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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 2  |  Page : 123-126

Advances in the treatment of recurrent implantation failure


Reproductive Medical Center of Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China

Date of Web Publication17-Oct-2017

Correspondence Address:
Ai-Jun Zhang
Reproductive Medical Center of Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.216860

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  Abstract 


Recurrent implantation failure (RIF) is a syndrome of complex etiology. Excluding the involvement of embryonic factors, RIF is characterized by women aged ≤40 years who fail to achieve clinical pregnancy after at least four high-quality embryos transfer in a minimum of three fresh or frozen cycles. However, current methods in the treatment of RIF are controversial. So far, there are no reports of any criteria or guidelines, and the mechanism of RIF is still not clear. Herein, we summarize the pathogenesis of RIF and highlight recent methods in its treatment, to provide reference for the basic and clinical research on RIF.

Keywords: Endometrial Receptivity; In vitro Fertilization; Pathogenesis; Recurrent Implantation Failure; Treatment


How to cite this article:
Guo F, Zhou MJ, Zhang AJ. Advances in the treatment of recurrent implantation failure. Reprod Dev Med 2017;1:123-6

How to cite this URL:
Guo F, Zhou MJ, Zhang AJ. Advances in the treatment of recurrent implantation failure. Reprod Dev Med [serial online] 2017 [cited 2020 Jul 4];1:123-6. Available from: http://www.repdevmed.org/text.asp?2017/1/2/123/216860




  Introduction Top


Recurrent implantation failure (RIF) is a clinical phenomenon that is characteristic of unsuccessfulin vitro fertilization (IVF) cycles. The concept of RIF has been not yet conclusive, but most fertility specialists agree that RIF is defined as failure to achieve clinical pregnancy in women aged ≤40 years after at least four high-quality embryos transfer in a minimum of three fresh or frozen cycles. RIF does not include the pregnancy failure induced by an abnormal uterine cavity, hydrosalpinx, or an abnormal karyotype after IVF or intracytoplasmic sperm injection (ICSI). The risk factors for RIF include an advanced maternal age, a low ovarian reserve, a thin endometrium, aneuploid embryos, and other unexplained or immunological factors.[1] Different from IVF failure which is caused by poor ovarian response, an insufficient number of high-quality embryos, an advanced maternal age, uterine factors, and other factors, RIF commonly occurs in women who fail to achieve clinical pregnancy after IVF treatment.[2] In fact, RIF is a subgroup of patients with good-quality embryos and patients who are younger than 40 years of age but fail to succeed in pregnancy. The broad definition of RIF is implantation failure due to uterine factors; however, women with RIF comprise a subgroup of patients aged <40 years of age with good-quality embryos who fail to achieve clinical pregnancy. At present, as the good-quality of embryos is a prerequisite before transferring, some scholars propose that it is more appropriate to define RIF as implantation failure due to uterine factors.[3] This review focuses on the role of endometrium which is the main object of embryo implantation process and the therapeutic methods which aim at improving endometrial receptivity.


  Current Researches on the Pathogenesis of RIF Top


Although recent studies have reported some of the cellular and biochemical changes associated with the pathogenesis of RIF, it remains a major challenge for clinicians and researchers to improve assisted reproductive technology (ART) pregnancy outcomes. Choi et al.[4] found that S100 calcium-binding protein P, Chemokine (C-X-C motif) ligand 13, and SIX homeobox 1 were downregulated in the endometrium of patients with RIF (RIFE). Leukemia inhibitory factor (LIF) signaling and a P4 response were dysregulated in RIFE while expression levels of estrogen receptor-α and progesterone receptor were not significantly altered in RIFE. In addition, the levels of genes involved in the JAK-STAT signaling pathway, such as interleukin (IL)-19, IL-4R, oncostatin M, and Bcl-2-related protein A1, were systematically downregulated in RIFE.

It is known that the proliferation of endometrium epithelial cells and stromal cells decreases at mid-secretory phase, which not only provides space for embryos to invade the epithelial cells, but also promotes stromal cell transformation into decidual cells, thus favoring the growth and development of embryos.[5] Telomerase activity is closely related to endometrium proliferation during human menstrual cycle.[6] Long et al.[7] found that compared to normal group, the expression of telomerase both in endometrial epithelial cells and stromal cells of RIF patients increased, which suggested that the overexpression of telomerase in RIFE might lead to interference of apoptosis and decidualization process of endometrial cells, and low expression level of telomerase may be the necessity for restricting cell proliferation and promoting embryo implantation. Through the analysis of RIF patients' peripheral blood, researchers found that the levels of metabolites such as valine and urea were remarkably upregulated in women with RIF compared with women with recurrent implantation success.[8] Immunological factors, especially cytokine network, may be important factors that affect endometrial receptivity and embryo implantation.[9]

Liang et al.[10] detected the pro- and anti-inflammatory cytokine levels in peripheral blood during the implantation window of RIF patients and fertile women (the control group), which turned out that interferon (IFN)-γ, IL-1β, IL-6, and IL-4 concentrations were higher, whereas the transforming growth factor (TGF)-β1 concentration was lower in RIF group compared with control group. Furthermore, the ratios of pro- and anti-inflammatory cytokines, such as IFN-γ/IL-4, IL-6/IL-10, IL-1β/TGF-β1, and TNF-α/TGF-β1, were significantly higher in RIF group. These findings showed that the peripheral blood of RIF patients had a shift toward pro-inflammation. Bastu et al.[11] reported that MUC1 and GdA expression levels were significantly lower in the serum and endometrium of RIF women during the implantation window period than those of healthy subjects, and there was a correlation between the two proteins. Thus, endometrial receptivity can be examined through a noninvasive blood test.


  Advances in the Treatment of Patients With RIF Top


Nowadays, there are a variety of methods to treat RIF clinically. The therapeutic approaches are summarized as follows:

Empirical therapies

Aspirin

Aspirin irreversibly inhibits cyclooxygenase activity and prostaglandin production, reduces the inflammatory response, promotes vasodilatation, and increases uterine blood flow.[12] Although aspirin can increase the likelihood of implantation and clinical pregnancy after IVF, approximately, three-fourths of studies do not recommend the use of aspirin to increase pregnancy rates,[13] and its use for this purpose is still controversial.[14]

Low-molecular-weitht heparin (LMWH)

Heparin is used as an anti-coagulation or anti-thrombin drug, because of the biological activity of inhibiting coagulation factors, including factor Xa and factor IXa and thrombin.[15] LMWH originates from unfractionated heparin by enzymatic or chemical depolymerization and has a biological activity similar to heparin but with increased bioavailability and half-life. A recent meta-analysis showed that, in women with RIF, the use of LMWH along with IVF procedure significantly improved the live-birth rate by 79%.[16]

Mechanical endometrial injury

This method includes hysteroscopy and/or endometrial scratch. Several studies showed that localized endometrial injury, such as endometrial biopsy or curettage, before ART can increase the likelihood of embryo implantation in women with RIF.[17],[18] For example, localized endometrial injury, such as that induced by endometrial biopsy or hysteroscopy before the IVF cycle, improves endometrial receptivity and embryo implantation. Endometrial injury also enhances decidualization, synchronizes endometrial maturation, and increases the secretion of cytokines, including IL. These biological effects are conducive to successful embryo implantation. In addition, endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle increased the rates of clinical pregnancy and live birth.[19] Similarly, hysteroscopy is beneficial for patients with RIF as it increased pregnancy rate after the procedure.[20] To improve the efficacy of endometrial injury, additional studies are needed to determine the extent of the endometrial injury, the number of endometrial biopsies, and the optimal time to perform biopsies.[21]

Immunotherapy

Several immunological factors are critical for successful embryo implantation; however, results on the efficacy of immunotherapy in patients with RIF are contradictory.[22]

  1. Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic-specific cytokine produced by bone marrow cells, stromal cells, fibroblasts, and macrophages. G-CSF improves macrophage phagocytosis, as well as oxidation, which is crucial for embryo implantation.[23] G-CSF also stimulates neutrophil proliferation, recruits dendritic cells, and regulates the T-cell response.[24] Several nonhematopoietic cell types, such as endothelial cells, placental cells, trophoblasts, and granulosa-lutein cells, express G-CSF receptors.[25] In addition, G-CSF affects embryo implantation by promoting vascular remodeling of the endometrium, local immunomodulation, and the expression of genes involved in cell adhesion.[26] G-CSF also prevents miscarriage in animal models and increases the thickness of the endometrium [27],[28]

    The subcutaneous injection of G-CSF can improve the outcome of patients with recurrent miscarriage,[29] and the intrauterine infusion of G-CSF in women with a thin endometrium increases the thickness of the endometrium and pregnancy rate. A thin endometrium is detrimental to ET and may cause RIF.[30] However, the infusion of G-CSF in women with a normal endometrium did not improve its thickness, embryo implantation, or the pregnancy rate.[24] Further studies or meta-analyses are needed to determine whether the intrauterine administration of G-CSF improves outcomes in women with RIF and to identify the optimal dose and duration of G-CSF administration.
  2. Intravenous immunoglobulin (IVIG) is a fat emulsion containing an immunoglobulin G antibody that promotes differential cell receptor expression, reduces natural killer (NK) cell activity, and regulates the Th1/Th2 response by increasing Th2 cell production, which is beneficial for clinical pregnancy.[31] The IVF success rate after the administration of IVIG increases in women with previous IVF failure, a high NK cell number, and/or an elevated Th1/Th2 ratio.[32] Meta-analysis also supports the use of IVIG in women with these immunological characteristics. However, IVIG and immunologic tests are expensive interventions, the optimal protocol for the administration of IVIG is undefined and the overall benefits of IVIG are still controversial.
  3. Intrauterine peripheral blood mononuclear cell (PBMC) administration: It is widely accepted that immunocytes play a vital role in the process of embryo implantation. In 2006, Japanese scientists first reported that administration of autologous PBMCs could significantly promote clinical pregnancy rate, implantation rate, and live birth rate in patients with repeated failure of IVF–ET.[33] Then, Okitsu et al.[34] demonstrated that only patients who had three or more implantation failures, the clinical pregnancy rate, and the implantation rate in the PBMC-treated group were significantly higher than those in the nontreated group. Recently, Yu et al.[35] have confirmed that intrauterine administration of autologous PBMC activated by human chorionic gonadotropin (hCG) effectively improves embryo implantation and IVF outcomes not only in patients with three or more IVF failures, but also in patients with thin endometrial thickness.[36] The underlying mechanism of intrauterine hCG-activated PBMC administration may be that it can promote trophoblast cell spreading and invasion into endometrium [37] and can increase the expression of endometrial factors which facilitate implantation.[38]


Steroids

Women with recurrent spontaneous abortion or RIF have a large number of NK cells in the serum and endometrium. Steroids reduce the NK cell number in the uterus, regulate the T-lymphocyte response, and reduce overall inflammation and stress-related hyperandrogenemia that occur during embryo transplantation, which is harmful for the implantation embryo.[39] The administration of a high dose of methylprednisolone for four consecutive days at the time of oocyte retrieval improves IVF outcomes.[40] Although results from subsequent studies were contradictory, the reason may be due to differences in the dose and duration of methylprednisolone. Furthermore, a prospective randomized trial of prolonged low-dose steroid use failed to show any benefits.[39]

Intralipid infusion

Intralipid infusion is a 20% fat emulsion that reduces the Th1/Th2 ratio and suppresses the abnormal NK cytotoxicity of peripheral NK cells, thereby increasing the likelihood of implantation and clinical pregnancy.[41] Further studies are needed to determine the efficacy of intralipid infusion in women with RIF.[42]


  Conclusion and Future Perspectives Top


RIF greatly affects the likelihood of clinical pregnancy after IVF cycles. However, there is little information on its pathogenesis and no consensus among clinicians and researchers on its diagnostic criteria and treatment. Further studies are needed to define the theoretical basis for the treatment of RIF, as well as to expand its treatment options.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (Grant Number 81370763).

Conflicts of interest

There are no conflicts of interest.



 
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