Follitropin alfa 450unit powder and solvent for solution for injection vials

Ovarian hyperstimulation syndrome (OHSS) is the main severe complication of ovarian stimulation for in vitro fertilization (IVF) cycles. The aim of the current study was to identify the interventions for the prevention of and reduction in the incidence and severity of OHSS in patients who undergo IVF not included in systematic reviews with meta-analyses of randomized controlled trials (RCTs) and assess and grade their efficacy and evidence base. The best available evidence for each specific intervention was identified, analyzed in terms of safety/efficacy ratio and risk of bias, and graded using the Oxford Centre for Evidence-Based Medicine (CEBM) hierarchy of evidence. A total of 15 interventions to prevent OHSS were included in the final analysis. In the IVF population not at a high risk for OHSS, follitropin delta for ovarian stimulation may reduce the incidence of early OHSS and/or preventive interventions for early OHSS. In high-risk patients, inositol pretreatment, ovulation triggering with low doses of urinary hCG, and the luteal phase administration of a GnRH antagonist may reduce OHSS risk. In conclusion, even if not supported by systematic reviews with homogeneity of the RCTs, several treatments/strategies to reduce the incidence and severity of OHSS have been shown to be promising.

Abstract licence: CC BY

BackgroundFollitropin δ may be an alternative to conventional follitropin α/β for controlled ovarian stimulation (COS) within assisted reproductive treatment (ART), but its efficacy and safety remain unknown. We performed a random-effects meta-analysis to compare the efficacy and safety of follitropin δ and follitropin α/β.MethodsWe searched randomized controlled trials comparing follitropin δ and follitropin α/β using MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO-ITCRP on December 14, 2022. The primary outcomes were the live birth rate and the incidence of moderate or severe ovarian hyperstimulation syndrome (OHSS). The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation approach. The protocol was registered on the Open Science Framework.ResultsThree studies involving 2682 participants were included in our meta-analysis. The results indicated that follitropin δ may result in little to no difference in live birth rates (risk ratio [RR], 1.12; 95% confidence interval [CI], 0.91-1.38; low certainty) and the incidence of moderate or severe OHSS (RR, 0.78; 95% CI, 0.48-1.26; low certainty) compared with follitropin α/β.ConclusionFollitropin δ may result in little to no difference in COS compared with follitropin α/β, especially in terms of live births and safety.

Abstract licence: CC BY

Abstract STUDY QUESTION How does the efficacy and safety of a fixed-ratio combination of recombinant human FSH plus recombinant human LH (follitropin alfa plus lutropin alfa; r-hFSH/r-hLH) compare with that of r-hFSH monotherapy for controlled ovarian stimulation (COS) in patients with poor ovarian response (POR)? SUMMARY ANSWER The primary and secondary efficacy endpoints were comparable between treatment groups and the safety profile of both treatment regimens was favourable. WHAT IS KNOWN ALREADY Although meta-analyses of clinical trials have suggested some beneficial effect on reproductive outcomes with r-hLH supplementation in patients with POR, the definitions of POR were heterogeneous and limit the comparability across studies. STUDY DESIGN, SIZE, DURATION Phase III, single-blind, active-comparator, randomized, parallel-group clinical trial. Patients were followed for a single ART cycle. A total of 939 women were randomized (1:1) to receive either r-hFSH/r-hLH or r-hFSH. Randomization, stratified by study site and participant age, was conducted via an interactive voice response system. PARTICIPANTS/MATERIALS, SETTING, METHODS Women classified as having POR, based on criteria incorporating the ESHRE Bologna criteria, were down-regulated with a long GnRH agonist protocol and following successful down-regulation were randomized (1:1) to COS with r-hFSH/r-hLH or r-hFSH alone. The primary efficacy endpoint was the number of oocytes retrieved following COS. Safety endpoints included the incidence of adverse events, including ovarian hyperstimulation syndrome (OHSS). Post hoc analyses investigated safety outcomes and correlations between live birth and baseline characteristics (age and number of oocytes retrieved in previous ART treatment cycles or serum anti-Müllerian hormone (AMH)). The significance of the treatment effect was tested by generalized linear models (Poisson regression for counts and logistic regression for binary endpoints) adjusting for age and country. MAIN RESULTS AND THE ROLE OF CHANCE Of 949 subjects achieving down-regulation, 939 were randomized to r-hFSH/r-hLH (n = 477) or r-hFSH (n = 462) and received treatment. Efficacy assessment: In the intention-to-treat (ITT) population, the mean (SD) number of oocytes retrieved (primary endpoint) was 3.3 (2.71) in the r-hFSH/r-hLH group compared with 3.6 (2.82) in the r-hFSH group (between-group difference not statistically significant). The observed difference between treatment groups (r-hFSH/r-hLH and r-hFSH, respectively) for efficacy outcomes decreased over the course of pregnancy (biochemical pregnancy rate: 17.3% versus 23.9%; clinical pregnancy rate: 14.1% versus 16.8%; ongoing pregnancy rate: 11.0% versus 12.4%; and live birth rate: 10.6% versus 11.7%). An interaction (identified post hoc) between baseline characteristics related to POR and treatment effect was noted for live birth, with r-hFSH/r-hLH associated with a higher live birth rate for patients with moderate or severe POR, whereas r-hFSH was associated with a higher live birth rate for those with mild POR. A post hoc logistic regression analysis indicated that the incidence of total pregnancy outcome failure was lower in the r-hFSH/r-hLH group (6.7%) compared with the r-hFSH group (12.4%) with an odds ratio of 0.52 (95% CI 0.33, 0.82; P = 0.005). Safety assessment: The overall proportion of patients with treatment-emergent adverse events (TEAEs) occurring during or after r-hFSH/r-hLH or r-hFSH use (stimulation or post-stimulation phase) was 19.9% and 26.8%, respectively. There was no consistent pattern of TEAEs associated with either treatment. LIMITATIONS, REASONS FOR CAUTION Despite using inclusion criteria for POR incorporating the ESHRE Bologna criteria, further investigation is needed to determine the impact of the heterogeneity of POR in the Bologna patient population. The observed correlation between baseline clinical characteristics related to POR and live birth rate, as well as the observed differences between groups regarding total pregnancy outcome failure were from post hoc analyses, and the study was not powered for these endpoints. In addition, the attrition rate for pregnancy outcomes in this trial may not reflect general medical practice. Furthermore, as the patient population was predominantly White these results might not be applicable to other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS In the population of women with POR investigated in this study, although the number of oocytes retrieved was similar following stimulation with either a fixed-ratio combination of r-hFSH/r-hLH or r-hFSH monotherapy, post hoc analyses showed that there was a lower rate of total pregnancy outcome failure in patients receiving r-hFSH/r-hLH, in addition to a higher live birth rate in patients with moderate and severe POR. These findings are clinically relevant and require additional investigation. The benefit:risk balance of treatment with either r-hFSH/r-hLH or r-hFSH remains positive. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Merck KGaA, Darmstadt, Germany. P.H. has received honoraria for lectures and unrestricted research grants from Ferring, Merck KGaA and MSD. D.R. is a former employee of EMD Serono, a business of Merck KGaA, Darmstadt, Germany. J.S., J.H. and W.C. are employees of EMD Serono Research and Development Institute, a business of Merck KGaA, Darmstadt, Germany. T.D.’H. and S.L. are employees of Merck KGaA, Darmstadt, Germany. TRIAL REGISTRATION NUMBER ClinicalTrials.gov identifier: NCT02047227; EudraCT Number: 2013-003817-16. TRIAL REGISTRATION DATE ClinicalTrials.gov: 24 January 2014; EudraCT: 19 December 2013. DATE OF FIRST PATIENT'S ENROLMENT 30 January 2014.

Abstract licence: CC BY-NC 4.0

Understanding the variability in ovarian response following administration of follicle-stimulating hormone medications in women undergoing in vitro fertilization may help inform prescribing decisions. A systematic review was conducted to compare the number of retrieved oocytes and fertility outcomes following the administration of different follicle-stimulating hormone medications. Databases were searched from inception to November 2024, including studies that compared two follicle-stimulating hormone medications, including follitropin alfa, follitropin beta, follitropin delta, and urofollitropin. Meta-analyses were performed in random effects models with the restricted maximum likelihood method. From 3867 identified articles, 26 (12613 participants) were included. More oocytes were retrieved with follitropin alfa compared to beta (mean difference 0.64, 95% CI 0.09-1.19). Compared to follitropin delta, more oocytes were retrieved with follitropin alfa and beta (1.38, 95% CI 0.09-2.67, and 1.40, 95% CI 0.41-2.39, respectively); however, higher total doses of follitropin alfa and beta were administered (199.29 IU, 95% CI 43.15-355.43 and 181.08 IU, 95% CI 55.67-306.49, respectively), and the risk of hyperstimulation increased (risk ratios 1.42, 95% CI 1.04-1.96 and 1.75, 95% CI 1.15-2.70, respectively). More oocytes were retrieved with urofollitropin compared to follitropin beta (1.12, 95% CI -1.63 to -0.62), with higher total doses of urofollitropin administered (782.32 IU, 95% CI -1493.79 to -70.85). Variability in ovarian response and hyperstimulation rates across the medications decreased when similar total doses were administered. Fertilization, pregnancy, and live birth rates were similar across the medications, despite differences in the number of retrieved oocytes. Additional research is required to evaluate oocyte quality across follicle-stimulating hormone medications.

Abstract licence: CC BY-NC-ND