Intrauterine infusion of granulocyte colony stimulating factor and reproductive outcomes in infertile women with history of recurrent implantation failure

• Despite the developments in fertility treatment protocols, repeated implantation failure (RIF) still remains a challenging problem for patients and clinicians, it causes deep impact on the quality of life and financial burden, because the majority of failed invitro fertilization- embryo transfer (IVF-ET) cycles exhibit lack of implantation, endometrial receptivity is the limiting factor for implantation and success of IVF programs. Repeated implantation failure (RIF) is defined as pregnancy failure after 2-6 times with at least 10 high quality embryos transferred into the uterus.
• Granulocyte-colony stimulating factors (G-CSF) is synthesized in the reproductive tract naturally, it is a hematopoietic lineage-specific cytokine which is known for its specific effects on the activation of intracellular signaling pathways that are associated with the cell proliferation, differentiation, and stimulation of hematopoietic cells of the neutrophilic granulocyte lineage; which act on macrophages of decidual cells and finally affect implantation.
• During the maturation of the pre-ovulatory follicle, G-CSF receptor expression increases; this also takes place in human endometrium and luteinized granulosa cells. G-CSF receptors also exist on the trophoblast with the highest G-CSF receptor expression occurs in the first trimester. G-CSF effect on recruitment of type 2 T helper cytokine secretion, activation of T regulatory cells, modulation of uterine natural killer and dendritic cells cytotoxicity, as well as endometrium angiogenesis as a result has an essential role on early cross talk between embryo and uterine endometrium. G-CSF stimulates the proliferation and differentiation of endometrial cells by CAMP increase in stromal cell through paracrine and autocrine signaling pathway.
• Studies showed that elevated G-CSF concentrations on follicular fluid increased implantation rate and can improve IVF outcome, it increase the proportion of embryos that develop to the blastocyst stage from 30-76%. Also G-CSF supplemented to the embryo culture medium improves implantation rate. G-CSF can be effective treatment in patient with history of implantation failure and can improve endometrium growth. Also G-CSF may increase pregnancy rate especially in women with thin endometrium.
• In a recent well-designed trial on patients with thin endometrium in which embryo transfer was cancelled with G-CSF treatment in subsequent frozen embryo transfer (FET) cycles, significantly higher implantation rate (31.5% versus 13.9%, P < .01) and clinical pregnancy rate (48.1% vs. 25%, P < .01) was found in those treated with G-CSF in comparison with controls but live birth rate was not statistically significant (33.3% vs. 17.3%).
• In a recent meta-analysis, it was found that the use of G-CSF was associated with significantly higher biochemical (RR 2.385 95% CI:1.414, 4.023) and clinical pregnancy rates (RR 2.312, 95% CI: 1.444, 3.701) among women with thin endometrium or repeated IVF failures in the general population when compared with no treatment or placebos.
• In one of two recent trials with similar patient selection and disease condition, 0.5 ml (300 µg/ml) G-CSF infusion intrauterine at the day of ovum pickup followed by grade A embryo transfer at day 3 was associated with significantly higher pregnancy and implantation rate. 3In the other trial however, the treated group received the same dose of G-CSF subcutaneously 30 min before blastocyst embryo transfer at day 5, there was higher clinical pregnancy, live birth rate and lower abortion rate; but all were not statistically significant.
• This study evaluates the effects of the single dose G-CSF intrauterine infusion in a group of patients with unexplained RIFs 3 days before ET of good quality embryos.

Inclusion Criteria:

1. Age group (18-38)
2. History of at least 2 previous IVF or ICSI trial failures with ET of at least 2 good quality embryos in each trial.
3. Endometrial cavity within normal anatomy as assessed with transvaginal ultrasound (TV-US) with or without hysteroscopy and HSG if needed.
4. Availability of good quality embryos (at least 2 grade A embryos) for ET in the investigated trial

Exclusion Criteria:

Any factor which may affect quality of embryos transferred or endometrial receptivity and embryo growth, like:

1. Severe male factor infertility
2. Poor ovarian reserve (according to ESHRE criteria) 1
3. Uterine anatomic factor (eg polyp, intramural fibroid, endometrial septum, intrauterine synechiae .. etc) as well as endometritis
4. Immunological disorder (eg: SLE, APS, … etc)
5. Thyroid or adrenal dysfunction
6. Thrombophilia history or tendency as proven by labs in suspected women
7. Untreated hyperprolactinemia
8. Genetic abnormalities in the infertile couple
9. Chronic hematologic, renal or liver disease

Infertility patients undergoing ICSI trials at Cairo university school of Medicine IVF unit.