A Randomised, Double Blind, Placebo-controlled Study to Evaluate the Efficacy of Recombinant Human G-CSF in Women With Unexplained Recurrent Miscarriage After IVF With PGT-A Screened Euploid Embryo Transfer

Recurrent pregnancy loss (RPL) defined as two or more consecutive miscarriages before 20 weeks' gestation affects 1-2% of couples worldwide and remains one of the most distressing, poorly resolved conditions in reproductive medicine. In nearly half of cases, no definitive cause is identified. This burden is especially pronounced in the UAE and wider GCC region, where delayed childbearing and the strong sociocultural weight placed on fertility amplify the psychological, marital, and financial toll of unexplained RPL.

Despite decades of research, treatment remains largely empirical. Immune dysregulation is increasingly implicated as a central mechanism, with proposed pathways including aberrant natural killer (NK) cell activation, impaired regulatory T-cell expansion, inadequate decidualization, and an unfavorable Th1/Th17 cytokine profile, collectively compromising endometrial receptivity and embryo survival. However, most supporting studies have been small, uncontrolled, and unable to distinguish maternal immunological causes from embryo genetic abnormalities, leaving clinicians with few evidence-based options.

Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine with immunomodulatory and endometrial effects, has emerged as a promising candidate. Preclinical and early clinical data suggest it enhances endometrial proliferation and vascularization, supports folliculogenesis and oocyte competence, and promotes immune tolerance by expanding regulatory T-cells while reducing NK cell cytotoxicity. Small trials in both recurrent implantation failure and RPL populations have reported benefits in implantation and live birth rates, though results have been inconsistent - largely due to the same methodological limitations noted above, plus a failure to control for embryo aneuploidy as a confounder.

Our own retrospective pilot study of 19 patients receiving intrauterine G-CSF supports this rationale: 70.5% achieved a positive β-hCG, 66.7% progressed to ongoing pregnancy, and no adverse effects were observed. These findings demonstrate both feasibility and preliminary efficacy at our centre. However, intrauterine infusion is invasive, costly, and less patient-friendly; existing literature suggests subcutaneous administration may achieve comparable efficacy with greater convenience, but this route has not yet been evaluated in this specific population.

The GEM Trial is designed to resolve these open questions directly. By enrolling women with unexplained RPL undergoing IVF with preimplantation genetic testing for aneuploidy (PGT-A), the trial eliminates embryo chromosomal abnormality as a confounder, enabling a precise, mechanistically targeted test of the immunological hypothesis. It will be the first placebo-controlled, genetically controlled trial of G-CSF in this population, and the first to formally assess subcutaneous delivery.