Abstract
Purpose
This retrospective cohort study aimed to assess and compare the outcomes between cumulative live birth of patients with and without PGT-A and also between prior unsuccessful IVF cycles and PGT-A cycles among patients who experienced IVF but without live birth delivery, and to clarify the effective usage of PGT-A as an in vitro fertilization (IVF) add-on.
Methods
A total of 2113 females undergoing IVF with at least one blastocyst were reviewed. Patients in the PGT-A and non-PGT-A groups were further categorized into first-time IVF and prior unsuccessful IVF groups (previous IVF experience but without live birth delivery).
Results
In the PGT-A group, there were additional oocyte retrieval cycles, fewer transfer cycles per patient, higher clinical pregnancy rates per embryo transfer, and lower miscarriage rates per clinical pregnancy as compared to the non-PGT-A group, all showing significant differences. However, the first-time IVF group with PGT-A had a significantly longer duration from the first oocyte retrieval to the first live birth delivery (LBD) and a significantly lower LBD rate per patient than the non-PGT-A group. The cumulative probability for a first LBD with PGT-A was inferior in the first-time IVF group for women < 35 years, marginally superior in the prior unsuccessful IVF group of women aged 38–40 years, and similar for other groups.
Conclusion
PGT-A should not be recommended to all patients; however, if the first IVF treatment failed, PGT-A may reduce the patient’s burden regardless of age.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10815-022-02683-x.
Keywords: Preimplantation genetic testing for aneuploidy (PGT-A), Effectiveness of PGT-A, Cumulative probability of live birth delivery (LBD), Prior unsuccessful IVF, In vitro fertilization (IVF)
Introduction
Preimplantation genetic testing for aneuploidy (PGT-A) has been provided routinely in several countries [1, 2]. However, its effectiveness remains controversial [3]. Several randomized controlled trials (RCT) demonstrated that PGT-A improves the ongoing pregnancy rate and decreases the miscarriage rate after the first embryo transfer [4–6], but it was not based on the intention-to-treat principle [7]. Cumulative pregnancy and live birth rates were not significantly different between the PGT-A and control groups [6, 8]. Large-scale multicenter RCT studies, such as the ESHRE Study, into the evaluation of oocyte Euploidy by microarray analysis (ESTEEM) [8] and Single Embryo Transfer of Euploid Embryo (STAR Trial) [9] concluded that PGT-A did not improve the overall pregnancy outcomes in all females. The Cochrane review provides a comprehensive discussion of the limitations of these studies [10]. The practice committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology (ART) found insufficient evidence to recommend the routine use of blastocyst biopsy with aneuploidy testing in all patients with infertility [11].
In vitro fertilization (IVF) mainly aims to achieve a live birth, and PGT-A is its add-on; therefore, it is important to evaluate the clinical effectiveness and cost-effectiveness of PGT-A in a clinical setting [12]. The effectiveness of treatment in medically assisted reproduction should be evaluated over multiple cycles [13]. The Harbin Consensus Conference Workshop Group recommended that the preferred primary outcome of all infertility trials is live birth or cumulative live birth, which is defined as the number of live births per female over a defined period (or number of treatment cycles) [14]. In this perspective, the effectiveness of PGT-A also needs to be evaluated based on cumulative live birth. After clarifying in which situation and for whom PGT-A is useful, the true effectiveness of PGT-A may be evaluated. A recent multicenter, randomized, controlled trial in China involving 27–37-year-old women with three or more good-quality blastocysts concluded that conventional IVF resulted in a cumulative live birth rate that was noninferior to the rate with PGT-A [15]. PGT-A is associated with several risks (such as damage from embryo biopsy, false-positive or false-negative results, and mosaic) that reduce the cumulative live birth rate. However, unless PGT-A causes damage to embryos, the cumulative live birth rate is not likely to decrease.
In 1988, the Japan Society of Obstetrics and Gynecology (JSOG) prohibited PGT-A for ethical reasons; egg donation is also prohibited, and adoption is uncommon in Japan. Couples with infertility problems who want to have children repeat infertility treatments. Otani Ladies Clinic was one of the two medical institutions announcing PGT-A practice in Japan outside the small trial by JSOG [16] during this study. After having repeated IVF failure [3, 17, 18] and recurrent miscarriage, patients visited our clinic because they wished to undergo PGT-A. Our clinic performs a single frozen embryo (blastocyst) transfer (FET), which is a major procedure of IVF; thus, our institution was an ideal setting for the assessmment of PGT-A effectiveness.
In this study, we aimed to compare the PGT-A group with the non-PGT-A group; the comparisons were made in two patient subgroups: first-time IVF and prior unsuccessful IVF groups. In addition, the comparisons between pior IVF cycles and PGT-A cycles were conducted in the same patients of the prior unsuccessful IVF group. We also sought to evaluate the outcomes, including cumulative live birth, and clarify which situation and which patient PGT-A is effective for.
Materials and methods
Study population
This retrospective cohort study, which focused on the pregnancy outcomes of IVF procedures, was conducted at the Otani Ladies Clinic in Kobe, Japan, from February 2015 to March 2019. The first oocyte retrieval was performed on January 1, 2016, the last FET was on March 31, 2019; the last confirmed delivery was on December 31, 2019.
Initially, all patients intending to undergo PGT-A underwent genetic counseling with their partner; they were asked about previous pregnancies and history of infertility treatment. Those who had prior IVF experience were asked about the number of oocyte retrieval cycles, which is defined by one complete cycle that includes all embryo transfers without any remaining viable cryopreserved embryos. Thereafter, patients were explained about PGT-A. Patients in whom ovarian stimulation was initiated and at least one blastocyst was successfully biopsied for the PGT-A test and vitrified were included in the PGT-A group. In contrast, patients who started their first IVF treatment during the same period and could vitrify at least one blastocyst for transfer without PGT-A were included in the non-PGT-A group. Patients who had undergone preimplantation genetic testing for monogenic disease, chromosomal translocation or rearrangement, or sex selection; those who had used donor oocytes, initiated a cycle with the intent of freezing all embryos for later use; those who received PGT-A with array CGH method; and those who had already experienced PGT-A were excluded. Written informed consent was obtained from all patients for the analysis of their de-identified data and publication of the study findings. The institutional review board of Otani Ladies Clinic approved the provision of PGT as well as the study protocol (Oct 26, 2014). The PGT-A group consisted 1317 female patients aged 27–48 years. Among them, 453 had no previous IVF experience (First-time IVF, PGT-A Group), whereas 702 had previous IVF experience but without live birth delivery (LBD) (prior unsuccessful IVF, PGT-A group) (Fig. 1, details are shown in Online Resource 1). The non-PGT-A group was composed of 796 female patients aged 21–50 years who started their first IVF treatment and transferred at least one blastocyst without PGT-A (First-time IVF, non-PGT-A Group) (Fig. 1). After their first oocyte retrieval, 433 patients achieved LBD; the remaining 363 failed to achieve LBD. Of these 363 patients, 186 continued oocyte retrieval and IVF treatment (prior unsuccessful IVF, non-PGT-A group) (Fig. 1, details are shown in Online Resource 2). We then compared First-time IVF, PGT-A Group with First-time IVF, non-PGT-A Group, and prior unsuccessful IVF, PGT-A group with prior unsuccessful IVF, non-PGT-A group (Fig. 1).
Fig. 1.
Flowchart: patient enrollment and group determination. Note: IVF in vitro fertilization, PGT-A preimplantation genetic testing for aneuploidy
Oocyte retrieval, embryo culture, biopsy, and FET
All the patients underwent controlled ovarian stimulation according to our routine protocols, including the GnRH antagonist, clomiphene, and clomiphene plus HMG/FSH protocols, depending on the patients’ characteristics. Ovulation was triggered by human chorionic gonadotropin administration 35 h before retrieval. For oocyte insemination, either conventional or intracytoplasmic sperm injection was performed. Embryos were cultured using standard incubation conditions (5% O2 and 6% CO2) and embryos that grew to blastocysts on day 5 or 6 of embryo culture were graded using the criteria described by Gardner et al. [19]. All embryos were separately vitrified and stored in liquid nitrogen. For PGT-A, on day 5 or 6 after oocyte retrieval, a trophectoderm biopsy was performed before vitrification, and embryos were graded again to confirm the impact of the biopsy. Single embryos according to the precedence of morphological grade were transferred one by one per cycle (either natural or hormone replacement cycles).
PGT-A
Next-generation sequencing-based PGT-A was performed in-house using a VeriSeq kit (Illumina) on a MiSeq system (Illumina) according to the manufacturer’s protocol and was analyzed using the Bluefuse Multi-Software (Illumina). After PGT-A, uniform euploid (putative diploid) embryos were prioritized for transfer and uniform aneuploid embryos were excluded. If patients did not have transferable euploid embryos, mosaic embryos or embryos with failed tests (no results) were transferred according to the patients’ intentions after appropriate consultation.
Outcomes
The primary outcome measures are the proportion of patients achieving a first live birth and the proportion of miscarriages. The secondary outcome measures are the live birth rate per embryo transfer and the time elapsed to achieve a first live birth. Clinical pregnancy was defined as the presence of gestational sacs on transvaginal ultrasound. Miscarriage was defined as the failure to deliver a live neonate after clinical pregnancy. Each of these measures was stratified into five maternal-age categories defined by the Society for Assisted Reproductive Technologies: < 35, 35–37, 38–40, 41–42, and > 42 years.
Statistical analysis was performed using STATA software (version 15.1; STATA Corp.). Data are presented as mean (SD) or number (percentage). We analyzed categorical variables through the chi-square test or Fisher’s extract test, and continuous variables through a t-test or Wilcoxon’s rank-sum test. The odds ratio (ORs) and the 95% confidence interval were estimated to compare the results between the PGT-A and non-PGT-A groups. The cumulative probability of the first live birth during the study period was estimated using the Kaplan–Meier method by conservative estimation, which assumed that females who did not return for treatment had no chance of achieving a live birth through ART [20]. Additionally, the survival curve of PGT-A and non-PGT-A was compared by the log-rank test.
All cases were followed up until LBD day or the last day of this study. In the non-PGT-A group, we could not follow up eight patients after clinical pregnancy. P values < 0.05 were considered statistically significant.
Results
Comparison of the clinical outcomes between the PGT-A and non-PGT-A groups
Table 1 summarizes the clinical outcomes. The mean number of oocyte retrieval cycles per patient was significantly higher in the PGT-A groups than the non-PGT-A subgroups. In the non-PGT-A groups, at least one embryo was transferred in all patients, but in the PGT-A groups, the percentage of patients that received an embryo transfer was 53.6% in the first-time IVF group and 49.0% in the prior unsuccessful IVF group. Compared with the non-PGT-A groups, the PGT-A groups had significantly smaller mean number of embryo transfer cycles per patient, significantly higher clinical pregnancy rate per embryo transfer, significantly lower miscarriage rate per clinical pregnancy and significantly higher LBD rate per embryo transfer. However, the LBD per patient was significantly lower in the PGT-A group than in the non-PGT-A group, particularly in those with first-time IVF; although it was also lower in the prior unsuccessful IVF subgroup of the PGT-A group, the difference was not statistically significant. The duration from the first oocyte retrieval to the first LBD was significantly longer in the first-time IVF group of the PGT-A group than in the non-PGT-A group. Conversely, such duration was shorter in the prior unsuccessful IVF subgroup of the PGT-A group than the non-PGT-A group, particularly in younger patients it was significantly shorter. Online Resources 1 and 2 enumerate the details of each outcome stratified into five maternal-age categories in the PGT-A and non-PGT-A groups, respectively. Online Resource 3 summarized the clinical outcome of embryo transfer according to the PGT-A result.
Table 1.
Comparison of the clinical outcomes between patients with and without PGT-A, according to the previous treatment experiences
| First-time IVF groups | PGT-A | Non-PGT-A | ||
| (n = 453) | (n = 796) | P value | OR (95% CI) | |
| Age (y), mean ± SD, (range) | 39.5 ± 2.96 (27–48) | 35.9 ± 4.24 (21–50) | 0.000 | |
| Oocyte retrieval/per patient, n (mean ± SD, range) | 1482/453 (3.27 ± 3.19, 1–25) | 1180/796 (1.48 ± 1.25, 1–15) | 0.000 | |
| PGT-A/retrieval, n (%) | 1052/1482 (71.0) | |||
| ET | ||||
| Patient ET/patient, n (%) | 243/453 (53.6) | 796/796 (100) | 0.000 | |
| ET/patient ET, n (mean ± SD, range) | 289/243 (1.19 ± 0.46, 1–4) | 1310/796 (1.65 ± 1.00, 1–8) | 0.000 | |
| CP/ET, n (%) | 200/289 (69.2) | 668/1310 (51.0) | 0.000 | 2.16 (1.63–2.87) |
| Miscarriage/CP, n (%) | 10/200 (5.0) | 161/660 (24.4) | 0.000 | 0.16 (0.08–0.32) |
| LBD | ||||
| LBD/patient, n (%) | 190/453 (41.9) | 499/788 (63.3) | 0.000 | 0.42 (0.33–0.53) |
| LBD/patient ET, n (%) | 190/243 (78.2) | 499/788 (63.3) | 0.000 | 2.08 (1.47–2.97) |
| LBD/ET, n (%) | 190/289 (65.7) | 499/1296 (38.5) | 0.000 | 3.07 (2.33–4.05) |
| Time to LBD (months), mean ± SD, (range) | 14.4 ± 4.66 (8–35) | 13.1 ± 3.83 (8–36) | 0.000 | |
| Prior unsuccessful IVF groups | PGT-A | Non-PGT-A | ||
| (n = 702) | (n = 186) | P value | OR (95% CI) | |
| Age (y), mean ± SD, (range) | 40.0 ± 3.04 (28–48) | 38.2 ± 4.02 (27–50) | 0.000 | |
| Oocyte retrieval/per patient, n (mean ± SD, range) | 2732/702 (3.89 ± 3.81, 1–26) | 570/186 (3.06 ± 1.86, 2–15) | 0.004 | |
| PGT-A/retrieval, n (%) | 1834/2732 (67.1) | |||
| ET | ||||
| Patient ET/patient, n (%) | 344/702 (49.0) | 186/186 (100) | 0.000 | |
| ET/patient ET, n (mean ± SD, range) | 417/344 (1.21 ± 0.51, 1–4) | 415/186 (2.23 ± 1.34, 1–8) | 0.000 | |
| CP/ET, n (%) | 283/417 (67.9) | 125/415 (30.1) | 0.000 | 4.90 (3.61–6.64) |
| Miscarriagea/CP, n (%) | 32/283 (11.3) | 56/122 (45.9) | 0.000 | 0.15 (0.09–0.26) |
| LBDa | ||||
| LBD/patient, n (%) | 251/702 (35.8) | 66/183 (36.1) | 0.938 | 0.99 (0.69–1.41) |
| LBD/patient ET, n (%) | 251/344 (73.0) | 66/183 (36.1) | 0.000 | 4.78 (3.20–7.16) |
| LBD/ET, n (%) | 251/417 (60.2) | 66/406 (16.3) | 0.000 | 7.79 (5.53–10.99) |
| Time to LBD (months), mean ± SD, (range) | 15.4 ± 5.41 (9–42) | 16.9 ± 6.07 (8–36) | 0.052 | |
ET embryo transfer, CP clinical pregnancy, LBD live birth delivery, PGT-A preimplantation genetic testing for aneuploidy, SD standard deviation
aThe data of the patients not followed after the clinical pregnancy was deleted from the denominators
Cumulative probability of the first LBD
In the first-time IVF groups, the cumulative probability of the first LBD was relatively higher in the non-PGT-A group than the PGT-A group in all age categories (Fig. 2a–ei); especially, it was significantly higher in patients aged < 35 years (Fig. 2ai). In the prior unsuccessful IVF groups, the cumulative probability of the first LBD was higher in the PGT-A group than in the non-PGT-A group in all age categories (Fig. 2a–cii); especially, it was significantly higher in patients aged 38–40 years (Fig. 2cii).
Fig. 2.
Comparison of the cumulative probability of the first live birth delivery rate (Kaplan–Meier estimate) with or without PGT-A, according to the previous treatment experiences. Note: Patient age: a < 35 years. b 35–37 years. c 38–40 years. d 41–42 years. e > 42 years. i, First-time IVF groups (PGT-A vs. non-PGT-A); ii, prior unsuccessful IVF groups (PGT-A vs. non-PGT-A). The horizontal axis shows the period from the first oocyte retrieval to the live birth delivery, and the vertical axis shows the proportion of patients with the first live birth delivery. P value shows the log-rank test results of the comparison between the PGT-A and non-PGT-A groups
Comparison of clinical results of prior unsuccessful IVF cycle and PGT-A cycle
In the prior unsuccessful IVF, PGT-A group, the mean number of embryo retrieval cycles per patient remained unchanged between prior IVF cycle and PGT-A cycle, but the number of patients who received transfer and the mean number of transfer cycles per patient significantly decreased. The number of patients with miscarriages also significantly decreased, and 38.5% of patients achieved first LBD with PGT-A (Table 2, details of each outcome stratified into five maternal-age categories are shown in Online Resource 4).
Table 2.
Clinical results of PGT-A cycles in comparison with those Prior unsuccessful IVF cycles
| Prior unsuccessful IVF PGT-A group, n = 702 | PGT-A cycle | Prior unsuccessful IVF cycle | P value | OR (95% CI) |
|---|---|---|---|---|
| Oocyte retrieval | ||||
| Patients retrieved, n (%) | 702/702 (100) | 699/702 (99.6) | 0.250 | |
| Cycles of retrieval/patients retrieved, n (mean ± SD, range) | 2732/702 (3.89 ± 3.81, 1–26) | 2673 /699 (3.82 ± 3.48, 1–28) | 0.668 | |
| Embryo transfer | ||||
| Patients transferred, n (%) | 344 /702 (49.0) | 648/702 (92.3) | 0.000 | 0.08 (0.06–0.11) |
| Cycles of transfer/patients transferred, n (mean ± SD, range) | 417/344 (1.21 ± 0.51, 1–4) | 2993/648 (4.62 ± 3.02, 1–20) | 0.000 | |
| Miscarriage | ||||
| Patients miscarried, n (%) | 28/702 (4.0) | 428/702 (61.0) | 0.000 | 0.03 (0.02–0.04) |
| Miscarriage/patients miscarried, n (mean ± SD, range) | 32/28 (1.14 ± 0.35, 1–2) | 769/428 (1.80 ± 0.96, 1–6) | 0.000 | |
| Live birth delivery | ||||
| Patients delivered, n (%) | 251/702 (35.8) | 0/702 (0) | 0.000 | |
PGT-A preimplantation genetic testing for aneuploidy, CI confidence interval, OR odds ratio
Discussion
To the best of our knowledge, this is the first large-scale study to report the cumulative outcomes of multicycle IVF and PGT-A treatments in patients with prior unsuccessful IVF cycles. It is also the first study to investigate treatment outcomes of prior unsuccessful IVF cycles and PGT-A cycles in the same patients.
In the first-time IVF and prior unsuccessful IVF groups of all age categories, the clinical pregnancy rate per transfer was significantly higher, and the miscarriage rate was significantly lower in the PGT-A groups than in the non-PGT-A groups. These results are consistent with the previous RCTs [4–6]. Conversely, multinational, multicenter RCTs found no difference in either ongoing pregnancy or miscarriage rates between the PGT-A and control groups [8, 9]. This discordance can be attributed to the differences between institutions with respect to technical expertise. The STAR trial highlighted the significant variability with respect to euploidy rates among clinics and genetic test laboratories participating in the trial (26–60%; P < 0.001). From stimulation to embryo transfer, PGT-A requires advanced clinical techniques, such as long-term embryo culture, harmless biopsy, and an accurate analysis of PGT. Without such technical and clinical expertise, PGT-A is not a secure and effective procedure [21].
Furthermore, the ratio of patients who received embryo transfer and the mean number of the embryo transfer cycles per patient were considerably lower in the PGT-A groups than in the non-PGT-A groups. However, the LBD rates per patient embryo transferred and per embryo transfer cycle significantly increased in the PGT-A groups. The same result was confirmed by different treatment outcomes in the prior IVF and PGT-A cycles among patients with a prior unsuccessful IVF cycle. The number of retrieval cycles was not significantly different between the prior IVF and PGT-A cycles, but the number of embryo transfer cycles and rate of miscarriage significantly decreased when using PGT-A. These results suggest that PGT-A may help reduce the patient’s burden by avoiding recurrent implantation failure and miscarriage despite the fact that a considerable number of patients could not get transferable embryos. Scriven showed that PGT-A improved the live birth event, considering that the transfer was only attempted once; PGT-A also decreased clinical miscarriages, embryo transfer procedures, and magnitude of favorable and unfavorable changes depending on the diagnostic accuracy [22]. Our result shows that his model is consistent with the actual clinical situation in Japan. As the JSOG prohibited PGT-A, Japanese patients suffer from repeated implantation failure and miscarriages [17].
In the first-time IVF groups, the cumulative probability of the first LBD rate (Kaplan–Meier estimate) was relatively lower in the PGT-A group than that in the non-PGT-A group; especially, it was significantly lower in patients aged < 35 years. This result was consistent with that of a recent RTC [15]. The PGT-A group also had a significantly larger mean number of oocyte retrieval cycles, significantly lower LBD per patient, and significantly longer time to LBD than the non-PTG-A group. Additionally, 76.6% of patients aged < 35 years and 57.9% of patients aged 35–37 years achieved LBD after the first oocyte retrieval with rare miscarriage (Online Resource 2). These results in young patients reflected the good prognosis of first-time IVF patients without PGT-A. Lee et al. assayed up to three complete ART cycles in ART-naive women of advanced maternal age and analyzed the cumulative live birth rate and cost-effectiveness of PGT-A. Their results showed that the cumulative live birth rate was comparable between the PGT-A and control groups, but the time to achieve live birth was significantly low in the PGT-A group [23, 24]. Notably, our results are not in agreement with this point, which may be attributable to differences with respect to the age distribution and stage of embryo transfer. The patients in their study were women aged ≥ 37 years (mean age: 40.06 years) and the transfer stage was mainly blastocyst in the PGT-A group, whereas most of the control group was transferred at the cleavage stage; however, in the present study, the mean age of patients in the first-time IVF non-PGT-A group was 35.9 years and the embryos were transferred at the blastocyst stage. Additionally, different sterility backgrounds of patients in the PGT-A and non-PGT-A groups may also explain this difference. Patients who are going to receive PGT-A typically have unfavorable conditions, such as recurrent miscarriage (Online Resource 4) and recurrent failure of non-ART infertility treatment; these factors are liable to increase oocyte retrieval cycles, lower LBD per patient, and prolong the time to LBD.
In conclusion, high-level technical and clinical expertise is essential in all steps of the PGT treatment. Overall, 54.4% of patients who start first IVF treatment without PGT-A achieve LBD without a large burden (Online Resource 2). PGT-A does not offer a superior cumulative probability of a first LBD. Therefore, PGT-A should not be recommended to all patients. However, if the first IVF treatment was unsuccessful, PGT-A may reduce the patient’s stress, which increases with repeated IVF failures and miscarriages associated with transferring aneuploid embryos [23]. Nonetheless, patient-centered counseling based on the situation of each patient is crucial.
This study had some limitations. Our data are merely clinical results of a single institution, and we did not conduct propensity score matching. Hence, the number and age distribution of patients were considerably different between groups; details of patient background were not checked. Moreover, the technical levels of IVF clinics where patients received previous treatment were not the same. We followed the patients until their first live birth, but they could easily deliver their next baby if they had already maintained some transferable embryos. Therefore, further follow-up of these patients during the entire reproductive period is required to evaluate the true effect of PGT-A.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Author contribution
All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Sachiko Ohishi and Tetsuo Otani. The first draft of the manuscript was written by Sachiko Ohishi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Data availability
Not available.
Declarations
Research involving human participants and/or animals
The institutional review board of Otani Ladies Clinic (Oct 26, 2014; Reference number 10320) (the name was changed to the institutional review board of Medical Corporation Association ART kai) approved the study protocol.
Informed consent
Written informed consent was obtained from all patients for the analysis of their de-identified data and publication of the study findings.
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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