RATIONALE: Ovarian stimulation is an essential step during in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI), needed to produce multiple follicles for follicle aspiration. The strategy of stimulating the ovaries with gonadotropins is well established and can be performed using different types of gonadotropins. This review update brings together all randomised studies that compare recombinant follicle stimulating hormone (rFSH) with urinary gonadotropins and other recombinant rFSH (including rFSH from a human cell line) and biosimilars. OBJECTIVES: To compare the effectiveness and safety of recombinant follicle-stimulating hormone (rFSH) with the three main types of urinary gonadotropins, rFSH derived from a human cell line (follitropin delta) and rFSH biosimilars for ovarian stimulation in women undergoing IVF or ICSI treatment cycles. SEARCH METHODS: We carried out an extensive search on 31 March 2025, according to Cochrane guidelines. The databases searched included: the Cochrane Gynaecology and Fertility Specialised Register of controlled trials, CENTRAL, MEDLINE and Embase. We also searched trials registries, reference lists and contacted experts in the field for additional studies. ELIGIBILITY CRITERIA: We included all randomised controlled trials reporting data comparing clinical outcomes of women undergoing IVF/ICSI cycles and using rFSH in comparison with human menopausal gonadotropin (HMG) or highly purified HMG (HP-HMG), purified urinary follicle-stimulating hormone (FSH-P), highly purified urinary FSH (FSH-HP), follitropin delta, and rFSH biosimilars for ovarian hyperstimulation. We used the Trustworthiness in RAndomised Controlled Trials (TRACT) checklist to assess trustworthiness and excluded potentially problematic studies from the analyses. OUTCOMES: We implemented the core outcome set for infertility. Our main outcomes were live birth, ovarian hyperstimulation syndrome (OHSS) (both critical outcomes) and clinical pregnancy. RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 1) to assess the risk of bias. SYNTHESIS METHODS: We combined data using a fixed-effect model to calculate an odds ratio (OR) or mean difference (MD). We summarised the overall certainty of evidence for the main outcomes using GRADE criteria. INCLUDED STUDIES: We included 59 studies (25 new studies) with a total of 18,119 women undergoing fertility treatment. SYNTHESIS OF RESULTS: rFSH versus HMG/HP-HMG Live birth is probably lower with rFSH compared to HMG/HP-HMG (OR 0.83, 95% CI 0.73 to 0.95; 15 studies, 4793 participants, moderate-certainty evidence). OHSS is probably higher with rFSH compared to HMG/HP-HMG (OR 1.42, 95% CI 1.12 to 1.80; 37 studies, 9813 participants, moderate-certainty evidence). Clinical pregnancy is probably lower with rFSH compared to HMG/HP-HMG (OR 0.87, 95% CI 0.76 to 0.98; 15 studies, 4839 participants, moderate-certainty evidence). rFSH versus FSH-HP Live birth: there is probably little or no difference in live birth between rFSH and FSH-HP (OR 1.02, 95% CI 0.86 to 1.21; 15 studies, 2956 participants, moderate-certainty evidence) OHSS: there is probably little or no difference in OHSS between rFSH and FSH-HP (OR 1.01, 95% CI 0.67 to 1.53; 18 studies, 3640 participants, moderate-certainty evidence). Clinical pregnancy: there is probably little or no difference in clinical pregnancy between rFSH and FSH-HP (OR 1.00, 95% CI 0.88 to 1.14; 22 studies, 4535 participants, moderate-certainty evidence). rFSH versus follitropin delta Live birth: there is probably little or no difference in live birth between rFSH and follitropin delta (OR 0.88, 95% CI 0.74 to 1.04; 3 studies, 2688 participants, moderate-certainty evidence). OHSS is probably higher with rFSH compared to follitropin delta (OR 1.62, 95% CI 1.18 to 2.23; 4 studies, 2988 participants, moderate-certainty evidence). Clinical pregnancy: there is no difference in clinical pregnancy between rFSH and follitropin delta (OR 0.94, 95% CI 0.80 to 1.11; 3 studies, 2688 participants, high-certainty evidence). rFSH versus biosimilars Live birth is probably higher with rFSH compared to biosimilars (OR 1.29, 95% CI 1.09 to 1.54; 8 studies, 2883 participants, moderate-certainty evidence). OHSS: there may be little or no difference in OHSS between rFSH and biosimilars (OR 0.77, 95% CI 0.57 to 1.06; 8 studies, 2883 participants, low-certainty evidence). Clinical pregnancy was probably higher with rFSH compared to biosimilars (OR 1.35, 95% CI 1.14 to 1.60; 7 studies, 2783 participants, moderate-certainty evidence). The certainty of the evidence ranged from low to moderate for live birth and OHSS, and from moderate to high for clinical pregnancy. The main limitations were risk of bias in the included studies - unclear selection bias and selective reporting, as well as high risk of other bias. Many studies were sponsored by the pharmaceutical industry. AUTHORS' CONCLUSIONS: Live birth and clinical pregnancies are probably lower with rFSH compared to HMG/HP-HMG, while OHSS is probably higher with rFSH when compared to HMG/HP-HMG. There is probably little to no difference in live birth, clinical pregnancy, or OHSS between rFSH and FSH-HP. When compared with follitropin delta, there is probably little or no difference in live birth or clinical pregnancy, while OHSS is probably higher with rFSH. When compared with biosimilars, live birth and clinical pregnancies are probably higher with rFSH, while there may be little or no difference in OHSS. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol (2005) https://doi.org/10.1002/14651858.CD005354 Review (2011) https://doi.org/10.1002/14651858.CD005354.pub2.
Berkhout et al. (Tue,) studied this question.