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Corifollitropin alfa for ovarian stimulation in in vitro fertilization: a systematic review and meta-analysis of randomized controlled trials
Corifollitropin alfa for ovarian stimulation in in vitro fertilization: a systematic review and meta-analysis of randomized controlled trials Mauro Cozzolino, M.D.,a,b Amerigo Vitagliano, M.D.,c Gustavo Nardini Cecchino, M.D.,a,b,d Guido Ambrosini, M.D.,c and Juan Antonio Garcia-Velasco, Ph.D.a,b a
IVIRMA Madrid, Madrid, Spain; b Department of Gynecology and Obstetrics, Rey Juan Carlos University, Madrid, Spain; Department of Women and Children's Health, Unit of Gynecology and Obstetrics, University of Padua, Padua, Italy; ~ o Paulo, Sa ~ o Paulo, Brazil and d Department of Gynecology, Federal University of Sa
c
Objective: To evaluate the effectiveness of corifollitropin alfa in improving the success of IVF. Design: Systematic review and meta-analysis. Setting: Not applicable. Patient(s): Infertile women undergoing conventional IVF or intracytoplasmic sperm injection (ICSI). Intervention(s): Randomized controlled trials (RCTs) of infertile women undergoing a single IVF/ICSI cycle with either corifollitropin alfa or a conventional ovarian stimulation protocol based on daily injections. The review protocol was registered in PROSPERO before starting the data extraction (CRD42018088605). Main Outcome Measure(s): Primary outcomes were live birth rate and/or ongoing pregnancy rate. Clinical pregnancy rate, miscarriage rate, multiple pregnancies, number of oocytes and embryos obtained, cancellation rate, and rate of ovarian hyperstimulation syndrome and ectopic pregnancy were considered as secondary outcomes. Result(s): Eight randomized controlled trials were included; 2,345 women were assigned to the intervention group and 1,995 to the control group. The analysis of 4,340 IVF cycles did not reveal any difference in live birth rate and/or ongoing pregnancy rate between groups (risk ratio [RR], 0.92; 95% confidence interval [CI], 0.80–1.05). Similarly, no difference was found in clinical pregnancy rate (RR, 0.96; 95% CI, 0.88–1.05; I2 ¼ 0%), miscarriage rate (RR, 0.94; 95% CI, 0.71–1.25; I2 ¼ 0%), or multiple pregnancy rate (RR, 1.22; 95% CI, 0.99–1.50; I2 ¼ 0%). Also, the rates of cycle cancellation, ovarian hyperstimulation syndrome, and ectopic pregnancy were similar in both groups. Sensitivity and subgroup analyses did not provide statistical changes to pooled results. Conclusion(s): Corifollitropin alfa seems to be an alternative for daily recombinant FSH injections in normal and poor responder patients undergoing ovarian stimulation in IVF/ICSI treatment cycles. (Fertil SterilÒ 2019;111:722-33. Ó2018 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo. Key Words: Corifollitropin alfa, poor responders, normal responder, ongoing pregnancy, live birth Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/41559-27033
T
he development of simplified and less invasive therapeutic approaches for controlled ovarian stimulation (COS) remains a challenge in the field of reproductive medicine (1–3). The use of daily SC injections
in the treatment of infertility tends to increase patient anxiety due to the possibility of mistakes. Therefore, innovative strategies to simplify ovarian stimulation protocols may diminish the overall stress and enhance
Received September 22, 2018; revised November 29, 2018; accepted November 30, 2018. J.A.G.-V reports grants from MSD, Ferring, Merck Serono, and Gedeon Richter. M.C. has nothing to disclose. A.V. has nothing to disclose. G.N.C. has nothing to disclose. G.A. has nothing to disclose. Reprint requests: Mauro Cozzolino, M.D., IVIRMA Madrid, Avenida del Talgo 68, 28023, Aravaca, Madrid, Spain (E-mail: [email protected]). Fertility and Sterility® Vol. 111, No. 4, April 2019 0015-0282/$36.00 Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2018.11.047 722
patient experience during assisted reproductive technology (ART) (4). Corifollitropin alfa is a novel recombinant molecule used for COS before IVF. It has similar pharmacodynamic properties as conventional recombinant FSH (rFSH) but maintains prolonged follicle-stimulating activity (5, 6). A single SC injection of corifollitropin alfa has the capacity to initiate and sustain multiple follicular growth for the first 7 days of COS, reducing the number of injections required during VOL. 111 NO. 4 / APRIL 2019
Fertility and Sterility® one treatment cycle (6, 7). Such a distinct pharmacokinetic profile may confer many practical advantages to corifollitropin alfa compared with daily drugs (7), such as higher patient cooperation and compliance, as well as lower risk of self-administration errors (5). Corifollitropin alfa is administered as a single injection on menstrual cycle day 2 or 3 (stimulation day 1). Daily injections of FSH are started on the eighth day of stimulation if necessary. A GnRH antagonist is associated with day 5 or 6 of stimulation to prevent a premature surge in LH (8). Nevertheless, the noninferiority of corifollitropin alfa compared with conventional stimulation protocols in terms of safety and IVF success is still the subject of intense debate. The available evidence comes from independent studies with heterogeneous design and patients. Thus, the present systematic review and meta-analysis aims to provide reliable and updated knowledge on the effectiveness and safety of corifollitropin alfa in women undergoing ART with either conventional IVF or intracytoplasmic sperm injection (ICSI).
METHODS Study Design This is a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the effectiveness of corifollitropin alfa in IVF. The study protocol was registered in PROSPERO before starting the literature search (CRD42018088605). The review was written following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Search Strategy Electronic databases (MEDLINE, Scopus, EMBASE, ScienceDirect, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov) were searched from their inception until May 2018. The key search terms were as follows: corifollitropin alfa OR long-acting recombinant follicle-stimulating hormone [Mesh/Entree] AND in vitro fertilization OR assisted reproductive techniques, embryo transfer, intracytoplasmic sperm injection (ICSI).
Outcomes Measures and Definitions Ongoing pregnancy rate (per woman [OPR]): A pregnancy beyond 12 weeks' gestation. Live birth rate (per woman [LBR]): The delivery of one or more living and viable infants. Clinical pregnancy rate (per woman [CPR]): The presence of a gestational sac on transvaginal ultrasound or another definitive pregnancy sign. Multiple pregnancy rate (per clinical pregnancy [MPR]): The presence of more than one gestational sac on transvaginal ultrasound. Miscarriage rate (per clinical pregnancy [MR]): Fetal loss before the 20th week of gestation. Total oocytes (per woman): The total number of oocytes retrieved at pick-up. Mature oocytes (per woman [MII]): The number of mature oocytes retrieved. Total embryos (per cycle): The total number of embryos obtained after fertilization. Cancelled cycles: Cycles cancelled due to inadequate ovarian response (poor/excessive). Ovarian hyperstimulation syndrome rate (per cycle [OHSS]): The overall incidence of OHSS and the incidence of moderate/severe OHSS for started cycle. Ectopic pregnancy rate (per women [EPR]): Defined as the presence of a gestational sac outside of the uterus.
Study Selection and Data Extraction Titles and abstracts were screened independently by two authors (M.C., A.V.). The same authors independently assessed studies for inclusion and extracted data about study features (design, country, and time of study), populations (number and characteristics of participants), type of intervention, ovarian stimulation cycles (drugs, timing of ovulation induction), and IVF outcomes. A manual search of references within the included studies was also performed to avoid any missing relevant data. Any disagreement concerning the extracted data was resolved by consensus, and, whenever necessary, a third reviewer was consulted (G.N.C.). RCTs selected for meta-analysis were read in full by M.C., A.V., and G.N.C.
Inclusion Criteria Only RCTs reported in the English language including infertile women undergoing a single IVF/ICSI cycle after COS with corifollitropin alfa were selected for this systematic review and meta-analysis. The control group was composed of infertile women undergoing COS with rFSH.
Study Outcomes The preferred primary outcome was the live birth rate whenever available. Alternatively, the ongoing pregnancy rate was used. Secondary outcomes included clinical pregnancy rate, miscarriage rate, multiple pregnancies, number of oocytes and embryos, and cancellation rate, as well as the rate of ovarian hyperstimulation syndrome and ectopic pregnancy. VOL. 111 NO. 4 / APRIL 2019
Assessment of Risk of Bias Two authors (M.C., A.V.) independently assessed the methodological quality of the included studies using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (9). Seven specific domains related to risk of bias were assessed: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective data reporting, and other bias. Authors' judgements were expressed as ‘‘low,’’ ‘‘high,’’ or ‘‘unclear’’ risk of bias. For the estimation of ‘‘selective data reporting,’’ we evaluated study protocols when available. If not available, studies were judged as unclear risk of bias. Results were compared, and disagreements were resolved by consensus. 723
ORIGINAL ARTICLE: ASSISTED REPRODUCTION Statistical Analysis
stimulation defined as <4 cumulus-oocyte complexes with at least 450 IU of rFSH per day (10).
Data analysis was performed by two authors (M.C., A.V.) using Review Manager Version 5.3 (the Cochrane Collaboration, Software Update). All analyses were carried out with an intention-to-treat approach (number of events per women randomized) using the random effects model (DerSimonian and Laird, assuming that the data being analyzed were drawn from a hierarchy of different populations). Dichotomous variables were analyzed using the risk ratio (RR) with a 95% confidence interval (CI). P< .05 was considered statistically significant. Heterogeneity was measured using Higgins I2. A subgroup analysis was performed to evaluate the specific influence of different dosages of the intervention and the characteristics of the study populations (poor responders, normal responders) on pooled results. In addition, we performed a sensitivity analysis by serially excluding each study and different study subgroups according to the methodological quality judgement from the pooled analysis for the primary outcomes. We assessed the publication bias using the funnel plot if at least 10 studies were included in the data analysis per Cochrane Handbook recommendations.
Stimulation regimen. Two of the studies were corifollitropin alfa dose finding (12, 14), but all other studies used 150 mg of corifollitropin alfa starting on menstrual cycle day 2 or 3, with the exception of one study that used 100 mg (13). One week later, from stimulation day 8 onward, treatment was continued with a fixed daily dose of rFSH varying from 150 to 450 IU. Drakopoulos et al. was the single study to use 300 IU of highly purified hMG starting on stimulation day 8 (11). In the control group, the rFSH dose ranged from 150 to 450 IU. Pituitary block was performed with GnRH antagonist (0.25 mg daily). In most studies, ovulation induction was triggered with 5,000–10,000 IU of urinary hCG when at least one follicle was R17–20 mm in mean diameter. However, two RCTs used 250 mg of recombinant hCG to trigger ovulation. Ovarian puncture was performed 34–36 hours after hCG and followed with conventional IVF or ICSI. A maximum of three embryos were transferred between days 2 and 5 after oocyte retrieval and luteal phase support carried out with vaginal or IM P.
RESULTS
Assessment of Risk of Bias
Study Selection
Random sequence generation. All studies except one (15) used an adequate method for random sequence generation (computer randomization or random number tables).
Of the initial 749 identified articles, 11 were assessed for eligibility (5, 10–16). Three studies were subsequently excluded after examination of the full text: two were not RCTs (6, 17), and one (3) aimed to evaluate patients’ degree of satisfaction with the use of corifollitropin alfa in an oocyte donation program. The remaining eight RCTs (5, 10–16) were selected for meta-analysis (Supplemental Fig. 1).
Included Studies The total patient pool included 4,340 participants undergoing a single IVF/ICSI cycle; 2,345 women were assigned to the intervention group and 1,995 to the control group. Two trials (12, 14) involved four study groups, three of which received corifollitropin alfa in different regimens. Study characteristics are summarized in Table 1. Patients. Most of the trials included patients < 40 years of age undergoing IVF/ICSI to overcome different causes of infertility (5, 11–14). However, two trials admitted women <42 year old (15, 16), and one trial included patients as old as 45 years without preimplantational genetic testing for aneuploidy (10). All RCTs comprised volunteers with regular spontaneous menstrual cycles and body mass index (BMI) of 18–32 kg/m2, except for one study that did not report details about the menstrual cycle and BMI (11). In this RCT, the mean BMI was 23.2 kg/m2 in both the intervention and control groups, which is compatible with a normal body composition. Two studies focused on a population of poor responders, one of which only accepted patients fulfilling the Bologna criteria for poor ovarian response (11), and the other only included subjects with a previous poor response to ovarian 724
Allocation concealment. Five studies did not provide any information on the method of allocation (5, 11, 12, 14, 15). Therefore, we judged these as ‘‘unclear’’ risk of bias. The remaining studies were at ‘‘low’’ risk of bias. Blinding of participants and personnel. The lack of blinding of participants and personnel was judged as unlikely to generate bias because all of the outcomes investigated are objective. Blinding of outcome assessment. No study was assessor blinded. Incomplete outcome data. Four studies were judged to be at ‘‘low’’ risk of bias (9, 11, 15, 16). The remaining studies were at ‘‘high’’ risk or ‘‘unclear’’ risk of bias due to a lack of outcome data. Selective data reporting. All studies were judged to be at ‘‘low’’ risk of selective data reporting (study protocol available), except for one (13). Other bias. No other sources of bias were detected (Supplemental Fig. 2). It must be noted that most studies included in this meta-analysis received support from the manufacturer of corifollitropin alfa, which may represent a potential source of bias (5, 12–16).
Effects of Intervention Analysis of 4,340 IVF cycles did not show any difference in LBR/OPR between groups (RR, 0.92; 95% CI, 0.80–1.05; P¼ .21; Fig. 1A), with low heterogeneity (I2 ¼ 23%). In this analysis, the OPR was used whenever the LBR was not VOL. 111 NO. 4 / APRIL 2019
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TABLE 1 General features of the studies evaluated in this systematic review and meta-analysis. Participants and main inclusion criteria (n)
Ovarian stimulation (drugs and techniques)
Single-center RCT
99 patients undergoing IVF-ICSI. Duration of infertility (years): group A, 4.2 3.1; group B, 4.9 3.6; group C, 5.6 4.3; group E, 4.0 3.2. Age, 18–39. Menstrual cycle length, 24–35 d. BMI, 18–29 kg/m2.
The Corifollitropin Alfa Dose-finding Study Group 2008 [NCT00598208]
Multicenter RCT
315 patients undergoing IVF-ICSI. Age, 20–39. Menstrual cycle length, 24–35 d. BMI 17–31 kg/m2.
Devroey et al. 2009 [NTC00696800]
Multicenter RCT
1,509 patients undergoing IVF-ICSI. Age, 18–36. BMI, 18–32 kg/m2. Menstrual cycle length, 24–35 d. Indication of COS before IVF or ICSI.
GnRH antagonist (ganirelix 0.25 mg/d); 10,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 2–5 d after oocyte retrieval, 1–3 embryos transferred.Luteal phase support with vaginal micronized P (600 mg/d) or IM P (50 mg/d). GnRH antagonist (ganirelix 0.25 mg/d); 0,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 2–5 d after oocyte retrieval, 1–3 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d). GnRH antagonist (ganirelix 0.25 mg/d); 5,000– 10,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 3– 5 d after oocyte retrieval, 1–2 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d) or IM P (50 mg/d).
Author and year
Study design
Devroey et al. 2004 [NCT02466204]
Control group
Main outcomes
Group A: 120 mg FSH-CTP (n ¼ 25) Group B: 180 mg FSH-CTP (n ¼ 24) Group C: 240 mg FSH-CTP (n ¼ 25) rFSH 150 IU/day starting from day 8 Cointerventions: none
Group E: rFSH 150 IU/day (n ¼ 24) Cointerventions: none
Cancellation rate Total oocytes MII oocytes Fertilization rate No. and quality of embryos obtained Embryos transferred OPR MPR EPR OHSS rate
Group A: 60 mg FSH-CTP (n ¼ 78) Group B: 120 mg FSH-CTP (n ¼ 77) Group C: 180 mg FSH-CTP (n ¼ 79) rFSH 150 IU/day starting from day 8 Cointerventions: none
Group E: rFSH 150 IU/day (n ¼ 81) Cointerventions: none
Group A: 150 mg corifollitropin alfa (n ¼ 757) rFSH %200 IU/day starting from day 8 Cointerventions: placebo rFSH 200 IU/day during the first 7 d
Group B: rFSH 200 IU/day (n ¼ 752) Cointerventions: placebo corifollitropin alfa 150 mg in the first day
Cancellation rate Total oocytes MII oocytes Fertilization rate No. and qualiyy of embryos obtained Embryos transferred Implantation rate OPR MPR OHSS rate Cancellation rate Duration of stimulation Total dose of rFSH Total oocytes Fertilization rate No. and quality of embryos obtained Embryos transferred Embryos cryopreserved CPR OPR MPR LBR EPR OHSS rate
725
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Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
Intervention group
Continued. Author and year Corifollitropin alfa Ensure Study Group 2010
Kolibianakis et al. 2015 [NCT02046655]
Participants and main inclusion criteria (n)
Ovarian stimulation (drugs and techniques)
Intervention group
Control group
Main outcomes
Multicenter RCT
396 patients undergoing IVF-ICSI. Age, 18–36. BMI, 18–32 kg/m2. Menstrual cycle length, 24–35 d.
GnRH antagonist (ganirelix 0.25 mg/d); 10,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 3 d after oocyte retrieval, 1–2 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d).
Group A: 100 mg corifollitropin alfa (n ¼ 268) rFSH % 200 IU/day starting from day 8 Cointerventions: none
Group B: rFSH % 150 IU/day during the first 7 d (n ¼ 128) rFSH % 200 IU/day starting from day 8 Cointerventions: none
Single-center RCT
79 patients undergoing ICSI. Age <45. Previous poor response to ovarian stimulation, defined as retrieval of %4 cumulusoocyte complexes in a previous IVF cycle. Regular spontaneous menstrual cycle (24– 35 d). BMI, 18–32 kg/m2. Basal FSH %20 IU/L. Absence of preimplantation genetic screening.
GnRH antagonist (ganirelix 0.25 mg/d); 250 mg of recombinant hCG at follicle size 17 mm (R2). Oocyte retrieval 36 h after hCG. ET 2 or 3 d after oocyte retrieval, 1–3 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d).
Group A: 150 mg corifollitropin alfa (n ¼ 40 patients) rFSH 450 IU/day starting from day 8 Cointerventions: none
Group B: rFSH 450 IU/day (n ¼ 39 patients) Cointerventions: none
Duration of stimulation Total dose of rFSH Dose of rFSH from day 8 onward Total oocyts retrieved MII oocytes Fertilization rate No. and quality of embryos obtained and transferred Embryos cryopreserved Implantation rate CPR OPR Twin pregnancy rate MR EPR OHSS rate Duration of stimulation Total oocytes MII oocytes Fertilization rate Quality of embryos on day 2 Embryos transferred CPR MPR LBR MR Adverse events
Study design
Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
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TABLE 1
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VOL. 111 NO. 4 / APRIL 2019
TABLE 1 Continued. Author and year
Study design
Participants and main inclusion criteria (n)
Ovarian stimulation (drugs and techniques)
Main outcomes
Multicenter RCT
1,390 patients undergoing IVF-ICSI. Age R 35 and <42. BMI, 18–32 kg/m2. Regular menstrual cycles (24–35 d).
GnRH antagonist (ganirelix 0.25 mg/d); 250 mg of recombinant hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 2 or 3 d after oocyte retrieval, 1–3 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d).
Group A: 150 mg corifollitropin alfa (n ¼ 694) rFSH 300 IU/day starting from day 8 Cointerventions: placebo rFSH 300 IU/day during the first 7 d
Group B: rFSH 300 IU/day (n ¼ 696) FSH < 300 IU/day starting from day 8 Cointerventions: placebo corifollitropin alfa 150 mg on the first day
Drakopoulos et al. 2017 [NCT01816321]
Multicenter RCT
152 patients undergoing IVF/ ICSI. Age <40 Previous poor ovarian response according to the Bologna criteria.
Group A: 150 mg corifollitropin alfa (n ¼ 77) Highly purified human menotropin 300 IU/day starting from day 8 Cointerventions: contraceptive pill
Group B: rFSH 300 IU/day (n ¼ 75) Cointerventions: contraceptive pill
Vuong et al. 2017 [NCT02466204]
Single-center RCT
GnRH antagonist (ganirelix 0.25 mg/d); 10,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 3 d after oocyte retrieval, 1–3 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d). GnRH antagonist (ganirelix 0.25 mg/d); 5,000– 10,000 IU of urinary hCG at follicle size 17 mm (R3) or GnRH agonist (triptorelin) when >19 follicles of R11 mm. Oocyte retrieval 34–36 h after ovulation induction. ET 3 d after oocyte retrieval, 2–3 embryos transferred. Luteal phase support with vaginal P gel (90 mg twice daily) or IM P (50 mg/d).
Cancellation rate Duration of stimulaion Total dose of rFSH Dose of rFSH from day 8 onward Total oocytes MII oocytes No. and quality of embryos obtained and transferred Embryos cryopreserved Implantation rate OPR MPR LBR Miscarriages rate EPR OHSS rate Cancellation rate Total oocytes MII oocytes Embryos transferred Embryos cryopreserved CPR OPR LBR
400 patients undergoing IVF-ICSI. Age, R35 and %42. Normal menstrual cycle (24–35 d). BMI, 17–31 kg/m2. € llerian hormone Antimu R1.38 ng/mL € llerian hormone (Antimu Gen II, Beckman Coulter) or antral follicle count, 7–20, measured within 2 mo of ovarian stimulation.
727
Note: FSH-CTP ¼ recombinant long-acting FSH. Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
Intervention group
150 mg corifollitropin alfa (n ¼ 200) rFSH % 300 IU/day starting from day 8 Cointerventions: none
rFSH 300 IU/day (n ¼ 200) Cointerventions: none
Cancellation rate Duration of stimulation Total dose of rFSH Total oocytes Metaphase II oocytes Fertilization rate No. and quality of embryos obtained and transferred Embryos cryopreserved Implantation rate CPR Ongoing pregnancy rate MPR LBR Cumulative LBR EPR OHSS rate Obstetric outcomes
Fertility and Sterility®
Control group
Boostanfar et al. 2015
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FIGURE 1
Pregnancy and LBRs with intervention (corifollitropin alfa) and control. (A) LBR or OPR. (B) CPR. Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
available (5, 11–13). Similarly, no difference was found in CPR (RR, 0.96; 95% CI, 0.88–1.05; I2 ¼ 0%; P¼ .33; Fig. 1B), MR (RR, 0.94; 95% CI, 0.71–1.25; I2 ¼ 0%; P¼ .68), or MPR (RR, 1.22; 95% CI, 0.99–1.50; I2 ¼ 0%; P¼ .07). The total number of oocytes, MII oocytes, and embryos obtained were significantly higher in the intervention group compared with controls (total oocytes: mean differences [MD] ¼ þ0.89 [95% CI, 0.13–1.64]; I2 ¼ 69%; P¼ .02; MII oocytes: MD ¼ þ1.13 [95% CI, 0.33–1.92]; I2 ¼ 82%; P¼ .006; total embryos: MD ¼ þ0.55 [95% CI, 0.14–0.96]; I2 ¼ 45%; P¼ .008; Figure 2A–2C). Considering the studies reporting cycle cancelation rate, no difference was observed due to either a poor (RR, 0.97, 95% CI, 0.68–1.39, I2 ¼ 0%, P¼ .86) or excessive ovarian response (RR, 1.85; 95% CI, 0.67–5.11; I2 ¼ 0%; P¼ .24). Regarding the main adverse events, no difference was observed in terms of overall OHSS rate (RR, 1.15; 95% CI, 0.83–1.57; I2 ¼ 0%; P¼ .40), as well as in the rate of moderate/severe OHSS (RR, 1.17; 95% CI, 0.54–2.56; I2 ¼ 0%; 728
P¼ .69) and EPR (RR, 0.72; 95% CI, 0.39–1.14; I2 ¼ 0%; P¼ .29; Fig. 3A–3C). Subgroup and sensitivity analysis. Subgroup analysis according to the dose of corifollitropin alfa (60, 100, 120, 150, 180, 240 mg), and patient characteristics (normal responders, poor responders) did not reveal significant differences between subgroups for the primary outcomes. Similarly, the serial exclusion of each study or different study subgroups according to study quality did not modify the pooled results.
Publication Bias and Quality of Evidence As fewer than 10 studies were included, the publication bias was not assessed.
DISCUSSION Several reasons have been described for discontinuing ART, such as spontaneous pregnancy, emotional distress, financial problems, and medical issues. The physical and mental strain VOL. 111 NO. 4 / APRIL 2019
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FIGURE 2
Oocytes and embryos with intervention (corifollitropin alfa) and control. (A) Total number of oocytes. (B) MII oocytes. (C) Embryos obtained. Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
experienced by women during fertility treatment is high and surely underestimated (18), and the psychological stress is the main reason why patients drop out (19). The daily frequency of hormone injections interferes with the way that patients experience ART (19). According to Hojgaard et al. (20), a simpler and shorter COS regimen is preferred despite the higher rates of cancellation. Verberg et al. (2) demonstrated a reduced dropout rate in a GnRH antagonist protocol compared with a GnRH agonist regimen, indicating that the duration of stimulation as well as the number of gonadotropin injections must be taken into account. VOL. 111 NO. 4 / APRIL 2019
From its introduction, COS for IVF has been based on daily administration of different gonadotropins. In recent years, concerns about improving and simplifying IVF treatment for both clinicians and patients have been the subject of intense debate. The emergence of corifollitropin alfa represented a breakthrough for COS protocols and a valid alternative to replace the first seven daily injections. In addition, it allowed for a reduction of the emotional burden related to ART, increasing the patients' degree of satisfaction (2, 3). In the study by Requena et al. (3), egg donors who underwent a previous cycle with rFSH were more satisfied after 729
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FIGURE 3
Main adverse events with intervention (corifollitropin alfa) and control. (A) Overall OHSS. (B) Moderate/severe OHSS rate. (C) EPR. Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
switching to corifollitropin alfa. Thus, it is reasonable to assume that such a novel hormone will also improve compliance. Moreover, the use of corifollitropin alfa has recently been related to a greater level of convenience and comfort for egg donors (3). The noninferiority of corifollitropin alfa in regard to daily doses of 150 or 200 IU of rFSH was demonstrated properly by the ENSURE and ENGAGE trials (5, 13). The most recent and direct evidence comes from the PURSUE study (15), in which a single SC injection of 150 mg of corifollitropin alfa was equivalent to daily administration of 300 IU of rFSH in a trial involving 1,390 women ages 35–42. An economic analysis based on the PURSUE study showed that, in Spain, COS with corifollitropin alfa is less expensive than daily doses of rFSH whenever it exceeds 250 IU per day (21). In fact, more than 250 IU are usually required for women ages 35–42 years, who make up the majority of infertile patients seeking ART (22). Kolibianakis et al. (10) compared corifollitropin alfa with 450 IU of daily follitropin beta and showed similar reproductive outcomes; however, corifollitropin alfa treatment undoubtedly simplifies IVF treatment. Thus, its use in poor responders is an interesting concept that deserves further 730
research, as it would greatly reduce the burden of ART. Furthermore, although the pharmacological cost varies widely, it is likely to be less than the cost of seven daily injections of 450 IU of rFSH in most countries. Similarly, Cruz et al. (23) carried out a cost-effectiveness analysis on egg donors who received treatment with corifollitropin alfa, rFSH, or highly purified hMG, expressing the results based on the cost per recovered oocyte and per MII oocyte, but no significant differences were reported between the treatments groups. In 2013, Polyzos et al. (17) reported that cancellation rates due to low ovarian response in patients undergoing COS with rFSH are similar to those using corifollitropin alfa.
Main Findings In the past few years, several RCTs have investigated the optimal dose of corifollitropin alfa, as well as its effectiveness during COS. Nevertheless, a deep analysis of the best evidence available was lacking. The present meta-analysis of eight RCTs included 4,340 participants undergoing a single IVF/ ICSI cycle: 2,345 women were included in the intervention group versus 1,995 in the control group. Pooling data from VOL. 111 NO. 4 / APRIL 2019
Fertility and Sterility® previous studies demonstrated no significant differences in the main reproductive outcomes, such as LBR/OPR and CPR. Similarly, women achieving pregnancy after COS with corifollitropin alfa presented with similar MRs and MPRs as those using rFSH. Regarding the ovarian response to COS, corifollitropin alfa yielded a higher number of oocytes and embryos than rFSH. Subgroup analysis according to corifollitropin alfa dose (60, 100, 120, 150, 180, 240 mg) and patient characteristics (normal responders, poor responders) did not show significant differences between subgroups for the primary outcomes. In addition, no difference was observed in the cycle cancellation rate due to poor or excessive ovarian response. Importantly, one study was excluded from the CPR analysis due to lack of data (12), three did not provide information on MR (11, 12, 14), and one did not evaluate MPR (11). The total number of oocytes, MII oocytes, and embryos obtained were significantly higher in the intervention group than in controls. In addition, the analysis of serious adverse events showed no significant difference in the overall rate of OHSS, moderate/severe OHSS, and EPR. Studies aiming to find the optimal dose were excluded from these analyses (11, 13), as well as the ones not providing information on the variable of interest. Three previous meta-analyses aimed to assess the effectiveness of corifollitropin alfa (24–26). In 2012, Mahmoud Youssef et al. (24) concluded that the use of corifollitropin alfa in a GnRH antagonist protocol seems to be a good alternative to daily rFSH injections for normal responders. Notably, only four RCTs were included in this first metaanalysis and half of them were phase II dose-finding trials, which clearly compromised safety profile analysis, as discussed elsewhere (27). After the exclusion of these phase II studies, our analysis of serious adverse events failed to detect any difference regarding the rates of OHSS and ectopic pregnancy. Later, Fensore et al. (25) showed that corifollitropin alfa resulted in a higher number of MII oocytes collected along with a higher number of cycles cancelled due to overstimulation. The authors concluded that corifollitropin alfa should be cautiously considered in cases where excessive ovarian response is expected. Importantly, one of the RCTs included is this meta-analysis comprised egg donors and the main objective was to evaluate the patient's degree of satisfaction instead of IVF outcomes (3). We did not detect any difference in the cycle cancelation rate due to poor or excessive ovarian response. Recently, Griesinger et al. (26) in their individual patient data meta-analysis demonstrated that a single dose of corifollitropin alfa is well tolerated and has a similar efficacy and safety profile compared with daily rFSH. Indeed, the use of corifollitropin alfa yielded, on average, one additional oocyte (26). Our results support this finding.
RCTs represent studies with the best level of clinical evidence, and including only this type of study definitely reduces statistical bias. In addition, sensitivity and subgroup analyses confirmed the consistency of our findings. A few limitations should be considered, first and most importantly, the substantial heterogeneity between studies in terms of patient characteristics, time of intervention, and ovarian stimulation protocols. On the other hand, this is a characteristic inherent to most meta-analyses. Second, both RCTs by Devroey et al. (5) and Boostanfar et al. (15) had greater weight in the analysis performed. Nonetheless, the serial exclusion of each single study did not modify the findings. Third, a potential selection bias must be recognized, as five out of eight RCTs were judged to be at ‘‘unclear’’ risk for proper randomized allocation concealment (5, 11, 12, 14, 15). Finally, half of the studies presented incomplete outcome data (5, 12– 14) and most of the studies received support from the manufacturer of corifollitropin alfa (5, 12–16). Unfortunately, we were not able to perform a metaanalysis comparing corifollitropin alfa with other stimulation protocols due to the lack of data. Very recently, Taronger et al. (28) published the first RCT comparing the use of corifollitropin alfa versus highly purified menotropin in patients at risk of poor ovarian response. Despite similar reproductive outcomes, they could not demonstrate the noninferiority of corifollitropin alfa in regard to the OPR due to a wide confidence interval.
Implications In conclusion, this systematic review and meta-analysis suggests that corifollitropin alfa is as effective as rFSH in terms of LBR, OPR, and CPR in both normal and poor responders. In addition, it offers an attractive option for patients undergoing COS for ART due to its equivalence, safety profile, and a potential reduction in treatment costs. In this sense, older women and poor responders requiring high doses of gonadotropins may benefit from the use of corifollitropin alfa. Although the increased number of eggs retrieved under the corifollitropin alfa regimen reflects the efficiency of this novel rFSH formulation, this finding must be evaluated further. New well-designed placebo-controlled RCTs are needed.
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Limitations To the best of our knowledge, this is the largest meta-analysis on the use of corifollitropin alfa for COS in poor and normal responders. Strict inclusion criteria, rigorous methodology, and large sample sizes represent further points of strength. VOL. 111 NO. 4 / APRIL 2019
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Boivin J, Takefman JE. Impact of the in-vitro fertilization process on emotional, physical and relational variables. Hum Reprod 1996;11:903–7. Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, de Klerk C, Fauser BC, et al. Why do couples drop-out from IVF treatment? A prospective cohort study. Hum Reprod 2008;23:2050–5. Requena A, Cruz M, Collado D, Izquierdo A, Ballesteros A, Munoz M, et al. Evaluation of the degree of satisfaction in oocyte donors using sustainedrelease FSH corifollitropin alpha. Reprod Biomed Online 2013;26:253–9. de Carvalho BR. Often times, we should look at IVF more simply. JBRA Assist Reprod 2016;20:1–2. Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC, et al. A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod 2009;24:3063–72. Ledger WL, Fauser BC, Devroey P, Zandvliet AS, Mannaerts BM. Corifollitropin alfa doses based on body weight: clinical overview of drug exposure and ovarian response. Reprod Biomed Online 2011;23:150–9. 731
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Fauser BC, Mannaerts BM, Devroey P, Leader A, Boime I, Baird DT. Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency. Hum Reprod Update 2009;15:309–21. 8. Lin YH, Seow KM, Chen HJ, Hsieh BC, Huang LW, Tzeng CR, et al. Effect of cetrorelix dose on premature LH surge during ovarian stimulation. Reprod Biomed Online 2008;16:772–7. 9. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58. 10. Kolibianakis EM, Venetis CA, Bosdou JK, Zepiridis L, Chatzimeletiou K, Makedos A, et al. Corifollitropin alfa compared with follitropin beta in poor responders undergoing ICSI: a randomized controlled trial. Hum Reprod 2015;30:432–40. 11. Drakopoulos P, Vuong TNL, Ho NAV, Vaiarelli A, Ho MT, Blockeel C, et al. Corifollitropin alfa followed by highly purified HMG versus recombinant FSH in young poor ovarian responders: a multicentre randomized controlled clinical trial. Hum Reprod 2017;32:2225–33. 12. Devroey P, Fauser BC, Platteau P, Beckers NG, Dhont M, Mannaerts BM. Induction of multiple follicular development by a single dose of long-acting recombinant follicle-stimulating hormone (FSH-CTP, corifollitropin alfa) for controlled ovarian stimulation before in vitro fertilization. J Clin Endocrinol Metab 2004;89:2062–70. 13. Corifollitropin alfa Ensure Study Group. Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women. Reprod Biomed Online 2010;21:66–76. 14. Corifollitropin Alfa Dose-finding Study Group. A randomized dose-response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation. Hum Reprod 2008;23: 2484–92. 15. Boostanfar R, Shapiro B, Levy M, Rosenwaks Z, Witjes H, Stegmann BJ, et al. Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization. Fertil Steril 2015;104: 94–103.e1. 16. Vuong NL, Pham DT, Phung HT, Giang NH, Huynh GB, Nguyen TTL, et al. Corifollitropin alfa vs recombinant FSH for controlled ovarian stimulation in women aged 35–42 years with a body weight R50 kg: a randomized controlled trial. Hum Reprod Open 2017;1:11.
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Polyzos NP, Devos M, Humaidan P, Stoop D, Ortega-Hrepich C, Devroey P, et al. Corifollitropin alfa followed by rFSH in a GnRH antagonist protocol for poor ovarian responder patients: an observational pilot study. Fertil Steril 2013;99:422–6. Verhaak CM, Smeenk JM, Eugster A, van Minnen A, Kremer JA, Kraaimaat FW. Stress and marital satisfaction among women before and after their first cycle of in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril 2001;76:525–31. Olivius C, Friden B, Borg G, Bergh C. Why do couples discontinue in vitro fertilization treatment? A cohort study. Fertil Steril 2004;81:258–61. Hojgaard A, Ingerslev HJ, Dinesen J. Friendly IVF: patient opinions. Hum Reprod 2001;16:1391–6. Barrenetxea G, Garcia-Velasco JA, Aragon B, Osset J, Brosa M, LopezMartinez N, et al. Comparative economic study of the use of corifollitropin alfa and daily rFSH for controlled ovarian stimulation in older patients: cost-minimization analysis based on the PURSUE study. Reprod Biomed Soc Online 2018;5:46–59. Martin JR, Mahutte NG, Arici A, Sakkas D. Impact of duration and dose of gonadotrophins on IVF outcomes. Reprod Biomed Online 2006;13:645–50. Cruz M, Alama P, Munoz M, Collado D, Blanes C, Solbes E, et al. Economic impact of ovarian stimulation with corifollitropin alfa versus conventional daily gonadotropins in oocyte donors: a randomized study. Reprod Biomed Online 2017;34:605–10. Mahmoud Youssef MA, van Wely M, Aboulfoutouh I, El-Khyat W, van der Veen F, Al-Inany H. Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis. Fertil Steril 2012;97:876–85. Fensore S, Di Marzio M, Tiboni GM. Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for in vitro fertilization: a meta-analysis. J Ovarian Res 2015;8:33. Griesinger G, Boostanfar R, Gordon K, Gates D, McCrary Sisk C, Stegmann BJ. Corifollitropin alfa versus recombinant follicle-stimulating hormone: an individual patient data meta-analysis. Reprod Biomed Online 2016;33:56–60. Mannaerts B, Verweij P, Gordon K. Comment on, ‘‘Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis.’’ Fertil Steril 2012;97:e22, author reply e23. Taronger R, Martínez-Cuenca S, Ferreros I, Rubio JM, Fernandez-Colom PJ, Martínez-Triguero ML, et al. 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. Eur J Obstet Gynecol Reprod Biol 2018;231:192–7.
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Fertility and Sterility® Corifolitropina alfa en la estimulacion ovarica en fecundaci on in vitro: revisi on sistem atica y meta-an alisis de estudios controlados y aleatorizados Objetivo: evaluar la efectividad de la corifolitropina alfa en la mejora del exito en FIV. ~o: Revisi Disen on sistematica y meta-analisis. Entorno: No aplicable. Paciente(s): mujeres infertiles sometidas a un tratamiento convencional de FIV o inyecci on intracitoplasmatica de espermatozoides (ICSI). nico ciclo de FIV/ICSI con corifoIntervencion(es): estudios controlados y aleatorizados (RCTs) en mujeres infertiles sometidas a un u litropina alfa o protocolo de estimulacion estandar basado en inyecciones diarias. El protocolo de revisi on se registr o en PROSPERO antes de el inicio de la extraccion de datos (CRD42018088605). Principal(es) medida(s) de resultado(s): los resultados primarios fueron la tasa de recien nacido vivo y/o la tasa de gestaci on. Se consideraron resultados secundarios la tasa de gestaci on clínica, la de aborto, la de gestaci on m ultiple, el n umero de ovocitos y de embriones obtenidos, la tasa de cancelaci on y la tasa de síndrome de hiperestimulaci on ovarica y de gestaci on m ultiple. Resultado(s): se incluyeron ocho estudios controlados y aleatorizados; 2.345 mujeres se asignaron al grupo de intervenci on y 1.995 al grupo control. El analisis de 4.340 ciclos de FIV no mostr o ninguna diferencia entre los grupos en cuanto a la tasa de recien nacido vivo y/o de gestaci on evolutiva (riesgo relativo [RR], 0,92; intervalo de confianza 95% [IC], 0,80–1,05). Analogamente, no se encontr o ninguna diferencia en la tasa de gestacion clínica (RR: 0,96; IC 95% ¼ 0,88–1,05; I2 ¼ 0%), ni en la de aborto (RR: 0,94; IC 95% ¼ 0,71–1,25; on m ultiple (RR: 1,22; IC 95% ¼ 0,99–1,50; I2 ¼ 0%). Así mismo, las tasas de cancelaci on de ciclo, de synI2 ¼ 0%) ni en la de gestaci drome de hiperestimulaci on ovarica y de gestaci on fueron similares en ambos grupos. La sensibilidad y los analisis de subgrupo no aportaron cambios estadísticos a los resultados agrupados. Conclusion(es): La corifolitropina alfa parece ser una alternativa a la inyecci on diaria de FSH en pacientes con normo respuesta y baja respuesta sometidas a un ciclo de estimulaci on ovarica para tratamiento de FIV/ICSI.
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IVIRMA Madrid, Madrid, Spain; b Department of Gynecology and Obstetrics, Rey Juan Carlos University, Madrid, Spain; Department of Women and Children's Health, Unit of Gynecology and Obstetrics, University of Padua, Padua, Italy; ~ o Paulo, Sa ~ o Paulo, Brazil and d Department of Gynecology, Federal University of Sa
c
Objective: To evaluate the effectiveness of corifollitropin alfa in improving the success of IVF. Design: Systematic review and meta-analysis. Setting: Not applicable. Patient(s): Infertile women undergoing conventional IVF or intracytoplasmic sperm injection (ICSI). Intervention(s): Randomized controlled trials (RCTs) of infertile women undergoing a single IVF/ICSI cycle with either corifollitropin alfa or a conventional ovarian stimulation protocol based on daily injections. The review protocol was registered in PROSPERO before starting the data extraction (CRD42018088605). Main Outcome Measure(s): Primary outcomes were live birth rate and/or ongoing pregnancy rate. Clinical pregnancy rate, miscarriage rate, multiple pregnancies, number of oocytes and embryos obtained, cancellation rate, and rate of ovarian hyperstimulation syndrome and ectopic pregnancy were considered as secondary outcomes. Result(s): Eight randomized controlled trials were included; 2,345 women were assigned to the intervention group and 1,995 to the control group. The analysis of 4,340 IVF cycles did not reveal any difference in live birth rate and/or ongoing pregnancy rate between groups (risk ratio [RR], 0.92; 95% confidence interval [CI], 0.80–1.05). Similarly, no difference was found in clinical pregnancy rate (RR, 0.96; 95% CI, 0.88–1.05; I2 ¼ 0%), miscarriage rate (RR, 0.94; 95% CI, 0.71–1.25; I2 ¼ 0%), or multiple pregnancy rate (RR, 1.22; 95% CI, 0.99–1.50; I2 ¼ 0%). Also, the rates of cycle cancellation, ovarian hyperstimulation syndrome, and ectopic pregnancy were similar in both groups. Sensitivity and subgroup analyses did not provide statistical changes to pooled results. Conclusion(s): Corifollitropin alfa seems to be an alternative for daily recombinant FSH injections in normal and poor responder patients undergoing ovarian stimulation in IVF/ICSI treatment cycles. (Fertil SterilÒ 2019;111:722-33. Ó2018 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo. Key Words: Corifollitropin alfa, poor responders, normal responder, ongoing pregnancy, live birth Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/41559-27033
T
he development of simplified and less invasive therapeutic approaches for controlled ovarian stimulation (COS) remains a challenge in the field of reproductive medicine (1–3). The use of daily SC injections
in the treatment of infertility tends to increase patient anxiety due to the possibility of mistakes. Therefore, innovative strategies to simplify ovarian stimulation protocols may diminish the overall stress and enhance
Received September 22, 2018; revised November 29, 2018; accepted November 30, 2018. J.A.G.-V reports grants from MSD, Ferring, Merck Serono, and Gedeon Richter. M.C. has nothing to disclose. A.V. has nothing to disclose. G.N.C. has nothing to disclose. G.A. has nothing to disclose. Reprint requests: Mauro Cozzolino, M.D., IVIRMA Madrid, Avenida del Talgo 68, 28023, Aravaca, Madrid, Spain (E-mail: [email protected]). Fertility and Sterility® Vol. 111, No. 4, April 2019 0015-0282/$36.00 Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2018.11.047 722
patient experience during assisted reproductive technology (ART) (4). Corifollitropin alfa is a novel recombinant molecule used for COS before IVF. It has similar pharmacodynamic properties as conventional recombinant FSH (rFSH) but maintains prolonged follicle-stimulating activity (5, 6). A single SC injection of corifollitropin alfa has the capacity to initiate and sustain multiple follicular growth for the first 7 days of COS, reducing the number of injections required during VOL. 111 NO. 4 / APRIL 2019
Fertility and Sterility® one treatment cycle (6, 7). Such a distinct pharmacokinetic profile may confer many practical advantages to corifollitropin alfa compared with daily drugs (7), such as higher patient cooperation and compliance, as well as lower risk of self-administration errors (5). Corifollitropin alfa is administered as a single injection on menstrual cycle day 2 or 3 (stimulation day 1). Daily injections of FSH are started on the eighth day of stimulation if necessary. A GnRH antagonist is associated with day 5 or 6 of stimulation to prevent a premature surge in LH (8). Nevertheless, the noninferiority of corifollitropin alfa compared with conventional stimulation protocols in terms of safety and IVF success is still the subject of intense debate. The available evidence comes from independent studies with heterogeneous design and patients. Thus, the present systematic review and meta-analysis aims to provide reliable and updated knowledge on the effectiveness and safety of corifollitropin alfa in women undergoing ART with either conventional IVF or intracytoplasmic sperm injection (ICSI).
METHODS Study Design This is a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the effectiveness of corifollitropin alfa in IVF. The study protocol was registered in PROSPERO before starting the literature search (CRD42018088605). The review was written following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Search Strategy Electronic databases (MEDLINE, Scopus, EMBASE, ScienceDirect, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov) were searched from their inception until May 2018. The key search terms were as follows: corifollitropin alfa OR long-acting recombinant follicle-stimulating hormone [Mesh/Entree] AND in vitro fertilization OR assisted reproductive techniques, embryo transfer, intracytoplasmic sperm injection (ICSI).
Outcomes Measures and Definitions Ongoing pregnancy rate (per woman [OPR]): A pregnancy beyond 12 weeks' gestation. Live birth rate (per woman [LBR]): The delivery of one or more living and viable infants. Clinical pregnancy rate (per woman [CPR]): The presence of a gestational sac on transvaginal ultrasound or another definitive pregnancy sign. Multiple pregnancy rate (per clinical pregnancy [MPR]): The presence of more than one gestational sac on transvaginal ultrasound. Miscarriage rate (per clinical pregnancy [MR]): Fetal loss before the 20th week of gestation. Total oocytes (per woman): The total number of oocytes retrieved at pick-up. Mature oocytes (per woman [MII]): The number of mature oocytes retrieved. Total embryos (per cycle): The total number of embryos obtained after fertilization. Cancelled cycles: Cycles cancelled due to inadequate ovarian response (poor/excessive). Ovarian hyperstimulation syndrome rate (per cycle [OHSS]): The overall incidence of OHSS and the incidence of moderate/severe OHSS for started cycle. Ectopic pregnancy rate (per women [EPR]): Defined as the presence of a gestational sac outside of the uterus.
Study Selection and Data Extraction Titles and abstracts were screened independently by two authors (M.C., A.V.). The same authors independently assessed studies for inclusion and extracted data about study features (design, country, and time of study), populations (number and characteristics of participants), type of intervention, ovarian stimulation cycles (drugs, timing of ovulation induction), and IVF outcomes. A manual search of references within the included studies was also performed to avoid any missing relevant data. Any disagreement concerning the extracted data was resolved by consensus, and, whenever necessary, a third reviewer was consulted (G.N.C.). RCTs selected for meta-analysis were read in full by M.C., A.V., and G.N.C.
Inclusion Criteria Only RCTs reported in the English language including infertile women undergoing a single IVF/ICSI cycle after COS with corifollitropin alfa were selected for this systematic review and meta-analysis. The control group was composed of infertile women undergoing COS with rFSH.
Study Outcomes The preferred primary outcome was the live birth rate whenever available. Alternatively, the ongoing pregnancy rate was used. Secondary outcomes included clinical pregnancy rate, miscarriage rate, multiple pregnancies, number of oocytes and embryos, and cancellation rate, as well as the rate of ovarian hyperstimulation syndrome and ectopic pregnancy. VOL. 111 NO. 4 / APRIL 2019
Assessment of Risk of Bias Two authors (M.C., A.V.) independently assessed the methodological quality of the included studies using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (9). Seven specific domains related to risk of bias were assessed: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective data reporting, and other bias. Authors' judgements were expressed as ‘‘low,’’ ‘‘high,’’ or ‘‘unclear’’ risk of bias. For the estimation of ‘‘selective data reporting,’’ we evaluated study protocols when available. If not available, studies were judged as unclear risk of bias. Results were compared, and disagreements were resolved by consensus. 723
ORIGINAL ARTICLE: ASSISTED REPRODUCTION Statistical Analysis
stimulation defined as <4 cumulus-oocyte complexes with at least 450 IU of rFSH per day (10).
Data analysis was performed by two authors (M.C., A.V.) using Review Manager Version 5.3 (the Cochrane Collaboration, Software Update). All analyses were carried out with an intention-to-treat approach (number of events per women randomized) using the random effects model (DerSimonian and Laird, assuming that the data being analyzed were drawn from a hierarchy of different populations). Dichotomous variables were analyzed using the risk ratio (RR) with a 95% confidence interval (CI). P< .05 was considered statistically significant. Heterogeneity was measured using Higgins I2. A subgroup analysis was performed to evaluate the specific influence of different dosages of the intervention and the characteristics of the study populations (poor responders, normal responders) on pooled results. In addition, we performed a sensitivity analysis by serially excluding each study and different study subgroups according to the methodological quality judgement from the pooled analysis for the primary outcomes. We assessed the publication bias using the funnel plot if at least 10 studies were included in the data analysis per Cochrane Handbook recommendations.
Stimulation regimen. Two of the studies were corifollitropin alfa dose finding (12, 14), but all other studies used 150 mg of corifollitropin alfa starting on menstrual cycle day 2 or 3, with the exception of one study that used 100 mg (13). One week later, from stimulation day 8 onward, treatment was continued with a fixed daily dose of rFSH varying from 150 to 450 IU. Drakopoulos et al. was the single study to use 300 IU of highly purified hMG starting on stimulation day 8 (11). In the control group, the rFSH dose ranged from 150 to 450 IU. Pituitary block was performed with GnRH antagonist (0.25 mg daily). In most studies, ovulation induction was triggered with 5,000–10,000 IU of urinary hCG when at least one follicle was R17–20 mm in mean diameter. However, two RCTs used 250 mg of recombinant hCG to trigger ovulation. Ovarian puncture was performed 34–36 hours after hCG and followed with conventional IVF or ICSI. A maximum of three embryos were transferred between days 2 and 5 after oocyte retrieval and luteal phase support carried out with vaginal or IM P.
RESULTS
Assessment of Risk of Bias
Study Selection
Random sequence generation. All studies except one (15) used an adequate method for random sequence generation (computer randomization or random number tables).
Of the initial 749 identified articles, 11 were assessed for eligibility (5, 10–16). Three studies were subsequently excluded after examination of the full text: two were not RCTs (6, 17), and one (3) aimed to evaluate patients’ degree of satisfaction with the use of corifollitropin alfa in an oocyte donation program. The remaining eight RCTs (5, 10–16) were selected for meta-analysis (Supplemental Fig. 1).
Included Studies The total patient pool included 4,340 participants undergoing a single IVF/ICSI cycle; 2,345 women were assigned to the intervention group and 1,995 to the control group. Two trials (12, 14) involved four study groups, three of which received corifollitropin alfa in different regimens. Study characteristics are summarized in Table 1. Patients. Most of the trials included patients < 40 years of age undergoing IVF/ICSI to overcome different causes of infertility (5, 11–14). However, two trials admitted women <42 year old (15, 16), and one trial included patients as old as 45 years without preimplantational genetic testing for aneuploidy (10). All RCTs comprised volunteers with regular spontaneous menstrual cycles and body mass index (BMI) of 18–32 kg/m2, except for one study that did not report details about the menstrual cycle and BMI (11). In this RCT, the mean BMI was 23.2 kg/m2 in both the intervention and control groups, which is compatible with a normal body composition. Two studies focused on a population of poor responders, one of which only accepted patients fulfilling the Bologna criteria for poor ovarian response (11), and the other only included subjects with a previous poor response to ovarian 724
Allocation concealment. Five studies did not provide any information on the method of allocation (5, 11, 12, 14, 15). Therefore, we judged these as ‘‘unclear’’ risk of bias. The remaining studies were at ‘‘low’’ risk of bias. Blinding of participants and personnel. The lack of blinding of participants and personnel was judged as unlikely to generate bias because all of the outcomes investigated are objective. Blinding of outcome assessment. No study was assessor blinded. Incomplete outcome data. Four studies were judged to be at ‘‘low’’ risk of bias (9, 11, 15, 16). The remaining studies were at ‘‘high’’ risk or ‘‘unclear’’ risk of bias due to a lack of outcome data. Selective data reporting. All studies were judged to be at ‘‘low’’ risk of selective data reporting (study protocol available), except for one (13). Other bias. No other sources of bias were detected (Supplemental Fig. 2). It must be noted that most studies included in this meta-analysis received support from the manufacturer of corifollitropin alfa, which may represent a potential source of bias (5, 12–16).
Effects of Intervention Analysis of 4,340 IVF cycles did not show any difference in LBR/OPR between groups (RR, 0.92; 95% CI, 0.80–1.05; P¼ .21; Fig. 1A), with low heterogeneity (I2 ¼ 23%). In this analysis, the OPR was used whenever the LBR was not VOL. 111 NO. 4 / APRIL 2019
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TABLE 1 General features of the studies evaluated in this systematic review and meta-analysis. Participants and main inclusion criteria (n)
Ovarian stimulation (drugs and techniques)
Single-center RCT
99 patients undergoing IVF-ICSI. Duration of infertility (years): group A, 4.2 3.1; group B, 4.9 3.6; group C, 5.6 4.3; group E, 4.0 3.2. Age, 18–39. Menstrual cycle length, 24–35 d. BMI, 18–29 kg/m2.
The Corifollitropin Alfa Dose-finding Study Group 2008 [NCT00598208]
Multicenter RCT
315 patients undergoing IVF-ICSI. Age, 20–39. Menstrual cycle length, 24–35 d. BMI 17–31 kg/m2.
Devroey et al. 2009 [NTC00696800]
Multicenter RCT
1,509 patients undergoing IVF-ICSI. Age, 18–36. BMI, 18–32 kg/m2. Menstrual cycle length, 24–35 d. Indication of COS before IVF or ICSI.
GnRH antagonist (ganirelix 0.25 mg/d); 10,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 2–5 d after oocyte retrieval, 1–3 embryos transferred.Luteal phase support with vaginal micronized P (600 mg/d) or IM P (50 mg/d). GnRH antagonist (ganirelix 0.25 mg/d); 0,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 2–5 d after oocyte retrieval, 1–3 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d). GnRH antagonist (ganirelix 0.25 mg/d); 5,000– 10,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 3– 5 d after oocyte retrieval, 1–2 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d) or IM P (50 mg/d).
Author and year
Study design
Devroey et al. 2004 [NCT02466204]
Control group
Main outcomes
Group A: 120 mg FSH-CTP (n ¼ 25) Group B: 180 mg FSH-CTP (n ¼ 24) Group C: 240 mg FSH-CTP (n ¼ 25) rFSH 150 IU/day starting from day 8 Cointerventions: none
Group E: rFSH 150 IU/day (n ¼ 24) Cointerventions: none
Cancellation rate Total oocytes MII oocytes Fertilization rate No. and quality of embryos obtained Embryos transferred OPR MPR EPR OHSS rate
Group A: 60 mg FSH-CTP (n ¼ 78) Group B: 120 mg FSH-CTP (n ¼ 77) Group C: 180 mg FSH-CTP (n ¼ 79) rFSH 150 IU/day starting from day 8 Cointerventions: none
Group E: rFSH 150 IU/day (n ¼ 81) Cointerventions: none
Group A: 150 mg corifollitropin alfa (n ¼ 757) rFSH %200 IU/day starting from day 8 Cointerventions: placebo rFSH 200 IU/day during the first 7 d
Group B: rFSH 200 IU/day (n ¼ 752) Cointerventions: placebo corifollitropin alfa 150 mg in the first day
Cancellation rate Total oocytes MII oocytes Fertilization rate No. and qualiyy of embryos obtained Embryos transferred Implantation rate OPR MPR OHSS rate Cancellation rate Duration of stimulation Total dose of rFSH Total oocytes Fertilization rate No. and quality of embryos obtained Embryos transferred Embryos cryopreserved CPR OPR MPR LBR EPR OHSS rate
725
Fertility and Sterility®
Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
Intervention group
Continued. Author and year Corifollitropin alfa Ensure Study Group 2010
Kolibianakis et al. 2015 [NCT02046655]
Participants and main inclusion criteria (n)
Ovarian stimulation (drugs and techniques)
Intervention group
Control group
Main outcomes
Multicenter RCT
396 patients undergoing IVF-ICSI. Age, 18–36. BMI, 18–32 kg/m2. Menstrual cycle length, 24–35 d.
GnRH antagonist (ganirelix 0.25 mg/d); 10,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 3 d after oocyte retrieval, 1–2 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d).
Group A: 100 mg corifollitropin alfa (n ¼ 268) rFSH % 200 IU/day starting from day 8 Cointerventions: none
Group B: rFSH % 150 IU/day during the first 7 d (n ¼ 128) rFSH % 200 IU/day starting from day 8 Cointerventions: none
Single-center RCT
79 patients undergoing ICSI. Age <45. Previous poor response to ovarian stimulation, defined as retrieval of %4 cumulusoocyte complexes in a previous IVF cycle. Regular spontaneous menstrual cycle (24– 35 d). BMI, 18–32 kg/m2. Basal FSH %20 IU/L. Absence of preimplantation genetic screening.
GnRH antagonist (ganirelix 0.25 mg/d); 250 mg of recombinant hCG at follicle size 17 mm (R2). Oocyte retrieval 36 h after hCG. ET 2 or 3 d after oocyte retrieval, 1–3 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d).
Group A: 150 mg corifollitropin alfa (n ¼ 40 patients) rFSH 450 IU/day starting from day 8 Cointerventions: none
Group B: rFSH 450 IU/day (n ¼ 39 patients) Cointerventions: none
Duration of stimulation Total dose of rFSH Dose of rFSH from day 8 onward Total oocyts retrieved MII oocytes Fertilization rate No. and quality of embryos obtained and transferred Embryos cryopreserved Implantation rate CPR OPR Twin pregnancy rate MR EPR OHSS rate Duration of stimulation Total oocytes MII oocytes Fertilization rate Quality of embryos on day 2 Embryos transferred CPR MPR LBR MR Adverse events
Study design
Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
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TABLE 1
VOL. 111 NO. 4 / APRIL 2019
VOL. 111 NO. 4 / APRIL 2019
TABLE 1 Continued. Author and year
Study design
Participants and main inclusion criteria (n)
Ovarian stimulation (drugs and techniques)
Main outcomes
Multicenter RCT
1,390 patients undergoing IVF-ICSI. Age R 35 and <42. BMI, 18–32 kg/m2. Regular menstrual cycles (24–35 d).
GnRH antagonist (ganirelix 0.25 mg/d); 250 mg of recombinant hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 2 or 3 d after oocyte retrieval, 1–3 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d).
Group A: 150 mg corifollitropin alfa (n ¼ 694) rFSH 300 IU/day starting from day 8 Cointerventions: placebo rFSH 300 IU/day during the first 7 d
Group B: rFSH 300 IU/day (n ¼ 696) FSH < 300 IU/day starting from day 8 Cointerventions: placebo corifollitropin alfa 150 mg on the first day
Drakopoulos et al. 2017 [NCT01816321]
Multicenter RCT
152 patients undergoing IVF/ ICSI. Age <40 Previous poor ovarian response according to the Bologna criteria.
Group A: 150 mg corifollitropin alfa (n ¼ 77) Highly purified human menotropin 300 IU/day starting from day 8 Cointerventions: contraceptive pill
Group B: rFSH 300 IU/day (n ¼ 75) Cointerventions: contraceptive pill
Vuong et al. 2017 [NCT02466204]
Single-center RCT
GnRH antagonist (ganirelix 0.25 mg/d); 10,000 IU of urinary hCG at follicle size 17 mm (R3). Oocyte retrieval 34–36 h after hCG. ET 3 d after oocyte retrieval, 1–3 embryos transferred. Luteal phase support with vaginal micronized P (600 mg/d). GnRH antagonist (ganirelix 0.25 mg/d); 5,000– 10,000 IU of urinary hCG at follicle size 17 mm (R3) or GnRH agonist (triptorelin) when >19 follicles of R11 mm. Oocyte retrieval 34–36 h after ovulation induction. ET 3 d after oocyte retrieval, 2–3 embryos transferred. Luteal phase support with vaginal P gel (90 mg twice daily) or IM P (50 mg/d).
Cancellation rate Duration of stimulaion Total dose of rFSH Dose of rFSH from day 8 onward Total oocytes MII oocytes No. and quality of embryos obtained and transferred Embryos cryopreserved Implantation rate OPR MPR LBR Miscarriages rate EPR OHSS rate Cancellation rate Total oocytes MII oocytes Embryos transferred Embryos cryopreserved CPR OPR LBR
400 patients undergoing IVF-ICSI. Age, R35 and %42. Normal menstrual cycle (24–35 d). BMI, 17–31 kg/m2. € llerian hormone Antimu R1.38 ng/mL € llerian hormone (Antimu Gen II, Beckman Coulter) or antral follicle count, 7–20, measured within 2 mo of ovarian stimulation.
727
Note: FSH-CTP ¼ recombinant long-acting FSH. Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
Intervention group
150 mg corifollitropin alfa (n ¼ 200) rFSH % 300 IU/day starting from day 8 Cointerventions: none
rFSH 300 IU/day (n ¼ 200) Cointerventions: none
Cancellation rate Duration of stimulation Total dose of rFSH Total oocytes Metaphase II oocytes Fertilization rate No. and quality of embryos obtained and transferred Embryos cryopreserved Implantation rate CPR Ongoing pregnancy rate MPR LBR Cumulative LBR EPR OHSS rate Obstetric outcomes
Fertility and Sterility®
Control group
Boostanfar et al. 2015
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
FIGURE 1
Pregnancy and LBRs with intervention (corifollitropin alfa) and control. (A) LBR or OPR. (B) CPR. Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
available (5, 11–13). Similarly, no difference was found in CPR (RR, 0.96; 95% CI, 0.88–1.05; I2 ¼ 0%; P¼ .33; Fig. 1B), MR (RR, 0.94; 95% CI, 0.71–1.25; I2 ¼ 0%; P¼ .68), or MPR (RR, 1.22; 95% CI, 0.99–1.50; I2 ¼ 0%; P¼ .07). The total number of oocytes, MII oocytes, and embryos obtained were significantly higher in the intervention group compared with controls (total oocytes: mean differences [MD] ¼ þ0.89 [95% CI, 0.13–1.64]; I2 ¼ 69%; P¼ .02; MII oocytes: MD ¼ þ1.13 [95% CI, 0.33–1.92]; I2 ¼ 82%; P¼ .006; total embryos: MD ¼ þ0.55 [95% CI, 0.14–0.96]; I2 ¼ 45%; P¼ .008; Figure 2A–2C). Considering the studies reporting cycle cancelation rate, no difference was observed due to either a poor (RR, 0.97, 95% CI, 0.68–1.39, I2 ¼ 0%, P¼ .86) or excessive ovarian response (RR, 1.85; 95% CI, 0.67–5.11; I2 ¼ 0%; P¼ .24). Regarding the main adverse events, no difference was observed in terms of overall OHSS rate (RR, 1.15; 95% CI, 0.83–1.57; I2 ¼ 0%; P¼ .40), as well as in the rate of moderate/severe OHSS (RR, 1.17; 95% CI, 0.54–2.56; I2 ¼ 0%; 728
P¼ .69) and EPR (RR, 0.72; 95% CI, 0.39–1.14; I2 ¼ 0%; P¼ .29; Fig. 3A–3C). Subgroup and sensitivity analysis. Subgroup analysis according to the dose of corifollitropin alfa (60, 100, 120, 150, 180, 240 mg), and patient characteristics (normal responders, poor responders) did not reveal significant differences between subgroups for the primary outcomes. Similarly, the serial exclusion of each study or different study subgroups according to study quality did not modify the pooled results.
Publication Bias and Quality of Evidence As fewer than 10 studies were included, the publication bias was not assessed.
DISCUSSION Several reasons have been described for discontinuing ART, such as spontaneous pregnancy, emotional distress, financial problems, and medical issues. The physical and mental strain VOL. 111 NO. 4 / APRIL 2019
Fertility and Sterility®
FIGURE 2
Oocytes and embryos with intervention (corifollitropin alfa) and control. (A) Total number of oocytes. (B) MII oocytes. (C) Embryos obtained. Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
experienced by women during fertility treatment is high and surely underestimated (18), and the psychological stress is the main reason why patients drop out (19). The daily frequency of hormone injections interferes with the way that patients experience ART (19). According to Hojgaard et al. (20), a simpler and shorter COS regimen is preferred despite the higher rates of cancellation. Verberg et al. (2) demonstrated a reduced dropout rate in a GnRH antagonist protocol compared with a GnRH agonist regimen, indicating that the duration of stimulation as well as the number of gonadotropin injections must be taken into account. VOL. 111 NO. 4 / APRIL 2019
From its introduction, COS for IVF has been based on daily administration of different gonadotropins. In recent years, concerns about improving and simplifying IVF treatment for both clinicians and patients have been the subject of intense debate. The emergence of corifollitropin alfa represented a breakthrough for COS protocols and a valid alternative to replace the first seven daily injections. In addition, it allowed for a reduction of the emotional burden related to ART, increasing the patients' degree of satisfaction (2, 3). In the study by Requena et al. (3), egg donors who underwent a previous cycle with rFSH were more satisfied after 729
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
FIGURE 3
Main adverse events with intervention (corifollitropin alfa) and control. (A) Overall OHSS. (B) Moderate/severe OHSS rate. (C) EPR. Cozzolino. Corifollitropin alfa for IVF/ICSI cycles. Fertil Steril 2018.
switching to corifollitropin alfa. Thus, it is reasonable to assume that such a novel hormone will also improve compliance. Moreover, the use of corifollitropin alfa has recently been related to a greater level of convenience and comfort for egg donors (3). The noninferiority of corifollitropin alfa in regard to daily doses of 150 or 200 IU of rFSH was demonstrated properly by the ENSURE and ENGAGE trials (5, 13). The most recent and direct evidence comes from the PURSUE study (15), in which a single SC injection of 150 mg of corifollitropin alfa was equivalent to daily administration of 300 IU of rFSH in a trial involving 1,390 women ages 35–42. An economic analysis based on the PURSUE study showed that, in Spain, COS with corifollitropin alfa is less expensive than daily doses of rFSH whenever it exceeds 250 IU per day (21). In fact, more than 250 IU are usually required for women ages 35–42 years, who make up the majority of infertile patients seeking ART (22). Kolibianakis et al. (10) compared corifollitropin alfa with 450 IU of daily follitropin beta and showed similar reproductive outcomes; however, corifollitropin alfa treatment undoubtedly simplifies IVF treatment. Thus, its use in poor responders is an interesting concept that deserves further 730
research, as it would greatly reduce the burden of ART. Furthermore, although the pharmacological cost varies widely, it is likely to be less than the cost of seven daily injections of 450 IU of rFSH in most countries. Similarly, Cruz et al. (23) carried out a cost-effectiveness analysis on egg donors who received treatment with corifollitropin alfa, rFSH, or highly purified hMG, expressing the results based on the cost per recovered oocyte and per MII oocyte, but no significant differences were reported between the treatments groups. In 2013, Polyzos et al. (17) reported that cancellation rates due to low ovarian response in patients undergoing COS with rFSH are similar to those using corifollitropin alfa.
Main Findings In the past few years, several RCTs have investigated the optimal dose of corifollitropin alfa, as well as its effectiveness during COS. Nevertheless, a deep analysis of the best evidence available was lacking. The present meta-analysis of eight RCTs included 4,340 participants undergoing a single IVF/ ICSI cycle: 2,345 women were included in the intervention group versus 1,995 in the control group. Pooling data from VOL. 111 NO. 4 / APRIL 2019
Fertility and Sterility® previous studies demonstrated no significant differences in the main reproductive outcomes, such as LBR/OPR and CPR. Similarly, women achieving pregnancy after COS with corifollitropin alfa presented with similar MRs and MPRs as those using rFSH. Regarding the ovarian response to COS, corifollitropin alfa yielded a higher number of oocytes and embryos than rFSH. Subgroup analysis according to corifollitropin alfa dose (60, 100, 120, 150, 180, 240 mg) and patient characteristics (normal responders, poor responders) did not show significant differences between subgroups for the primary outcomes. In addition, no difference was observed in the cycle cancellation rate due to poor or excessive ovarian response. Importantly, one study was excluded from the CPR analysis due to lack of data (12), three did not provide information on MR (11, 12, 14), and one did not evaluate MPR (11). The total number of oocytes, MII oocytes, and embryos obtained were significantly higher in the intervention group than in controls. In addition, the analysis of serious adverse events showed no significant difference in the overall rate of OHSS, moderate/severe OHSS, and EPR. Studies aiming to find the optimal dose were excluded from these analyses (11, 13), as well as the ones not providing information on the variable of interest. Three previous meta-analyses aimed to assess the effectiveness of corifollitropin alfa (24–26). In 2012, Mahmoud Youssef et al. (24) concluded that the use of corifollitropin alfa in a GnRH antagonist protocol seems to be a good alternative to daily rFSH injections for normal responders. Notably, only four RCTs were included in this first metaanalysis and half of them were phase II dose-finding trials, which clearly compromised safety profile analysis, as discussed elsewhere (27). After the exclusion of these phase II studies, our analysis of serious adverse events failed to detect any difference regarding the rates of OHSS and ectopic pregnancy. Later, Fensore et al. (25) showed that corifollitropin alfa resulted in a higher number of MII oocytes collected along with a higher number of cycles cancelled due to overstimulation. The authors concluded that corifollitropin alfa should be cautiously considered in cases where excessive ovarian response is expected. Importantly, one of the RCTs included is this meta-analysis comprised egg donors and the main objective was to evaluate the patient's degree of satisfaction instead of IVF outcomes (3). We did not detect any difference in the cycle cancelation rate due to poor or excessive ovarian response. Recently, Griesinger et al. (26) in their individual patient data meta-analysis demonstrated that a single dose of corifollitropin alfa is well tolerated and has a similar efficacy and safety profile compared with daily rFSH. Indeed, the use of corifollitropin alfa yielded, on average, one additional oocyte (26). Our results support this finding.
RCTs represent studies with the best level of clinical evidence, and including only this type of study definitely reduces statistical bias. In addition, sensitivity and subgroup analyses confirmed the consistency of our findings. A few limitations should be considered, first and most importantly, the substantial heterogeneity between studies in terms of patient characteristics, time of intervention, and ovarian stimulation protocols. On the other hand, this is a characteristic inherent to most meta-analyses. Second, both RCTs by Devroey et al. (5) and Boostanfar et al. (15) had greater weight in the analysis performed. Nonetheless, the serial exclusion of each single study did not modify the findings. Third, a potential selection bias must be recognized, as five out of eight RCTs were judged to be at ‘‘unclear’’ risk for proper randomized allocation concealment (5, 11, 12, 14, 15). Finally, half of the studies presented incomplete outcome data (5, 12– 14) and most of the studies received support from the manufacturer of corifollitropin alfa (5, 12–16). Unfortunately, we were not able to perform a metaanalysis comparing corifollitropin alfa with other stimulation protocols due to the lack of data. Very recently, Taronger et al. (28) published the first RCT comparing the use of corifollitropin alfa versus highly purified menotropin in patients at risk of poor ovarian response. Despite similar reproductive outcomes, they could not demonstrate the noninferiority of corifollitropin alfa in regard to the OPR due to a wide confidence interval.
Implications In conclusion, this systematic review and meta-analysis suggests that corifollitropin alfa is as effective as rFSH in terms of LBR, OPR, and CPR in both normal and poor responders. In addition, it offers an attractive option for patients undergoing COS for ART due to its equivalence, safety profile, and a potential reduction in treatment costs. In this sense, older women and poor responders requiring high doses of gonadotropins may benefit from the use of corifollitropin alfa. Although the increased number of eggs retrieved under the corifollitropin alfa regimen reflects the efficiency of this novel rFSH formulation, this finding must be evaluated further. New well-designed placebo-controlled RCTs are needed.
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4. 5.
Limitations To the best of our knowledge, this is the largest meta-analysis on the use of corifollitropin alfa for COS in poor and normal responders. Strict inclusion criteria, rigorous methodology, and large sample sizes represent further points of strength. VOL. 111 NO. 4 / APRIL 2019
6.
Boivin J, Takefman JE. Impact of the in-vitro fertilization process on emotional, physical and relational variables. Hum Reprod 1996;11:903–7. Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, de Klerk C, Fauser BC, et al. Why do couples drop-out from IVF treatment? A prospective cohort study. Hum Reprod 2008;23:2050–5. Requena A, Cruz M, Collado D, Izquierdo A, Ballesteros A, Munoz M, et al. Evaluation of the degree of satisfaction in oocyte donors using sustainedrelease FSH corifollitropin alpha. Reprod Biomed Online 2013;26:253–9. de Carvalho BR. Often times, we should look at IVF more simply. JBRA Assist Reprod 2016;20:1–2. Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC, et al. A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod 2009;24:3063–72. Ledger WL, Fauser BC, Devroey P, Zandvliet AS, Mannaerts BM. Corifollitropin alfa doses based on body weight: clinical overview of drug exposure and ovarian response. Reprod Biomed Online 2011;23:150–9. 731
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Fauser BC, Mannaerts BM, Devroey P, Leader A, Boime I, Baird DT. Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency. Hum Reprod Update 2009;15:309–21. 8. Lin YH, Seow KM, Chen HJ, Hsieh BC, Huang LW, Tzeng CR, et al. Effect of cetrorelix dose on premature LH surge during ovarian stimulation. Reprod Biomed Online 2008;16:772–7. 9. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58. 10. Kolibianakis EM, Venetis CA, Bosdou JK, Zepiridis L, Chatzimeletiou K, Makedos A, et al. Corifollitropin alfa compared with follitropin beta in poor responders undergoing ICSI: a randomized controlled trial. Hum Reprod 2015;30:432–40. 11. Drakopoulos P, Vuong TNL, Ho NAV, Vaiarelli A, Ho MT, Blockeel C, et al. Corifollitropin alfa followed by highly purified HMG versus recombinant FSH in young poor ovarian responders: a multicentre randomized controlled clinical trial. Hum Reprod 2017;32:2225–33. 12. Devroey P, Fauser BC, Platteau P, Beckers NG, Dhont M, Mannaerts BM. Induction of multiple follicular development by a single dose of long-acting recombinant follicle-stimulating hormone (FSH-CTP, corifollitropin alfa) for controlled ovarian stimulation before in vitro fertilization. J Clin Endocrinol Metab 2004;89:2062–70. 13. Corifollitropin alfa Ensure Study Group. Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women. Reprod Biomed Online 2010;21:66–76. 14. Corifollitropin Alfa Dose-finding Study Group. A randomized dose-response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation. Hum Reprod 2008;23: 2484–92. 15. Boostanfar R, Shapiro B, Levy M, Rosenwaks Z, Witjes H, Stegmann BJ, et al. Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization. Fertil Steril 2015;104: 94–103.e1. 16. Vuong NL, Pham DT, Phung HT, Giang NH, Huynh GB, Nguyen TTL, et al. Corifollitropin alfa vs recombinant FSH for controlled ovarian stimulation in women aged 35–42 years with a body weight R50 kg: a randomized controlled trial. Hum Reprod Open 2017;1:11.
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Polyzos NP, Devos M, Humaidan P, Stoop D, Ortega-Hrepich C, Devroey P, et al. Corifollitropin alfa followed by rFSH in a GnRH antagonist protocol for poor ovarian responder patients: an observational pilot study. Fertil Steril 2013;99:422–6. Verhaak CM, Smeenk JM, Eugster A, van Minnen A, Kremer JA, Kraaimaat FW. Stress and marital satisfaction among women before and after their first cycle of in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril 2001;76:525–31. Olivius C, Friden B, Borg G, Bergh C. Why do couples discontinue in vitro fertilization treatment? A cohort study. Fertil Steril 2004;81:258–61. Hojgaard A, Ingerslev HJ, Dinesen J. Friendly IVF: patient opinions. Hum Reprod 2001;16:1391–6. Barrenetxea G, Garcia-Velasco JA, Aragon B, Osset J, Brosa M, LopezMartinez N, et al. Comparative economic study of the use of corifollitropin alfa and daily rFSH for controlled ovarian stimulation in older patients: cost-minimization analysis based on the PURSUE study. Reprod Biomed Soc Online 2018;5:46–59. Martin JR, Mahutte NG, Arici A, Sakkas D. Impact of duration and dose of gonadotrophins on IVF outcomes. Reprod Biomed Online 2006;13:645–50. Cruz M, Alama P, Munoz M, Collado D, Blanes C, Solbes E, et al. Economic impact of ovarian stimulation with corifollitropin alfa versus conventional daily gonadotropins in oocyte donors: a randomized study. Reprod Biomed Online 2017;34:605–10. Mahmoud Youssef MA, van Wely M, Aboulfoutouh I, El-Khyat W, van der Veen F, Al-Inany H. Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis. Fertil Steril 2012;97:876–85. Fensore S, Di Marzio M, Tiboni GM. Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for in vitro fertilization: a meta-analysis. J Ovarian Res 2015;8:33. Griesinger G, Boostanfar R, Gordon K, Gates D, McCrary Sisk C, Stegmann BJ. Corifollitropin alfa versus recombinant follicle-stimulating hormone: an individual patient data meta-analysis. Reprod Biomed Online 2016;33:56–60. Mannaerts B, Verweij P, Gordon K. Comment on, ‘‘Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis.’’ Fertil Steril 2012;97:e22, author reply e23. Taronger R, Martínez-Cuenca S, Ferreros I, Rubio JM, Fernandez-Colom PJ, Martínez-Triguero ML, et al. 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. Eur J Obstet Gynecol Reprod Biol 2018;231:192–7.
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Fertility and Sterility® Corifolitropina alfa en la estimulacion ovarica en fecundaci on in vitro: revisi on sistem atica y meta-an alisis de estudios controlados y aleatorizados Objetivo: evaluar la efectividad de la corifolitropina alfa en la mejora del exito en FIV. ~o: Revisi Disen on sistematica y meta-analisis. Entorno: No aplicable. Paciente(s): mujeres infertiles sometidas a un tratamiento convencional de FIV o inyecci on intracitoplasmatica de espermatozoides (ICSI). nico ciclo de FIV/ICSI con corifoIntervencion(es): estudios controlados y aleatorizados (RCTs) en mujeres infertiles sometidas a un u litropina alfa o protocolo de estimulacion estandar basado en inyecciones diarias. El protocolo de revisi on se registr o en PROSPERO antes de el inicio de la extraccion de datos (CRD42018088605). Principal(es) medida(s) de resultado(s): los resultados primarios fueron la tasa de recien nacido vivo y/o la tasa de gestaci on. Se consideraron resultados secundarios la tasa de gestaci on clínica, la de aborto, la de gestaci on m ultiple, el n umero de ovocitos y de embriones obtenidos, la tasa de cancelaci on y la tasa de síndrome de hiperestimulaci on ovarica y de gestaci on m ultiple. Resultado(s): se incluyeron ocho estudios controlados y aleatorizados; 2.345 mujeres se asignaron al grupo de intervenci on y 1.995 al grupo control. El analisis de 4.340 ciclos de FIV no mostr o ninguna diferencia entre los grupos en cuanto a la tasa de recien nacido vivo y/o de gestaci on evolutiva (riesgo relativo [RR], 0,92; intervalo de confianza 95% [IC], 0,80–1,05). Analogamente, no se encontr o ninguna diferencia en la tasa de gestacion clínica (RR: 0,96; IC 95% ¼ 0,88–1,05; I2 ¼ 0%), ni en la de aborto (RR: 0,94; IC 95% ¼ 0,71–1,25; on m ultiple (RR: 1,22; IC 95% ¼ 0,99–1,50; I2 ¼ 0%). Así mismo, las tasas de cancelaci on de ciclo, de synI2 ¼ 0%) ni en la de gestaci drome de hiperestimulaci on ovarica y de gestaci on fueron similares en ambos grupos. La sensibilidad y los analisis de subgrupo no aportaron cambios estadísticos a los resultados agrupados. Conclusion(es): La corifolitropina alfa parece ser una alternativa a la inyecci on diaria de FSH en pacientes con normo respuesta y baja respuesta sometidas a un ciclo de estimulaci on ovarica para tratamiento de FIV/ICSI.
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