Supplementary Material for: Comparative effectiveness of r-hFSH:r-hLH in a 2:1 ratio versus HP-hMG alone in ovarian stimulation for medically assisted reproduction treatment using IVF/ICSI: A systematic review and meta-analysis

Introduction
Investigation of the number of oocytes recovered from different ovarian stimulation (OS) protocols is essential, as oocyte number is positively associated with the number of good-quality embryos obtained; however, there are few data comparing the number of oocytes retrieved following OS with recombinant or urinary gonadotropins.
Methods
A systematic review and meta-analysis of published evidence was performed to compare the number of oocytes retrieved with recombinant human follicle stimulating hormone:recombinant human luteinizing hormone (r-hFSH:r-hLH) in a 2:1 ratio versus highly purified human menopausal gonadotropin (HP-hMG) alone from Day 1 of OS. The literature search was conducted according to PRISMA guidelines (https://www.prisma-statement.org/) using Medline, EMBASE, Biosis, Scisearch, and TOXCENTER on STN. Studies were included if they reported on r-hFSH:r-hLH in a 2:1 ratio versus HP-hMG alone, both administered from Day 1 of OS, and the results for the number of oocytes retrieved were presented for both interventions. Data were extracted from the full articles independently by two reviewers (JES and BH). Results were analyzed using a random-effects meta-analysis model. Any potential risk of bias was assessed using the ROBINS-I tool. Secondary outcomes were the number of mature (MII) oocytes, clinical pregnancy rate, ongoing pregnancy rate, and live birth rate.
Results
Six studies were included in the meta-analysis (5287 cycles): four non-interventional studies, one non-interventional cross-over study and one randomized controlled trial. The number of oocytes per cycle was significantly higher in women treated with r-hFSH:r-hLH 2:1 compared with those treated with HP-hMG alone (mean difference 1.43, 95% CI 0.18–2.69; P = 0.025). Clinical pregnancy rate per started cycle was significantly higher with r-hFSH:r-hLH 2:1 compared with HP-hMG (rate ratio 1.18, 95% CI 1.06 to 1.33; P = 0.004; five studies). There were insufficient data to draw any firm conclusions on the other secondary outcomes.
Conclusions
The higher number of oocytes retrieved with r-hFSH:r-hLH is a pertinent finding, owing to the well-established positive association between oocyte number and reproductive outcomes. Although we report a higher clinical pregnancy rate for r-hFSH:r-hLH, limited data prevented us from drawing firm conclusions regarding live birth outcomes.