Munoz E, Taboas E, Alvarez M, Gil E, Perez A, Portela S, Martinez-Chapela M, Saucedo E, Garrido N
Reproductive Medicine, IVIRMA Global Research Alliance, IVIRMA Vigo, Vigo, Spain.
Department of Gynecology and Obstetrics, University of Cauca, Popayan, Colombia.
Hum Reprod. 2024 May 22. doi: 10.1093/humrep/deae106.
Does the use of preimplantation genetic testing for aneuploidies (PGT-A), personalized embryo transfer with endometrial receptivity assay (pET-ERA), or the use of donated oocytes modify the incidence of biochemical pregnancy loss (BPL) in frozen single embryo transfer (FSET)?
Following FSET, BPL incidence does not differ between own and donated oocytes, and the use of PGT-A with euploid embryo transfer or pET-ERA results in a similar incidence of BPL compared to cycles without embryo or endometrial analysis.
BPL occurs frequently after IVF, and many factors have been associated with its incidence. The etiology of BPL is not well known, but the most probable cause seems to be either a low-quality embryo or impaired endometrial maintenance. The impact of techniques diagnosing embryonic ploidy or endometrial receptivity on BPL incidence and the BPL incidence between own and donated oocytes have not been analyzed.
STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study analyzing the incidence of BPL over 3741 cycles of FSET derived from own (2399 cycles) and donated (1342 cycles) oocytes between January 2013 and January 2022 in 1736 of which PGT-A, pET-ERA, or both were applied.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We defined BPL as a pregnancy diagnosed only by serum β-hCG > 10 UI/l followed by a decrease that does not result in a clinical pregnancy. Clinical pregnancy was defined as the presence of gestational sac on transvaginal ultrasound. We compared BPL rates among patients undergoing 2399 FSETs from own oocytes, which comprised 1310 cycles of embryos analyzed by PGT-A, 950 cycles of untested embryos, 30 cycles of untested embryos with pET-ERA, and a subgroup of 109 cycles analyzed by both PGT-A and pET-ERA. We also included a total of 1342 FSET cycles from donated oocytes comprising 132, 1055, 140, and 15 cycles in the same groups, respectively.
In FSET from own oocytes, the overall BPL rate per embryo transfer was 8.2% (95% CI [7.09-9.33]). In untested embryo transfers, the BPL rate was 7.5% [5.91-9.37]. In the PGT-A group, the BPL rate was 8.8% [7.32-10.47]. In the pET-ERA group, the rate was 6.7% [0.82-22.07]. In the PGT-A+ERA group, the rate was 6.5% [2.65-12.90]. No significant differences were found (P = 0.626). A multivariate analysis considering clinically meaningful variables that were significantly different among groups, taking the untested embryos/endometrium group as a reference, showed comparable incidences among groups. For PGT-A, the adjusted odds ratio (AdjOR) was 1.154 [0.768-1.735] (P = 0.49) and for PGT-A+ERA 0.885 [0.330-2.375] (P = 0.808). Because of a low number of registered cases in the pET-ERA group, and to prevent statistical errors and convergence issues, this group was excluded from further analysis. In FSET of donated oocytes, the overall BPL rate per embryo transfer was 4.9% [3.76-6.14]. In the PGT-A group, the BPL rate was 6.8% [3.16-12.55]. In the pET-ERA group, the rate was 5.0% [2.03-10.03]. In untested embryo transfers, the rate was 4.7% [3.46-6.10]. No cases occurred in the PGT-A+ERA group, and no significant differences were found (P = 0.578). The multivariate analysis showed comparable incidences among groups. For PGT-A the AdjOR was 1.669 [0.702-3.972] (P = 0.247) and for pET-ERA 1.189 [0.433-3.265] (P = 0.737). The PGT-A+ERA group was eliminated from the model to prevent statistical errors and convergence issues because no BPL cases were registered in this group. In the multivariate analysis, when the sources of oocytes were compared, own versus donated, no significant differences were found in the incidence of BPL.
LIMITATIONS, REASONS FOR CAUTION: This was a retrospective cohort study with potential biases. In addition, we were unable to control differences among groups due to modifications in medical or laboratory protocols during this long time period, which may modify the relationships being addressed. Factors previously associated with BPL, such as immunological conditions other than thyroid autoimmunity, were not considered in this study. Limited sample sizes of some groups may limit the statistical power for finding differences that can be present in the general population.
BPL may be related to a mechanism not associated with the chromosomal constitution of the embryo or the transcriptome of the endometrium. More studies are needed to explore the factors associated with this reproductive issue.
STUDY FUNDING/COMPETING INTEREST(S): No specific funding was available for this study. None of the authors have a conflict of interest to declare with regard to this study.
This trial was registered at clinicaltrials.gov (NCT04549909).
使用非整倍体植入前基因检测（PGT-A）、结合子宫内膜容受性检测的个性化胚胎移植（pET-ERA）或使用捐赠卵母细胞是否会改变冷冻单胚胎移植（FSET）中生化妊娠丢失（BPL）的发生率？
FSET后，自身卵母细胞和捐赠卵母细胞的BPL发生率无差异，与未进行胚胎或子宫内膜分析的周期相比，使用PGT-A进行整倍体胚胎移植或pET-ERA导致的BPL发生率相似。
BPL在体外受精后频繁发生，许多因素与其发生率相关。BPL的病因尚不清楚，但最可能的原因似乎是胚胎质量低或子宫内膜维持受损。尚未分析诊断胚胎倍性或子宫内膜容受性的技术对BPL发生率的影响以及自身卵母细胞和捐赠卵母细胞之间的BPL发生率。
研究设计、规模、持续时间：这是一项回顾性队列研究，分析了2013年1月至2022年1月期间1736例FSET的3741个周期中BPL的发生率，这些周期来自自身（2399个周期）和捐赠（1342个周期）的卵母细胞，其中1736例应用了PGT-A、pET-ERA或两者。
参与者/材料、设置、方法：我们将BPL定义为仅通过血清β-hCG>10 UI/l诊断的妊娠，随后下降且未导致临床妊娠。临床妊娠定义为经阴道超声检查发现妊娠囊。我们比较了接受2399次自身卵母细胞FSET的患者中的BPL率，其中包括1310个通过PGT-A分析胚胎的周期、950个未检测胚胎的周期、30个未检测胚胎且进行pET-ERA的周期，以及109个同时通过PGT-A和pET-ERA分析的亚组周期。我们还纳入了总共1342个来自捐赠卵母细胞的FSET周期，分别在相同组中包括132、1055、140和15个周期。
在自身卵母细胞的FSET中，每次胚胎移植的总体BPL率为8.2%（95%CI[7.09-9.33]）。在未检测胚胎移植中，BPL率为7.5%[5.91-9.37]。在PGT-A组中，BPL率为8.8%[7.32-10.47]。在pET-ERA组中，该率为6.7%[0.82-22.07]。在PGT-A+ERA组中，该率为6.5%[2.65-12.90]。未发现显著差异（P=0.626）。多变量分析考虑了组间有显著差异的临床有意义变量，以未检测胚胎/子宫内膜组作为参考，显示各组发生率相当。对于PGT-A，调整后的优势比（AdjOR）为1.154[0.768-1.735]（P=0.49），对于PGT-A+ERA为0.885[0.330-2.375]（P=0.808）。由于pET-ERA组登记病例数较少，为防止统计误差和收敛问题，该组被排除在进一步分析之外。在捐赠卵母细胞的FSET中，每次胚胎移植的总体BPL率为4.9%[3.76-6.14]。在PGT-A组中，BPL率为6.8%[3.16-12.55]。在pET-ERA组中，该率为5.0%[2.03-10.03]。在未检测胚胎移植中，该率为4.7%[3.46-6.10]。PGT-A+ERA组未发生病例，未发现显著差异（P=0.578）。多变量分析显示各组发生率相当。对于PGT-A，AdjOR为1.669[0.702-3.972]（P=0.247），对于pET-ERA为1.189[0.433-3.265]（P=0.737）。由于该组未登记BPL病例，为防止统计误差和收敛问题，PGT-A+ERA组被排除在模型之外。在多变量分析中，比较卵母细胞来源时，自身与捐赠的卵母细胞，BPL发生率未发现显著差异。
局限性、注意事项：这是一项存在潜在偏倚的回顾性队列研究。此外，由于在此长时间内医疗或实验室方案的修改，我们无法控制组间差异，这可能会改变所探讨的关系。本研究未考虑先前与BPL相关的因素，如除甲状腺自身免疫外的免疫状况。一些组的样本量有限可能会限制发现一般人群中可能存在差异的统计效力。
BPL可能与一种与胚胎染色体构成或子宫内膜转录组无关的机制有关。需要更多研究来探索与这个生殖问题相关的因素。
研究资金/竞争利益：本研究没有特定资金。在本研究方面，没有作者存在利益冲突需要声明。
本试验在clinicaltrials.gov注册（NCT04549909）。
