Controlled ovarian stimulation protocols for assisted reproduction: a network meta-analysis.

backgroundControlled 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.

objectivesWe aimed to assess the relative effectiveness and safety of COS protocols in clinical practice. SEARCH

methodsWe 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

resultsWe included 338 studies investigating a total of 15 pairwise comparisons between different COS protocols in 59,086 women. Of these, 226 trials included only women with predicted normal response or whose predicted response was unstated, 31 trials included only women with predicted high response and 81 trials included only women with predicted low response. Primary outcome (effectiveness) - LBR or OPR per woman randomised Pituitary suppression methods In women with predicted normal response, short antagonist protocols probably result in little to no difference in LBR or OPR versus long agonist protocols (RR 0.95, 95% CI 0.84 to 1.07; 8 studies, 2817 women; I AUTHORS'

conclusionsShort 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.