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Chin Med J (Engl)
Chin Med J (Engl)
CM9
Chinese Medical Journal
0366-6999
2542-5641
Lippincott Williams & Wilkins Hagerstown, MD

CMJ-2023-1039
10.1097/CM9.0000000000003041
00016
3
Correspondence
Preimplantation genetic testing for aneuploidy could not improve cumulative live birth rate among 1003 couples with recurrent pregnancy loss
Zhao Shaotong 1 2 3 4 5 6
Lyu Chunzi 1 2 3 4 5 6
Liu Yingbo 1 2 3 4 5 6
Wang Xiyao 1 2 3 4 5 6
Zhang Zhaowen 1 2 3 4 5 6
Lv Hong 1 2 3 4 5 6
Ni Tianxiang 1 2 3 4 5 6
Yan Junhao 1 2 3 4 5 6
Yin Yanjie
1 Center for Reproductive Medicine, Shandong University, Jinan, Shandong 250012, China
2 Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong 250012, China
3 Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China
4 Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong 250012, China
5 Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong 250012, China
6 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China
Correspondence to: Tianxiang Ni, Center for Reproductive Medicine, Shandong University, Jinan, Shandong 250012, China E-Mail: tianxiangni907@163.com;
Junhao Yan, Center for Reproductive Medicine, Shandong University, Jinan, Shandong 250012, China E-Mail: yyy306@126.com
17 4 2024
05 9 2024
137 17 21342136
30 10 2023
Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

OPEN-ACCESSTRUE
SDCT
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pmcTo the Editor: Recurrent pregnancy loss (RPL) is defined as two or more consecutive spontaneous pregnancy losses before 24 weeks of gestation; it affects 1–2% of couples.[1] Some causes of RPL are uterine anatomical abnormalities, abnormal chromosomes in parents or embryos, antiphospholipid syndrome, and certain autoimmune disorders.[2] However, the etiology of 40–50% of RPL couples remains unclear and is defined as unexplained RPL (uRPL). Approximately 41% of pregnancy losses can be attributed to fetal aneuploidy,[3] common in couples with advanced maternal age (AMA). Although Preimplantation Genetic Testing for Aneuploidy (PGT-A) has been considered a potential technique to improve pregnancy outcomes, currently there is no consensus on its application. A recent retrospective SART-CORS study indicated that PGT-A increases the rate of live births and clinical pregnancies for frozen embryo transfer (FET) in RPL couples.[4] However, a multicenter, prospective study did not find any benefits of PGT-A in improving the live birth rate per patient or reducing the rate of miscarriage in RPL couples.[5] Nonetheless, these studies included only a single embryo transfer (ET) cycle or assessed the efficacy of PGT-A in terms of live birth rate per transfer, which does not have sufficient clinical significance.

To determine whether PGT-A impact the cumulative live birth rate after in vitro fertilization (IVF) in women with RPL, we included 1003 uRPL couples with ≥21-year-old females from January 2015–2022 at the Reproductive Center of Shandong University (Jinan, Shandong, China). Patients provided informed consent and the study was approved by the Reproductive Center of Shandong University’s Ethics Committee ([2021] IRB No. [140]).

The sample size met design requirement. uRPL was defined as two or more consecutive miscarriages with no distinct causes. The exclusion criteria for patients were parental chromosomal abnormalities, uterine anatomical abnormalities, endocrine dysfunction, autoimmune disorders, thrombosis, and infection. The uRPL couples were divided into PGT-A and conventional IVF (control) groups according to whether they underwent PGT-A. The cumulative pregnancy outcomes after a single oocyte retrieval were followed up and analyzed. The primary outcome was cumulative live birth rate following a single oocyte retrieval. The other pregnancy outcomes included cumulative rates of clinical pregnancy, and pregnancy loss after all ET cycles following a single oocyte retrieval, rates of clinical pregnancy and pregnancy loss after the first ET. These pregnancy outcomes were defined as described previously.[6,7]

Ovarian stimulation, PGT-A, endometrial preparation luteal-phase support and statistical analysis were described in detail in the Supplementary Methods, http://links.lww.com/CM9/B923.

A total of 1003 couples with a history of uRPL were included in this study. Among them, 799 underwent PGT-A (392 in <35 years subgroup, 407 in ≥35 years subgroup), while 204 were not treated with PGT-A and comprised the control group (142 in <35 years subgroup, 62 in ≥35 years subgroup). The baseline characteristics of RPL couples were shown in Supplementary Tables 1 and 2, http://links.lww.com/CM9/B923. The majority of them were comparable between the PGT-A group and the control group among the younger and older women. Moreover, we summarized the oocyte retrieval and embryo development protocols [Supplementary Tables 3 and 4, http://links.lww.com/CM9/B923].

We found that the cumulative rates of live birth (53.32% [209/392] vs. 61.97% [88/142], χ2 = 3.164, P = 0.077) and clinical pregnancy loss (19.64% [55/280] vs. 18.42% [21/114], χ2 = 0.078, P = 0.888) were similar between the two groups among women aged <35 years [Table 1]. Also, the cumulative live birth rate in women ≥35-year-old was similar between the two groups (28.75% [117/407] vs. 30.65% [19/62], χ2 = 0.094, P = 0.765). However, couples in the PGT-A group showed significantly lower cumulative rates of biochemical pregnancy loss (10.13% [16/158] vs. 32.56% [14/43], χ2 = 13.394, P = 0.001) and clinical pregnancy loss (20.89% [33/158] vs. 37.21% [16/43], χ2 = 4.885, P = 0.030) than those in the control group [Table 1].

Table 1 Comparison of cumulative pregnancy outcomes between PGT-A and non-PGT-A patients with RPL undergoing FET.

Characteristics	RPL	Statistic values	P-value	
PGT-A	Non-PGT-A	
<35 years					
No. of cases, n	392	142			
Cycles of ET, n	450	221			
Live births/women, n/N (%)	209/392 (53.32)	88/142 (61.97)	3.164	0.077	
Biochemical pregnancies/women, n/N (%)	280/392 (71.43)	114/142 (80.28)	4.224	0.045*	
Clinical pregnancies/women, n/N (%)	253/392 (64.54)	106/142 (74.65)	4.833	0.029*	
Ongoing pregnancies/women, n/N (%)	218/392 (55.61)	94/142 (66.20)	4.808	0.029*	
Pregnancy loss/biochemical pregnancies, n/N (%)					
Biochemical	41/280 (14.64)	18/114 (15.79)	0.084	0.876	
Clinical	55/280 (19.64)	21/114 (18.42)	0.078	0.888	
First	42/280 (15.00)	16/114 (14.04)	0.060	0.876	
Second	14/280 (5.00)	5/114 (4.39)	0.067	1.000	
≥35 years					
No. of cases, n	407	62			
Cycles of ET, n	260	99			
Live births/women, n/N (%)	117/407 (28.75)	19/62 (30.65)	0.094	0.765	
Biochemical pregnancies/women, n/N (%)	158/407 (38.82)	43/62 (69.35)	20.483	<0.001*	
Clinical pregnancies/women, n/N (%)	148/407 (36.36)	31/62 (50.00)	4.239	0.049*	
Ongoing pregnancies/women, n/N (%)	127/407 (31.20)	20/62 (32.26)	0.028	0.884	
Pregnancy loss/biochemical pregnancies, n/N (%)					
Biochemical	16/158 (10.13)	14/43 (32.56)	13.394	0.001*	
Clinical	33/158 (20.89)	16/43 (37.21)	4.885	0.030*	
First	24/158 (15.19)	11/43 (25.58)	2.538	0.118	
Second	9/158 (5.70)	4/43 (9.30)	–	0.482	
*P <0.05 represents significance difference. ET: Embryo transfer; FET: Frozen embryo transfer; PGT-A: Pre-implantation genetic testing for aneuploidy; RPL: Recurrent pregnancy loss; –: No statistic value with Fisher’s exact test.

We also analyzed pregnancy outcomes after the first ET. The results did not differ significantly between the two groups in younger women. Interestingly, a lower biochemical pregnancy rate (33.66% [137/407] vs. 50.00% [31/62], χ2 = 6.248, P = 0.015) and a higher biochemical pregnancy loss rate (8.03% [11/137] vs. 35.48% [11/31], P <0.001) were detected in the older patients of the PGT-A group [Supplementary Table 5, http://links.lww.com/CM9/B923].

In addition, case-control matching for baseline characteristics, results of oocyte retrieval and embryo culture of PGT-A and non-PGT-A patients was performed [Supplementary Tables 6–9, http://links.lww.com/CM9/B923]. After case-control matching, the pregnancy outcomes, especially the rates of live birth and clinical pregnancy loss were in agreement with those of the subgroup analyses mentioned above [Supplementary Tables 10 and 11, http://links.lww.com/CM9/B923].

Then we applied logistic regression analysis to adjust potential confounders, including age, body mass index (BMI), AMH, follicle-stimulating hormone (FSH), ovarian stimulation protocols, endometrial thickness on hCG trigger day, prior spontaneous miscarriages, and antral follicle count. Consistent with the results of stratification analyses, no association was found by the logistic regression analysis between PGT-A treatment with cumulative live birth rate and clinical pregnancy loss rate among women aged <35 years [Supplementary Table 12, http://links.lww.com/CM9/B923]. Conversely, in women aged ≥35 years, PGT-A treatment was correlated with decreased cumulative clinical pregnancy loss rate (OR = 0.408, 95% CI: 0.173–0.966, P <0.05; Supplementary Table 13, http://links.lww.com/CM9/B923).

This study included 1003 uRPL couples with FETs following a single oocyte retrieval. The results showed no evidence of favorable effects of PGT-A treatment on improving the cumulative live birth rate in uRPL couples regardless of maternal age (<35 years or ≥35 years). However, the risk of clinical pregnancy loss was lower after PGT-A among women with AMA (≥35 year-old) than following the conventional method. Our results showed that RPL couples had a comparable cumulative live birth rate after PGT-A. A retrospective cohort study of fertile RPL patients revealed a similar live birth rate after intent-to-treat analysis between couples with PGT-A and those under expectant management alone.[8] The ineffectiveness of PGT-A could be mainly ascribed to the high mosaicism proportion and inevitable false-positive results from trophectoderm biopsies, which leads to substantial embryo waste. Euploid embryos after PGT-A could not be obtained from about 15.8% of women aged <35 years, while the proportion was 40.5% in women aged ≥35 years in our study. In addition, trophectoderm biopsy could be a detrimental factor for embryo development and implantation potential, which was considered to be another important reason. Nonetheless, PGT-A could be beneficial in reducing the risk of pregnancy loss among AMA women rather than young women. This result could be ascribed to increased embryo aneuploidy due to AMA. Nonetheless, the decreased pregnancy loss rate did not translate into improved live birth rate because of the high proportion of no euploid embryo for transfer.

The strengths of the present study are as follows. First, we performed stratified analysis according to female age and selected appropriate outcome measures, such as cumulative rates of live birth and clinical pregnancy loss following a single oocyte retrieval, which were clinically relevant. We also implemented stringent inclusion and exclusion criteria; only RPL couples undergoing PGT-A or conventional IVF for the first time were enrolled to eliminate the confounding effects. The limitations of this study were its single-center design and retrospective nature. Hence, all variables could not be controlled.

In summary, there is no evidence that PGT-A improves the cumulative live birth rate in RPL couples regardless of maternal age, which could be because a large number of viable embryos were not utilized. However, PGT-A may be a favorable approach to reduce the risk of pregnancy loss in RPL women aged ≥35 years.

Acknowledgments

The authors would like to express their gratitude to Jingfu Yang for his invaluable assistance during data collection. The authors are appreciative of every member from the IVF and PGT laboratory for their extraordinary contributions to laboratory procedures.

Funding

This work was supported by grants from the National Key Research and Development Program (No. 2021YFC2700604), General Program of National Natural Science Foundation of China (No. 82171648), Shandong Provincial Key Research and Development Program (No.2021LCZX02), Youth Program of National Natural Science Foundation of China (No.82101752), Youth Program of Shandong Provincial Natural Science Foundation of China (No. ZR2021QH075), Taishan Scholars Program for Young Experts of Shandong Province (No. tsqn202312388), the Shandong Provincial Medical and Health Science and Technology Development Program (No.2019WS171) and the Shandong Provincial Natural Science Foundation (No. ZR2020MH072).

Supplementary Material

SUPPLEMENTARY MATERIAL

Shaotong Zhao and Chunzi Lyu contributed equally to this work.

How to cite this article: Zhao ST, Lyu CZ, Liu YB, Wang XY, Zhang ZW, Lv H, Ni TX, Yan JH. Preimplantation genetic testing for aneuploidy could not improve cumulative live birth rate among 1003 couples with recurrent pregnancy loss. Chin Med J 2024;137:2134–2136. doi: 10.1097/CM9.0000000000003041
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