Ovarian stimulation with corifollitropin alfa followed by hp-hMG compared to hp-hMG in patients at risk of poor ovarian response undergoing ICSI: A randomized controlled trial

Accepted Manuscript Title: Ovarian stimulation with corifollitropin alfa followed by hp-hMG compared to hp-hMG in patients at risk of poor ovarian response undergoing ICSI: a randomized controlled trial Authors: Roser Taronger, Susana Mart´ınez-Cuenca, Inmaculada Ferreros, Jos´e M. Rubio, Pedro J. Fern´andez-Colom, M. Luisa Mart´ınez-Triguero, Antonio Pellicer PII: DOI: Reference:

S0301-2115(18)31035-2 https://doi.org/10.1016/j.ejogrb.2018.10.034 EURO 10582

To appear in:

EURO

Received date: Revised date: Accepted date:

19-6-2018 23-9-2018 10-10-2018

Please cite this article as: Taronger R, Mart´ınez-Cuenca S, Ferreros I, Rubio JM, Fern´andez-Colom PJ, Mart´ınez-Triguero ML, Pellicer A, Ovarian stimulation with corifollitropin alfa followed by hp-hMG compared to hp-hMG in patients at risk of poor ovarian response undergoing ICSI: a randomized controlled trial, European Journal of Obstetrics and Gynecology (2018), https://doi.org/10.1016/j.ejogrb.2018.10.034 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Ovarian stimulation with corifollitropin alfa followed by hp-hMG compared to hp-hMG in patients at risk of

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poor ovarian response undergoing ICSI: a randomized

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controlled trial.

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Roser Taronger a, b, c, Susana Martínez-Cuenca a, b, c, Inmaculada Ferreros d, José

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M. Rubio a, b, c, Pedro J. Fernández-Colom a, b, c, M. Luisa Martínez-Triguero e,

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Antonio Pellicer a, b, c, f

a. Department of Obstetrics and Gynaecology, Reproduction Unit. University and

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Polytechnic Hospital La Fe, Valencia, Spain.

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b. The Health Research Institute La Fe (IIS La Fe) c. Spanish Clinical Research Network, SCReN-IIS La Fe, PT17/0017/0035

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d. IVI-RMA, IVI Foundation, Valencia, Spain. e. Department of Clinical analysis. University and Polytechnic Hospital La Fe,

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Valencia, Spain.

f. IVI-RMA, Valencia, Spain; Department of Paediatrics, Obstetrics and Gynaecology, School of Medicine, Valencia University, Valencia, Spain.

Author for correspondence: Name: Roser Taronger

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Address: Department of Obstetrics and Gynaecology, Reproduction Unit. University and Polytechnic Hospital La Fe. Avda. Fernando Abril Martorell 106. 46026 València, Spain. Telephone number: 961244233. Fax number: 961246250

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e-mail address: [email protected]

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Abstract

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Objective

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To compare the results of two ovarian stimulation protocols for IVF in patients at risk of

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poor ovarian response: corifollitropin alfa followed by hp-hMG versus daily administration of hp-hMG. We intended to demonstrate the non-inferiority of the

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protocol with corifollitropin alfa. Study design

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This is a prospective, randomized, non-inferiority, controlled study. We compared two ovarian stimulation protocols for IVF in 234 patients, under 40 years of age and at risk

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of poor ovarian response. First protocol was a single injection of 150 μg corifollitropin alfa and the second, a daily injection of 300 IU of hp-hMG during the first week of ovarian stimulation. In both groups, if necessary, a daily injection of 300 IU of hp-hMG was dispensed until the criteria for hCG administration are met. For the primary and secondary outcomes, results were analysed by using a one-sided chi-square test or a Fisher exact test, as appropriate, with a level of significance of 0.05.

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For continuous variables, parametric (independent t-test) or non-parametric (Mann– Whitney test) tests were used depending on the normality of the distribution. Statistical significance was set at P < 0.05. Results The ongoing pregnancy rate, live birth rate (15.2 vs 20.2) (P = 0.33), and the cumulative

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live birth rate (15.2 vs 22.0) (P = 0.19) per started cycle did not show significant

differences between the corifollitropin alfa and hp-hMG groups, and the difference

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estimated between treatments was -5% [95% CI: (-15.1, 5.0)]. Conclusions

It was not possible to probe non-inferiority of the protocol with corifollitropin alfa

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followed by hp-hMG compared to hp-hMG in patients at risk of poor ovarian response

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undergoing ICSI.

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TRIAL REGISTRATION NUMBER:

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KEY WORDS: Corifollitropin alfa, poor ovarian response, hp-hMG, in vitro fertilization.

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EudraCT number: 2013-002027-42. Trial registration date: 2013-08-14

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Introduction

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Low response to controlled ovarian stimulation (COS) is estimated to happen in 10 to

25% of assisted reproduction techniques (ART) (1) (2). This wide range of prevalence

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can be explained by a lack of consensus on the parameters by which a low response is defined (3). In 2011 a group of experts from the ESHRE agreed on a set of criteria,

known as "The Bologna Criteria ", that determine the low ovarian response to

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homogenise the study groups and reach meaningful conclusions. They standardized the

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definition of "Poor Ovarian Response" (POR) when at least two of the criteria they

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described were met (4). The ovarian response is decisive for the success of ART since

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cycles with low response are associated with higher cancellation rates and lower rates of

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pregnancy and new-born (5) (6) (7).

There is insufficient evidence to recommend most of the treatments proposed to

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improve pregnancy rates in patients with low ovarian reserve (8). However, some

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publications suggest that the addition of growth hormone (GH) (9) and the administration of testosterone prior to stimulation could improve the ovarian response in women with POR (10) (11).

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Ovarian stimulation with corifollitropin alfa (CFA) produces significantly more oocytes compared to rFSH administered daily in normal responder patients. Probably this is due to the higher blood levels of FSH that are reached during the first days of the stimulation (12) (13). For this reason, the use of CFA may be beneficial in patients with

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a poor response, considering that the number of oocytes retrieved is a determinant of the success of IVF and might be an interesting tool in POR patients. Several studies have suggested that ovarian stimulation with CFA followed by rFSH or hp-hMG in patients with POR may be beneficial. However, these statements can’t yet

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be considered conclusive because they were prospective and retrospective pilot studies based on a small number of individuals, and only compared CFA with rFSH. (14) (15)

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(16). Given this uncertainty, we designed a prospective trial to verify whether the

combination of CFA followed by hp-hMG may be the best alternative treatment in

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Materials and methods

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patients at risk of poor ovarian response.

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This study has been carried out in the Human Reproduction Unit of the University and

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Polytechnic Hospital La Fe of Valencia (Spain), between 2013 and 2017, was reviewed and approved by the Hospital Ethics Committee and registered in the EudraCT number:

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2013-002027-42 (2013-08-14).

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Study population

We included women under 40 years of age with indication of IVF/ICSI, who were at

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risk of poor ovarian response because they met at least one of the following three criteria: a history of medical or surgical treatment as a risk factor for POR; a previous poor response with a conventional stimulation (≤ 3 oocytes); an abnormal ovarian

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reserve test (ORT), anti-Müllerian hormone (AMH) < 8 pmol/L or antral follicle count (AFC) < 7. Exclusion criteria were anovulation, presence of uterine pathology, uncorrected hydrosalpinx, severe male factor, FSH > 20 mIU/ml, non-detectable AMH levels, or AFC < 3.

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Design, stimulation and treatment procedure The study was designed as a prospective, randomized, single centre, controlled, parallel, open label and non-inferiority trial to compare two COS protocols. A total of 437 patients were recruited. An assessment of the ovarian reserve was performed on the 2nd to 4th day of the menstrual cycle prior to treatment, by determination of FSH, E2, AMH

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and AFC. The patients who met the selection criteria were placed to start treatment with

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the following menstruation.

Block randomization to one of the two treatment arms was performed in the clinical trials section of the hospital's Pharmacy Department using the web-based program

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http://www.randomization.com. A total of 234 women were randomized: CFA group

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(n= 117) received a single injection of 150 μg CFA (Elonva ®), after the assessment of

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ovarian response on day 8th, 300 IU of hp-hMG was added until the criteria for

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ovulation triggering were accomplished; hp-hMG group (n= 117) received 300 IU of hp-hMG (Menopur ®) at continuous daily dose. In both groups, Ganirelix

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(Orgalutran®) at a dose of 0.25 mg/24 h was added when follicles were ≥14 mm.

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Ovulation was triggered with rHCG (Ovitrelle 250 μg ®) when there were ≥1 follicles ≥17 mm (Figure 1). Criteria for cycle cancellation were non-compliance with the

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protocol and non-ovarian response after 15 days of stimulation. Follicular puncture was performed at 36-38 hours after rhCG administration. The reproduction technique used was ICSI. The embryos were classified according to the

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criteria of the Spanish association for the study of the biology of reproduction (17). Embryo transfer was performed in D+2 / D+3 of embryonic development. Luteal phase was supported with 400 mg/day of progesterone (Utrogestan®, Seid, Barcelona).

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The clinical pregnancy was established by the presence of a gestational sac with positive foetal heartbeat. Periodic monitoring and follow-up of gestation were performed at weeks 12, 20-24 and at the end of gestation.

Outcomes

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The primary outcome was ongoing pregnancy rate (20-24 weeks). Additionally, due to the long and slow process of recruiting patients, we have also been able to obtain the

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current birth rate.

Secondary outcomes included cancellation rate, total dose of gonadotropins used, days required for stimulation, serum levels of E2 on the day of rhCG, number of aspirated

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follicles, the number of recovered MII oocytes, fertilization rate, number of viable

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embryos 48 hours post-fertilization, embryo quality, number of embryos transferred and

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the number of cycles with vitrified embryos. In addition, we calculated the rate of

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positive pregnancy test and clinical pregnancy by started cycle, oocyte retrieval, and embryo transfer, also the cumulative rate of ongoing pregnancy, live birth and

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miscarriage.

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Statistical analysis

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A sample size of at least 234 subjects (117 per group) was calculated to be the minimum required to demonstrate non-inferiority with a power of 80% using a -5% non-inferiority margin for the lower limit of the one-sided 95% CI, assuming a 5% loss

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and an ongoing pregnancy rate of 11%. Demographics and baseline characteristics were provided by descriptive summary measures expressed as mean and standard deviation or as median and interquartile range for continuous variables, and number and percentage for categorical variables. For the primary and secondary outcomes, results were analysed by using a one-sided chi-square

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test or Fisher exact test, as appropriate. For continuous variables, parametric (independent t-test) or non-parametric (Mann–Whitney test) tests were used, depending on the normality of the distribution. Statistical significance was set at P < 0.05. All analysis was performed in STATA 13 Statistical software. Analyses were performed in intent-to-treat and per-protocol. Only the per-protocol

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results were shown.

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Results

A total of 234 patients were randomized, 117 per treatment arm, between September 2013 and September 2016. In the CFA arm 5 patients were excluded and finally

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analysed 112. In the hp-hMG arm 109 patients were analysed because 8 were excluded

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Patient Characteristics

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(Figure 2). Follow-up of pregnant women ended in June 2017.

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The study groups were comparable in terms of clinical and demographic characteristics (Table 1). The mean age (SD) of the patients was 35.2 (2.86) years. The most frequent

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cause of infertility in both groups, besides the low ovarian reserve, was unexplained infertility. Considering the selection of patients according to three criteria it should be

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noted that all the women had some abnormal ORT.

Primary outcomes

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The ongoing pregnancy rates did not differ significantly between CFA and hp-hMG group. The 95% confidence interval (CI) for the estimated difference in ongoing pregnancy rates between treatment groups was -15.1 to 5.0, so it was not possible to conclude non-inferiority of the CFA against hp-hMG. (Table 2)

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Secondary outcomes Characteristics of ovarian stimulation. There were differences in the mean duration of the days of stimulation, hp-hMG doses from the 8th day of the COS, E2 levels and progesterone levels on the day of hCG, between the study groups. No significant

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differences were observed in other efficacy endpoints measures. (Table 3) Results of the cycle and laboratory. We found significant differences in the mean

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number (SD) of recovered MII oocytes (P = 0.04), the number of embryos on the day of transfer and also in the number of cycles with vitrified embryos between the study

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groups. We did not find significant differences in other results. (Table 3)

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Pregnancy outcomes. The results were calculated by started cycle, oocyte retrieval and

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embryo transfer. Table 4 describes in detail the biochemical, clinical, ongoing and

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neonatal pregnancy rates, with no significant differences found in any of them. There were also no differences in the rates of miscarriage.

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A total of 14 frozen embryo transfers were performed (CFA= 6 and hp-hMG= 8), resulting in 4 pregnancies. The cumulative rates of ongoing pregnancy, live birth, and

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miscarriage did not show significant differences either.

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No ectopic gestations and no adverse secondary effects to ovarian stimulation were observed in any of those in either study group.

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Discussion We designed the present trial to compare two protocols for ovarian stimulation, in patients at risk of poor ovarian response because they met at least one of the Bologna criteria. Women were randomized to receive a single injection of 150 μg of CFA (Elonva ®) (n = 117) or daily administration of 300 IU of hp-hMG (Menopur ®) (n =

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117). To date, this is the prospective randomized trial with the highest number of patients at risk of low ovarian response, the first one that compares these two protocols and presents their results by cumulative rate of new-born. Studies published so far on CFA treatment in patients with low ovarian reserve are

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characterized by a reduced number of patients. All reported that stimulation with CFA produces a slightly higher number of oocytes in comparison with other gonadotropins,

probably due to higher blood levels of FSH that are reached during the first days of the

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stimulation. The authors suggest that the use of CFA supplemented with rFSH or hphMG from the 8th day of stimulation in protocols with antagonist or agonist is

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promising, since it can simplify ovarian stimulation without compromising results (14)

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(15) (16) (18) (19) (20) (21). We could not confirm these conclusions because we

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observed significant differences in the number of obtained MII oocytes, and although

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we did not find statistical significance in the ongoing pregnancy and live birth rates, we showed differences that may be relevant for clinical practice. These differences have

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been reflected in the analysis of non-inferiority that was inconclusive.

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A recent review (22) on the treatments applied to patients with low ovarian reserve mentions the stimulation with CFA followed by hp-hMG (described by Polyzos et al. in

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2013 (15) ), as the only alternative for improvement in results. In this retrospective pilot study 47 patients had been treated with this novel protocol, the author published ongoing pregnancy rates of 28% in 29 women <40 years old, but raised the need for

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new prospective studies confirming the promising results and the possible benefit of this treatment. The results obtained in our study did not conclude that the combination of CFA + hp-hMG is a relevant alternative treatment for patients with low reserve. The ongoing pregnancy rate per cycle (15.2%) is very far from those published by Polyzos in the pilot study in 2013 (28%) and later in 2015 (20% and 26.7%), which compares

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the results of two pilot studies with the same combination of gonadotropins in protocols with GnRH agonists in patients < 40 years (19). In addition, recently the same group (23) reported the results of an RCT, which included 152 patients POR < 40 years old, comparing administration of CFA followed by 300 IU hp-hMG with daily administration of 300 IU rFSH. The ongoing pregnancy rates did not differ significantly

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between the treatment groups (14.3% vs 14.7%) (OR= 1.03) and is similar to that

obtained in our trial (15.2% vs 20.2%) (P= 0.33). They conclude, like us, that CFA

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followed by hp-hMG does not increase ongoing pregnancy rates compared with other gonadotropins in young poor responders.

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The most frequent cause of infertility in both groups was unexplained infertility (71.4%

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vs 55.1%), in these patients the only piece of evidence justifying their sterility was

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altered ovarian reserve markers. As described in the literature and observed in our trial,

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gestation rates in patients with decreased ovarian reserve (7-28%) are considerably lower than those published in the general population (28-41%) (13) (24) (25) (26) (27)

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(28). Decreased ovarian reserve is identified as a cause of unexplained infertility, without knowing the mechanisms involved in follicular exhaustion (29). It has been

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suggested that ovarian reserve testing should be performed in women over 35 years of

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age and in those younger than 35 years with risk factors for a decrease in ovarian reserve (30). In this group of difficult patients, it is clear that, to optimize the results in IVF, it is important to predict ovary factor. Therefore, we question the inclusion of

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patients with proven low reserve in the unexplained infertility group and we propose that we should consider the "ovarian factor/low ovarian reserve" as a cause of infertility "per se". The cancellation rate of our trial was lower (3.6 and 5.5%) than in other studies in POR patients, which was 32.6% in women treated with CFA (16) and 17.6% in those treated

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with FSHr at high doses (31). This low cancellation rate was due to the design of the study protocol, in which we only cancelled those cycles with absolute lack of follicular development. Oocyte retrieval was performed in 36 cycles with ≤ 2 follicles (> 17 mm), if these cycles were cancelled or converted to insemination as in other studies, the cancellation rate would have been 21.4% and 20.2% in the arms of CFA and hp-hMG

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respectively, similar to that described in the literature.

In our study, only 6.2% of the cycles of the arm with CFA did not require additional

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doses of hp-hMG, this figure contrasts with those published in patients with normal

response (32.9%) and over 35 years (34%) treated with the CFA (13) (32). In women

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with low reserve, we observed a higher percentage of patients with a slow response, i.e.,

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longer stimulations, who need to begin and end the stimulation with higher doses of

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gonadotropins (33).

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The main limitation of the study was that it was not possible to include patients of ≥ 40

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years per protocol in our hospital, so 87.8% of women expected a low response because they had one of the three criteria of Bologna (abnormal ORT) and only 12.2% met the

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definition of POR of the "Bologna criteria”.

In conclusion, ovarian stimulation with CFA followed by hp-hMG compared to hp-

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hMG, in patients at risk of poor ovarian response, did not show statistically significant differences in the ongoing pregnancy rate and live birth rate per started cycle. Although

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there were no statistical significance, as the differences in gestation and birth rates between the groups was greater than 5%, these differences may be relevant for clinical practice in patients with low ovarian response. In addition, the estimated difference between treatments was -5% [95% CI: (-15.1, 5.0)] so it was not possible to conclude non-inferiority of CFA followed by hp-hMG versus hp-hMG.

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Acknowledgments The authors are grateful for the collaboration of the entire team of the Reproduction Unit of the University and Polytechnic Hospital La Fe, the Reproductive Medicine

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Group of the Health Research Institute La Fe (IIS La Fe), the Research Support and

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Management Unit of the IVI Foundation, and its director Dr Nicolas Garrido.

Authors’ roles

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R.T., S.M-C., J.M.R. and A.P.: contributed to the conception and design of the work,

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acquisition, analysis, and interpretation of data, drafting the manuscript and revising it

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critically for important intellectual content. I.F.: contributed to the analysis and

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interpretation of data of the work, drafting the manuscript and revising it critically for important intellectual content. P.J.F-C. and M.L.M-T.: contributed to the acquisition

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and interpretation of data for the work, and revising it critically for important intellectual content. All authors read and approved the final version of the manuscript to

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be published.

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Funding

This work was supported by: The Health Research Institute La Fe (IIS La Fe) and Spanish Clinical Research Network, SCReN-IIS La Fe, PT17/0017/0035. No external

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funding was used for this study.

Conflict of interest None of the authors have any conflicts of interest to declare.

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in IVF-ICSI cycles? Hum Fertil. 2010;13(1):41–51.

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2014;28(4):469–74. Available from: http://dx.doi.org/10.1016/j.rbmo.2013.11.010 Revelli A, Pittatore G, Casano S, Canosa S, Evangelista F, Benedetto C. Efficacy

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and safety of late-start Corifollitropin-alfa administration for controlled ovarian

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hyperstimulation in IVF: a cohort, case-control study. J Assist Reprod Genet.

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Reproductive Endocrinology and Infertility Committee, Family Physicians Advisory Committee, Maternal-Fetal Medicine Committee, Executive and

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Council of the Society of Obstetricians, Liu K, Case A. Advanced reproductive age and fertility. J Obstet Gynaecol Can [Internet]. 2011 Nov;33(11):1165–75.

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Lefebvre J, Antaki R, Kadoch IJ, Dean NL, Sylvestre C, Bissonnette F, et al. 450

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IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor

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La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in

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FIGURE 1 Schematic presentation of the treatment groups. COS = controlled ovarian stimulation; hp-hMG = highly purified hMG; P = progesterone; rhCG = recombinant hCG.

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FIGURE 2

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Flow diagram according to the CONSORT guidelines. CFA = corifollitropin alfa; hphMG = highly purified hMG.

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Table 1. Baseline characteristics Note: Data are presented as median (interquartile range) or n (%). BMI= body mass index; AI= artificial insemination; IVF/ICSI= in vitro fertilization/intracytoplasmic sperm injection;

22 OCP= oral contraceptive pill; AFC= antral follicle count; FSH= follicle stimulating hormone; E2= estradiol; AMH= antimüllerian hormone; COS= controlled ovarian stimulation; ORT= ovarian reserve test.

Table 2. Results of primary outcomes Note: Data are presented as mean (SD) or n (%). LBR= live birth rate

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Table 3. Cycle outcomes.

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Note: Data are presented as mean (standard deviation) or n (%). OR= oocytes retrieval; COS= controlled ovarian stimulation; hp-hMG= highly purified human menopausal gonadotropin; E 2= estradiol; hCG= human chorionic gonadotropin; P= progesterone ET= embryo transfer

Table 4. Pregnancy outcomes.

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Note: *Per protocol analysis. CFA= corifollitropin alfa; hp-hMG= highly purified hMG; OR= oocytes retrieval; ET= embryo transfer. Ongoing pregnancy = gestation > 20 week. LBR= live birth rate.

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(n= 109)

8.3 (3.30) 52.5 (38.58) 3.9 (2.33) 5.8 (1.86) 5.8 (2.01)

35.4 (33-38) 22.2 (20-24) 27.4 (26-28) 44 (40.4) 8 (7.3) 44.8 (20-60) 25 (22.9)

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8.2 (3.65) 58.2 (50.41) 4.1 (2.34) 6 (1.74) 6.3 (2.26)

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Selection criteria, n (%) Risk factors of poor respone and abnormal ORT Previous cycles ≤ 3 oocytes and abnormal ORT Abnormal ORT (only)

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(n= 112) 35.1 (33-37) 22.5 (20-25) 26.9 (25-28) 44 (39.3) 4 (3.6) 50 (25-60) 26 (23.2)

AMH (pM/ml), AFC (in the previous menstrual cycle) AFC (on the start day of the COS) Cause of infertility besides poor ovarian reserve, n (%) Unexplained Male factor Tubal factor Endometriosis

hp-hMG

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Demographic parameters Age (years) BMI (Kg/m2) Duration menstrual cycle (days) Previous IA, n (%) Previous IVF/ICSI, n (%) Seminal count (106/ml) Previous OCP, n (%) Ovarian reserve profile, mean (SD) FSH (mIU/ml), E2 (pg/ml),

CFA

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Table 1. Baseline characteristics

80 (71.4) 17 (15.2) 11 (9.8) 4 (3.6)

6 (5.4) 4 (3.6) 102 (91.1)

60 (55.0) 26 (23.9) 13 (11.9) 10 (9.2)

10 (9.2) 7 (6.4) 92 (84.4)

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Note: Data are presented as median (interquartile range) or n (%). BMI= body mass index; AI= artificial insemination; IVF/ICSI= in vitro fertilization/intracytoplasmic sperm injection; OCP= oral contraceptive pill; AFC= antral follicle count; FSH= follicle stimulating hormone; E2= estradiol; AMH= antimüllerian hormone; COS= controlled ovarian stimulation; ORT= ovarian reserve test.

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Table 2. Results of primary outcome hp-hMG

(n= 112) 17 15.2 15.7 22.4

(n= 109) 22 20.2 21.4 29.7

Estimated difference P-value [95% CI] -5 [-15.1 ; 5.0] -5.6 [-16.1 ; 4.9] -7.3 [-21.4 ; 6.6]

0,33 0,29 0,30

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Ongoing pregnancy and LBR (n) Per started cycle (%) Per oocytes retrieval (%) Per embryo transfer (%)

CFA

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Note: Data are presented as mean (SD) or n (%). LBR= live birth rate

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Table 3. Cycle outcomes.

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Stimulation characteristics Cancelled cycles before OR, n (%) Duration of COS (days) Cycles with COS > 7 days, n (%) Dose hp-hMG (IU) from 8º day COS E2 day hCG (pg/ml) P day hCG (ng/ml) Endometrial thickness day hCG (mm) Total follicles day hCG Cycle Outcomes Cycles with OR, n (%) Nº of aspirated follicles Nº of oocytes retrieved

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Hp-hMG

P value

(n= 112)

(n= 109)

4 (3.6) 10.4 (1.99) 105 (93.8) 1070.8 (546.13) 1320 (634.20) 1.0 (0.51) 9.9 (1.70) 8.2 (3.60)

6 (5.5) 9.9 (2.07) 100 (91.7) 899.3 (600.43) 1611 (765.40) 0.8 (0.44) 9.9 (1.65) 8.5 (3.63)

0.49 0.03 0.57 0.03 <0.01 ≤0.01 0.76 0.47

108 (96.4) 5.5 (2.82) 4.2 (2.79)

103 (94.5) 5.7 (3.14) 4.9 (3.15)

0.49 0.82 0.13

25 Nº of mature oocyte (MII) Fertilization rate Nº of embryos on D +2/3 Nº of embryos transferred Top quality embryos transferred Cycles with ET, n (%) Cycles with vitrified embryos, n (%)

3.1 (2.25) 64.7 (34.39) 1.7 (1.31) 1.7 (0.48) 1.1 (0.76) 76 (67.9) 9 (8.0)

3.8 (2.61) 63.3 (34.02) 2.2 (1.74) 1.7 (0.45) 1.2 (0.76 74 (67.9) 18 (16.5)

0.04 0.77 0.05 0.34 0.60 0.99 0.05

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Table 4. Pregnancy outcomes.

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Note: Data are presented as mean (standard deviation) or n (%). OR= oocytes retrieval; COS= controlled ovarian stimulation; hp-hMG= highly purified human menopausal gonadotropin; E2= estradiol; hCG= human chorionic gonadotropin; P= progesterone ET= embryo transfer

hp-hMG (n= 109)*

Pregnancy Biochemical pregnancy, n Biochemical pregnancy / cycle, % Biochemical pregnancy / OR, % Biochemical pregnancy / ET, % Clinical pregnancy, n Clinical pregnancy / cycle, % Clinical pregnancy / OR, % Clinical pregnancy / ET, % Ongoing pregnancy and Live birth, n Ongoing pregnancy and LBR / cycle, % Ongoing pregnancy and LBR / OR, % Ongoing pregnancy and LBR / ET, % Miscarriage, n (%)

23 20.5 21.3 30.3 21 18.8 19.4 27.6 17 15.2 15.7 22.4 6 (26.1)

27 24.8 26.2 36.5 26 23.9 25.2 35.1 22 20.2 21.4 29.7 5 (18.5)

Cumulative pregnancy Biochemical pregnancy / cycle, n (%) Clinical pregnancy / cycle, n (%) Ongoing pregnancy and Live birth, n Ongoing pregnancy and LBR/ cycle, % Ongoing pregnancy and LBR / OR, % Ongoing pregnancy and LBR / ET, %

24 (21.4) 22 (19.6) 17 15.2 15.7 20.7

30 (27.5) 29 (26.6) 24 22.0 23.3 29.3

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CFA (n= 112)*

P value

0.44 0.40 0.42 0.35 0.31 0.32 0.33 0.29 0.30 0.52

0.29 0.22 0.19 0.17 0.21

26 Miscarriage rate, n (%)

7 (29.2)

6 (20.0)

0.43

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Note: *Per protocol analysis. CFA= corifollitropin alfa; hp-hMG= highly purified hMG; OR= oocytes retrieval; ET= embryo transfer. Ongoing pregnancy = gestation > 20 week. LBR= live birth rate.