Corifollitropin alfa (CFA) is a long-acting recombinant follicle stimulating hormone (rFSH) used for the controlled ovarian stimulation (COS) during in vitro fertilization (IVF) programs [1].

The molecular structure of CFA is a heterodimer composed by the FSH $\alpha$-subunit and a chimeric $\beta$-subunit constituted by the fusion of the FSH $\beta$-subunit and the C-terminal peptide (CTP) of the human chorionic gonadotropin (hCG) $\beta$-subunit [2, 3]. The addition of the CTP to new recombinant proteins allows to prolog their circulating lifetime [2]. In fact, contrarily to conventional recombinant FSH (rFSH) preparations characterized by a relatively short half-life and rapid metabolic clearance, a single injection of CFA can initiate and sustain the multiple follicular growth for the first seven days of COS, due to a slower absorption and a much longer elimination half time [1, 4, 5, 6]. For this reason, the main clinical advantage offered by CFA is represented by the reduced number of subcutaneous injections that are needed during one treatment cycle, resulting in a mitigation of the patient burden [1, 2, 5, 6].

CFA is administered as a single injection from day 2 or 3 of menstrual cycle and, if needed, daily injections of rFSH are given from day 8 of stimulation [7]. Age and weight of patients are factors to consider when determining the optimal CFA dose. The optimal doses are 100 $\mu$g in women who weigh less than or equal to 60 kilograms and 36 years old or younger; and 150 $\mu$g in women weighing more than 60 kilograms regardless of age and women who weigh 50 kilograms or more and who are older than 36 years of age [6].

The clinical effectiveness and safety of CFA compared to daily rFSH during COS represent the topic of several randomized controlled trials (RCTs). The aim of this study is to provide an updated meta-analysis pooling the data of the RCTs published to date on this matter.

The results of this study are reported according to the guidelines outlined in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) [8].

The present meta-analysis pooled the data from twelve RCTs focusing on the clinical effectiveness and safety of CFA compared to conventional daily rFSH.

The analysis shows that treatment with CFA results in an increased number of total oocytes retrieved at ovum pick-up and increased number of MII oocytes compared to patients receiving daily conventional rFSH during COS. No statistically significant differences were noted for the other outcomes analyzed in this study.

Previous meta-analyses have been published with the aim to compare the ovarian stimulation with CFA and daily rFSH [25, 26, 27, 28]. With respect to the latest recently published meta-analysis [28], the strengths of the present study comprise that our data updated the results by including four additional studies [17, 21, 23, 24] and 640 more patients. More to the point, the present meta-analysis also combined the data regarding five outcomes previously not examined by Cozzolino and colleagues (2019) (duration of stimulation, cancellation rate, fertilization rate, implantation rate and miscarriage rate). We also included RCTs on egg donors [17, 21] and poor responders [18, 20, 24] that represent two subgroups of IVF patients.

The number of retrieved oocytes at ovum pick-up represents one of the main parameters in the comparison between gonadotropins according to the European Medicines Agency (EMA) [9]. This parameter was considered as primary endpoint in the majority of the studies included in the present meta-analysis [14, 15, 16, 24]. The CFA protocol resulted in an higher number of oocytes retrieved at ovum pick up compared to daily rFSH [14, 16, 24]. These data reveal the efficacy of this novel FSH formulation but advises against the possible increased risk of developing OHSS during COS with CFA [6]. The present meta-analysis reassured about this concern considering that no differences in OHSS incidence have been found between CFA and daily rFSH treatments (OR 1.08, 95% CI [0.79, 1.49], p = 0.63). However, the heterogeneity between the included studies in relation to the patients’ characteristics and the ovarian stimulation protocols recall the need for specific studies on this matter. In this context, the study of Tarlatzis et al. [29] was conducted with the aim to assess the incidence of OHSS after CFA treatment by pooling the cases of OHSS from three large phase III trials primarily designed to analyse the efficacy of CFA treatment in a GnRH antagonist protocol [15, 16, 30]. The pooled data demonstrated that the risk of OHSS tends to be slightly higher with CFA than with daily rFSH treatment, but the overall incidence of OHSS (5.6%) together with the timing of occurrence and the severity in all the three phase III trials are in line with those obtained with daily rFSH treatment [29].

In addition, some RCTs included in the present meta-analysis were carried on considering the ongoing pregnancy rate (defined as presence of at least one fetus with heart activity at least 10 weeks after embryo transfer) as primary outcome instead of the number of oocytes retrieved at ovum pick-up [15, 19, 20]. No significant differences were noted between the percentage of women getting pregnant following treatment with CFA or rFSH in the studies of Devroey et al. [15] and Drakopoulos et al. [20]. In addition, Boostanfar et al. [19] confirmed the non-inferiority of CFA to daily rFSH with respect to the vital pregnancy rate (defined as the presence of at least one fetus with heart activity assessed at least $\ge$5 weeks after embryo transfer) [19].

It is noteworthy that several studies different from RCTs have been published with the aim to compare the clinical efficacy of CFA and the treatment with daily gonadotropins. The majority of these studies suggested that CFA represents an efficient alternative to daily rFSH formulations [31, 32, 33]. Contrarily to these data, Siristatidis et al. [34] found that live birth and clinical pregnancy rates were significantly reduced in women treated with CFA compared to those treated with follitropin beta, suggesting that CFA does not represent an equally method of ovarian stimulation compared with follitropin beta [34].

Three of the studies included in the present meta-analysis were carried out on poor responder patients [18, 20, 24] demonstrating that those treated with CFA showed a higher number of oocytes [24], and higher cryopreserved embryos [20], together with a shorter length of stimulation and reduced suspended treatments [24] compared to those treated with daily rFSH. In the current study, the subgroup analysis performed in order to compare “normal” versus “poor” responders reveals a significantly higher number of oocytes retrieved (MD 1.05, 95% CI [0.28, 1.82], p = 0.01), number of MII oocytes (MD 1.27, 95% CI [0.43, 2.11], p = 0.003), and cancellation rate (OR 1.37, 95% CI [1.03, 1.80], p = 0.03) in the group of normal responders receiving CFA.

In this context, the retrospective study performed by Adrisani et al. [35] added significant information in this field [35]. The treatments with CFA and daily gonadotropins resulted comparable in terms of clinical outcomes in poor responders with antral follicle count (AFC) $>$5. On the contrary, women with AFC $\le$5 treated with CFA experienced a lower number of total oocytes, MII oocytes, and total embryos compared to those with AFC $\le$5 treated only with daily gonadotropins [35].

Regarding the methodological quality of the trials included in the present meta-analysis, six studies are open label-designed [13, 14, 17, 18, 20, 24] and three studies are double blind-designed [15, 16, 19]. A potential selection bias must be recognized since two studies not reported the methods of randomization and allocation [13, 23] and in the study of Requena et al. [17] patients were assigned to each protocol directly by investigators. In addition, not all the studies detailed the blinding of participant and personnels and no study was assessor-blinded. We have graphically detected the presence of publication bias using both funnel and normal quantile plots. However, since the number of studies, for almost all the outcomes, is less than ten, this latter has been judged more reliable in revealing the presence of publication bias. In addition it was recognized a clinical heterogeneity among the trials about the inclusion criteria of the patients and the ovarian stimulation protocols, with particular regard for the starting dose of daily rFSH. At this purpose, the subgroup analysis highlighted a higher number of both oocytes retrieved (MD 0.82, 95% CI [0.29, 1.35], p = 0.002), MII oocytes (MD 0.91, 95% CI [0.33, 1.50], p = 0.002), and embryos obtained (MD 0.61, 95% CI [0.45, 0.77], p 0.0001) in patients treated with CFA for the group where daily doses greater than 150 IU of rFSH were given.

The main limitations of the present meta-analysis are related to the existing heterogeneity among the included studies, as represented by discrepancies in COS. In fact, in addition to differences in the starting dose of daily rFSH, two authors (Requena et al. [17] and Cruz et al. [21]) investigated oocyte donors and assigned an oral contraceptive pill to patients on day 1 or 2 of menses of the previous cycle before starting the assigned stimulation protocol.

In addition, differences in primary endpoints considered, methodological quality and patients characteristics among the studies represent possible sources of bias.

In view of the EMA statement that recommended to consider the number of oocytes retrieved as the primary endpoint to compare gonadotropins, our study demonstrated that CFA treatment represents an effective method in comparison to daily rFSH. The association between CFA and increased number of retrieved oocytes at ovum pick-up together with a higher number of MII oocyte is possibly due to the capacity of CFA to recruit an increased cohort of developing follicles. However, given the existing heterogeneity between the studies, further comparable RCTs are needed.

MCB—conceptualization, methodology, literature search, writing original draft, data curation, formal analysis; SF—conceptualization, methodology, literature search, writing original draft, data curation, formal analysis; MDM—conceptualization, methodology, literature search, writing original draft, writing-review and editing, investigation; GMT—conceptualization, methodology, literature search, writing original draft, writing-review and editing, investigation, supervision. All authors read and approved the final version of the manuscript.

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This research received no external funding.

The authors declare no conflict of interest.