Clinical Endocrinology (2016) 84, 720–728
doi: 10.1111/cen.12983
ORIGINAL ARTICLE
Luteal-phase ovarian stimulation vs conventional ovarian stimulation in patients with normal ovarian reserve treated for IVF: a large retrospective cohort study Ningling Wang1, Yun Wang1, Qiuju Chen, Jing Dong, Hui Tian, Yonglun Fu, Ai Ai, Qifeng Lyu and Yanping Kuang Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
Summary Objective We have previously reported a new luteal-phase ovarian stimulation (LPS) strategy for infertility treatment. The purpose of this study was to systematically assess the efficiency and safety of this strategy by comparing it with conventional ovarian stimulation protocols. Design Retrospective cohort study. Subjects Patients with normal ovarian reserve undergoing ovum pick-up (OPU) cycles between April 2012 and September 2013 were enrolled: 708 patients underwent the LPS protocol compared with 745 patients who underwent the mild treatment protocol and 1287 patients who underwent the short-term protocol. Measurements Number of mature oocytes retrieved and topquality embryos obtained, implantation rate, pregnancy rate, live birth and ongoing pregnancy rate and neonatal outcomes. Results The numbers of mature oocytes retrieved and top-quality embryos obtained per OPU cycle were significantly increased in the LPS group (109 76 and 46 43, respectively) compared with the mild treatment group (37 30 and 18 18, respectively, both P < 0001) or the short-term group (91 55 and 37 31, respectively, both P < 0001). Moreover, the total gonadotrophin used was also the highest in the LPS group. No significant differences were identified in the implantation rate (355% vs 348%, P > 005), pregnancy rate (462% vs 437%, P > 005) or live birth and ongoing pregnancy rate (444% vs 417%, P > 005) per frozen-thawed embryo transfer (FET) cycle in the LPS and mild treatment groups, respectively. However, the LPS protocol achieved a higher implantation rate (355% vs 318%, P = 0012), pregnancy rate (462% vs 419%, P = 0041), Correspondence: Yanping Kuang, Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, 639 Zhizaoju Rd, Shanghai 200001, China. Tel.: +86 21 23271699 5539; Fax: +86 21 53078108; E-mail: kuangyanp@ 126.com
and live birth and ongoing pregnancy rate (444% vs 392%, P = 0012) compared with the short-term protocol. Neonatal outcomes in the LPS group were similar to the other two groups. Conclusions The available data suggest that LPS is a feasible strategy for infertility treatment and complements the available follicular-phase ovarian stimulation strategies. (Received 31 May 2015; returned for revision 12 October 2015; finally revised 15 November 2015; accepted 16 November 2015)
Introduction With the rapid development of assisted reproductive technology, controlled ovarian stimulation strategies have been widely used for infertility treatment.1 The long-term GnRH agonist (GnRHa) protocol initiates GnRHa injection in the mid-luteal phase of the previous menstrual cycle, and ovarian stimulation begins with or after the onset of the subsequent menstrual period.2,3 In contrast to the long-term protocol, the short-term protocol is initiated in the early follicular phase, specifically between cycle days 2 and 3. The short-term protocol favours the dual effect of the GnRHa administration with an initial release of endogenous gonadotrophins and a subsequent decrease in gonadotrophin secretion related to hypophyseal desensitization.4,5 Recently, mild ovarian stimulation regimens have received increasing attention and have been recognized as simpler, safer and more patientfriendly protocols because of their ability to reduce the incidence of ovarian hyperstimulation syndrome (OHSS), unnecessary discomfort and medical expenses.6,7 In addition to these differences, these regimens share a point in common: ovarian stimulation is initiated in the early follicular phase. However, increasing evidence has indicated that multiple waves of antral follicles developed during the human menstrual cycle, and small antral follicles were also identified in the luteal phase.8 Whether these luteal-phase antral follicles could be routinely recruited and develop to embryos after fertilization remains unclear and represents a substantial challenge to reproductive specialists.
1
Equal contributors.
720
© 2015 John Wiley & Sons Ltd
LPS strategy for infertility treatment 721 Furthermore, for fertility preservation in cancer patients, limited studies have retrieved oocytes during the luteal phase via administration of an follicle-stimulating hormone (FSH) and GnRH antagonist.9,10 Nevertheless, the duration of stimulation was long, and the efficacy was low.11 We have recently established a relatively efficient LPS protocol, which primarily comprises an aromatase inhibitor (letrozole), human menopausal gonadotropin (hMG), and GnRHa. This strategy has been proven to be feasible in producing competent oocytes/embryos for women with infertility.12 However, a relatively small sample size and a lack of strict-control groups limited the findings in our previous study. Therefore, it is necessary to conduct a larger cohort study to systematically assess the efficiency and safety of this new ovarian stimulation strategy. In this study, the mild ovarian stimulation approach and the standard GnRHa short-term protocol were selected as the control groups to evaluate the LPS strategy for infertility treatment based on different measurements, including the number of mature oocytes retrieved, number of top-quality embryos obtained, implantation rate, pregnancy rate, live birth and ongoing pregnancy rate and neonatal outcomes. Our aim is to test the hypothesis that LPS is an effective and safe strategy for infertility treatment.
Methods Data collection and design This retrospective cohort study was conducted in the Department of Assisted Reproduction of the Ninth People’s Hospital of Shanghai Jiaotong University, School of Medicine. The study was approved by the ethical review committee of the Ninth People’s Hospital of Shanghai and the Shanghai Jiaotong University Medical Centre, China. The characteristics and cycle parameters of the patients were recorded in the database of our centre. We screened the database according to the following search criteria: time between April 2012 and September 2013; and the use of the LPS protocol, mild ovarian stimulation protocol or short-term protocol. For better comparison and analysis, only patients with a normal ovarian reserve and infertility caused by tubal or male factor or unexplained infertility were considered. The ovum pick-up (OPU) cycles were selected based on the following inclusion/exclusion criteria. The inclusion criteria were as follows: women aged 20–35 years; and a body mass index (BMI) of 18–28 kg/m2. The exclusion criteria were as follows: basal FSH value >10 IU/L, LH > 10 IU/L, oestradiol > 80 ng/ml or progesterone > 05 ng/ ml; or the presence of other coexisting diseases, such as polycystic ovary syndrome, endometriosis or adenomyosis, ovary operation history, uterine malformation, intrauterine adhesion, diminished ovary reserve, abnormal endometrium, uterine leiomyoma, luteinized unruptured follicle syndrome (LUFS), hyperprolactinaemia, endometrial tuberculosis or conization of cervix. The corresponding frozen-thawed embryo transfer (FET) cycles of the OPU cycles were also screened out for analysis. The pregnancy outcomes were scored by 15 October 2014. The study © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2016), 84, 720–728
design and participant selection procedure are presented in Figure S1. Regimens A detailed description of the LPS procedure has been presented in our previous publication.12 Briefly, ovarian stimulation was initiated for patients with antral follicles 005); however, it was significantly higher than the short-term group (P = 0041). Consistent with this finding, the rate of live birth and ongoing pregnancy was also significantly higher in the LPS group compared with the short-term group (P = 0012). The rate of pregnancy loss after conception was not significantly different between the groups (212% in the LPS group, 199% in the mild treatment group and 242% in the short-term group). A multivariate logistic regression model was conducted (Table 4). The dependent variable comprised the live birth and ongoing pregnancy rate, and the independent variables included maternal age, BMI, duration of infertility, number of previous IVF attempts, number of transferred embryos, type of transferred embryos, endometrial thickness and type of stimulation protocol. The final results indicated significant positive (favourable) effects of the number of transferred embryos (OR = 161, 95%CI: 126–207) and endometrial thickness (OR = 107, 95% CI: 103–110); however, negative (adverse) effects of previous IVF attempts (OR = 094, 95%CI: 088–100), cleavage-stage embryo transferred (OR = 070, 95%CI: 054–092) and shortterm protocol (OR = 080, 95%CI: 067–096) were identified on the outcome. Table 5 presents the neonatal outcomes and congenital malformations of all foetuses and infants at the end of the research period. No significant differences were identified for the children’s gender, birth weight or gestation between the groups (all
Table 2. Cycle characteristics of the three groups
Variable Duration of ovarian stimulation – days Total dose of hMG – IU Total dose of letrozole – mg Total dose of clomiphene – mg Number of mature oocytes per cycle Number of normal fertilization Top-quality embryos (Grades I+II) per cycle† Cancellation rate (%) Ovarian hyperstimulation syndrome‡ Sex hormones on trigger day No. of cycles evaluated (%) FSH – IU/L LH – IU/L Oestradiol – pg/ml§ Progesterone – ng/ml Sex hormones on second day of trigger No. of cycles evaluated (%) FSH – IU/L LH – IU/L Oestradiol – pg/ml§ Progesterone – ng/ml
LPS group (N = 727)
Mild treatment group (N = 830)
Short-term group (N = 1385)
P value 1*
P value 2*
104 18 2319 4374 208 51 0 109 76 80 62 46 43 90 (124) 0
96 20 572 3216 114 56 2452 73 37 30 29 24 18 18 182 (219) 0
82 17 1583 4723 0 0 91 55 68 45 37 31 138 (10) 1 (007)
doi: 10.1111/cen.12983
ORIGINAL ARTICLE
Luteal-phase ovarian stimulation vs conventional ovarian stimulation in patients with normal ovarian reserve treated for IVF: a large retrospective cohort study Ningling Wang1, Yun Wang1, Qiuju Chen, Jing Dong, Hui Tian, Yonglun Fu, Ai Ai, Qifeng Lyu and Yanping Kuang Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
Summary Objective We have previously reported a new luteal-phase ovarian stimulation (LPS) strategy for infertility treatment. The purpose of this study was to systematically assess the efficiency and safety of this strategy by comparing it with conventional ovarian stimulation protocols. Design Retrospective cohort study. Subjects Patients with normal ovarian reserve undergoing ovum pick-up (OPU) cycles between April 2012 and September 2013 were enrolled: 708 patients underwent the LPS protocol compared with 745 patients who underwent the mild treatment protocol and 1287 patients who underwent the short-term protocol. Measurements Number of mature oocytes retrieved and topquality embryos obtained, implantation rate, pregnancy rate, live birth and ongoing pregnancy rate and neonatal outcomes. Results The numbers of mature oocytes retrieved and top-quality embryos obtained per OPU cycle were significantly increased in the LPS group (109 76 and 46 43, respectively) compared with the mild treatment group (37 30 and 18 18, respectively, both P < 0001) or the short-term group (91 55 and 37 31, respectively, both P < 0001). Moreover, the total gonadotrophin used was also the highest in the LPS group. No significant differences were identified in the implantation rate (355% vs 348%, P > 005), pregnancy rate (462% vs 437%, P > 005) or live birth and ongoing pregnancy rate (444% vs 417%, P > 005) per frozen-thawed embryo transfer (FET) cycle in the LPS and mild treatment groups, respectively. However, the LPS protocol achieved a higher implantation rate (355% vs 318%, P = 0012), pregnancy rate (462% vs 419%, P = 0041), Correspondence: Yanping Kuang, Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, 639 Zhizaoju Rd, Shanghai 200001, China. Tel.: +86 21 23271699 5539; Fax: +86 21 53078108; E-mail: kuangyanp@ 126.com
and live birth and ongoing pregnancy rate (444% vs 392%, P = 0012) compared with the short-term protocol. Neonatal outcomes in the LPS group were similar to the other two groups. Conclusions The available data suggest that LPS is a feasible strategy for infertility treatment and complements the available follicular-phase ovarian stimulation strategies. (Received 31 May 2015; returned for revision 12 October 2015; finally revised 15 November 2015; accepted 16 November 2015)
Introduction With the rapid development of assisted reproductive technology, controlled ovarian stimulation strategies have been widely used for infertility treatment.1 The long-term GnRH agonist (GnRHa) protocol initiates GnRHa injection in the mid-luteal phase of the previous menstrual cycle, and ovarian stimulation begins with or after the onset of the subsequent menstrual period.2,3 In contrast to the long-term protocol, the short-term protocol is initiated in the early follicular phase, specifically between cycle days 2 and 3. The short-term protocol favours the dual effect of the GnRHa administration with an initial release of endogenous gonadotrophins and a subsequent decrease in gonadotrophin secretion related to hypophyseal desensitization.4,5 Recently, mild ovarian stimulation regimens have received increasing attention and have been recognized as simpler, safer and more patientfriendly protocols because of their ability to reduce the incidence of ovarian hyperstimulation syndrome (OHSS), unnecessary discomfort and medical expenses.6,7 In addition to these differences, these regimens share a point in common: ovarian stimulation is initiated in the early follicular phase. However, increasing evidence has indicated that multiple waves of antral follicles developed during the human menstrual cycle, and small antral follicles were also identified in the luteal phase.8 Whether these luteal-phase antral follicles could be routinely recruited and develop to embryos after fertilization remains unclear and represents a substantial challenge to reproductive specialists.
1
Equal contributors.
720
© 2015 John Wiley & Sons Ltd
LPS strategy for infertility treatment 721 Furthermore, for fertility preservation in cancer patients, limited studies have retrieved oocytes during the luteal phase via administration of an follicle-stimulating hormone (FSH) and GnRH antagonist.9,10 Nevertheless, the duration of stimulation was long, and the efficacy was low.11 We have recently established a relatively efficient LPS protocol, which primarily comprises an aromatase inhibitor (letrozole), human menopausal gonadotropin (hMG), and GnRHa. This strategy has been proven to be feasible in producing competent oocytes/embryos for women with infertility.12 However, a relatively small sample size and a lack of strict-control groups limited the findings in our previous study. Therefore, it is necessary to conduct a larger cohort study to systematically assess the efficiency and safety of this new ovarian stimulation strategy. In this study, the mild ovarian stimulation approach and the standard GnRHa short-term protocol were selected as the control groups to evaluate the LPS strategy for infertility treatment based on different measurements, including the number of mature oocytes retrieved, number of top-quality embryos obtained, implantation rate, pregnancy rate, live birth and ongoing pregnancy rate and neonatal outcomes. Our aim is to test the hypothesis that LPS is an effective and safe strategy for infertility treatment.
Methods Data collection and design This retrospective cohort study was conducted in the Department of Assisted Reproduction of the Ninth People’s Hospital of Shanghai Jiaotong University, School of Medicine. The study was approved by the ethical review committee of the Ninth People’s Hospital of Shanghai and the Shanghai Jiaotong University Medical Centre, China. The characteristics and cycle parameters of the patients were recorded in the database of our centre. We screened the database according to the following search criteria: time between April 2012 and September 2013; and the use of the LPS protocol, mild ovarian stimulation protocol or short-term protocol. For better comparison and analysis, only patients with a normal ovarian reserve and infertility caused by tubal or male factor or unexplained infertility were considered. The ovum pick-up (OPU) cycles were selected based on the following inclusion/exclusion criteria. The inclusion criteria were as follows: women aged 20–35 years; and a body mass index (BMI) of 18–28 kg/m2. The exclusion criteria were as follows: basal FSH value >10 IU/L, LH > 10 IU/L, oestradiol > 80 ng/ml or progesterone > 05 ng/ ml; or the presence of other coexisting diseases, such as polycystic ovary syndrome, endometriosis or adenomyosis, ovary operation history, uterine malformation, intrauterine adhesion, diminished ovary reserve, abnormal endometrium, uterine leiomyoma, luteinized unruptured follicle syndrome (LUFS), hyperprolactinaemia, endometrial tuberculosis or conization of cervix. The corresponding frozen-thawed embryo transfer (FET) cycles of the OPU cycles were also screened out for analysis. The pregnancy outcomes were scored by 15 October 2014. The study © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2016), 84, 720–728
design and participant selection procedure are presented in Figure S1. Regimens A detailed description of the LPS procedure has been presented in our previous publication.12 Briefly, ovarian stimulation was initiated for patients with antral follicles 005); however, it was significantly higher than the short-term group (P = 0041). Consistent with this finding, the rate of live birth and ongoing pregnancy was also significantly higher in the LPS group compared with the short-term group (P = 0012). The rate of pregnancy loss after conception was not significantly different between the groups (212% in the LPS group, 199% in the mild treatment group and 242% in the short-term group). A multivariate logistic regression model was conducted (Table 4). The dependent variable comprised the live birth and ongoing pregnancy rate, and the independent variables included maternal age, BMI, duration of infertility, number of previous IVF attempts, number of transferred embryos, type of transferred embryos, endometrial thickness and type of stimulation protocol. The final results indicated significant positive (favourable) effects of the number of transferred embryos (OR = 161, 95%CI: 126–207) and endometrial thickness (OR = 107, 95% CI: 103–110); however, negative (adverse) effects of previous IVF attempts (OR = 094, 95%CI: 088–100), cleavage-stage embryo transferred (OR = 070, 95%CI: 054–092) and shortterm protocol (OR = 080, 95%CI: 067–096) were identified on the outcome. Table 5 presents the neonatal outcomes and congenital malformations of all foetuses and infants at the end of the research period. No significant differences were identified for the children’s gender, birth weight or gestation between the groups (all
Table 2. Cycle characteristics of the three groups
Variable Duration of ovarian stimulation – days Total dose of hMG – IU Total dose of letrozole – mg Total dose of clomiphene – mg Number of mature oocytes per cycle Number of normal fertilization Top-quality embryos (Grades I+II) per cycle† Cancellation rate (%) Ovarian hyperstimulation syndrome‡ Sex hormones on trigger day No. of cycles evaluated (%) FSH – IU/L LH – IU/L Oestradiol – pg/ml§ Progesterone – ng/ml Sex hormones on second day of trigger No. of cycles evaluated (%) FSH – IU/L LH – IU/L Oestradiol – pg/ml§ Progesterone – ng/ml
LPS group (N = 727)
Mild treatment group (N = 830)
Short-term group (N = 1385)
P value 1*
P value 2*
104 18 2319 4374 208 51 0 109 76 80 62 46 43 90 (124) 0
96 20 572 3216 114 56 2452 73 37 30 29 24 18 18 182 (219) 0
82 17 1583 4723 0 0 91 55 68 45 37 31 138 (10) 1 (007)
