Original Article
Treatment of G-CSF in unexplained, repeated implantation failure: A systematic review and meta-analysis

https://doi.org/10.1016/j.jogoh.2020.101866Get rights and content

Abstract

Backgroud

Repeated implantation failure (RIF) is a stressful situation for subfertile women undergoing in vitro fertilisation (IVF) treatment and caregivers. Granulocyte-colony stimulating factor (G-CSF) seems to play an important role in assisted reproductive techniques. However, it is currently unknown whether G-CSF is effective in improving results for patients with RIF.

Objective

To describe and summarize current evidence of the effect of the granulocyte colony stimulating factor (G-CSF) in treating RIF.

Method

Relevant scientific literature was thoroughly searched by computer in domestic and foreign database from the inceptions to November 2019. And relevant randomized controlled trials (RCTs) assessing the efficacy of G-CSF in unexplained RIF were included. The meta-analysis was conducted by Stata 12. 0 software, and we estimated relative risks (RRs) and associated 95 % confidence intervals (CIs) of G-CSF on implantation rate (IR), the clinical pregnancy rate (CPR), the abortion rate (AR) in patients with unexplained RIF using fixed-effect model. Besides, Subgroup analysis was performed according to the different administration methods.

Result

A total of eleven articles were included for the final meta-analysis with sample sizes ranging from 13 to 107 patients. The G-CSF was associated with an increased IR [RR = 2.346, 95 %CI (1.615–3.409), I2 = 0. 0%] and CPR [RR = 1.910, 95 %CI (1.562–2.337), I2 = 0.0 %] in patients with unexplained RIF. When further stratified by the method of administration, the subgroup analysis revealed that both intrauterine injection and subcutaneous injection are capable of improving IR[subcutaneous injection:RR = 2.400, 95 %CI (1. 268−4. 542), I2 = 0.0 %; intrauterine injection:RR = 2.317, 95 %CI (1.462–3.673), I2 = 0.0 %] and CPR[subcutaneous injection: RR = 2. 022, 95 %CI (1.443–2.832), I2 = 0. 0%; intrauterine injeciton: RR = 1.848, 95 %CI (1.438–2.376), I2 = 0. 0%]. G-CSF was not associated with AR in patients with unexplained RIF [RR = 2.092, 95 %CI (0.815–5.369), I2 = 0.0 %].

Conclusion

The current evidence support G-CSF’s positive effect on the implantation rate and clinical pregnancy rate of patients with unexplained RIF, especially when administrated by subcutaneous injection. There is no conclusive evidence for the association between G-CSF and the abortion rate. Moreover, few of the included articles reported side effects of G-CSF, so its safety remains to be investigated.Thus, future research should evaluate.

Introduction

In vitro fertilization-embryo transplant (IVF-ET) has emerged as a common treatment for infertile patients. However, the clinical pregnancy rate has been hovering around 30–40 % [1], which is a difficult bottleneck to break through. Of all the causes, repeated implantation failure (RIF) contributes much to the unsatisfactory pregnancy outcome. However, the diagnosis of RIF is not uniform since it was proposed [2]. It is generally defined as infertile women under the age of 40 who fail to obtain clinical pregnancy after transferring at least four high-quality embryos in at least three fresh or frozen cycles by IVF or intracytoplasmic sperm injection [3]. Due to variations in definitions for RIF, The incidence or prevalence of the disease is rarely reported [4]. Studies have shown that the etiologies of RIF are intricate, including maternal factors (reproductive organ lesions, endometrial receptivity, thrombotic diseases, autoimmune diseases), and embryonic factors (chromosomal abnormalities, zona pellucida sclerosis, poor embryo culture environment and embryo transfer operations), etc [5]. At present, clinicians attempt to eliminate maternal factors by correcting the abnormal anatomical structure, inhibiting the frequency of uterine contraction, and improving the endometrium receptivity, etc [6]. Besides, various methods are utilized to assess the treatment effects by means of morphological, metabonomics and genetic screening before embryo implantation, so as to improve culture and transfer strategies [7]. For RIF patients with unknown reasons, pathological factors of immune cell imbalance and abnormal cytokine secretion have become the hot shot in scholars' researches. Accordingly, immunotherapy has made considerable progress in unexplained RIF, such as granulocyte colony stimulating factor (G-CSF), intrauterine perfusion of peripheral blood monocytes, oral immunosuppressive agents, etc [8].

G-CSF is widely distributed. in various tissues and cells, such as fibroblasts, monocytes, macrophages, natural killer (NK) cells, especially NK cells in the uterus [9]. Animal and human studies have illustrated that G-CSF contributes to successful pregnancy by improving ovarian function, correcting pathological changes in the endometrium and promoting embryo implantation [10,11]. Currently, G-CSF has attracted much attention in the treatment of RIF. RCTs have been widely conducted to evaluate its efficacy but the results are with controversial. A double-blind RCT conducted by Davari Tanha F et al. showed that G-CSF did not affect clinical pregnancy rates or abortion rates [12]. However, Scarpellini et al. [13] found that the pregnancy rate in the G-CSF group was 43. 1%, significantly higher than that of 21.6 % in the control group (p < 0.001). Such inconsistencies may be due to small sample sizes, inconsistent test baselines and ethnic or regional differences.

In order to compare different research results more scientifically and objectively, scholars carried out extensive meta-analysis on this issue. However, the current meta-analysis shows many shortcomings. For example, Zhao [14] et al. published a meta-analysis on the effects of G-CSF in ART in 2016, including six studies. They reported that the pregnancy rate in G-CSF group was significant increased (RR 2.51, 95 %CI 1.36–4.63;I2 = 0%). However, this analysis combined data from different study designs (including prospective and retrospective studies) and patients (such as RIF, thin endometrium, and unselected groups), which might affect the accuracy of results. In addition, Kamath MS et al. 'S meta-analysis [15] in 2017 showed that the pregnancy rate of RIF in G-CSF group was significantly higher than that in the placebo group. Nevertheless, only two articles were included, which obviously contributed to bias in the outcome. On consideration of the controversial results and the deficiencies of today's meta-analyses, we thus conducted a meta-analysis that included as many eligible RCTs as possible, so as to valuate the therapeutic effect of G-CSF on unexplained RIF objectively and accurately.

Section snippets

Search strategy

Our study followed the Meta-analysis of Observational Studies in Epidemiology guidelines [16], and studies were investigated in the following databases from the time of inception to Nov. 2019: the China National Knowledge Infrastructure (CNKI), China Wanfang Database, China Weipu Database, Chinese biomedical literature database and PubMed, EMBASE, Cochrane library, Web of Science. The following medical subject heading (MeSH) words were combined according to different retrieval methods of each

Characteristics of the included studies

On the whole, a total of eleven out of 869 articles were selected for the final meta-analysis [[19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]], involving twelve trails and 1035 patients with unexplained RIF, of which 525 patients were in the treatment group and 510 were in the control group(Fig. 1). Of the twelve RCTs in eleven articles, both groups received conventional treatment of IVF-ET. The treatment group recieved G-CSF additionally, and the control group received saline

The implantation rate (IR)

Totally five studies investigated IR after different intervention in the two groups, and the fixed-effect model was utilized for comparison on account of a low heterogeneity after data consolidation (I2 = 0.0 % <50 %). The results revealed that G-CSF could better increase IR than the control group [RR = 2. 346, 95 %CI (1. 615−3. 409), I2 = 0.0 %] (P < 0. 05). Subgroup analysis was conducted according to different methods of administration. Among these studies, four studies adopted intrauterine

Discussion

With the continuous development of life science and medicine, human assisted reproduction technology has made breakthroughs in many aspects, but embryo implantation, termed as "black box", is an extremely complex and delicate process regulated by various cell molecules and signaling pathways. Most studies have always regarded maternal and embryo factors as the main reason for implantation failure, but in recent years, people have focused on the immune factors, especially in patients with

Statement

The ethical approval is not necessary. Because the research form belongs to meta-analysis which is based on existing Clinical randomized controlled trials, and all the articles included have passed the ethical approval and informed consent.

Contribution

Ying Jiang and Qi Zhao were responsible for the selection of research and literature selection; Yuling Zhang and Xvwu Qian were responsible for meta-analysis; Ying Jiang and Lu Zhou were in charge of writing the draft; Jing Lin and Yan Chen were responsible for the collation of literature information, and took charge of the examination and modification of articles; Xvwu Qian was responsible for the examination and submission of articles.

Disclosure

No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication.

Fund project

Medical science and technology plan of ningbo city. Project No. 2018A18

Declaration of Competing Interest

On behalf of all authors, the corresponding author states that there are no conflicts of interest.

Acknowledgments

The authors thank all patients for their participation. Special thanks are also extended to colleagues at the department of gynecology, Ningbo Municipal Hospital of Traditional Chinese Medicine.

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      However, negative results were reported in later studies [80,81]. Several meta-analyses demonstrated that G-CSF could significantly increase the pregnancy rate of RIF patients [26,82–85]. A retrospective study compared the effect of subcutaneous G-CSF and intrauterine perfusion of G-CSF in RIF patients, they found that systemic administration of G-CSF was better than intrauterine perfusion in RIF patients [86], and their recent study demonstrated that the combination of intrauterine and intrauterine perfusion G-CSF could strengthen the role of G-CSF on pregnancy outcome [79].

    • Repeated implantation failure

      2022, Management of Infertility: A Practical Approach

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      Currently, it is generally defined as the failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three frozen or fresh cycles in infertile women under the age of 40 years (Coughlan et al., 2014). For RIF patients, especially when no other cause can be identified, immune system imbalances, including elevated levels and activities of NK cells, presence of anti-phospholipid antibodies, dysregulated cytokines, imbalances in helper T cell (Th1 and Th2 reactions), and increased Th1/Th2 cell ratios have been evaluated (Achilli et al., 2018; Jiang et al., 2020). Immunotherapy has been proposed as one of the therapeutic options for RIF.

    • The Impact of New Immunological Therapeutic Strategies on Recurrent Miscarriage and Recurrent Implantation Failure

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      Scarpellini et al. revealed that G-CSF could effectively treat unexplained RM patients, with the number of live births in women treated with G-CSF being 82.8% [39]. The current evidence reveals that the G-CSF positively affects the embryo implantation and clinical pregnancy rates of unexplained RIF patients via subcutaneous administration [40,41]. However, the intrauterine administration of G-CSF in RIF patients do not show beneficial effects on live birth rates [42].

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