|Year : 2018 | Volume
| Issue : 2 | Page : 100-104
Clinical Results of In Vitro Fertilization or Intracytoplasmic Sperm Injection Treatments in Women Aged 40 Years and above
Ting-Yu Zhang, Qin-Zhi Bu, Chun-Ying Su
Reproductive Medical Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
|Date of Submission||21-Apr-2018|
|Date of Web Publication||4-Oct-2018|
Reproductive Medical Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052
Source of Support: None, Conflict of Interest: None
Objective: The study was designed to estimate the live birth rate (LBR) and cumulative LBR (CLBR) in patients aged ≥40 years undergoing in vitro fertilization or intracytoplasmic sperm injection treatments during their first and multiple ovarian stimulation cycle(s).
Methods: A total of 697 advanced women underwent 1,293 treatment cycles, and 973 fresh embryo transfers were performed. The LBR and CLBR were analyzed with respect to an increase in the maternal age by every year.
Results: A declining trend in LBR and CLBR of the first cycle was seen with an increase in maternal age. The LBR in women aged 40 years was significantly higher than that in women aged ≥44 years (18.39% and 4.39%, respectively); the CLBR in women aged 40 years was also significantly higher than that in women aged 42, 43, and ≥44 years (22.40%, 9.09%, 9.09%, and 4.80%, respectively). However, there was no significant difference (P > 0.05) in the rate of miscarriage among all groups. For those who underwent multiple cycles, the number of live-born babies decreased rapidly after three ovarian stimulation cycles; the LBR in patients aged 40 years was significantly higher than that in patients aged 42 years and ≥44 years (15.24%, 5.20%, and 4.49%, respectively), and the CLBR in patients aged 40–41 years was significantly higher than that in patients aged ≥42 years. The CLBR in all groups gradually plateaued after three cycles; women aged 40–41 years achieved relatively reasonable CLBR, while the CLBR was <10% in women aged ≥42 years.
Conclusions: Women aged 40–41 years had a low but acceptable outcome in the first three ovarian stimulation cycles. The success rate quickly decreased, and for women aged ≥42 years, the decision to continue after three ovarian stimulation cycles should be made cautiously.
Keywords: Advanced Age; Clinical Results; Cumulative Live Birth Rate; Live Birth Rate
|How to cite this article:|
Zhang TY, Bu QZ, Su CY. Clinical Results of In Vitro Fertilization or Intracytoplasmic Sperm Injection Treatments in Women Aged 40 Years and above. Reprod Dev Med 2018;2:100-4
|How to cite this URL:|
Zhang TY, Bu QZ, Su CY. Clinical Results of In Vitro Fertilization or Intracytoplasmic Sperm Injection Treatments in Women Aged 40 Years and above. Reprod Dev Med [serial online] 2018 [cited 2020 Sep 22];2:100-4. Available from: http://www.repdevmed.org/text.asp?2018/2/2/100/242754
| Introduction|| |
In recent years, the number of women delaying childbearing has increased globally. It was reported that the birth rate in women aged 40–44 years almost doubled in the USA between 1990 and 2013. In Korea, the percentage of women aged ≥40 years who underwent fresh in vitro fertilization (IVF) cycles increased from 11.9% in 2009 to 19.7% in 2010. Following the two-child policy implemented in China, the percentage of infertile women aged ≥40 years in the Center for Reproductive Medicine has been sharply increasing, while their fecundity has significantly decreased. Therefore, an increasing number of older women wish to become mothers by means of assisted reproductive technology (ART). Although ART might overcome the age-related decline in fertility to some extent, the success rates are also markedly low., Physicians often face several critical questions: (1) what is the chance of conception in one ovarian stimulation cycle? (2) Is there an upper limit of ovarian stimulation cycles using their autologous oocytes for infertility treatments?
The purpose of the present study was to estimate the live birth rate (LBR) and cumulative LBR (CLBR) in patients aged ≥40 years undergoing IVF and intracytoplasmic sperm injection (ICSI) treatments during their first ovarian stimulation cycle and multiple ovarian stimulation cycles. We also analyzed how outcomes changed with each additional year of increase in maternal age.
| Methods|| |
All clinical data of women aged 40 years and above undergoing their first IVF/ICSI cycles were captured in the Data Managing System in the Reproductive Medicine Center of the First Affiliated Hospital of Zhengzhou University between January 1, 2012 and December 31, 2014, and the outcomes of consecutive cycles were recorded. All the couples were followed until either discontinuation of treatment or delivery of a live-born infant, the deadline was December 31, 2016. In all, 697 women were enrolled, and there were 1,293 consecutive cycles, 320 canceled cycles, and 973 fresh transplant cycles.
The inclusion criteria included patients aged ≥40 years and the causative factors for infertility such as tubal and pelvic factors, endometriosis or anovulation, male factor, and advanced age. The main exclusion criteria included patients with preimplantation genetic diagnosis or screening, patients with donor egg or sperm, and patients with a uterine malformation.
Gonadotropin-releasing hormone (GnRH) agonist long protocol, GnRH agonist short protocol, GnRH agonist ultra-long protocol, GnRH agonist modified ultra-long protocol, and mild stimulation protocol were performed depending on the estimated ovarian response, based on the detailed information from previous studies., Luteal phase supplementation was continued until a pregnancy test was performed. If the test was positive, progesterone (P) supplementation was continued for another 5 weeks.
Clinical pregnancy was defined as ultrasound visualization of an intrauterine sac with an audible fetal heartbeat. Live birth was defined as the delivery of at least one liveborn infant after ≥28 weeks of gestation. The denominator of LBR per cycle was the number of fresh transplant cycles, the denominator of CLBR per woman was the number of initial cycles, and the number of initial cycles in the first ovulation cycle was the same as the women who underwent ART in this study.
Statistical analyses were performed using IBM SPSS Statistics version 21.0 (IBM Corp, Armonk, New York, USA). Data were expressed as numbers (percentage) for categorical variables, mean ± standard deviation (SD) for continuous variables following normal distribution, and median (interquartile range) for continuous variables following an abnormal distribution. Analysis of variance and Chi-square test were used as appropriate. The two-tailed value of P < 0.05 was considered statistically significant. P value was corrected according to Bonferroni adjustment when making multiple comparisons among groups in categorical variables.
| Results|| |
Six hundred and ninety-seven advanced women underwent 1,293 treatment cycles and 973 fresh transplant cycles were conducted. The cancellation rate was 24.7%. The demographic details of the 697 women were shown in [Table 1]. The mean ± SD of age and body mass index during the first cycle was 41.93 ± 1.91 and 23.58 ± 2.90, respectively. Median follicle-stimulating hormone level was 8.11 mIU/mL and E2 level was 41.97 pg/mL. Most of the women were second infertility (77.76%), and the main causes of infertility were tubal and pelvic factors (47.06%), advanced age (33.72%), or male factor (17.07%). The primary fertilization type and ovarian stimulation protocol were IVF (82.93%) and GnRH agonist long protocol (86.08%), respectively.
|Table 1: Clinical characteristics of the patients (x̄ ± s, M [P25, P75])|
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The data from all 697 patients, subdivided by 1-year age increment during the first ovarian stimulation cycle, were shown in [Table 2]. All groups were similar in terms of gonadotropin dose, gonadotropin duration, endometrial thickness, the number of embryos available, and high-quality embryos. A significant difference (P < 0.05) was seen in the number of mature/MII oocytes and transferred embryos. A declining trend in clinical pregnancy rate (CPR), LBR, and CLBR was noted with an increase in age, and the CPR of women aged 40–41 years (20.53%–31.03%) was significantly higher than that in women aged ≥43 years (7.89%–13.98%). The LBR of women aged 40 years was significantly higher than that in women aged ≥44 years (18.39% and 4.39%, respectively). The CLBR of women aged 40 years was significantly higher than that in women aged 42, 43, and ≥44 years (22.40%, 9.09%, 9.09%, and 4.80%, respectively). However, there was no statistical significance (P > 0.05) in the rate of miscarriage in all groups.
|Table 2: IVF/ICSI-embryo transfer parameters of women aged ≥40 years in the first ovarian stimulation cycle|
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[Table 3] shows the LBR and CLBR of women aged ≥40 years in multiple ovarian stimulation cycles. The number of live-born babies decreased rapidly after cycle 3. Overall, an increasing trend in the cycle cancellation rate and a declining trend in LBR and CLBR were seen with an increase in maternal age. The cycle cancellation rate of patients aged 40–41 years (18.71%–19.94%) was significantly lower than that in patients aged ≥43 years (30.20%–31.72%). The LBR in patients aged 40 years was significantly higher than that in patients aged 42 years and ≥44 years (15.24%, 5.20%, and 4.49%, respectively). The CLBR in patients aged 40–41 years (23.12%–27.60%) was significantly higher than that in patients aged ≥42 years (8.80%–10.10%).
|Table 3: The LBR and CLBR of women aged ≥40 years in multiple ovarian cycles|
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[Figure 1] shows the CLBR per woman of multiple ovarian stimulation cycles according to the age of woman during the first cycle. Women aged 40–41 years could achieve relatively reasonable CLBR, while the CLBR decreased obviously in women aged ≥42 years, the CLBR of all groups gradually plateaued after three ovarian stimulation cycles.
|Figure 1: CLBR per woman of multiple cycles according to age of woman at first cycle. CLBR: Cumulative live-birth rate.|
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| Discussion|| |
The present study compared the LBR and CLBR in patients aged ≥40 years in the first ovarian stimulation cycle and multiple ovarian stimulation cycles, with every 1-year increase in maternal age. A low but reasonable CLBR (14.38%–22.40%) in the first ovarian stimulation cycle and (23.12%–27.60%) in the multiple ovarian stimulation cycles was observed for patients aged 40–41 years. Most of the live births (98.4%) took place during the first three ovarian stimulation cycles.
Maternal age is the most important factor determining the success rate of pregnancy in ART. Especially in women aged ≥40 years, a single additional year of age can lead to a drastic decline in fertility. The present study found a decline in the number of mature/MII oocytes with an increase in the maternal age. However, the number of available embryos and high-quality embryos was similar. A CPR of ≤10% and a LBR of ≤5% among infertile women aged ≥43 years have been reported, indicating that the clinical outcomes declined drastically in comparison with patients aged 41 and 42 years., Our results showed that the rate of CPR and LBR in the first ovarian stimulation cycle gradually decreased after 42 years and significantly decreased after 44 years and above. The CPR was <10%, and the LBR was <5% among infertile women aged ≥44 years, which was similar to the previous studies. In addition, the rate of CLBR per woman was <10% after 42 years and <5% after 44 years, similar to the drastic decline in reproductive outcomes compared with women aged 40–41 years. Although no significant difference was noted in the rate of miscarriage across all age groups, the miscarriage rate reached up to over 40%. It could be mainly due to a decrease in egg quality. It has been reported that the maternal age was linked to a chromosomal abnormality.,
Several investigators have sought to account for the clinical pregnancy and LBR per cycle.,, A further strength of our study was the analysis of CLBR after multiple ovarian stimulation cycles. A woman undergoing fertility counseling seeks to know the probability of taking home a baby at the end of her treatment and an upper limit for ovarian stimulation cycles using their autologous oocytes. As reported in a previous study, the cancellation rate increased with every year of increase in maternal age, from 9.3% at age 40 years to 55.0% at age 45 years. Our results indicated that the cycle cancellation rate increased gradually after 42 years and increased significantly after ≥44 years. The LBR and CLBR dropped significantly after 42 years; in addition, the number of live-born babies declined rapidly after three ovulation cycles. There were five live births in the third ovarian stimulation cycle and only two live births after ≥4 cycles. Klipstein et al. reported that the CLBR dropped with an increase in the age of women at the beginning of the cycle. The CLBR was 25.3% in the 40th year after 3 cycles, stayed below 20% through the end of the 42nd year, and dropped to <10% after 43 years. Furthermore, there were no live births in women aged ≥44 years after 3 cycles. Kim et al. also found that the CLBR was 3% in patients aged 43 and 44 years after 4 cycles, and repeated attempts did not result in an increase in the CLBR in patients aged ≥45 years. Our results were similar to those of the previous studies. Subsequently, we analyzed the CLBR per woman in multiple ovarian stimulation cycles, based on the age of woman at the first cycle [Figure 1]. It was found that women aged 40–41 years could achieve a relatively reasonable CLBR, while the CLBR was <10% in women aged ≥42 years, the CLBR of all groups gradually reached a plateau after three ovarian stimulation cycles, indicating that 98.4% live births were achieved during the first three ovarian stimulation cycles. It was similar to an earlier study, which showed that over 90.0% of live births in the general population were achieved during the first three cycles.
The cancellation rate and IVF treatment costs for advanced women are frequently high. The cancellation rate was about 15%–30% among women aged >40 years, even in a preselected IVF population., It has also been reported that the expense of live births for those over 40 years was 2.5 times higher or more than that for those aged 35–39 years. In IVF cycles with LBR <5%, the cost of ART was very high and significantly exceeded that of the donor cycles. In addition, the safety, economic, and psychosocial impact of fertility treatments on children or older parents has been discussed. Other researchers reported that the incidence of complications and neonatal morbidity greatly increased., Therefore, it is very important to undergo a detailed counseling before ART. Our goal was to calculate the LBR and CLBR in the first ovarian stimulation cycle and multiple ovarian stimulation cycles to provide counseling data for a couple's primary questions before undergoing IVF procedures. However, some limitations of the study should be admitted, such as it is a single-center retrospective cohort study; other factors influencing the clinical outcome, such as endometrial preparation programs and male factor, were not considered when analyzing CLBR.
In conclusion, women aged 40–41 years had low but acceptable outcome using their own oocytes in the first three ovarian stimulation cycles, the success rate rapidly decreased with increasing maternal age, and cautious decision should be considered women aged ≥42 years after three cycles, which could facilitate individualized advisory in a large population of patients considering IVF treatments.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Matthews TJ. Births: Final data for 2013. Natl Vital Stat Rep 2015;64:1-65. doi: 10.1111/ajt.13201.
Lee GH, Song HJ, Lee KS, Choi YM. Current status of assisted reproductive technology in Korea, 2010. Clin Exp Reprod Med 2015;42:8-13. doi: 10.5653/cerm.2015.42.1.8.
Spandorfer SD, Bendikson K, Dragisic K, Schattman G, Davis OK, Rosenwaks Z. Outcome of in vitro
fertilization in women 45 years and older who use autologous oocytes. Fertil Steril 2007;87:74-6. doi: 10.1016/j.fertnstert.2006.05.081.
Ron-El R, Raziel A, Strassburger D, Schachter M, Kasterstein E, Friedler S. Outcome of assisted reproductive technology in women over the age of 41. Fertil Steril 2000;74:471-5. doi: 10.1016/s0015-0282(00)00697-x.
Hu L, Bu Z, Guo Y, Su Y, Zhai J, Sun Y. Comparison of different ovarian hyperstimulation protocols efficacy in poor ovarian responders according to the bologna criteria. Int J Clin Exp Med 2014;7:1128-34.
Du QY, Wang EY, Huang Y, Guo XY, Xiong YJ, Yu YP, et al.
Blastocoele expansion degree predicts live birth after single blastocyst transfer for fresh and vitrified/warmed single blastocyst transfer cycles. Fertil Steril 2016;105:910-19. doi: 10.1016/j.fertnstert.2015.12.014
Hull MG, Fleming CF, Hughes AO, McDermott A. The age-related decline in female fecundity: A quantitative controlled study of implanting capacity and survival of individual embryos after in vitro
fertilization. Fertil Steril 1996;65:783-90. doi: 10.1016/s0015-0282(16)58214-4.
Klipstein S, Regan M, Ryley DA, Goldman MB, Alper MM, Reindollar RH. One last chance for pregnancy: A review of 2,705 in vitro
fertilization cycles initiated in women age 40 years and above. Fertil Steril 2005;84:435-45. doi: 10.1016/j.fertnstert.2005.02.020.
Serour G, Mansour R, Serour A, Aboulghar M, Amin Y, Kamal O, et al.
Analysis of 2,386 consecutive cycles of in vitro
fertilization or intracytoplasmic sperm injection using autologous oocytes in women aged 40 years and above. Fertil Steril 2010;94:1707-12. doi: 10.1016/j.fertnstert.2009.09.044.
Vialard F, Lombroso R, Bergere M, Gomes DM, Hammoud I, Bailly M, et al.
Oocyte aneuploidy mechanisms are different in two situations of increased chromosomal risk: Older patients and patients with recurrent implantation failure after in vitro
fertilization. Fertil Steril 2007;87:1333-9. doi: 10.1016/j.fertnstert.2006.11.042.
Hornick JE, Duncan FE, Sun M, Kawamura R, Marko JF, Woodruff TK, et al.
Age-associated alterations in the micromechanical properties of chromosomes in the mammalian egg. J Assist Reprod Genet 2015;32:765-9. doi: 10.1007/s10815-015-0453-y.
Tsafrir A, Simon A, Revel A, Reubinoff B, Lewin A, Laufer N, et al.
Retrospective analysis of 1217 IVF cycles in women aged 40 years and older. Reprod Biomed Online 2007;14:348-55. doi: 10.1016/s1472-6483(10)60878-4.
Kim HO, Sung N, Song IO. Predictors of live birth and pregnancy success after in vitro
fertilization in infertile women aged 40 and over. Clin Exp Reprod Med 2017;44:111-7. doi: 10.5653/cerm.2017.44.2.111.
Witsenburg C, Dieben S, Van der Westerlaken L, Verburg H, Naaktgeboren N. Cumulative live birth rates in cohorts of patients treated with in vitro
fertilization or intracytoplasmic sperm injection. Fertil Steril 2005;84:99-107. doi: 10.1016/j.fertnstert.2005.02.013.
Orvieto R, Bar-Hava I, Yoeli R, Ashkenazi J, Rabinerson D, Bar J, et al.
Results of in vitro
fertilization cycles in women aged 43-45 years. Gynecol Endocrinol 2004;18:75-8. doi: 10.1080/09513590310001651849.
Maheshwari A, Scotland G, Bell J, McTavish A, Hamilton M, Bhattacharya S. Direct health services costs of providing assisted reproduction services in older women. Fertil Steril 2010;93:527-36. doi: 10.1016/j.fertnstert.2009.01.115.
Henne MB, Stegmann BJ, Neithardt AB, Catherino WH, Armstrong AY, Kao TC, et al.
The combined effect of age and basal follicle-stimulating hormone on the cost of a live birth at assisted reproductive technology. Fertil Steril 2008;89:104-10. doi: 10.1016/j.fertnstert.2007.02.016.
Caplan AL, Patrizio P. Are you ever too old to have a baby? The ethical challenges of older women using infertility services. Semin Reprod Med 2010;28:281-6. doi: 10.1055/s-0030-1255175.
Wennberg AL, Opdahl S, Bergh C, Aaris Henningsen AK, Gissler M, Romundstad LB, et al.
Effect of maternal age on maternal and neonatal outcomes after assisted reproductive technology. Fertil Steril 2016;106:1142-49.e14. doi: 10.1016/j.fertnstert.2016.06.021.
Kenny LC, Lavender T, McNamee R, O'Neill SM, Mills T, Khashan AS. Advanced maternal age and adverse pregnancy outcome: Evidence from a large contemporary cohort. PLoS One 2013;8:e56583. doi: 10.1371/journal.pone.0056583.
[Table 1], [Table 2], [Table 3]