Controlled ovarian stimulation (COS) protocols for assisted reproduction: a Cochrane systematic review and network meta-analysis

Abstract Study question What is the relative effectiveness and safety of existing COS protocols for women undergoing assisted reproductive technology (ART) treatment? Summary answer There was no difference in live birth between all protocols, but short antagonist protocols may reduce ovarian hyperstimulation syndrome in women with predicted normal/high response. What is known already Controlled ovarian stimulation is an essential step in most ART cycles. It involves the administration of exogenous gonadotrophins to induce multifollicular growth, usually in addition to drugs that prevent untimely ovulation by suppressing the pituitary gland. Different treatment combinations may be used in COS. These vary according to the type of drugs administered for pituitary suppression (e.g., gonadotrophin-releasing hormone [GnRH] agonists, antagonists) and ovarian stimulation (e.g., urinary or recombinant gonadotrophins). Drug dosages, timing and routes of administration also vary between different regimens. However, there is no consensus on how the existing COS protocols rank according to their effectiveness and safety. Study design, size, duration We searched the following databases to November 2021: MEDLINE, EMBASE, CINAHL, CENTRAL and ClinicalTrials.gov. We included randomised controlled trials (RCTs) comparing at least two COS protocols using GnRH agonists or antagonists for pituitary suppression; and human menopausal gonadotrophin (hMG), urinary or recombinant follicle-stimulating hormone (u/rFSH), with or without luteinising hormone (LH) for ovarian stimulation. The primary outcomes were the rates of live birth (LBR) and ovarian hyperstimulation syndrome (OHSS) per participant after one stimulation cycle. Participants/materials, setting, methods Two reviewers independently selected studies and extracted data. We conducted pairwise and network meta-analyses (NMA) according to participants’ predicted response to COS (normal, high and low). 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 ratio (RR) with 95% confidence interval (CI) and considered I2>50% as representing substantial heterogeneity. For each outcome, we generated ranking plots comparing different interventions. Main results and the role of chance In total, our searches identified 9464 studies. The primary analysis included 68 RCTs assessing 17861 women and 34 different COS protocols. The evidence showed that in women with predicted normal or high response, the use of short GnRH antagonist protocols may result in little to no difference in LBR (RR 0.98, 95% CI 0.85 to 1.13; 6 studies; 2063 women; I2 = 0%; low-certainty evidence) and a reduction in OHSS (RR 0.88, 95% CI 0.78 to 0.99; 7 studies; 2246 women; I2 = 0%; low-certainty evidence) compared with long GnRH agonist protocols. The rankogram comparing different COS protocols showed a probability of 98% that short GnRH antagonist regimens are the best treatment to prevent OHSS. Sensitivity analyses including all studies showed that in women with predicted normal response undergoing long GnRH agonist cycles for pituitary suppression, the use of rFSH for ovarian stimulation may result in decreased fresh-cycle LBR compared to hMG (RR 0.80, 95% CI 0.68 to 0.95; 7 studies; 1575 women; I2 = 1%; low-certainty evidence). For the remaining interventions (e.g., agonist flare or progestogens for pituitary suppression, in combination with various gonadotrophin regimens) the evidence was uncertain of an effect or insufficient for quantitative synthesis. Limitations, reasons for caution The high number of interventions resulted in disconnected networks, limiting our ability to perform NMA for some comparisons. The certainty of the evidence was limited by serious risk of bias. Finally, the lack of data on cumulative LBR and differences in oocyte yield made comparisons between FSH preparations potentially unbalanced. Wider implications of the findings Our findings suggest that the use of short GnRH antagonist protocols may result in reduced OHSS rates in women with predicted normal or high ovarian response without compromising live birth rates. There is a paucity of high-quality RCTs comparing different gonadotrophin preparations (e.g., hMG versus rFSH) for COS. Trial registration number N/A