What is the impact of granulocyte colony-stimulating factor (G-CSF) in subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles on recurrent implantation failure: a systematic review and meta-analysis?

Abstract

Background Among recurrent implantation failure (RIF) patients, the rate of successful implantation remains relatively low due to the complex etiology of the condition, including maternal, embryo and immune factors. Effective treatments are urgently needed to improve the outcomes of embryo transfer for RIF patients. In recent years, many researchers have focused on immunotherapy using granulocyte colony-stimulating factor (G-CSF) to regulate the immune environment. However, the study of the G-CSF for RIF patients has reached conflicting conclusions. The aim of this systematic review and meta-analysis was performed to further explore the effects of G-CSF according to embryo transfer cycle (fresh or frozen) and administration route (subcutaneous injection or intrauterine infusion) among RIF patients. Method The PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for literature published from the initial to October 2020. The meta-analysis, random-effects model and heterogeneity of the studies with I2 index were analyzed. Stata 15 was used for statistical analysis. Results A total of 684 studies were obtained through the databases mentioned above. Nine RCTs included 976 RIF patients were enrolled in this meta-analysis. Subgroup analysis indicated that G-CSF improved the clinical pregnancy rate for both the fresh and frozen embryo transfer cycles (fresh RR: 1.74, 95% CI: 1.27–2.37, I2 = 0.0%, n = 410; frozen RR: 1.44, 95% CI: 1.14–1.81, I2 = 0.0.%, n = 366), and for both subcutaneous injection and intrauterine infusion (subcutaneous RR: 1.73, 95% CI: 1.33–2.23, I2 = 0.0%, n = 497; intrauterine RR: 1.39, 95% CI: 1.09–1.78, I2 = 0.0%, n = 479), but the biochemical pregnancy rate of the RIF group was also higher than that of the control group (RR: 1.85, 95% CI: 1.28–2.68; I2 = 20.1%, n = 469). There were no significant differences in the miscarriage rate (RR: 1.13, 95% CI: 0.25–5.21: I2 = 63.2%, n = 472) and live birth rate (RR: 1.43, 95% CI: 0.86–2.36; I2 = 52.5%; n = 372) when a random-effects model was employed. Conclusion The administration of G-CSF via either subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles for RIF patients can improve the clinical pregnancy rate. However, whether G-CSF is effective in improving livebirth rates of RIF patients is still uncertain, continued research on the utilization and effectiveness of G-CSF is recommended before G-CSF can be considered mainstream treatment for RIF patients.

Recurrent implantation failure: A comprehensive summary from etiology to treatment

“…It is also produced by decidual cells, which prompted its use as an adjunct treatment (locally or systemically) for patients with a history of RIF or RPL and thin endometrium ( 85 , 245 , 246 ). A meta-analysis showed an increase in clinical rates of intrauterine infusion or subcutaneous injection of G-CSF during both fresh and frozen embryo transfer ( 247 ). However, the method of administration and dosage of G-CSF should be carefully selected.…”

Efficacy of granulocyte colony-stimulating factor for infertility undergoing IVF: a systematic review and meta-analysis

“…3 ) of G-CSF could be beneficial for CPR, and subcutaneous injection was indicated as the more beneficial administration. Likewise, numerous studies claimed a beneficial role of G-CSF on pregnancy outcome in women undergoing IVF with a history of RIF [ 9 , 10 , 14 , 17 , 22 , 27 ].…”

Treatment options for endometrial hypoproliferation

“…If ES does not reach 7 mm, increase to micronized estradiol 4 mg intravaginal daily for 14--20 days [72] hCG FET: hCG 150 IU SC on D 7-14 [16] hCG 150 IU IM on D 8-12 [17] G-CSF FRESH: G-CSF 30 mU (300 mcg/1 ml) intrauterine 6 --12 h before hCG. Repeat on the day of OPU if ES<7 mm [20] G-CSF 100,000 IU/kg SC daily for 15 days þ 30 mU (300 mcg/1 ml) intrauterine 6 --12 h before hCG [73] FET: G-CSF (300 mcg/1 m) intrauterine infusion on D14 of the FET cycle [22] G-CSF 1.5 mg/kg/d SC from the ET day to the day of b -hCG test [74] GnRHa FRESH: Triptorelin 0.1 mg sc injections 3 times (OPU day/ ET day/ ETþ3) [26] Vitamins & supplements Aspirin FET: Aspirin 81 mg/day starting 1 week before initiation of E treatment. Continue until 9 weeks after ET in case of a positive pregnancy [28] Sildenafil FRESH: Sildenafil 25 mg  4/day intravaginal from Day 1 of stimulation until the day of hCG administration [31,32,36] FET: Sildenafil (25x4/dav intravaginal) from Day 1 of E until the day of P start Pentoxyfilline Tocopherol FRESH or FET: PTX (800 mg/day PO) þ Vit E (1000 IU/day) start 3--4 months prior to cycle and continue until serum hCG confirms pregnancy [39] Vit E (3Ã600 mg/d/po) D1-throughout the menstrual cycle.…”