Efficacy of Recombinant Human G-CSF in Women With Unexplained Recurrent Miscarriage

Official title

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

Overview

Recurrent pregnancy loss (RPL), commonly referred to as recurrent miscarriage, affects approximately 1-2% of couples attempting to conceive. In nearly half of these cases, no definitive cause can be identified despite thorough clinical evaluation. A circumstance that is both distressing and disorienting for affected families, particularly in settings such as the United Arab Emirates (UAE), where childbearing carries significant personal and cultural weight. One leading hypothesis is that the underlying problem may not lie with the embryo itself, but with the way the mother's immune system responds to a developing pregnancy. Under normal physiological conditions, the maternal body must establish immune tolerance toward an embryo that is genetically half-foreign in origin. In some women, this tolerance mechanism may be impaired, reducing the likelihood that a pregnancy will successfully implant and progress. This study will evaluate whether granulocyte colony-stimulating factor (G-CSF) a naturally occurring substance that normally stimulates the production of immune cells can help address this issue by modulating an overactive immune response and enhancing the uterine environment's capacity to support pregnancy. Notably, the study will enroll only women whose embryos have undergone genetic testing and been confirmed to be chromosomally normal. This eliminates embryo quality as a contributing factor to pregnancy loss and allows for a clearer assessment of whether G-CSF itself influences outcomes. Earlier small-scale studies, including preliminary work conducted at our own centre, have shown encouraging results. This new trial builds on that foundation by enrolling a larger cohort, comparing G-CSF against a placebo (an inactive comparison treatment), and evaluating a simpler route of administration; subcutaneous injection, rather than direct infusion into the uterus. Together, these design features aim to provide the most reliable evidence to date on whether this treatment can meaningfully help couples affected by unexplained recurrent pregnancy loss.

Detailed description

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.

If successful, the GEM Trial could establish a new standard of care for unexplained RPL offering a more convenient, evidence-based treatment option to thousands of couples and positioning the UAE as a global leader in reproductive immunology research.

Interventions

• Drug Placebo control
  Subcutaneous injection of Recombinant G-CSF daily from embryo transfer until 12 weeks' gestation
• Drug Recombinant G-CSF
  Subcutaneous injection of Recombinant G-CSF daily from embryo transfer until 12 weeks' gestation

Primary outcome measures

• Clinical pregnancy rate [Time frame: From enrollment to 16 weeks gestation]

Secondary outcome measures (6)

• Live birth rate [Time frame: From enrollment to approximately 40 weeks' gestation.]
• Ongoing Pregnancy Rate [Time frame: From 16 weeks to 34 weeks gestation.]
• Early Pregnancy Loss rate [Time frame: From FET (Fetal Embryo Transfer) to 12 weeks gestation]
• Rate of Adverse pregnancy outcomes (APOs) [Time frame: From enrollment to approximately 40 weeks gestation]
• Rate of Adverse events [Time frame: From enrollment up to approximately 40 weeks gestation (delivery)]
• Rate of immunogenicity [Time frame: From enrollment to up to approximately 40 weeks gestation (delivery)]

Eligibility criteria

Inclusion:

• Women aged 18-44 years
• ≥2 unexplained pregnancy losses
• Undergoing IVF with PGT-A tested embryos
• BMI 19-35 kg/m² 6.

Exclusion:

• Parental karyotype abnormalities
• Correctable uterine abnormalities
• Systemic autoimmune disease / thrombophilia
• Uncontrolled systemic illness (e.g. diabetes, infection)
• Previous G-CSF therapy
• Hypersensitivity to rhG-CSF or E. coli proteins
• HIV, malignancy within 5 years, or severe cardiovascular/respiratory history

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United Arab Emirates · 1 center

• Fakih IVF Fertility Centre LLC — Abu Dhabi

Publications

• Impact of Intrauterine Infusion vs Subcutaneous G-CSF Injection on Endometrial Immunomodulation and Angiogenesis in Infertile Women undergoing IUI; Zainab AbdulQaderMahmood, LubnaAmerAl-Anbari, ManalTahaAl-Obaidi, 2025 Trends in Immunotherapy|Volume 09|Issue 03
• P-347 A comparative RCT of Intrauterine-GCSF versus Subcutaneous-GCSF in Thin Endometrium in IVF-ICSI Cycles, P C Jindal, M Singh, Human Reproduction, Volume 36, Issue Supplement_1, July 2021, deab130.346
• GCSF in patients with thin endometrium-subcutaneous or intrauterine?, Shilpa Singal, R.K. Sharma, Nupur Ahuja, Fertility Science and research 10.4103/2394-4285.288714
• Scarpellini F, Sbracia M. Use of granulocyte colony-stimulating factor for the treatment of unexplained recurrent miscarriage: a randomised controlled trial. Hum Reprod. 2009 Nov;24(11):2703-8. doi: 10.1093/humrep/dep240. Epub 2009 Jul 17. PMID 19617208
• Eftekhar M, Miraj S, Najafian A. Efficacy of intrauterine infusion of G-CSF in infertile women: a systematic review and meta-analysis. Int J Reprod Biomed. 2016;14(9):557-566.
• Santjohanser C, Hosseini M, Schönleber J, et al. G-CSF in patients with recurrent miscarriage and recurrent implantation failure: a prospective, randomized, double-blind, placebo-controlled trial. Hum Reprod. 2013;28(1):72-79.
• Barad DH, Yu Y, Kushnir VA, Shohat-Tal A, Lazzaroni E, Lee HJ, Gleicher N. A randomized clinical trial of endometrial perfusion with granulocyte colony-stimulating factor in in vitro fertilization cycles: impact on endometrial thickness and clinical pregnancy rates. Fertil Steril. 2014 Mar;101(3):710-5. doi: 10.1016/j.fertnstert.2013.12.016. Epub 2014 Jan 11. PMID 24424357
• Wurfel W. Treatment with granulocyte colony-stimulating factor in patients with repetitive implantation failures and/or recurrent spontaneous abortions. J Reprod Immunol. 2015 Apr;108:123-35. doi: 10.1016/j.jri.2015.01.010. Epub 2015 Feb 21. PMID 25740726

Identifiers

NCT: NCT07724405 · FAKIH-2025-10 · DOH/ADHRTC/2026/34566666666666

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗