Edited by: John Lui Yovich, Pivet Medical Center, Australia
Reviewed by: Thor Haahr, Aarhus University, Denmark; Peter John Lutjen, Monash University, Australia
This article was submitted to Reproduction, a section of the journal Frontiers in Endocrinology
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Recently a novel system, the POSEIDON criteria, was developed to classify infertility patients with low prognosis undergoing assisted reproductive technology (ART) treatment (
Among the four groups based on the POSEIDON criteria, group 1 is undoubtedly the best prognostic group considering their younger age and normal ovarian reserve, while group 4 has the worst prognosis due to the advanced age and diminished ovarian reserve. However, an interesting question is who would achieve better pregnancy outcome, the older women (group 2) with normal ovarian reserve or the young women (group 3) with diminished ovarian reserve. The cumulative live birth rate (CLBR) is considered a preferable measure of success of IVF treatment (
The characteristics and prognosis of patients should be used to develop clinical management strategies. The objective of this study is to characterize the low prognosis patients in order to facilitate treatment decision making. In this study, the baseline characteristics and outcomes of patient groups defined by the POSEIDON criteria were analyzed, and CLBR resulting from one aspirated
This retrospective study included 18,455 fresh aspirated IVF cycles with subsequent frozen embryo transfers from January 2014 to January 2017 in our center. The live birth outcome was followed up for at least 2 years until Jan 2019. The study was approved by the Ethics Committee for the Clinical Application of Human Assisted Reproductive Technology of Northwest Women's and Children's Hospital (No. 2018002). The ethics committee approved this study waived the need to obtain informed consent. All research was performed in accordance with relevant guidelines and regulations.
All fresh IVF/ICSI cycles and subsequently frozen embryo transfers from oocyte retrievals performed in our clinic from January 2014 to January 2017 were included in the analysis. The following cycles were excluded: (1) donated oocyte cycles (
Patients were categorized according to POSEIDON criteria:
Low prognosis patients Group 1 ( Group 2 ( Group 3 ( Group 4 ( Non-low prognosis patients Group 5 ( Group 6 (
Flow chart and data processing procedure are listed in
Flow chart and data processing.
Demographics and baseline characteristics.
879 | 482 | 858 | 1306 | 664 | 13708 | ||
<0.001 | |||||||
2014 | 114 (13.0%) | 79 (16.4%) | 184 (21.4%) | 285 (21.8%) | 96 (14.5%) | 4154 (30.3%) | |
2015 | 296 (33.7%) | 150 (31.1%) | 227 (26.5%) | 344 (26.3%) | 200 (30.1%) | 4251 (31.0%) | |
2016-2017.01 | 469 (53.4%) | 253 (52.5%) | 447 (52.1%) | 677 (51.8%) | 368 (55.4%) | 5303 (38.7%) | |
Age of female | 29.9 ± 2.8 | 39.1 ± 3.3 | 30.2 ± 2.9 | 40.5 ± 3.5 | 30.9 ± 4.6 | 29.9 ± 4.3 | <0.001 |
<0.001 | |||||||
≤ 30 | 487 (55.4%) | 0 (0.0%) | 438 (51.0%) | 0 (0.0%) | 356 (53.6%) | 8375 (61.1%) | |
>30, ≤ 35 | 392 (44.6%) | 63 (13.1%) | 420 (49.0%) | 104 (8.0%) | 202 (30.4%) | 3823 (27.9%) | |
>35, ≤ 40 | 0 (0.0%) | 262 (54.4%) | 0 (0.0%) | 594 (45.5%) | 85 (12.8%) | 1224 (8.9%) | |
>40 | 0 (0.0%) | 157 (32.6%) | 0 (0.0%) | 608 (46.6%) | 21 (3.2%) | 286 (2.1%) | |
<0.001 | |||||||
≥24 | 228 (26.1%) | 124 (26.2%) | 217 (25.6%) | 416 (32.3%) | 180 (27.3%) | 3622 (26.7%) | |
≥18.5, <24 | 529 (60.6%) | 315 (66.6%) | 560 (66.0%) | 813 (63.2%) | 422 (64.0%) | 8705 (64.1%) | |
<18.5 | 116 (13.3%) | 34 (7.2%) | 72 (8.5%) | 57 (4.4%) | 57 (8.6%) | 1248 (9.2%) | |
Basal FSH (IU/ml) | 7.4 ± 2.7 | 8.4 ± 3.5 | 9.3 ± 5.5 | 11.1 ± 7.0 | 6.6 ± 2.0 | 6.8 ± 2.6 | <0.001 |
<0.001 | |||||||
Primary | 526 (59.8%) | 123 (25.5%) | 513 (59.8%) | 274 (21.0%) | 356 (53.6%) | 7979 (58.2%) | |
Secondary | 353 (40.2%) | 359 (74.5%) | 345 (40.2%) | 1032 (79.0%) | 308 (46.4%) | 5729 (41.8%) | |
<0.001 | |||||||
≤ 2 | 306 (34.9%) | 193 (40.3%) | 309 (36.3%) | 509 (39.7%) | 255 (38.6%) | 5267 (38.9%) | |
>2, ≤ 5 | 391 (44.6%) | 134 (28.0%) | 394 (46.2%) | 319 (24.9%) | 264 (39.9%) | 5899 (43.5%) | |
>5 | 179 (20.4%) | 152 (31.7%) | 149 (17.5%) | 454 (35.4%) | 142 (21.5%) | 2385 (17.6%) | |
<0.001 | |||||||
<4 | 0 (0.0%) | 0 (0.0%) | 521 (60.7%) | 885 (67.8%) | 0 (0.0%) | 0 (0.0%) | |
≥4, <10 | 484 (55.1%) | 380 (78.8%) | 337 (39.3%) | 421 (32.2%) | 148 (22.3%) | 3844 (28.0%) | |
≥10 | 395 (44.9%) | 102 (21.2%) | 0 (0.0%) | 0 (0.0%) | 516 (77.7%) | 9864 (72.0%) | |
<0.001 | |||||||
Pelvic-tubal factor | 588 (67.3%) | 342 (71.4%) | 536 (62.9%) | 761 (59.3%) | 445 (67.5%) | 8809 (64.9%) | |
Ovarian factor | 73 (8.4%) | 36 (7.5%) | 169 (19.8%) | 283 (22.1%) | 48 (7.3%) | 1156 (8.5%) | |
Male factor | 94 (10.8%) | 38 (7.9%) | 36 (4.2%) | 39 (3.0%) | 82 (12.4%) | 1747 (12.9%) | |
Endometriosis | 27 (3.1%) | 2 (0.4%) | 49 (5.8%) | 33 (2.6%) | 7 (1.1%) | 198 (1.5%) | |
Uterine factor | 10 (1.1%) | 17 (3.5%) | 22 (2.6%) | 83 (6.5%) | 6 (0.9%) | 223 (1.6%) | |
Other reasons | 82 (9.4%) | 44 (9.2%) | 40 (4.7%) | 84 (6.5%) | 71 (10.8%) | 1438 (10.6%) | |
0.509 | |||||||
No | 2 (0.2%) | 0 (0.0%) | 2 (0.2%) | 0 (0.0%) | 1 (0.2%) | 15 (0.1%) | |
Yes | 877 (99.8%) | 482 (100.0%) | 856 (99.8%) | 1306 (100.0%) | 663 (99.8%) | 13693 (99.9%) | |
<0.001 | |||||||
0 | 514 (58.7%) | 116 (24.3%) | 506 (59.2%) | 248 (19.2%) | 356 (53.8%) | 7895 (57.7%) | |
1 | 214 (24.4%) | 132 (27.6%) | 196 (22.9%) | 306 (23.7%) | 166 (25.1%) | 3048 (22.3%) | |
≥2 | 148 (16.9%) | 230 (48.1%) | 153 (17.9%) | 737 (57.1%) | 140 (21.1%) | 2738 (20.0%) | |
<0.001 | |||||||
0 | 820 (93.6%) | 293 (61.2%) | 790 (92.3%) | 646 (50.0%) | 588 (88.8%) | 12020 (87.8%) | |
1 | 54 (6.2%) | 158 (33.0%) | 65 (7.6%) | 560 (43.3%) | 63 (9.5%) | 1511 (11.0%) | |
≥2 | 2 (0.2%) | 28 (5.8%) | 1 (0.1%) | 86 (6.7%) | 11 (1.7%) | 157 (1.1%) | |
NA | |||||||
>10 | 0 (0.0%) | 0 (0.0%) | 4 (1.7%) | 6 (1.1%) | 559 (84.2%) | 0 (0.0%) | |
>4, ≤ 10 | 539 (61.3%) | 210 (43.6%) | 30 (12.4%) | 57 (10.6%) | 105 (15.8%) | 0 (0.0%) | |
≤ 4 | 340 (38.7%) | 272 (56.4%) | 208 (86.0%) | 473 (88.2%) | 0 (0.0%) | 0 (0.0%) |
The protocol for ovarian stimulation (OS) was determined individually according to female age, body mass index (BMI), basal follicle stimulating hormone (FSH) and antral follicle count (AFC). 94.33% of IVF patients received recombinant and/or urinary gonadotrophins (rFSH/hMG) in GnRH agonist protocol or GnRH antagonist protocol followed by IVF or ICSI. For women with diminished ovarian reserve, the mild stimulation protocol or luteal phase ovarian stimulation or natural cycle was used. Human menopausal gonadotrophin (hMG, Li Zhu, China) was added in mild ovulation protocol or Shanghai protocol according to patients' response to stimulation. Human chorionic gonadotrophin (hCG) 4,000–10,000 IU or recombinant hCG (r-hCG, MerckSerono S.p.A.) 250μg was administered when 2-3 follicles reached the size of 17 mm or higher. Thirty-six hours later, oocyte retrieval was performed using transvaginal ultrasonography-guided aspiration. The ovarian stimulation parameters of each group are listed in
Ovarian stimulation parameters.
N | 879 | 482 | 858 | 1306 | 664 | 13708 | |
<0.001 | |||||||
GnRH agonist | 494 (56.4%) | 198 (41.1%) | 356 (41.7%) | 428 (33.1%) | 555 (84.1%) | 12321 (90.1%) | |
GnRH antagonist | 293 (33.4%) | 189 (39.2%) | 274 (32.1%) | 409 (31.6%) | 96 (14.5%) | 1215 (8.9%) | |
Other | 89 (10.2%) | 95 (19.7%) | 223 (26.1%) | 456 (35.3%) | 9 (1.4%) | 139 (1.0%) | |
<0.001 | |||||||
Recombinant-FSH | 325 (37.9%) | 104 (22.3%) | 154 (18.8%) | 83 (7.1%) | 343 (52.3%) | 8300 (60.7%) | |
Urinary -FSH | 533 (62.1%) | 362 (77.7%) | 664 (81.2%) | 1090 (92.9%) | 313 (47.7%) | 5372 (39.3%) | |
<0.001 | |||||||
≤ 150 | 20 (4.4%) | 7 (3.1%) | 30 (6.5%) | 34 (5.8%) | 48 (13.7%) | 1682 (18.9%) | |
>150, ≤ 300 | 253 (56.0%) | 40 (17.9%) | 201 (43.3%) | 110 (18.9%) | 233 (66.6%) | 5749 (64.6%) | |
>300 | 179 (39.6%) | 176 (78.9%) | 233 (50.2%) | 439 (75.3%) | 69 (19.7%) | 1469 (16.5%) | |
Total Gn dose IU | 2999.9 ± 1100.2 | 3060.8 ± 1184.4 | 2950.7 ± 1273.0 | 2919.3 ± 1357.4 | 2783.8 ± 1039.2 | 2356.3 ± 971.2 | <0.001 |
Total Gn days | 10.3 ± 2.8 | 9.5 ± 2.9 | 9.4 ± 3.5 | 8.5 ± 3.7 | 11.1 ± 2.8 | 10.4 ± 2.2 | <0.001 |
HMG dose | 1119.7 ± 1090.8 | 1213.8 ± 1112.8 | 1195.0 ± 1133.8 | 1306.1 ± 1162.5 | 1224.7 ± 1165.9 | 804.6 ± 845.7 | <0.001 |
The oocyte processing and embryo development procedures as well as the embryo scoring system were described in our previous articles (
The primary outcome was cumulative live birth (CLB) defined as at least one live birth resulting from one aspirated ART cycle in the fresh ET or in the subsequent FET in relation to the number of oocytes retrieved. The numerator of CLBR calculation was the sum of live births achieved in the FETs and live births in fresh cycles. Only the first delivery was counted in the analysis if a patient achieved multiple deliveries. The CLBR was defined the cumulative live birth per transvaginal oocyte aspiration accordant to terminology definition (
The data processing and statistical analysis were performed using EmpowerStats software (
As shown in
Oocytes and embryo parameters and CLBRs.
N | 879 | 482 | 858 | 1306 | 664 | 13708 | |
Number of Oocytes/AFC | 74.00% | 67.30% | 145.30% | 101.20% | 90.50% | 91.40% | <0.001 |
Cycles of 0 oocyte retrieved (%) | 14 (1.6%) | 20 (4.1%) | 56 (6.5%) | 157 (12.0%) | 1 (0.2%) | 60 (0.4%) | <0.001 |
Number of oocytes | 7.4 ± 4.8 | 5.1 ± 3.7 | 4.3 ± 3.7 | 2.9 ± 2.9 | 12.6 ± 6.2 | 12.3 ± 6.7 | <0.001 |
Number of 2PN | 4.4 ± 3.3 | 3.3 ± 2.5 | 2.8 ± 2.5 | 2.0 ± 2.0 | 7.0 ± 4.3 | 7.4 ± 4.6 | <0.001 |
Number of day 3 usable embryos | 3.4 ± 2.8 | 2.6 ± 2.2 | 2.3 ± 2.2 | 1.6 ± 1.7 | 5.0 ± 3.7 | 6.2 ± 4.2 | <0.001 |
Number of day 3 good quality embryos | 1.8 ± 2.1 | 1.5 ± 1.8 | 1.3 ± 1.7 | 0.9 ± 1.3 | 2.5 ± 2.7 | 3.7 ± 3.3 | <0.001 |
Cumulative live births (rate %) | 392 (44.6%) | 118 (24.5%) | 305 (35.5%) | 166 (12.7%) | 355 (53.5%) | 9164 (66.9%) | <0.001 |
Inconsistent with the distribution pattern of number of oocytes and embryos by group, the CLBRs in the order from highest to lowest was 44.6% in group 1(
Logistic regression analysis for CLBRs.
1 | 1 | 1 |
2 | 0.4 (0.3, 0.5), |
0.6 (0.4, 0.8), |
3 | 0.7 (0.6, 0.8), |
0.9 (0.7, 1.2), |
4 | 0.2 (0.1, 0.2), |
0.4 (0.3, 0.6), |
5 | 1.4 (1.2, 1.7), |
1.3 (0.9, 1.7), |
6 | 2.5 (2.2, 2.9), |
2.0 (1.6, 2.4), |
Pregnancy outcomes per transfer both fresh and frozen embryo transfer in low prognosis patients.
Transfer cycle (fresh ET + FET) | 1,126 | 602 | 781 | 976 | 1,199 | 18,862 | |
Number of embryos transferred | 1.8 ± 0.5 | 1.9 ± 0.5 | 1.7 ± 0.5 | 1.7 ± 0.6 | 1.9 ± 0.5 | 1.7 ± 0.5 | <0.001 |
Implantation rate | 34.40% | 21.26% | 40.45% | 19.19% | 29.49% | 48.24% | <0.001 |
Pregnancy loss rate/ transfer | 9.68% | 10.80% | 9.99% | 9.22% | 9.84% | 9.47% | 0.896 |
Miscarriage | 7.46% | 9.14% | 6.91% | 8.20% | 6.84% | 6.56% | 0.059 |
in first trimester/ transfer |
Trend chart of key events in low prognosis patients. There was a crossing of trend lines between group 2 (red) and group 3 (blue) after embryo transfer. X axis represents the average number of AFC, number of oocytes, number embryos, number of good quality embryos, rate of implantation and rate of cumulative live birth. The Y axis on the left represents the number of the first four variables (
SWOT analysis of 4 groups of low prognosis patients defined by POSEIDON criteria.
The main finding of this retrospective study in POSEIDON criteria-defined population was that the CLBR was highest in group 1, followed by group 3 and group 2, and lowest in group 4. According to our results, the CLBR from the young women with poor ovarian reserve (group 3) was slightly lower than that from young women with good ovarian reserve and previous low responder (group 1). Though the patients in group 2 (age ≥ 35; AFC ≥ 5) had better ovarian reserve, more oocytes and more embryos, the CLBR and implantation rate, on the other way round, were lower than in group 3 patients with poorer ovarian reserve, fewer oocytes and fewer embryos. This finding may facilitate the development of management strategies for low prognosis patients.
The innovative POSEIDON criteria aim at identifying and stratifying low prognosis patients into four distinct groups based on female age, AFC and ovarian response in the previous cycle (
Our results are consistent with previous studies (
In terms of the management of patients in group 2, more attention should be paid to develop strategies of improving the oocyte quality rather than oocyte quantity or embryo quantity. Because more embryos are achieved on day 3 in group 2, culturing embryos to blastocyst stage for transfer is a good option. Day 5–6 embryos have lower rate of segmental aneuploidy (
The patients in group 3 (age < 35; AFC < 5) had a poor ovarian reserve, who were expected poor responders with poor pregnancy outcome. Interestingly, the oocytes output rate (145.3% oocytes retrieved per AFC) in group 3 was significantly higher than in the other groups, though FSH starting dose was not significantly increased (
The patients in group 5 were the non-low prognosis patients who had good ovarian response (more than 9 oocytes in previous retrieval), however most of these patients failed to live birth in previous IVF cycle. Comparing with another non-low prognosis patients with first IVF treatment (group 6), though the patients in group 5 have more AFC and number of oocytes retrieved, the embryo development and pregnancy outcome were inferior to that in group 6. Therefore, the failure in first IVF patients with good ovarian response may be the poor prognosis for subsequently IVF treatment.
Pelvic-tubal factor is the most common cause of infertility, accounting for about 10.8–78.3% of infertile women in China (
Limitations are related to the retrospective nature of the study and the fact that the data was from a single center also weakens the universality of our observations. Other potential limitations could be that non-GnRH analog protocol was used in some women with diminished ovarian reserve rather than in those with normal ovarian reserve. The fresh cycles that failed to yield any oocyte were not included in this study, for example, cycles with cancellation of ovarian stimulation.
The results of this study may provide new insights for the development of management strategies for low prognosis patients. A SWOT analysis was performed to help the management for poor prognosis patients in clinic, which was drawn from the POSEIDON reports (1, 2, 4, 5) and the data in this study. The responsiveness of antral follicles to gonadotrophin was extremely higher in group 3 than in the other groups. Considering the gratifying CLBR outcome in group 3, in order to increase oocyte yield, we suggest to try more ovarian stimulations but not harder ovarian stimulation through excessive daily gonadotrophin dose. Though the patients in group 2 have more ovarian reserve as well as more oocytes and embryos, the CLBR was lower than expected. The management strategy for group 2 should be improving the live birth rate rather than increasing number of oocytes retrieved.
In conclusion, inconsistent with the distribution pattern of oocyte quantity and embryo quantity by patient group, the CLBRs in the order from highest to lowest were in group 1 (young women with good ovarian reserve), group 3 (young women with poor ovarian reserve), group 2 (women at advanced age with good ovarian reserve), and at last group 4 (women at advanced age with poor ovarian reserve.
The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.
The study was approved by the Ethics Committee for the Clinical Application of Human Assisted Reproductive Technology of Northwest Women's and Children's Hospital (No. 2018002). The ethics committee that approved this study waived the need to obtain informed consent. All of the research was performed in accordance with the relevant guidelines and regulations.
WS and JS conceived and designed the study. WS and WZ drafted and revised the manuscript. WS, ZZ, and WZ analyzed and interpreted the data. LT, ZZ, and HZ collected and cleared the data. All authors have read and approved the final version of the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank all the clinicians, scientists and embryologists in the Northwest Women and Children's Hospital for their assistance with the data collection, and all the patients for their contribution to this study. We gratefully thank Dr. Xinglin Chen from Department of Epidemiology and Biostatistics, X&Y solutions Inc. in Boston for her contribution to the statistical support.