Comparative efficacy and safety of metformin, anti-obesity agents, and myoinositol in improving IVF/ICSI outcomes and reducing ovarian hyperstimulation syndrome in women with polycystic ovary syndrome: a systematic review and network meta-analysis

To compare the efficacy and safety of metformin, anti-obesity agents, and inositol with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). A comprehensive search was conducted in PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov for studies published in English up to October 26, 2024. Randomized controlled trials (RCTs) evaluating metformin, anti-obesity agents, and inositol were included. A network meta-analysis was performed using frequency statistical methods. Subgroup analyses were conducted based on controlled ovarian stimulation (COS) protocols and body mass index(BMI). The research protocol was registered with PROSPERO (registration code CRD42024502823). 20 RCTs were included with 1,827 patients assessed six different agents. Nineteen trials were rated low risk, with one rated moderate risk. Pairwise meta-analysis showed that metformin did not improve pregnancy outcomes but was associated with a reduced ovarian hyperstimulation syndrome (OHSS) risk (OR = 0.52, 95% CI 0.33-0.83), particularly in agonist protocols, along with lower E2 levels on the trigger day (SMD = -0.56, 95% CI -0.90 to -0.21) and increased side effects (OR = 6.85, 95% CI 4.32-10.86). Network meta-analysis confirmed no significant differences in pregnancy outcomes for these agents compared to controls, though both myoinositol and metformin reduced OHSS risk. Myoinositol was linked to a shorter gonadotropin duration (SMD = -1.21, 95% CI -2.03 to -0.38) and fewer side effects (OR = 0.23, 95% CI 0.06-0.83) compared to controls. Metformin led to lower E2 levels, a higher number of mature oocytes, and increased side effects (SMD = -376.52, 95% CI -610.83 to -142.22; SMD = 2.23, 95% CI 0.36-4.10; OR = 6.85, 95% CI 4.32-10.86) than controls. No studies reported an increased risk of fetal abnormalities. Metformin and myoinositol may reduce OHSS risk in PCOS patients but did not significantly improve pregnancy outcomes. Metformin may lower OHSS risk in agonist protocol, reduce E2 levels on trigger day and increase mature oocytes but cause more side effects, while myoinositol may shorten gonadotropin duration with fewer side effects. Further robust RCTs are needed to confirm these findings.