Recombinant human granulocyte– colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial

Abstract

STUDY QUESTION Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss? SUMMARY ANSWER rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss. WHAT IS KNOWN ALREADY The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates. STUDY DESIGN, SIZE, DURATION A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK. PARTICIPANTS/MATERIALS, SETTING, METHODS One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte – colony stimulating factor 130 μg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat. MAIN RESULTS AND THE ROLE OF CHANCE A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29–34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26–33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7–1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) par...

Intrauterine perfusion immunotherapies in recurrent implantation failures: Systematic review

“…The authors observed that the use of subcutaneous G‐CSF (1 µg/kg/d) starting on the sixth day after ovulation significantly increases the number of live births in the treated group (29/35, 82.8%) compared with the control (16/33, 48.5%; OR: 5.1, 95% CI 1.5‐18.4, P = .0061) 45 . New studies evaluating the use of G‐CSF in cases of RM and patients undergoing assisted ART (in cases of thin endometrium or RIF) have also been published 46‐48 . G‐CSF can be administered via either the subcutaneous (SC) route or IU infusion.…”

Vitamin D Promotes Trophoblast Cell Induced Separation of Vascular Smooth Muscle Cells in Vascular Remodeling via Induction of G-CSF

“…However, changes in serum G-CSF may not reflect local concentrations within the maternal-fetal interface and its paracrine/autocrine effects are likely to be more important for a contribution to the etiology of complications of pregnancy. Pre-conception administration of G-CSF may also be beneficial for a subset of women with recurrent pregnancy loss or recurrent implantation failure, although the mechanism of action is not yet fully understood ( Santjohanser et al, 2013 ; Eapen et al, 2019 ; Kamath et al, 2020 ; Rocha et al, 2020 ).…”

Characterization of Isoforms of the Ovine Granulocyte Colony Stimulating Factor

“…In this study, three recombinant fusion proteins, consisting of sGCSF isoforms, were investigated and the results demonstrated that these confer a myelopoietic effect in response to oral delivery in a mouse model. Recombinant human and bovine fusion proteins have been reported to be effective for the development of oral vaccines or drug candidates (Eapen et al . 2019; Nguyen 1994; Stephens et al .…”

“…The recombinant human GCSF transcript variant B has been commercially available since 1992 (Fraser et al . 1994); however, several unanswered questions need to be addressed by clinical trials (Eapen et al . 2019; Nguyen 1994).…”