|Year : 2020 | Volume
| Issue : 4 | Page : 233-238
Prediction of cumulative live birth rate in women aged 40 years and over undergoing In vitro fertilization/intracytoplasmic sperm injection
Lei Jia1, Pan-Yu Chen1, Ying-Chun Guo1, Zhi-Qiang Zhang1, Xiao Gong2, Jing-Bo Chen1, Cong Fang1
1 Reproductive Medicine Research Center, Sixth Affiliated Hospital of Sun Yat.Sen University, Tianhe District, Guangzhou 510275, China
2 Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
|Date of Submission||19-Jun-2020|
|Date of Decision||25-Sep-2020|
|Date of Acceptance||12-Oct-2020|
|Date of Web Publication||31-Dec-2020|
Reproductive Medicine Research Center, Sixth Affiliated Hospital of Sun Yat-Sen University, Tianhe District, Guangzhou 510275
Source of Support: None, Conflict of Interest: None
Objective: To investigate cumulative live birth rate (cLBR) per oocyte retrieval in infertile patients aged 40 years and over undergoing their first in vitro fertilization/intracytoplasmic sperm injection cycles and to identify the possible predictors.
Methods: A total of 1,613 patients at a university hospital in China from January 2013 to May 2017 were enrolled in this retrospective study. All data for fresh and subsequent frozen-thawed cycles were analyzed. Multivariate logistic regression analysis with stepwise selection of possible predictors for cLBR was performed, and Loess curve was constructed to determine the association between cLBR and the number of oocytes retrieved.
Results: cLBR significantly increased with the number of oocytes retrieved and reached up to 75% when > 20 oocytes were retrieved ( P < 0.001). Variables of antral follicle count (AFC) and the number of oocytes retrieved were selected using multiple logistic regression analysis with stepwise selection to predict the significance of cLBR. cLBR demonstrated an obvious upward trend as the number of oocytes retrieval increased in the Loess curve.
Conclusions: For patients aged 40 years and over, AFC and the number of oocytes retrieved were two key predictors for cLBR and maximization of ovarian reserve exploitation was pivotal to increase the chance of live birth.
Keywords: Advanced Maternal Age; Cumulative Live Birth Rate; In vitro Fertilization; Number of Oocytes Retrieved
|How to cite this article:|
Jia L, Chen PY, Guo YC, Zhang ZQ, Gong X, Chen JB, Fang C. Prediction of cumulative live birth rate in women aged 40 years and over undergoing In vitro fertilization/intracytoplasmic sperm injection. Reprod Dev Med 2020;4:233-8
|How to cite this URL:|
Jia L, Chen PY, Guo YC, Zhang ZQ, Gong X, Chen JB, Fang C. Prediction of cumulative live birth rate in women aged 40 years and over undergoing In vitro fertilization/intracytoplasmic sperm injection. Reprod Dev Med [serial online] 2020 [cited 2021 Apr 15];4:233-8. Available from: https://www.repdevmed.org/text.asp?2020/4/4/233/305931
| Introduction|| |
Assisted reproductive technology (ART) can be used to overcome infertility with tubal disease and male factors, but little progress has been made in reducing the effect of increasing age on fecundability., Two factors that have the greatest effect on the age-related decrease in fertility are diminished ovarian reserve and impaired oocyte quality, which leads to an increase in embryo aneuploidy. Currently, no therapy can overcome these barriers and we can only try to limit age-related decline in fecundity to some extent. The number of oocytes retrieved is considered to be an important predictive factor for pregnancy outcome.,,,,,,, However, no consensus has been reached about the optimal number of oocytes to achieve a live birth. Results from two large studies, showed that live birth rate (LBR) increased up to 15 oocytes and over 15 oocyte retrieved may only contribute to the risk of ovarian hyper-stimulation syndrome (OHSS). However, these two retrospective studies only focused on the relationship between number of oocytes retrieved and LBR in fresh cycle.
Cumulative LBR (cLBR), which represents pregnancy outcomes in one complete cycle, should be given more attention in the investigation of the optimal number of oocytes retrieved for better outcomes, especially in elder patients with LBRs in the fresh cycles. Until now, the association between oocyte number and cLBR remains controversial.,, Previous studies illustrated that cLBR increased with the increasing number of oocytes retrieved, while others demonstrated that cLBR rose up to 10–15 oocytes and then plateaued., Nevertheless, these results referring women aged <40 years (except for one study focused on women aged 18–45) have rendered inadequate strategy in pursuit of pregnancy among older women. Therefore, we set out to analyze available clinic-based data to provide evidence on the optimal number of oocytes retrieved for guiding ART among women aged 40 years and over.
| Methods|| |
We conducted a retrospective study of patients aged 40 years and over undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles at the Reproductive Medicine Center of the Sixth Affiliated Hospital of Sun Yat-Sen University from January 2013 to May 2017. This study was approved by the Institutional Ethics Committee (2017ZSLYEC-016S) and all patients provided informed consent to extract clinic-based data from their records for this analysis before ovarian stimulation.
The inclusion criteria were (1) patients aged 40 years and over and (2) patients undergoing their first IVF/ICSI cycles. Couples were excluded if female patients were diagnosed with systemic diseases, uterine cavity abnormalities, endometrial adhesion, adenomyosis, untreated hydrosalpinx, immunologic disease, or had any contraindications to progesterone and gonadotropins (Gn) use, or underwent the preimplantation genetic testing. Male patients whose sperm was collected by surgery were not enrolled in this study because of the possible compromise with embryo quality. Patients with cycle cancellation (n = 198), no oocyte retrieved (n = 187), and no available embryos (n = 636) were excluded. Finally, women who had not achieved a live birth but still had frozen embryos remaining were excluded (n = 49).
A total of 1,613 patients undergoing their first IVF/ICSI cycles were included in this study, including 694 fresh transfer cycles and all subsequent 1,451 frozen-thawed transfer cycles. All patients were categorized into five groups based on the number of oocytes retrieved: 1–5, 6–10, 11–15, 16–20, and >20 oocytes.
Controlled ovarian stimulation protocols were routine treatment protocols performed at our reproductive center, including midluteal long GnRH agonist protocol, antagonist protocol, natural cycle, modified natural cycle, mild stimulation protocol, and progestin-primed ovarian stimulation. Oocyte retrieval was performed 36–38 h after triggering. Collected cumulus–oocyte complexes were cultured for 2–4 h in G-IVF medium (Vitrolife Sweden AB, Goteborg, Sweden) and subsequently inseminated by conventional IVF or ICSI. Pronuclear checking was performed 16–18 h after insemination. The grading criteria for cleavage-stage embryos in our center are as follows: Grade 1, the size of blastomeres was uniform with fragmentation <5%; Grade 2, the blastomere size was slightly uneven with fragmentation 5%–20%; Grade 3, the blastomere size was heterogeneous or with fragmentation 21%–50%; and Grade 4, fragmentation >50%. The transferable embryos were defined as Grade 1 and 2 with at least 4 cells (except for embryos with 4 cells and Grade 2) 72 h after oocytes retrieval. Embryos met the standard of transferable embryo could be transferred, frozen, or extended culture to the blastocyst stage. Moreover, the embryos on day 3 with at least 6 cells and Grade 1–2 were classified as good-quality embryos. Blastocysts were evaluated based on the Gardner grading system. Good or top-quality blastocysts (at least 3BB) were transferred or vitrified (VT101, KITAZATO, Japan) on day 5 and day 6. No more than two embryos were transferred.
The primary outcome was cLBR, defined as the delivery of at least one live born baby (>24 weeks of gestation) resulting from one complete aspirated IVF/ICSI cycle, including the fresh and subsequent frozen-thawed cycles.
Statistical analyses were performed using R version 3.3.1. One-way ANOVA and Pearson Chi-square tests were used to ascertain significant differences among the five groups. Multivariate logistic regression model was constructed using cLBR as the dependent variable and oocyte number as the main independent variable after adjusting for other confounders that were identified in our univariate analysis. To further identify the predictors of cLBR, except for the variables with P < 0.2 determined by the univariate analysis, we also included the clinically relevant factors (duration of infertility and insemination method) in the multivariate logistic regression analysis with stepwise regression analysis. Finally, four factors (female age, type of infertility, antral follicle count (AFC), and oocyte number) were chosen to be included in the multivariable logistic regression analysis with stepwise selection. The likelihood of cLBR and certain factors was determined as an odds ratio (OR) with 95% confidence interval (CI). The Loess curve was constructed to present the association between LBR in the fresh cycle, cLBR, and the number of oocytes retrieved. P < 0.05 was considered statistically significant.
| Results|| |
Patients' basic characteristics and major IVF outcomes are presented in [Table 1]. The mean age of all patients at oocyte retrieval was 41.9 years (range 40–49 years) and patients in the 1–5 oocyte group were significantly older ( P < 0.001). Basal follicle-stimulating hormone (FSH) had a downward trend with increasing number of oocytes retrieved ( P < 0.001); AFC and the number of oocytes retrieved increased simultaneously (all P < 0.001).
|Table 1: The basic characteristics and IVF outcomes among women aged 40 years and over|
Click here to view
A total of 224 (13.9%) patients achieved a live birth following one complete cycle. As shown in [Table 1], the number of transferable embryos significantly increased when the number of oocytes retrieved increased ( P < 0.001). cLBR significantly increased when the number of oocytes retrieved increased (1–5 oocytes: 8.9%, 6–10 oocytes: 19.1%, 11–15 oocytes: 24.0%, 16–20 oocytes: 47.1%, >20 oocytes: 75%, Chi-square test for trend, P < 0.001).
To investigate the effect of maternal age on LBR in the fresh cycle and cLBR, data from 1,613 cycles were analyzed year by year [Table 2]. Elderly age at oocyte retrieval was associated with a decreased AFC, number of oocytes aspirated, number of transferable embryos, LBR in the fresh cycle, and cLBR. cLBR was 22.4% and 17.5% in women aged 40 and 41 years, respectively. Only three live births occurred among women aged 45 years, and none occurred in those aged over 45 years. The trend toward decreasing LBR in the fresh cycle and cLBR with increasing advanced maternal age was observed.
|Table 2: Clinical outcomes based on the year-by-year analysis for 1,613 oocyte aspirated cycles|
Click here to view
Results of the logistic regression analyses are presented in [Table 3]. The 1–5 oocyte group was used as a reference. After adjusting for variables including age, type of infertility, duration of infertility, BMI, basal FSH, AFC, and insemination method, the adjusted ORs for cLBR steadily increased from 1.82 (1.27–2.60) in the 6–10 oocyte group to 17.96 (4.70–88.34) in the >20 oocyte group. Age, type of infertility, and AFC had a significant effect on cLBR. However, for the duration of infertility, BMI, basal FSH, and insemination method, the effect was not significant. Finally, four effective variables – age, type of infertility, AFC, and the number of oocytes retrieved – were selected to contribute to the multivariable logistic regression analysis with stepwise selection. AFC (OR, 1.05; 95% CI, 1.01–1.09; P = 0.007) and the number of oocytes retrieved (6–10 oocytes: OR, 1.84, 95% CI, 1.29–2.62, P = 0.01; 11–15 oocytes: OR, 1.96, 95% CI, 1.16–3.25, P = 0.010; 16–20 oocytes: OR, 6.02, 95% CI, 2.76–13.05, P < 0.001; >20 oocytes: OR, 19.44, 95% CI, 5.08–95.80, P < 0.001) were key factors predictive of cLBR. Thus, the ORs for cLBR appeared significantly increased when the number of oocytes retrieved increased. To present the association among LBR in the fresh cycle, cLBR, and the number of oocytes retrieved, Loess curve was constructed [Figure 1], which revealed that LBR in the fresh cycle presented a relatively stable curve, while the cLBR presented an obvious upward trend.
|Figure 1: LBR and cLBR with respect to the number of oocytes retrieved are presented by Loess curve. LBR: Live birth rate; cLBR: Cumulative LBR.|
Click here to view
| Discussion|| |
Our study demonstrated that cLBR steadily increased with increasing number of oocytes, reaching 75.0% when >20 oocytes were retrieved. Loess curve revealed that cLBR increased rapidly when the number of oocytes increased beyond 10, but increased moderately when the number was between 1 and 10 oocytes. Furthermore, AFC and the number of oocytes retrieved were two key factors predictive of cLBR. These findings indicate that in women nearing the end of their reproductive lifespan, maximization of ovarian reserve exploitation may increase their chances of live birth.
The association between the number of oocytes retrieved and LBR in one fresh cycle,, and one complete cycle,,,, has previously been demonstrated. A landmark report of 400,135 cycles in the UK from the HFEA data demonstrated that LBR increased when 15 oocytes were retrieved, plateaued, and then declined when >20 oocytes were retrieved. Another large retrospective study of 256,381 cycles in the USA concluded that LBR increased at first and then plateaued when 15 oocytes were retrieved. However, these two analyses focused only on fresh cycles, whereas frozen-thawed cycles or cycles with a freeze-all strategy were excluded. Although a large number of patients were included in these two studies, it was unilateral to predict the effect of oocyte number with one oocyte retrieved on ART outcomes, especially for patients aged over 40 years with limited LBRs in the fresh cycles.
Over the past decades, there has been a considerable debate about the impact of oocyte yield on cLBR. Several studies have found that cLBR per aspiration is in line with the number of oocytes retrieved.,, A multicenter retrospective study of 15,000 women reported that cLBR steadily increased with the number of oocytes retrieved and no plateau was observed in women aged below 40 years with a good prognosis. Another cohort study among women aged 18–40 years in Belgium drew a similar conclusion. Similar trend was observed in our study for women aged over 40 years. A potential explanation for these findings is that the increasing number of oocytes aspirated increases the number of transferable embryos, which produces more embryos available for transfer. The goal of ART in younger women with good prognosis is to transfer the minimum number of embryos that can achieve a live birth without a multiple birth, while for elderly women, maximizing the chance of taking a baby home focuses on how to generate the largest number of transferable embryos. Different from findings of studies on LBR of fresh cycles, a plateau was not detected when more than 15 oocytes were retrieved in our study. A potential explanation for this is the improvement of vitrification techniques.
Marta Devesa et al. found that patients aged over 41 years would not benefit from the increase in the number of oocytes retrieved with regard to cLBR, whereas our study found that in women aged over 40 years, with the increase in the number of oocytes retrieved, cLBR also increased, and there was no sign of the so-called “plateau.” As women aged, the number of oocytes decreased and the quality worsened, which led to an increase in the proportion of aneuploid embryos. To obtain a live birth, we can only increase the probability of obtaining euploid embryos by increasing the number of oocytes retrieved. This conclusion applied to almost all elderly women. However, it should be noted that in our study, patients with a larger number of oocytes retrieved were far less than those with a small number of oocytes retrieved, which might affect our conclusions.
However, a high number of oocytes aspirated are associated with a higher risk of OHSS., Moderate and severe OHSS occurs in approximately 3%–8% of ART cycles among women of all ages. Our data demonstrated that the overall incidence of moderate-severe OHSS was only 0.6%. A possible explanation for these results is the adoption of frozen-thaw cycles and the high proportion of low responders in our study population. Nevertheless, additional treatment burden and risks related to extreme ovarian response such as ovarian torsion or even abdominal bleeding should be carefully taken into consideration.
For most women, the end of the fourth decade of life marks the end of their reproductive life. Our data demonstrated that the LBR quickly fell from the age of 43 years and rare pregnancies occurred at the age of 46 years and over. We sought to identify a favorable chance for live births in this older reproductive age group of women. In addition to the number of oocytes, age-related decline in oocyte quality is also a vital factor affecting pregnancy in older women. It is generally accepted that reduced pregnancy and higher abortion rate in women with advanced maternal age are correlated with an increased aneuploidy rate in the embryos.,, A large retrospective study involving 15,169 trophectoderm biopsies demonstrated that aneuploidy rate was 33% and 53% at the ages of 42 and 44 years, respectively. Another retrospective study manifested that the aneuploidy rate in the mature oocytes is nearly 75% in women aged 40 years old. Remarkably, for patients aged over 40 years, the most effective strategy to improve the cLBR is increasing the number of oocytes aspirated, which increases the chances to have a euploid embryo.
There are limitations of the present study that should be considered. Although we included more than 1,600 oocyte aspirated cycles and tried to minimize confounding bias by controlling for numbers of known confounders, the study was still limited by the retrospective nature of the analysis. Moreover, low responders (0–5 retrieved oocytes) accounted for approximately 65% in our study, which led to the limited sample of high oocyte yield population. Besides, patients of advanced maternal age with poor ovarian response who frequently correlated with cycle cancellation, no oocyte retrieval, and no available embryo to transfer were not included in the present study, which may lessen the reliability of the conclusion. Of note, since all patients were included in the present study although there were missing values of anti-Müllerian hormone (AMH) and the AMH level differs in each laboratory depending on the assay used, we adopted the basal FSH (between day 1 and day 4) and AFC as alternative markers to evaluate the ovarian reserve. In addition, due to the lack of fixed protocols such as the treatment dosage and duration of treatment and evidence-based therapeutic strategies to improve ovarian response and clinical outcomes, the pretreatment with the Coenzyme CQ10, dehydroepiandrosterone, or testosterone for advanced-age patients was not considered as the possible predictor. Prospective controlled studies with remarkable sample are needed.
Collectively, for patients aged 40 years and over, AFC and the number of oocytes retrieved are two key predictors for cLBR and maximization of ovarian reserve exploitation is pivotal to increase the chance of live birth.
Financial support and sponsorship
This study was supported by the National Natural Science Foundation of China (81871214, 81801449); the National Key R&D Program of China (2017YFC1001603); and the Medical Scientific Technology Research Foundation of Guangdong Province of China (A20200226).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Farquhar CM, Bhattacharya S, Repping S, Mastenbroek S, Kamath MS, Marjoribanks J, et al.
Female subfertility. Nat Rev Dis Primers 2019;5:7. doi: 10.1038/s41572-018-0058-8.
Seshadri S, Morris G, Serhal P, Saab W. Assisted conception in women of advanced maternal age. Best Pract Res Clin Obstet Gynaecol 2020;7:?S1521-6934:30123-1. doi: 10.1016/j.bpobgyn.2020.06.012.
Cimadomo D, Fabozzi G, Vaiarelli A, Ubaldi N, Ubaldi FM, Rienzi L, et al.
Impact of maternal age on oocyte and embryo competence. Front Endocrinol (Lausanne) 2018;9:327. doi: 10.3389/fendo.2018.00327.
Ben-Meir A, Burstein E, Borrego-Alvarez A, Chong J, Wong E, Yavorska T, et al
. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell 2015;14:887-95. doi: 10.1111/acel.12368.
Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A, et al.
Association between the number of eggs and live birth in IVF treatment: An analysis of 400 135 treatment cycles. Hum Reprod 2011;26:1768-74. doi: 10.1093/humrep/der106.
Steward RG, Lan L, Shah AA, Yeh JS, Price TM, Goldfarb JM, et al.
Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: An analysis of 256,381 in vitro
fertilization cycles. Fertil Steril 2014;101:967-73. doi: 10.1016/j.fertnstert.2013.12.026.
Briggs R, Kovacs G, MacLachlan V, Motteram C, Baker HW. Can you ever collect too many oocytes? Hum Reprod 2015;30:81-7. doi: 10.1093/humrep/deu272.
Zhou J, Wang B, Hu Y, Sun H. Association between the number of oocytes retrieved and cumulative live birth rate in women aged 35-40 years undergoing long GnRH agonist IVF/ICSI cycles. Arch Gynecol Obstet 2017;296:1005-12. doi: 10.1007/s00404-017-4503-9.
Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, et al.
Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod 2016;31:370-6. doi: 10.1093/humrep/dev316.
Polyzos NP, Drakopoulos P, Parra J, Pellicer A, Santos-Ribeiro S, Tournaye H, et al
. Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro
fertilization/intracytoplasmic sperm injection: A multicenter multinational analysis including ~15,000 women. Fertil Steril 2018;110:661-670.e1. doi: 10.1016/j.fertnstert.2018.04.039.
Chen YH, Wang Q, Zhang YN, Han X, Li DH, Zhang CL, et al.
Cumulative live birth and surplus embryo incidence after frozen-thaw cycles in PCOS: How many oocytes do we need? J Assist Reprod Genet 2017;34:1153-9. doi: 10.1007/s10815-017-0959-6.
Malchau SS, Henningsen AA, Forman J, Loft A, Nyboe Andersen A, Pinborg A, et al.
Cumulative live birth rate prognosis based on the number of aspirated oocytes in previous ART cycles. Hum Reprod 2019;34:171-80. doi: 10.1093/humrep/dey341.
Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, et al
. International Committee for Monitoring Assisted Reproductive Technology; World Health Organization. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril 2009;92:1520-4. doi: 10.1016/j.fertnstert. 2009.09.009.
Devesa M, Tur R, RodrÍguez I, Coroleu B, MartÍnez F, Polyzos NP, et al.
Cumulative live birth rates and number of oocytes retrieved in women of advanced age. A single centre analysis including 4500 women =38 years old. Hum Reprod 2018;33:2010-7. doi: 10.1093/humrep/dey295.
Magnusson Å, Källen K, Thurin-Kjellberg A, Bergh C. The number of oocytes retrieved during IVF: A balance between efficacy and safety. Hum Reprod 2018;33:58-64. doi: 10.1093/humrep/dex334.
Mourad S, Brown J, Farquhar C. Interventions for the prevention of OHSS in ART cycles: An overview of Cochrane reviews. Cochrane Database Syst Rev 2017;1:CD012103. doi: 10.1002/14651858.CD012103.pub2.
Staessen C, Platteau P, Van Assche E, Michiels A, Tournaye H, Camus M, et al.
Comparison of blastocyst transfer with or without preimplantation genetic diagnosis for aneuploidy screening in couples with advanced maternal age: A prospective randomized controlled trial. Hum Reprod 2004;19:2849-58. doi: 10.1093/humrep/deh536.
Rubio C, Bellver J, Rodrigo L, Castillón G, Guillén A, Vidal C, et al
. In vitro
fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: A randomized, controlled study. Fertil Steril 2017;107:1122-9. doi: 10.1016/j.fertnstert.2017.03.011.
Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, et al.
The nature of aneuploidy with increasing age of the female partner: A review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril 2014;101:656-63.e1. doi: 10.1016/j.fertnstert.2013.11.004.
Fragouli E, Alfarawati S, Spath K, Jaroudi S, Sarasa J, Enciso M, et al.
The origin and impact of embryonic aneuploidy. Hum Genet 2013;132:1001-13. doi: 10.1007/s00439-013-1309-0.
[Table 1], [Table 2], [Table 3]