affecting implantation, the embryo is the main determinant of implantation success or failure and a cumulative live birth of can be achieved with five euploid blastocysts. In this case, the prevalence of true unexplained RIF would be even if live birth rate is taken into consideration as the outcome measure.
RIF 一词是指在没有已知病理的情况下，由于一种或多种异常情况导致胚胎植入失败，而这些异常情况会系统性地阻止胚胎植入。植入失败可由胚胎或子宫因素造成。在一组接受连续胚胎移植的患者中，如果其中一部分患者有明确的子宫因素异常，那么一些没有这些异常的患者将在每次连续胚胎移植中实现着床，不再进行下一次胚胎移植，并从分母中消失，而有这些子宫异常的患者将持续失败，继续进行后续移植，并留在分母中。这将增加每个后续移植周期中患有这些异常的妇女的比例，而每次胚胎移植的植入率和活产率将随着该组妇女的增多而逐渐下降（2022 年卢加诺 RIF 研讨班参与者的写作组，2023 年）。在之前的一项研究中，通过将染色体非整倍体囊胚移植包括在内，排除了最常见的阻碍植入的随机事件，即染色体非整倍体，但并未观察到这种富集（Pirtea 等人，2021 年）。他们的研究结果表明，在没有其他已知植入失败原因的妇女中，经过三次极性囊胚移植后，真正的不明原因 RIF 的发生率将 （Pirtea 等人，2021 年）。 我们的观察进一步证明，即使在移植第四个和第五个优倍囊胚后，也不会出现这种富集现象，这表明，在没有明显影响植入的因素时，胚胎是决定植入成败的主要因素，五个优倍囊胚可实现 的累积活产率。在这种情况下，即使将活产率作为结果衡量标准，真正原因不明的 RIF 的发生率也将达到 。

Figure 1. Cumulative live birth rate after subsequent euploid blastocyst transfer. Red line shows the cumulative live birth. Blue dotted lines show upper and lower bounds of the CI.
图 1.随后的优倍囊胚移植后的累积活产率。红线表示累积活产率。蓝色虚线表示 CI 的上限和下限。

While the retrospective design is a limitation of the current study, the difficulty of conducting a prospective study should be acknowledged. Based on the prior study by Pirtea et al. (2021), it is reasonable to assume that more than of women will achieve a live birth with the first three euploid blastocysts in the absence of another known reason for failure. Given the inevitable dropouts from further treatment due to multiple reasons, a minority of eligible patients would continue for the fourth euploid transfer. This is supported by the fact that only of the 123987 women starting treatment in 26 clinics over 10 years were found to be eligible for the current study, when we excluded women who had undergone an embryo transfer in other clinics or with unscreened embryos in the participating clinics or had any of the known factors associated with implantation failure other than randomly occurring embryo aneuploidy in order to limit heterogeneity. Whether patients who continued with a subsequent transfer are systematically different from those who dropped out is unknown, and women with high ovarian reserve and/or financial means might have been more likely to pursue further transfers. There may have been differences between clinical protocols, embryology, and genetic laboratory practices between the participating clinics, but transfer outcomes were not significantly different (Table 2). To ensure the largest possible sample size to provide more reliable estimates, we opted to include Day 7 blastocysts, women with a BMI over , patients whose transfer date was modified based on the ERA, despite the former two having been associated with lower implantation rates (Cimadomo et al., 2023) and the latter being considered non beneficial (Cozzolino et al., 2020, 2022; Doyle et al., 2022). Such cycles were a minority, and sensitivity analyses excluding these cycles yielded consistent results with the overall analysis. While nonobstructive azoospermia was an exclusion criterion, we included few cases where donor sperm or testicular sperm was used due to other reasons. Sensitivity analysis limited to cases with autologous ejaculate sperm also provided consistent results. Since the unit of analysis was one euploid blastocyst transferred, not the number of transfer cycles, some patients who received doubleembryo transfers were included in the analyses if both embryos implanted or neither implanted to allow tracing of each blastocyst. A sensitivity analysis limited to women who only underwent SETs also yielded similar results with the overall findings. The consistency between all the sensitivity analyses and the overall analysis provide assurance in the reliability of our estimates. The confinement of the study sample with women receiving the fourth euploid blastocyst and not reporting the cumulative results of the first three euploid blastocyst transfers in the participating centers may be regarded another limitation, but the idea was to build up on the former study by Pirtea et al. (2021). While we cannot directly compare the outcomes of the first three euploid blastocysts with the fourth and fifth for the entire study population, similar implantation and live birth rates achieved by the first and the fourth euploid blastocyst among the women who were treated at RMA New Jersey and were also included in the study by Pirtea et al. (2021) provide some assurance for the estimates. The small number of women who underwent a fifth euploid blastocyst transfer in the same center prevents a robust estimate, but live birth rate observed in seven women can be considered supportive of our conclusions.
虽然回顾性设计是当前研究的一个局限，但也应承认进行前瞻性研究的难度。根据 Pirtea 等人（2021 年）之前的研究，如果没有其他已知的失败原因，我们可以合理地假设，超过 的女性会通过前三个极性囊胚获得活产。考虑到由于多种原因不可避免地要放弃进一步治疗，少数符合条件的患者会继续进行第四次卵裂囊胚移植。为了限制异质性，我们排除了在其他诊所进行过胚胎移植的妇女，或在参与研究的诊所中胚胎未经筛查的妇女，或除了随机出现的胚胎非整倍体外，有任何与植入失败相关的已知因素的妇女，结果发现 10 年来在 26 家诊所开始治疗的 123987 名妇女中，只有 符合当前研究的条件，这一事实也证明了这一点。继续进行后续移植的患者与放弃移植的患者是否存在系统性差异尚不清楚，卵巢储备功能强和/或经济条件好的女性可能更倾向于继续移植。参与研究的诊所在临床方案、胚胎学和基因实验室实践方面可能存在差异，但移植结果并无显著不同（表 2）。为了确保尽可能大的样本量以提供更可靠的估计值，我们选择将第 7 天囊胚、BMI 超过 的女性、根据 ERA 更改移植日期的患者包括在内，尽管前两者与较低的植入率有关（Cimadomo 等人，2009 年；Michael 等人，2009 年）。2023 年），后者被认为是无益的（Cozzolino 等人，2020 年，2022 年；Doyle 等人，2022 年）。此类周期只占少数，排除这些周期的敏感性分析结果与总体分析结果一致。虽然非梗阻性无精子症是一项排除标准，但我们纳入的因其他原因而使用捐献精子或睾丸精子的病例很少。仅限于使用自体射精精子的敏感性分析也得出了一致的结果。由于分析单位是移植的一个单倍体囊胚，而不是移植周期的次数，因此，如果两个胚胎都着床或两个胚胎都不着床，一些接受双胚胎移植的患者也被纳入分析范围，以便对每个囊胚进行追踪。一项仅限于只接受 SET 的妇女的敏感性分析也得出了与总体结果相似的结果。所有敏感性分析与总体分析的一致性保证了我们估计结果的可靠性。研究样本仅限于接受第四个极性囊胚移植的妇女，而没有报告参与中心前三个极性囊胚移植的累积结果，这可能被认为是另一个局限性，但我们的想法是在 Pirtea 等人（2021 年）前一项研究的基础上更进一步。虽然我们不能直接比较整个研究人群中前三个极性囊胚与第四、第五个极性囊胚的结果，但在新泽西州 RMA 接受治疗并被纳入 Pirtea 等人（2021 年）研究的妇女中，第一个和第四个极性囊胚的植入率和活产率相似，这为估算结果提供了一些保证。 由于在同一中心进行第五次囊胚移植的妇女人数较少，因此无法做出可靠的估计，但在七名妇女中观察到的 活产率可被视为支持我们的结论。
It should be noted that the current study is not about the effectiveness of PGT-A, rather we use euploid blastocyst transfers as a model to study the prevalence and etiology of RIF. In this context, PGT-A serves to exclude blastocysts with full chromosome aneuploidies, which have negligible potential for clinical pregnancy and live birth, to decrease the noise in the data (Tiegs et al., 2021). On the other hand, euploidy alone is not the only determinant of an embryo's potential for live birth (Cimadomo et al., 2023). First and foremost, even though current embryo testing strategies enable detection of segmental aneuploidies, the resolution of the commonly used tests may vary and they cannot detect gene mutations that may prevent implantation even with
需要注意的是，当前的研究并不是关于 PGT-A 的有效性，而是以单倍体囊胚移植为模型，研究 RIF 的发生率和病因。在这种情况下，PGT-A 的作用是排除具有全染色体非整倍体的囊胚，以减少数据中的噪声（Tiegs 等人，2021 年）。另一方面，非整倍体并非决定胚胎活产潜力的唯一因素（Cimadomo 等人，2023 年）。首先，尽管目前的胚胎检测策略可以检测节段性非整倍体，但常用检测方法的分辨率可能会有所不同，而且它们无法检测出基因突变，而这些突变可能会阻碍胚胎植入，即使是在以下情况下
a normal chromosomal copy number. There are other embryonic factors that determine an euploid blastocyst's potential for live birth, e.g. morphological quality, developmental rate, as well as those that are yet to be determined (Cimadomo et al., 2023).
染色体拷贝数正常。还有其他胚胎因素决定着优倍囊胚的活产潜能，如形态质量、发育速度，以及那些尚未确定的因素（Cimadomo et al.）

Overall, our observation of similar implantation and live birth rates with the fourth and fifth euploid blastocyst transfers lend further credit to the notion that unexplained RIF is most often due to an embryonic factor, while an endometrial factor cannot be completely ruled out. Thus, each new embryo represents another opportunity for live birth and cumulative live birth can reach up to after five euploid blastocyst transfers.
总之，我们观察到第四和第五次极性囊胚移植的植入率和活产率相似，这进一步证实了不明原因的 RIF 最常见的原因是胚胎因素，而子宫内膜因素不能完全排除。因此，每一个新胚胎都代表着另一个活产机会，在五次极性囊胚移植后，累积活产可达 。

Given that obvious maternal reasons for possible implantation failure, such as communicating hydrosalpinges, intracavitary pathology, adenomyosis, and obesity, can be identified even prior to the first transfer cycle or whenever they develop during the course of treatment, and stimulation cycle and embryo-related factors are already observed in the laboratory during each cycle, the term RIF would have limited use in the clinical setting. When proper preconception evaluation, including thyroid function test, is completed and uterine anatomy is reliably assessed, perhaps parental karyotyping is the only remaining assessment to be done in the case of unexplained failures. The recent ESHRE Good Practice Recommendations on RIF advise against investigations for microbiome profiling, uterine or peripheral natural killer cell testing, T lymphocyte assessment, cytokine levels, HLA-C compatibility, mitochondrial DNA testing, sperm DNA fragmentation or FISH analysis as well as against interventions such as endometrial injury, intravenous immunoglobulin, intralipid, peripheric blood mononuclear cells, platelet-rich plasma infusions, human chorionic gonadotropin, or low-molecular-weight heparin injections in routine clinical practice (ESHRE Working Group on Recurrent Implantation Failure, 2023). Honest and compassionate counseling of the patient/couple about possible etiology and future prognosis, including hearing, acknowledging, and respecting their concerns and feelings, avoiding unnecessary tests and interventions of unproven value and offering a new embryo transfer could preserve their motivation and funds, prevent dropouts, and help them reach their reproductive goals. Preplanning for the possibility of requiring multiple embryo transfers can help patients maintain hope after a single failed transfers and can reduce the chance of treatment discontinuation (Faustini et al., 2023; Harrison et al., 2021, 2023). When the couple already has a frozen embryo available for transfer, the decision to procced can be easier, but whether starting a new stimulation cycle is worthwhile would be a subjective decision that depends on the probability of achieving a euploid blastocyst, which is determined by female age and ovarian reserve status (Reig et al., 2023). When treatment costs are not covered by third parties, financial constraints also play a role in discontinuing treatment.
鉴于可能导致植入失败的明显母体原因，如交流性鞘膜积液、腔内病变、子宫腺肌症和肥胖，甚至在第一个移植周期之前或在治疗过程中出现时就可以确定，而且在每个周期中实验室都会观察到刺激周期和胚胎相关因素，因此 RIF 一词在临床环境中的用途有限。如果完成了适当的孕前评估（包括甲状腺功能测试），并对子宫解剖结构进行了可靠的评估，那么在出现不明原因的失败时，父母核型分析也许是唯一需要进行的评估。最近 ESHRE 关于 RIF 的良好操作建议建议不要进行微生物组分析、子宫或外周自然杀伤细胞检测、T 淋巴细胞评估、细胞因子水平、HLA-C 相容性、线粒体 DNA 检测、精子 DNA 片段或 FISH 分析等检查，也不要进行子宫内膜损伤等干预、静脉注射免疫球蛋白、注射脂质体、外周血单核细胞、输注富血小板血浆、人绒毛膜促性腺激素或在常规临床实践中注射低分子量肝素（ESHRE 复发性植入失败工作组，2023 年）。就可能的病因和未来的预后向患者/夫妇提供真诚和富有同情心的咨询，包括倾听、承认和尊重他们的担忧和感受，避免不必要的检查和价值未经证实的干预措施，并提供新的胚胎移植，这可以保持他们的积极性和资金，防止辍学，并帮助他们实现生殖目标。 预先计划可能需要进行多次胚胎移植，可帮助患者在一次移植失败后保持希望，并可降低治疗中断的几率（Faustini 等人，2023 年；Harrison 等人，2021 年、2023 年）。当夫妇双方已经有一个可用于移植的冷冻胚胎时，做出移植的决定会更容易，但是否值得开始一个新的刺激周期将是一个主观的决定，这取决于获得高倍囊胚的概率，而高倍囊胚是由女性年龄和卵巢储备状态决定的（Reig 等，2023 年）。当第三方不承担治疗费用时，经济上的限制也会对终止治疗产生影响。

In conclusion, our results suggest that once obvious etiology for implantation failure is excluded, in patients who received three prior euploid blastocysts without implantation, the fourth and the fifth euploid blastocysts achieve similar live birth rates. Moreover, among women who were treated at RMA New Jersey, where data from the first three transfers were available, the fourth euploid blastocyst achieved a live birth rate as high as the first one. These observations are against a perceivable enrichment of a true RIF population until five consecutive euploid blastocyst transfers, thereby suggesting the prevalence of such an entity would be . It should also be noted that, whether the sixth euploid blastocyst also achieves a similar implantation/live birth rate remains unknown, and further studies will be needed to determine the outcomes of sixth and subsequent transfers.
总之，我们的研究结果表明，一旦排除了植入失败的明显病因，在之前接受过三次优倍囊胚但未植入的患者中，第四次和第五次优倍囊胚的活产率相似。此外，在新泽西州生殖医学中心接受治疗的妇女中，前三次移植的数据可用，第四个极性囊胚的活产率与第一个囊胚一样高。这些观察结果表明，在连续五次优倍囊胚移植之前，真正的 RIF 群体是不会富集的，从而表明这种实体的流行率为 。还应该注意的是，第六次优倍囊胚是否也能达到类似的植入率/活产率仍是未知数，需要进一步研究以确定第六次及以后移植的结果。
Our results in combination with others support encouraging patients with additional attempts with own gametes, whenever clinically reasonable (Cimadomo et al., 2021).
我们的研究结果与其他研究结果相结合，支持鼓励患者在临床合理的情况下使用自己的配子进行更多尝试（Cimadomo 等人，2021 年）。

Supplementary data are available at Human Reproduction online.
补充数据可在人类生殖在线查阅。

Data are not available for public.
数据不公开。

P.G.: data collection and drafting the manuscript. B.A.: study design, data collection and analysis, and drafting the manuscript. A.A.: data collection and critical review of the manuscript. D.C.: data collection and critical review of the manuscript. A.V.: data collection and critical review of the manuscript. H.F.: critical review of the manuscript. F.U.: critical review of the manuscript. J. G.-V.: conception of the study idea, study design, and critical review of the manuscript. E.S.: conception of the study idea, study design, and critical review of the manuscript.
P.G.：数据收集和手稿起草。B.A.：研究设计、数据收集和分析以及手稿起草。A.A.：数据收集和审稿。D.C.：数据收集和审稿。A.V.：数据收集和审稿。H.F.：审稿。F.U.：审稿。J. G.-V.：研究构思、研究设计和稿件审阅。E.S.：研究构思、研究设计和审稿。

No funding has been received for this study.
本研究未获得任何资助。

None of the authors have any conflict of interest associated with the present work.
所有作者均与本研究工作无任何利益冲突。

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(C) The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com
(C) 作者 2024 年。由牛津大学出版社代表欧洲人类生殖与胚胎协会出版。保留所有权利。如需授权，请发送电子邮件至journals.permissions@oup.com
Human Reproduction, 2024, 39, 974-980
《人类生殖》，2024 年，39 期，974-980 页
https://doi.org/10.1093/humrep/deae040
Original Article 原文