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

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.

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

We followed standard Cochrane methodology to conduct extensive electronic searches to 11 June 2024.

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.

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.

We 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; I² = 0%; moderate-certainty evidence). Network evidence also suggested that ovarian stimulation without pituitary suppression may reduce the LBR or OPR compared with short GnRH antagonist protocols (RR 0.71, 95% CI 0.57 to 0.90; low-certainty evidence) and with GnRH agonist flare protocols (RR 0.52, 95% CI 0.36 to 0.75; low-certainty evidence). Primary outcome (safety) - OHSS per woman randomised Pituitary suppression methods In women with predicted normal response, short GnRH antagonist protocols may reduce OHSS compared with long GnRH agonist protocols (RR 0.88, 95% CI 0.78 to 0.99; 7 studies, 2650 women; I² = 0%; low-certainty evidence). Short GnRH antagonist protocols In women with predicted high response receiving short GnRH antagonist protocols, hMG may reduce OHSS compared with rFSH (RR 0.45, 95% CI 0.3 to 0.68; 1 study, 619 women; low-certainty evidence). Secondary outcomes Clinical pregnancy Pituitary suppression methods In women with predicted normal response, network evidence suggested that ovarian stimulation without pituitary suppression lowers the clinical pregnancy rate compared with short GnRH antagonist protocols (RR 0.76, 95% CI 0.61 to 0.93; low-certainty evidence) and with GnRH agonist flare protocols (RR 0.60, 95% CI 0.44 to 0.82; low-certainty evidence). Cancellation Short GnRH antagonist protocols In women with predicted high response undergoing short GnRH antagonist protocols, hMG may increase cancellation compared with rFSH (RR 5.98, 95% CI 1.78 to 20.10; 1 study, 619 women; low-certainty evidence). For the remaining networks and participant subgroups (normal- and low-responding women), the evidence did not confidently identify differences between COS protocols and is not reported in the abstract. Oocyte number Pituitary suppression methods In women with predicted normal response, short GnRH antagonist protocols (MD -0.75, 95% CI -1.49 to -0.02; 17 studies, 4062 women; I² = 94%; low-certainty evidence), GnRH agonist flare protocols (MD -3.30, 95% CI -4.87 to -1.73; 1 study, 240 women; I² = 96%; low-certainty evidence) and protocols without pituitary suppression (MD -5.80, 95% CI -11.24 to -0.36; 2 studies, 714 women; low-certainty evidence) may lower the oocyte number compared with long GnRH agonist protocols, respectively. In women with predicted low response, short GnRH antagonist protocols may reduce the oocyte number versus long agonist protocols (MD -1.25, 95% CI -2.01 to -0.50; low-certainty evidence). Long GnRH agonist protocols In women with predicted normal response receiving long GnRH agonist protocols, combining rFSH and rLH reduces the oocyte number compared with rFSH alone (MD -0.81, 95% CI -1.33 to -0.28; 6 trials, 1289 women; I² = 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.

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.