Controlled ovarian stimulation protocols for assisted reproduction: a network meta-analysis
Pedro Melo, Abey Eapen, Yealin Chung, Yadava Jeve, Malcolm J Price, Sesh Kamal Sunkara, Nick Macklon, Yacoub Khalaf, Aurelio Tobias, Frank J. Broekmans, Mohammed Khairy, Ioannis Gallos, Arri Coomarasamy
Abstract
BACKGROUND: Controlled ovarian stimulation (COS) is an essential step in most assisted conception cycles. Different treatment combinations (termed protocols) exist in COS, yet there is no consensus on their relative effectiveness and safety. OBJECTIVES: We aimed to assess the relative effectiveness and safety of COS protocols in clinical practice. SEARCH METHODS: We followed standard Cochrane methodology to conduct extensive electronic searches to 11 June 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing at least two COS protocols using any form of pituitary suppression (gonadotrophin-releasing hormone (GnRH) agonists, antagonists or progestogens) and human menopausal gonadotropin (hMG), urinary or recombinant follicle-stimulating hormone (u/rFSH), with or without luteinising hormone (LH) and/or oral medications (e.g. clomifene or letrozole), for ovarian stimulation. The primary outcomes were the rates of live birth or ongoing pregnancy (LBR or OPR) and ovarian hyperstimulation syndrome (OHSS) per participant after one stimulation cycle. The secondary outcomes were the rates of clinical pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and cycle cancellation per participant, and the number of oocytes, cleavage-stage embryos, blastocyst-stage embryos and cryopreserved embryos per participant. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We conducted pairwise and network meta-analyses (NMA) according to participants' predicted response to COS (normal/unselected, high or low). For each outcome and subgroup of women, we grouped treatment protocols into the following different networks: all pituitary suppression methods; all long GnRH agonist protocols; all short GnRH antagonist protocols; all GnRH agonist flare protocols; all protocols using progestogens for pituitary suppression; and all protocols using ovarian stimulation in the absence of pituitary suppression. Using the Cochrane RoB 1 tool, we restricted our primary analyses to RCTs at low risk of 'selection' and 'other' biases. We presented effect estimates as risk ratios (RR) for dichotomous outcomes, or mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI). We used Review Manager and Stata 18 for the meta-analyses. MAIN RESULTS: = 0%; high-certainty evidence). Remaining evidence For the remaining networks, patient subgroups and secondary outcomes, the evidence did not confidently identify differences between COS protocols. AUTHORS' CONCLUSIONS: Short GnRH antagonist protocols may reduce OHSS rates in women with predicted normal response without compromising LBR or OPR. Ovarian stimulation without pituitary suppression may reduce the LBR or OPR compared with short GnRH antagonist protocols and with GnRH agonist flare protocols. In women with predicted high response receiving short GnRH antagonist protocols, hMG may reduce OHSS compared with rFSH. We were unable to meta-analyse results from 169 trials due to serious risk of selection or other biases, a lack of outcome data, or because of data reported in an unsuitable format for meta-analysis (e.g. per cycle); this led to underpowered analyses for several outcomes and pairwise comparisons. Future trials should focus on evaluating the effect of different COS protocols upon cumulative live birth rates, accounting for all embryo transfers (fresh and/or frozen) after a single stimulation cycle per participant.