Is there a Role of Intravenous Immunoglobulin in Immunologic Recurrent Pregnancy Loss?

Yang, Xiuhua; Meng, Tao

doi:https://doi.org/10.1155/2020/6672865

Journal of Immunology Research

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Review Article | Open Access

Volume 2020 | Article ID 6672865 | https://doi.org/10.1155/2020/6672865

Is there a Role of Intravenous Immunoglobulin in Immunologic Recurrent Pregnancy Loss?

Xiuhua Yang¹and Tao Meng¹

Academic Editor: Jagadeesh Bayry

Received04 Oct 2020

Revised15 Dec 2020

Accepted22 Dec 2020

Published28 Dec 2020

Abstract

Recurrent pregnancy loss (RPL) commonly refers to three or more miscarriages that occur before 20 weeks of pregnancy. The immunological cause of RPL could be either an auto- or alloimmune-related event or both. Because of the discovery of immunological abnormalities in RPL patients in clinical practice, several immunomodulatory therapies were introduced to maintain the immune balance at the maternal-fetal interface. Intravenous immunoglobulin (IVIg) is one of the immunomodulators. In recent years, several studies have analyzed the therapeutic effect of IVIg on RPL patients with antiphospholipid syndrome (APS) or unexplained RPL. However, their results are controversial. IVIg can be used in RPL patients with APS who have previously failed in other treatments. It is recommended that IVIg infusion could be considered used before conception in RPL patients who have cellular immune abnormalities such as increased natural killer (NK) cell counts, NK cell cytotoxicity, or increased T helper (Th)1/Th2 ratio, depending on the cut-off values of each hospital. The aim of this review was to summarize the mechanisms, efficacy, pharmacokinetics, and side effects associated with passive immunization using IVIg in immunologic RPL, according to the literature published in recent years. We hope that more obstetricians will be able to understand the timing and indication of IVIg properly in immunologic RPL patients and effectively enhance pregnancy outcomes for mothers and neonates.

1. Introduction

Recurrent pregnancy loss (RPL) commonly refers to three or more miscarriages that occur before 20 weeks of pregnancy [1]. The American Society for Reproductive Medicine also considers it to be two or more times [2]. The incidence of RPL in couples of childbearing age is 5% [3]. It can be divided into two types: primary RPL (previously no child) and secondary RPL (consecutive abortions after a live child). The etiology of RPL includes genetic, environmental, anatomical, endocrine, immune, and microbial infection factors [4–6]. However, nearly half of the RPL patients are called unexplained RPL due to unknown etiology. After a detailed analysis of these unexplained RPL patients, these women are often combined with immune abnormalities, i.e., abnormal immune tolerance at the maternal-fetal interface [7].

The immunological cause of RPL could be either an auto- or alloimmune-related event or both. Autoimmune abortion refers to the fact that there are autoimmune antibodies in the maternal body, such as anti-phospholipid antibodies (APAs), which kill decidual or trophoblast cells, thus affecting the development of the placenta and fetus [8, 9]. APAs occur in one fifth of patients with RPL [10]. Alloimmune miscarriages refer to the impairment of the maternal alloimmune response to paternally generated molecules on trophoblasts leading to unacceptability of the semiallogeneic fetus [11, 12]. Furthermore, many RPL patients have cellular immune abnormalities, including increased T helper (Th)1/Th2 cell ratios, higher natural killer (NK) cell counts or NK cytotoxicity, and aberrant regulatory T cell (Treg)/TH17 ratios [2–5, 7, 8, 13, 14].

Because of the discovery of immunological abnormalities in RPL patients in clinical practice, several immunomodulatory therapies were introduced to maintain the immune balance at the maternal-fetal interface. Intravenous immunoglobulin (IVIg) is one of the immunomodulators. It is extracted from the plasma of 3,000 or more donors and includes more than 95% unmodifed immunoglobulin G. IVIg is an important contributor to many autoimmune and inflammatory diseases [15–17]. The immunosuppressive properties of IVIg are as follows, including the downregulating of the functions of B cells [12], anti-idiotypic suppression of autoantibodies [18], reduction of Fc receptor-induced phagocytosis [19], adding the regulatory function of T cells [8], inhibiting the complement activation system [20], and controlling the expressions and functions of cytokines [21].

More than 20 years ago, IVIg was used for the first time in the prevention of RPL with a live birth rate of 80-82 percent [22, 23]. Likewise, Lee et al. reported that the live birth rate of RPL women with cellular immune abnormality who were treated with IVIg was 84.7%, which was similar to that of RPL women with normal cellular immunity who did not receive IVIg (89.7%) [24]. In recent years, several studies and randomized controlled trials have analyzed the therapeutic effect of IVIg on immunologic RPL patients. However, their results are controversial. Some studies have indeed shown that IVIg can significantly improve the pregnancy outcome of RPL patients [25–27], while other studies suggested that IVIg has no obvious therapeutic effect [28–30]. Therefore, the lack of sufficient evidence is the reason IVIg is not included in the clinical treatment guidelines for RPL [31]. This conclusion was mainly suggested by Daya et al. [32] and from the meta-analysis of six studies conducted by the German RSA/IVIG Group [33], Christiansen et al. [34], Stephenson et al. [35], Perino et al. [36], Coulam et al. [37], and Kipron et al. [38]. Different experimental results may be due to different RPL definitions. Some experiments have defined RPL more than two times, while others have defined it more than three times. RPL patients who have been treated with IVIg may have different types of immune abnormalities. In the meantime, clinicians may lack an in-depth understanding of the mechanism of IVIg in immunologic RPL. Understanding how IVIg might act to prevent immunologic abortions is important in selecting and assessing the efficiency of patients likely to benefit from this treatment. The aim of this review was to summarize the mechanisms, efficacy, pharmacokinetics, and side effects associated with passive immunization using IVIg in immunologic RPL. Two independent researchers searched the articles in Pubmed with the following medical subject headings (MeSH): “intravenous immunoglobulin,” “recurrent pregnancy loss,” “recurrent miscarriages,” “autoimmunity,” or “cellular immunity.” All articles were published in English from January 1994 to September 2020. We ruled out letters. We hope that more obstetricians will be able to understand the timing and indication of IVIg properly in immunologic RPL patients and effectively enhance pregnancy outcomes for mothers and neonates.

2. Mechanisms of IVIg in RPL

IVIg plays its immunomodulatory role through certain mechanisms of action that work together to exert a cooperative effect on RPL in the process of integration. The following possible theories may explain why passive IVIg immunotherapy can play an active role in the prevention of RPL (Table 1) [39–41].

3. IVIg in APS Patients with RPL

IVIg was used to prevent RPL associated with APS, and a better fetal outcome was reported, 70–100% [42–46]. In one report, 38 APS patients who had three or more early pregnancy abortions were included and received 300 mg/kg IVIg every three weeks from the determination of pregnancy to 16-17 weeks [46]. Out of the 38 patients, 34 women (89.4%) passed through the first trimester, and 31 females (81.4%) gave birth at full term [46]. In another study conducted by Triolo et al., 30 out of 40 patients received IVIg, 62.5% of the patients gave birth at 38-40 weeks of gestation, 12.5% gave birth at 29-35 weeks of gestation, and the remaining 25% had miscarriages [47]. In vivo IVIg has also been shown to be effective in preventing RPL and to reduce the rate of fetal abortion in murine RPL models associated with APS [28, 48].

In patients treated with IVIg, maternal and fetal outcomes were better than those who were treated with low-dose aspirin (LDA) and heparin and or steroids [49, 50]. A prospective study was carried out in two centers, patients in one of which were treated with prednisone and LDA (control group, ) and the other used IVIg (experimental group, ) [50]. The results showed that the birth weight of newborns in the experimental group was significantly higher than that in the control group, and the incidence of pregnancy-induced hypertension and gestational diabetes in the control group was significantly higher than that in the experimental group [50]. IVIg has the function of neutralizing autoantibodies, as a result of which it can be considered used in RPL patients with APS who have previously failed in other treatments [27, 50, 51].

Nevertheless, there are some negative findings. In a randomized controlled study, Triolo et al. confirmed that low-molecular-weight (LMW) heparin and aspirin showed a higher live birth rate than IVIg in patients with RPL associated with APS (84% vs. 57%) [52]. In another prospective study, 85 RPL patients with APS aged 18-39 years from 2002 to 2006, and these patients were randomly divided into LMW heparin plus the LDA group and IVIg group [53]. The live birth rate of the former was significantly higher than that of the latter (72.5% vs. 39.5%, ) [53]. In another study, the control group received LDA plus heparin and placebo, while the experimental group received LDA plus heparin and IVIg (1 g/kg/month) [54]. No miscarriage occurred in either group [54]. The incidence of preeclampsia (44% vs. 11%) and preterm delivery (100% vs. 33%) in the experimental group was slightly higher than that in the control group. The incidence of fetal distress (0 vs. 33%), fetal growth restriction (14% vs. 33%), and neonatal admission to the neonate intensive care unit (NICU) (14% vs. 44%) in the experimental group was mildly lower than that in the control group. However, there was no statistical difference about these outcomes [54].

These studies have changed a lot depending on the dose of IVIg, the time of administration, and the concomitant therapies used (e.g., LDA, LMW heparin, and prednisone). Although many studies believe that anticoagulant therapy is essential for APS patients, IVIg is effective for APS patients who do not receive heparin treatment. In other words, anticoagulation is not completely effective for APS patients. Some patients may benefit from IVIg and LDA or heparin because IVIg can neutralize APAs.

4. IVIg in Unexplained RPL

The reason IVIg can be used to treat unexplained RPL is that many patients with unexplained RPL have autoimmune disorders. The impact of IVIg on unexplained RPL has been reported by nine randomized placebo-controlled trials so far, but their findings are not consistent [27, 29, 30, 33–37, 55] (Table 2).

Previous randomized controlled trials (RCTs) indicated that the effect of IVIg on secondary RPL was considered slightly effective [26]. The difference between secondary RPL and primary RPL is the immune effect of male-specific minor histocompatibility (HY) antigens on the former [56]. The results of Cochrane systematic review with meta-analysis published in 2014 showed that IVIg had no better effect on RPL patients than placebo [57]. This meta-analysis, however, had only one outcome (live birth after 20 weeks of gestation) and only one subgroup (studies for cure) and did not include two recently published placebo-controlled trials [29, 30]. One year later, a systematic review and meta-analysis found that there was an RR of 0.92 for no live birth by IVIg for all participating patients [58]. The disadvantage of RCT studies in patients with primary RPL is that the number of samples is too limited to achieve meaningful differences after statistical analysis [59]. Wang et al. recently published a review [60]. The results showed that a RR for birth of primary RPL after IVIg treatment was 0.88 (95% CI 0.71–1.08; ), and that of secondary RPL was 1.26 (95% CI 0.99–1.60; , one-sided test ) [60]. IVIg has a moderately important therapeutic role in secondary immunologic RPL, according to their meta-analysis [60]. It was recommended that the application of IVIg in the secondary immunologic RPL can be considered [60].

As time passes, we have a deeper understanding of the etiology and pathogenesis of RPL. Recent studies have shown that many factors, such as genetic polymorphisms, pathogenic microorganisms, glycoproteins, and new immunopathogenic factors, may trigger RPL [61]. These pathogenic factors were not identified before 1994, so these factors in the series of unidentified RPL patients were not included in the study during that period. Some subgroups of unexplained RPL patients may benefit, but not all of them may benefit from IVIg. Therefore, the lack of awareness of unexplained RPL pathogenesis hinders people from conducting a well-controlled clinical study.

5. IVIg in RPL Patients with Cellular Immunity Abnormalities

5.1. IVIg in RPL Patients with Th1/Th2 Ratio Abnormalities

Yamada et al. confirmed that the abundant IVIg administration induced the expression of cytokines [Interferon γ (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), IL-10] in peripheral blood and reduced Th1/Th2 lymphocyte ratios [62]. Szereday et al. concluded that when lymphocytes from RPL patients and polyclonal IgG were cocultured, the expression of cytokines changed [63]. In essence, the expression of IL-12 (Th1-type reaction) decreased, while that of IL-10 (Th2-type reaction) increased [63]. Because of this result, an in vitro study of RPL patients showed that the binding capability of activated T cells and extracellular matrix (including collagen IV, fibronectin, and elastin) increased, and this phenomenon can be neutralized by IgG [64]. These results indicate that the placenta’s extracellular matrix can absorb and affect the immune response in a way that improves the outcome of pregnancy [64].

Thirty-two patients were treated with IVIg (experimental group) in a sample of forty-four RPL women, and the other twelve patients were known as the control group [65]. The Th1/Th2 ratio in the experimental group decreased significantly at the end of treatment (), twenty-eight cases (87.5%) in the experimental group had live birth, and only five cases (41.6%) in the control group delivered live fetuses successfully [65]. The IVIg administration decreased Th1 cells and led to a shift toward Th2 cells in RPL patients with APS [66]. These results showed that treatment with IVIg tends to be an important therapeutic method that can improve the pregnancy success rate through a change to Th2 reactions.

5.2. IVIg in RPL Patients with Treg/Th17 Ratio Abnormalities

There is strong evidence that IVIg enhances the suppressive activity of Treg cells [67, 68]. The research suggested that the mixture of IVIg in the Treg cell culture system increased the expression of forkhead box protein P3 (FOXP3), IL-10, and transforming growth factor (TGF)-β and induced the suppressive effect of Treg cells [68]. The combining ability of Treg cells to IVIg is stronger than that of conventional T cells [67], which shows that Treg cells can be easily changed by IVIg. Furthermore, IVIg can increase the number of existing Treg cells, rather than induce Treg cells from naive T cells [69]. The number of Treg cells increased considerably in the early stage of pregnancy [70, 71]. As a result, the promotion of IVIg on Treg cells benefited RPL patients whose Treg cells decreased.

The number and differentiation of Th17 cells decreased after adding IVIg to a human CD4⁺ T cell culture system [72]. Since IVIg does not contain anti-IL-17 antibodies, its effect has nothing to do with IL-17 neutralization. IVIg decreased Th17 cell proliferation and IL-17 production, and this function was not regulated through anti-IL-17 antibodies [72, 73]. When IVIg was added to CD4⁺ T cells without antigen-presenting cells (APCs), the function of Th17 cells immediately decreased, including the production of inflammatory cytokines [74]. Sha et al. [75] indicated that IVIg combined with hCG may inhibit the differentiation of Th17 cells in pregnant females with unexplained RPL and may increase the differentiation of Treg cells. They believed that Treg cells improved the mother’s immune tolerance so that the embryo could develop to full term [75]. IVIg diminished the differentiation of naive CD4 T cells into Th1 and Th17 cells and concurrently promoted an increment of Treg cells [76]. In addition, Kim et al. [77] found that IVIg could play a role in women with activated immune effectors or inhibitory immune modifiers in vivo.

Another study included 94 patients with RPL whose blood was collected when the pregnancy test was positive [78]. On the same day, 44 patients received IVIg 400 mg/kg/month intravenously until 32 weeks after gestation. Another 50 RPL patients without IVIg were described as the control group. Once these patients reached 32 weeks, their peripheral blood was obtained again. The results showed that the number and function of Th17 cells decreased significantly in the experimental group, while Treg cells increased significantly. The numbers of successful pregnancies in the experimental group and the control group were 38 out of 44 (86.3%) and 21 out of 50 (42%), respectively. This experiment showed that IVIg could change the Treg/Th17 ratio in peripheral blood, improve Treg cell response, and reduce Th17 reaction in RPL patients with cellular immunity abnormalities. Based on the latest findings of the same team, the addition of IVIg stimulates Treg cells and decreases the reactions of exhausted Treg cells during pregnancy in RPL patients with cellular immune anomalies [79].

A number of empirical studies have presented the plausible actions of IVIg on Treg/Th17 ratio in other autoimmune diseases. Regarding Treg cells, several mechanisms were reported by many labs. For instance, one study involved 11 autoimmune rheumatic patients, and according to the results, the anti-inflammatory roles of IVIg treatment could result in increased Treg cells, which further promoted immune tolerance [80]. In patients with Kawasaki disease (KD), the protein and mRNA levels of FOXP3 undoubtedly contributed to the rapid recovery of patients following IVIg infusion [81]. The improvement of Treg cells discovered in the treatment of IVIg and regular medication could alleviate symptoms of patients with eosinophilic granulomatosis with polyangiitis (EGPA) [82]. Besides, IVIg treatment is regulatable via the immunomodulatory effect of dendritic cells (DCs), constructing an approach that increases antigen-specific and inhibitory Treg cells [83]. It was also shown that IVIg advanced Tregs through the generation of cyclooxygenase (COX)-2-dependent prostaglandin E2 (PGE2) in human DCs [84]. In studies involving animals, the number of platelets in mice increased following the administration of IVIg to immune thrombocytopenia (ITP) mice. In combination with lower levels of antibodies, Treg cells was produced by thyroid, and spleen was normalized [85]. IVIg can surge the ratio of Treg/Th17 through the IL-10 dependent pathway, which proved to be effective when treating collagen-induced arthritis (CIA) patients [86].

5.3. IVIg and NK Cells in RPL Patients

At the maternal-fetal interface, higher numbers and/or cytotoxicity of NK cells in peripheral blood can change to an inappropriate environment. Many studies have shown that CD56⁺ NK cells decrease in RPL women treated with IVIg [87–91]. In the research by Kwak et al. [87], the treatment of IVIg decreased the count and activity of CD56⁺ and CD56⁺/16⁺ NK populations and increased the rate of successful pregnancy in RPL women. In another research, NK cells were increased in pregnant () and nonpregnant RPL women (), and NK cells significantly decreased after the first IVIg treatment [88]. The success rate for RPL pregnant women treated with IVIg was 92.3% [88]. Heilmann et al. [92] performed an assay that suggested a relationship between the decrease of NK cells and pregnancy outcome. The findings of this assay suggested that the count of NK cells (CD3⁻, CD56⁺, and CD16⁺) decreased in patients who delivered after IVIg treatment [92]. In RPL patients who received IVIg in the second trimester, the percentage of NK cells was significantly reduced [93]. Another study included 90 RPL patients with the IVIg administration [94]. 82.0% of these patients had a successful pregnancy outcome [94]. They indicated that with appropriate treatment, low-dose IVIg treatment was safe and effective for women with immunological miscarriage and characterized by increased NK cells [94]. In a study of women with RPL and increased expression of NK cells, live birth rates with IVIg were found to be 96.3 percent vs. 30.8 percent in women without IVIg administration [95]. In vivo, researchers found that IVIg restrained the increase in the count of CD44^bright subsets in uterine samples of unexplained RPL mice [96].

Expression percentiles of inhibitory CD94 on NK cells were significantly added after the administration of IVIg () [97]. Mechanisms for the potential efficacy of IVIg treatment for RPL may include increased levels of CD94 and the following inhibition of cytotoxicity of NK cells. Clark et al. found that in the case of miscarriage, a soluble CD200 molecule, including IVIg, inhibits the cytotoxic response of NK cells [98, 99]. The CD56^bright subset of NK cells expressed at the fetal-maternal interface present receptors for CD200 that combine with CD200R2/3 on APCs, which subsequently stimulate CD4⁺ CD25⁺ Treg cells [100]. And these Treg cells can prevent miscarriage [101]. A large amount of IVIg was effective in fourteen unexplained RPL patients, and NK cells decreased from before injection to after injection [102]. IVIg was able to minimize NK cells in peripheral blood from 22 percent to 12 percent seven days after infusion in 14 patients with six or more abortions () [103]. The decrease of NK cells in the successful group (−58.8%) seemed to be more significant than that in the failed group (−14.8%, ) [103]. A study was conducted in 2019 including 78 patients with RPL whose peripheral blood was collected when the pregnancy test was positive [104]. After IVIg treatment, NK cell count and cytotoxicity decreased significantly after 32 weeks of gestation, and the levels of inhibitory receptors increased significantly, while those of activated receptors decreased significantly [104]. The pregnancy outcome of the experimental group was better compared to the control group (86.8% vs. 45%; ) [104].

NKT cells are a subgroup of thymus-dependent (T) cells that are essentially CD4⁺ but have NK lineage surface markers. NKT cells in peripheral blood (not in the decidua) are more likely to respond to Th2 during normal pregnancy [105]. In the same way as NK cells, NKT cells in the endometrium can induce inflammatory reactions, promote the production of Th1 cytokines, and lead to the development of RPL. IVIg is one of the therapeutic methods for patients with RPL associated with NK/NKT-like cell enlargement [106, 107]. A subgroup of women with high NKT, balanced by IVIg, showed a higher rate of successful pregnancy [108].

5.4. Cut-off Values for Cellular Immunity Abnormalities in RPL

To assess cellular immune abnormalities in patients with RPL, NK cell percentage and cytotoxicity assays as well as Th1/Th2 cell ratios in peripheral blood are needed. However, the published cut-off values of NK cell percentages in peripheral blood of RPL women differed from one study to another. Some experiments considered NK cell percent levels more than 12 percent of mononuclear cells to be a cut-off for the high NK cell expression related to bad pregnancy outcomes [109]. Another research considered the percentage to be more than 12.5 percent [110]. The percentage of NK cells, over 16.1 percent in Korean RPL women, is considered abnormal [111]. An Australian study sets the cut-off value to 18% [110]. The cut-off values of NK cell cytotoxicity and Th1/Th2 ratio were also various in different laboratories [24, 112], so there may be some deviation in analyzing the results of these experiments.

6. IVIg and Basophils in RPL Patients

Basophils are scarce granulocytes. Regardless of their low numbers, only 0.5% of leukocytes, they have crucial biological effects [113, 114]. Basophils are related to numerous allergic diseases, such as asthma, nasitis, and atopic dermatitis [115, 116]. Neonates and children born from the cesarean section have higher levels of basophils, so they face a higher likelihood of developing allergic diseases and asthma, which suggests the intrauterine origin of these inflammatory diseases [117]. Admittedly, basophils do not have the characteristics of traditional APCs [118–122]; however, they can play an immune role through the secretion of cytokines, and those tend to the Th2 type immune response and promote B cell differentiation. Reportedly, IL-3, granulocyte–macrophage colony-stimulating factor (GM-CSF), thymic stromal lymphopoietin (TSLP), IL-33, different toll-like receptor ligands, and allergen-specific IgE supply activating pathways to basophils [123–128].

IVIg has the capacity to promote the activation of IL-3–primed human basophils and reinforced IL-4 in basophils by combing with basophil surface-bound IgE [129]. According to the findings, IVIg can improve the Th2 immune response by acting on basophils. The finding showed that 10 mg/mL of IVIg could activate basophils, which was demonstrated by elevated expressions of CD69 and IL-4 [130]. Basophils are also able to decrease Th1 and Th17 responses by secreting IL-4 [131] and increase the expression of the inhibitory Fc receptor FcγRIIB on macrophages to reduce the inflammation reaction [132]. Through these mechanisms, IVIg could have a vital role for inducing basophils in the treatment of RPL.

7. IVIg and Autophagy in RPL Patients

Autophagy refers to an over activated programmed cell death, which is unlike apoptosis [133]. Autophagy is encountered across a variety of fields of the reproductive system, from zygote formation to parturition [134]. Autophagy has the capacity to enhance the ovarian dysfunction induced by insulin [135], and it occurs in the procedure of implantation [136] and decidualization [137]. Impaired autophagy can induce the production of IL-1β to promote inflammatory reaction at the maternal fetal interface, which could be the underlining reason for RPL with APS [138]. Autophagy inhibition of trophoblast cells elevates NK cytotoxicity through insulin-like growth factor-2 (IGF-2) and impairs trophoblast invasion via paternally expressed gene 10 (PEG10), and both these factors lead to RPL [139].

It was shown that IVIg treatment induced autophagy in peripheral blood mononuclear cells (PBMCs) and downregulated certain inflammatory mediators in peripheral blood, such as IL-8, TNF-α, IL-1β, and IL-17A [140]. Extensive analysis indicated that IVIg-increased autophagy solely arose in monocytes, DCs, and M1 macrophages, rather than M2 macrophages [140]. With regards to the mechanism, autophagy promoted via IVIg relies on F(ab)2; however, it does not rely on sialylation and requires the endocytosis effect of IgG from innate cells [140]. Despite the use of large doses of IVIg to induce autophagy in patients with autoimmune illnesses, research has shown that autophagy can be promoted remarkablely when the concentration of IgG reaches 10 mg in healthy people [140]. Since IVIg is an aggregation of IgG extracted from healthy people, it may imply that IgG is crucial for maintaining normal immune homeostasis. These findings partly elaborate the action of IVIg infusion in the treatment of females with RPL by inducing autophagy.

8. The Heterogeneity of IVIg Studies in RPL

Patient populations included in the placebo-controlled studies and the treatment protocols performed were quite heterogeneous, and it is doubtful how much information is obtained from the integration of all women in the meta-analysis of these studies. Another confounding factor is the dosage of IVIg, which makes it difficult to compare different studies. There is currently no study on the IVIg dosage so that the optimum dosage cannot be determined. Placebos used in the study also affect outcomes, and some placebos may interfere with pregnancy outcomes. Albumin has been reported to be able to regulate ovarian hormone, which may be beneficial to patients with RPL [141]. Moreover, chromosomal abnormality is a common cause of abortion. IVIg can only work in patients with normal chromosomes. Thus, the incidence of aneuploid embryos may influence the findings of IVIg, having an illusion of futility, while the administration may be helpful in those pregnancies where it may help. To ensure that the embryo chromosome is normal, we need to improve the embryo karyotyping method earlier.

In alloimmune diseases affecting pregnancy outcomes, such as fetal alloimmune thrombocytopenia (FNAIT) [142] or haemolytic disease of the fetus [143], the usual dose of IVIg is much higher (about 1 g/kg/body weight), and the frequency is much higher (usually once per week). Over the years, the dosage applied in most of the protocols has not been according to dosage-result trials. A majority of people adhere to the protocol of the first report that used IVIg in FNAIT [144]. The setting of 1.0 g/kg was identical to the treatments for idiopathic thrombocytopenic purpura [145–147] and in newborns with alloimmune thrombocytopenia [148, 149]. Two empirical studies have investigated the effect of 0.5 g/kg/week and 1 g/kg/week on FNAIT with standard risk (no occurrence of intraventricular hemorrhage in the previous child), and according to the results, the former was similar to the latter [150, 151]. Besides, the therapeutic effect of 2 g/kg/week was also discussed [152, 153]; however, the setting of the control groups in both studies was not strict. Reportedly, antibodies passing through the placenta do not increase with an increase in maternal IgG [150], which suggested that the Fc receptor of the placental transport may be saturated. Additionally, IVIg is expensive and in short supply, and there is a probable risk of disease transmission. These problems indicate that it is essential to consider using the minimum dosage to achieve the therapeutic effect. A large-scale worldwide study could investigate this problem afterwards.

9. The Timing of Using IVIg

The timing of treatment with IVIg, either in preconception or after implantation, may also influence the outcome. Sapir et al. [154] found that IVIg treatment before conception improved the chance of live delivery in primary RPL patients, whereas in secondary RPL patients, IVIg following embryo implantation showed a higher success rate. On the contrary, it was found that IVIg treatment obtained by RPL patients before conception was not as helpful as administered after pregnancy was established [26]. In the meta-analysis by Wang et al. [60], similar findings were reported containing more number of RCTs. The RR for live birth in women who had IVIg before pregnancy was 1.69 in contrast to those who got a placebo (95% CI 1.33–2.14; ) [60]. It is worth noting that many RCT studies reported by Hutton et al. [26] and Wang et al. [60] were repetitive. In murine researches, the CD200 check point inhibitor (expressed in IVIg) can induce DCs, which might induce the Treg reaction if given before conception and decrease pregnancy failure rate [155]. These contrary studies influencing interventional treatment need an investigation for making sure the ideal administration timing.

10. Pharmacokinetics of IVIg in Pregnancy

After IVIg infusion, serum IgG concentrations were reported to show multicompartmental first-order kinetics to decrease rapidly for 1–7 days, followed by a more gradual rate of decrease [156]. As for low-molecular-weight immunoglobulin parts, including Fab and Fv, are absorbed through the kidneys, the majority of intact IgG has disappeared due to concentration-dependent catabolism [157]. Pregnancy did not play an important role in the weight-adjusted dose of exogenously received IVIg [158]. Since the half-life of IVIg is 18 to 25 days, it is suitable to use IVIg every 3-4 weeks. Time of termination of the IVIg administration and the need for further laboratory tests should be decided by the obstetrician according to the condition of the patient.

11. Side Effects of IVIg

The deficiencies of IVIg treatment are the possible risk of viral contagion, including HIV, hepatitis, and prions. There are no reports of viral transmission caused by IVIg therapy to date. Most patients have good tolerance to IVIg, with no more than 5% of patients having common side effects, such as headaches, myalgia, fever, chills, dizziness, nausea, and vomiting. In addition, treatment with IVIg does not cause premature birth [17]. Ruiz et al. [91] reported that the function of this therapy is to reduce the tumor-killing functions of NK cells. Therefore, the therapy should only be performed with the knowledge that it may induce some kind of cancer. The anaphylactic reaction was found in IgA deficient (<7 mg/dL) patients immediately after IVIg. The sugar stabilizer of IVIg is associated with renal dysfunction after high-dose IVIg infusion [159–161]. As a result, every patient receiving IVIg needs to be tested for IgA and renal function in advance. The use of IVIg did not lead to serious side effects on neonates [162]. The prenatal IVIg administration was not related to premature maturation or other abnormal neonatal immune response [163]. The extent of the side effects depends on the patient’s age, the dosage of IVIg, and the intravenous infusion speed [164]. For patients with congenital heart disease or possible heart disease, IVIg should be injected gradually to prevent excessive liquid load and heart damage [165, 166]. For some patients with hereditary thrombotic tendencies, APS, or other thrombotic conditions, IVIg is a substance that promotes blood hypercoagulability and may cause thrombosis. There are reports of thrombosis after IVIg treatment [167]. Thus, for patients with hypercoagulable conditions, LMW heparin should be added during the application of IVIg.

12. Cost of IVIg

IVIg is expensive and can cost $800 per infusion at frequently used doses (400 mg/kg every 3-4 weeks) without additional hospitalization cost in China. However, the cost of this therapy can be balanced by a reduction in unsatisfactory maternal and fetal outcomes that often require expensive hospitalizations. As long as the logistical and financial issues involved in carrying out such a study are not resolved, IVIg may continue to be applied empirically, and the argument over its administration will go on.

13. Conclusions

In general, there is very limited evidence for the effect of IVIg in RPL, according to the literature. Two recent meta-analyses of IVIg use in RPL found no evidence of improved live birth rates [58, 168]. High-quality clinical studies are difficult to perform because neither couples nor obstetricians are willing to be randomly on placebo. According to the studies in the literature, a multicentered RCT study is needed to conclude definitely whether IVIg will help prevent RPL or not. Insulation of RPL with immune abnormalities could clearly increase the therapeutic effect of the IVIg administration in patients with RPL. It is recommended that IVIg infusion can be considered used before conception in RPL patients who have cellular immune abnormalities such as increased NK cell counts, NK cell cytotoxicity, or increased Th1/Th2 ratio, depending on the cut-off values of each hospital. There is a strong basis for providing this treatment to well-deserved patients who are eligible for treatment and who can afford the infusion or where the cost of treatment can be covered by medical insurance.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Acknowledgments

This work was supported by the Natural Science Foundation of Liaoning Province [grant number 2020-MS-167].

References

P. Egerup, A. M. Kolte, E. C. Larsen, M. Krog, H. S. Nielsen, and O. B. Christiansen, “Recurrent pregnancy loss: what is the impact of consecutive versus non-consecutive losses?” Human Reproduction, vol. 31, no. 11, pp. 2428–2434, 2016.
View at: Publisher Site | Google Scholar
J. Y. Kwak-Kim, H. S. Chung-Bang, S. C. Ng et al., “Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF,” Human Reproduction, vol. 18, no. 4, pp. 767–773, 2003.
View at: Publisher Site | Google Scholar
K. Aoki, S. Kajiura, Y. Matsumoto et al., “Preconceptional natural-killer-cell activity as a predictor of miscarriage,” The Lancet, vol. 345, no. 8961, pp. 1340–1342, 1995.
View at: Publisher Site | Google Scholar
S. K. Lee, J. Y. Kim, S. E. Hur et al., “An imbalance in interleukin-17-producing T and Foxp3⁺ regulatory T cells in women with idiopathic recurrent pregnancy loss,” Human Reproduction, vol. 26, no. 11, pp. 2964–2971, 2011.
View at: Publisher Site | Google Scholar
J. Y. H. KWAK, K. D. BEAMAN, A. GILMAN-SACHS, J. E. RUIZ, D. SCHEWITZ, and A. E. BEER, “Up-regulated expression of CD56+, CD56+/CD16+, and CD19+ cells in peripheral blood lymphocytes in pregnant women with recurrent pregnancy losses,” American Journal of Reproductive Immunology, vol. 34, no. 2, pp. 93–99, 1995.
View at: Publisher Site | Google Scholar
X. Yang, E. Yang, W. J. Wang et al., “Decreased HLA-C1 alleles in couples of KIR2DL2 positive women with recurrent pregnancy loss,” Journal of Reproductive Immunology, vol. 142, p. 103186, 2020.
View at: Publisher Site | Google Scholar
W. J. Wang, F. J. Liu, H. M. Qu et al., “Regulation of the expression of Th17 cells and regulatory T cells by IL-27 in patients with unexplained early recurrent miscarriage,” Journal of Reproductive Immunology, vol. 99, no. 1-2, pp. 39–45, 2013.
View at: Publisher Site | Google Scholar
S. Klaesson, O. Ringdén, L. Markling, M. Remberger, and I. Lundkvist, “Immune modulatory effects of immunoglobulins on cell-mediated immune responses in vitro,” Scandinavian Journal of Immunology, vol. 38, no. 5, pp. 477–484, 1993.
View at: Publisher Site | Google Scholar
M. Ballow, “The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders,” The Journal of Allergy and Clinical Immunology, vol. 127, no. 2, pp. 315–323, 2011.
View at: Publisher Site | Google Scholar
H. B. Ford and D. J. Schust, “Recurrent pregnancy loss: etiology, diagnosis, and therapy,” Reviews in Obstetrics and Gynecology, vol. 2, no. 2, pp. 76–83, 2009.
View at: Google Scholar
M. R. Virro, E. E. Winger, and J. L. Reed, “Intravenous immunoglobulin for repeated IVF failure and unexplained infertility,” American Journal of Reproductive Immunology, vol. 68, no. 3, pp. 218–225, 2012.
View at: Publisher Site | Google Scholar
N. Kondo, T. Ozawa, K. Mushiake et al., “Suppression of immunoglobulin production of lymphocytes by intravenous immunoglobulin,” Journal of Clinical Immunology, vol. 11, no. 3, pp. 152–158, 1991.
View at: Publisher Site | Google Scholar
S. Saito, A. Nakashima, T. Shima, and M. Ito, “Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy,” American Journal of Reproductive Immunology, vol. 63, no. 6, pp. 601–610, 2010.
View at: Publisher Site | Google Scholar
A. Fukui, S. Fujii, E. Yamaguchi, H. Kimura, S. Sato, and Y. Saito, “Natural killer cell subpopulations and cytotoxicity for infertile patients undergoing in vitro fertilization,” American Journal of Reproductive Immunology, vol. 41, no. 6, pp. 413–422, 1999.
View at: Publisher Site | Google Scholar
P. Imbach, S. Barandun, V. d'Apuzzo et al., “High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood,” The Lancet, vol. 1, no. 8232, pp. 1228–1231, 1981.
View at: Google Scholar
M. D. Kazatchkine and S. V. Kaveri, “Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin,” The New England Journal of Medicine, vol. 345, no. 10, pp. 747–755, 2001.
View at: Publisher Site | Google Scholar
I. Schwab and F. Nimmerjahn, “Intravenous immunoglobulin therapy: how does IgG modulate the immune system?” Nature Reviews. Immunology, vol. 13, no. 3, pp. 176–189, 2013.
View at: Publisher Site | Google Scholar
F. Rossi, G. Dietrich, and M. D. Kazatchkine, “Anti-idiotypes against autoantibodies in normal immunoglobulins: evidence for network regulation of human autoimmune responses,” Immunological Reviews, vol. 110, no. 1, pp. 135–149, 1989.
View at: Publisher Site | Google Scholar
R. P. Kimberly, J. E. Salmon, J. B. Bussel, M. K. Crow, and M. W. Hilgartner, “Modulation of mononuclear phagocyte function by intravenous gamma-globulin,” Journal of Immunology, vol. 132, no. 2, pp. 745–750, 1984.
View at: Google Scholar
J. Kulics, E. Rajnavölgyi, G. Füst, and J. Gergely, “Interaction of C3 and C3b with immunoglobulin G,” Molecular Immunology, vol. 20, no. 8, pp. 805–810, 1983.
View at: Publisher Site | Google Scholar
J. P. Andersson and U. G. Andersson, “Human intravenous immunoglobulin modulates monokine production in vitro,” Immunology, vol. 71, no. 3, pp. 372–376, 1990.
View at: Google Scholar
O. B. Christiansen, O. Mathiesen, J. G. Lauritsen, and N. Grunnet, “Intravenous immunoglobulin treatment of women with multiple miscarriages,” Human Reproduction, vol. 7, no. 5, pp. 718–722, 1992.
View at: Publisher Site | Google Scholar
G. Mueller-Eckhardt, O. Heine, J. Neppert, W. Künzel, and C. Mueller-Eckhardt, “Prevention of recurrent spontaneous abortion by intravenous immunoglobulin,” Vox Sanguinis, vol. 56, no. 3, pp. 151–154, 2017.
View at: Google Scholar
S. K. Lee, J. Y. Kim, A. R. Han et al., “Intravenous immunoglobulin G improves pregnancy outcome in women with recurrent pregnancy losses with cellular immune abnormalities,” American Journal of Reproductive Immunology, vol. 75, no. 1, pp. 59–68, 2016.
View at: Publisher Site | Google Scholar
R. B. Stricker and E. E. Winger, “Update on treatment of immunologic abortion with low-dose intravenous immunoglobulin,” American Journal of Reproductive Immunology, vol. 54, no. 6, pp. 390–396, 2005.
View at: Publisher Site | Google Scholar
B. Hutton, R. Sharma, D. Fergusson et al., “Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review,” BJOG, vol. 114, no. 2, pp. 134–142, 2007.
View at: Publisher Site | Google Scholar
O. B. Christiansen, B. Pedersen, A. Rosgaard, and M. Husth, “A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage,” Human Reproduction, vol. 17, no. 3, pp. 809–816, 2002.
View at: Publisher Site | Google Scholar
G. Mueller-Eckhardt, “Immunotherapy with intravenous immunoglobulin for prevention of recurrent pregnancy loss: European experience,” American Journal of Reproductive Immunology, vol. 32, no. 4, pp. 281–285, 1994.
View at: Publisher Site | Google Scholar
M. D. Stephenson, W. H. Kutteh, S. Purkiss et al., “Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial,” Human Reproduction, vol. 25, no. 9, pp. 2203–2209, 2010.
View at: Publisher Site | Google Scholar
O. B. Christiansen, E. C. Larsen, P. Egerup, L. Lunoee, L. Egestad, and H. S. Nielsen, “Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomised, double-blind, placebo-controlled trial,” BJOG, vol. 122, no. 4, pp. 500–508, 2015.
View at: Publisher Site | Google Scholar
A. Youssef, N. Vermeulen, E. Lashley, M. Goddijn, and M. L. P. van der Hoorn, “Comparison and appraisal of (inter)national recurrent pregnancy loss guidelines,” Reproductive Biomedicine Online, vol. 39, no. 3, pp. 497–503, 2019.
View at: Publisher Site | Google Scholar
S. Daya, J. Gunby, F. Porter, J. Scott, and D. A. Clark, “Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage,” Human Reproduction Update, vol. 5, no. 5, pp. 475–482, 1999.
View at: Publisher Site | Google Scholar
The German RSA/IVIG Group, “Intravenous immunoglobulin in the prevention of recurrent miscarriage,” British Journal of Obstetrics and Gynaecology, vol. 101, no. 12, pp. 1072–1077, 1994.
View at: Publisher Site | Google Scholar
O. B. Christiansen, O. Mathiesen, M. Husth et al., “Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin,” Human Reproduction, vol. 10, no. 10, pp. 2690–2695, 1995.
View at: Publisher Site | Google Scholar
M. D. Stephenson, K. Dreher, E. Houlihan, and V. Wu, “Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial,” American Journal of Reproductive Immunology, vol. 39, no. 2, pp. 82–88, 1998.
View at: Publisher Site | Google Scholar
A. Perino, A. Vassiliadis, A. Vucetich et al., “Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study,” Human Reproduction, vol. 12, no. 11, pp. 2388–2392, 1997.
View at: Publisher Site | Google Scholar
C. B. Coulam, L. Krysa, J. J. Stern, and M. Bustillo, “Intravenous immunoglobulin for treatment of recurrent pregnancy loss,” American Journal of Reproductive Immunology, vol. 34, no. 6, pp. 333–337, 1995.
View at: Publisher Site | Google Scholar
D. D. Kiprov, R. D. Nachtigall, R. C. Weaver, A. Jacobson, E. K. Main, and M. R. Garovoy, “The use of intravenous immunoglobulin in recurrent pregnancy loss associated with combined alloimmune and autoimmune abnormalities,” American Journal of Reproductive Immunology, vol. 36, no. 4, pp. 228–234, 1996.
View at: Publisher Site | Google Scholar
O. B. Christiansen, H. S. Nielsen, and B. Pedersen, “Active or passive immunization in unexplained recurrent miscarriage,” Journal of Reproductive Immunology, vol. 62, no. 1-2, pp. 41–52, 2004.
View at: Publisher Site | Google Scholar
A. H. Lazarus, “Adoptive-transfer effects of intravenous immunoglobulin in autoimmunity,” Journal of Clinical Immunology, vol. 30, Supplement 1, pp. S20–S23, 2010.
View at: Google Scholar
W. A. Sewell and S. Jolles, “Immunomodulatory action of intravenous immunoglobulin,” Immunology, vol. 107, no. 4, pp. 387–393, 2002.
View at: Publisher Site | Google Scholar
M. F. Diejomaoh, M. M. Al-Azemi, A. Bandar et al., “A favorable outcome of pregnancies in women with primary and secondary recurrent pregnancy loss associated with antiphospholipid syndrome,” Archives of Gynecology and Obstetrics, vol. 266, no. 2, pp. 61–66, 2002.
View at: Publisher Site | Google Scholar
A. L. Clark, D. W. Branch, R. M. Silver, E. N. Harris, S. Pierangeli, and J. A. Spinnato, “Pregnancy complicated by the antiphospholipid syndrome: outcomes with intravenous immunoglobulin therapy,” Obstetrics and Gynecology, vol. 93, no. 3, pp. 437–441, 1999.
View at: Publisher Site | Google Scholar
C. A. Omwandho, H. R. Tinneberg, A. G. Tumbo-Oeri, T. K. Roberts, and J. Falconer, “Recurrent pregnancy losses and the role of immunotherapy,” Archives of Gynecology and Obstetrics, vol. 264, no. 1, pp. 3–12, 2000.
View at: Publisher Site | Google Scholar
O. Blétry, A. S. Blanc, and A. M. Piette, “Intravenous immunoglobulin therapy for the antiphospholipid syndrome,” La Revue de Médecine Interne, vol. 20, Supplement 4, pp. 410s–413s, 1999.
View at: Publisher Site | Google Scholar
K. Marzusch, J. Dietl, R. Klein, D. Hornung, A. Neuer, and P. A. Berg, “Recurrent first trimester spontaneous abortion associated with antiphospholipid antibodies: a pilot study of treatment with intravenous immunoglobulin,” Acta Obstetricia et Gynecologica Scandinavica, vol. 75, no. 10, pp. 922–926, 1996.
View at: Publisher Site | Google Scholar
G. Triolo, A. Ferrante, A. Accardo-Palumbo et al., “IVIG in APS pregnancy,” Lupus, vol. 13, no. 9, pp. 731–735, 2016.
View at: Google Scholar
R. Bakimer, B. Guilburd, N. Zurgil, and Y. Shoenfeld, “The effect of intravenous γ-globulin on the induction of experimental antiphospholipid syndrome,” Clinical Immunology and Immunopathology, vol. 69, no. 1, pp. 97–102, 1993.
View at: Publisher Site | Google Scholar
H. J. Carp, V. Toder, E. Gazit et al., “Further experience with intravenous immunoglobulin in women with recurrent miscarriage and a poor prognosis,” American Journal of Reproductive Immunology, vol. 46, no. 4, pp. 268–273, 2001.
View at: Google Scholar
E. VAQUERO, H. VALENSISE, S. MENGHINI et al., “Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin,” American Journal of Reproductive Immunology, vol. 45, no. 3, pp. 174–179, 2001.
View at: Publisher Site | Google Scholar
H. J. Carp, R. A. Asherson, and Y. Shoenfeld, “Intravenous immunoglobulin in pregnancies complicated by the antiphospholipid syndrome: what is its role?” Journal of Clinical Rheumatology, vol. 7, no. 5, pp. 291–294, 2001.
View at: Publisher Site | Google Scholar
G. Triolo, A. Ferrante, F. Ciccia et al., “Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies,” Arthritis and Rheumatism, vol. 48, no. 3, pp. 728–731, 2003.
View at: Publisher Site | Google Scholar
S. Dendrinos, E. Sakkas, and E. Makrakis, “Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome,” International Journal of Gynaecology and Obstetrics, vol. 104, no. 3, pp. 223–225, 2009.
View at: Publisher Site | Google Scholar
D. W. Branch, A. M. Peaceman, M. Druzin et al., “A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy,” American Journal of Obstetrics and Gynecology, vol. 182, Part 1, no. 1, pp. 122–127, 2000.
View at: Publisher Site | Google Scholar
B. Jablonowska, A. Selbing, M. Palfi, J. Ernerudh, S. Kjellberg, and B. Lindton, “Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study,” Human Reproduction, vol. 14, no. 3, pp. 838–841, 1999.
View at: Publisher Site | Google Scholar
O. B. Christiansen, B. Pedersen, H. S. Nielsen, and A. M. Nybo Andersen, “Impact of the sex of first child on the prognosis in secondary recurrent miscarriage,” Human Reproduction, vol. 19, no. 12, pp. 2946–2951, 2004.
View at: Publisher Site | Google Scholar
L. F. Wong, T. F. Porter, and J. R. Scott, “Immunotherapy for recurrent miscarriage,” Cochrane Database System Reviews, vol. 2014, no. 10, article Cd000112, 2014.
View at: Google Scholar
P. Egerup, J. Lindschou, C. Gluud, and O. B. Christiansen, “The effects of intravenous immunoglobulins in women with recurrent miscarriages: a systematic review of randomised trials with meta-analyses and trial sequential analyses including individual patient data,” PLoS One, vol. 10, no. 10, article e0141588, 2015.
View at: Google Scholar
D. A. Clark, C. B. Coulam, S. Daya, and G. Chaouat, “Unexplained sporadic and recurrent miscarrage in the new millennium: a critical analysis of immune mechanisms and treatments,” Human Reproduction Update, vol. 7, no. 5, pp. 501–511, 2001.
View at: Publisher Site | Google Scholar
S. W. Wang, S. Y. Zhong, L. J. Lou, Z. F. Hu, H. Y. Sun, and H. Y. Zhu, “The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis,” Reproductive Biomedicine Online, vol. 33, no. 6, pp. 720–736, 2016.
View at: Publisher Site | Google Scholar
J. Alijotas-Reig and C. Garrido-Gimenez, “Current concepts and new trends in the diagnosis and management of recurrent miscarriage,” Obstetrical & Gynecological Survey, vol. 68, no. 6, pp. 445–466, 2013.
View at: Publisher Site | Google Scholar
H. Yamada, M. Morikawa, I. Furuta et al., “Intravenous immunoglobulin treatment in women with recurrent abortions: increased cytokine levels and reduced Th1/Th2 lymphocyte ratio in peripheral blood,” American Journal of Reproductive Immunology, vol. 49, no. 2, pp. 84–89, 2003.
View at: Publisher Site | Google Scholar
L. Szereday, P. Späth, and J. Szekeres-Bartho, “Natural killer cell activity and cytokine production after in vitro immunoglobulin treatment of lymphocytes derived from pregnant women with or without risk for spontaneous abortion,” American Journal of Reproductive Immunology, vol. 42, no. 5, pp. 282–287, 1999.
View at: Publisher Site | Google Scholar
M. Jerzak, T. Rechberger, and A. Górski, “Intravenous immunoglobulin therapy influences T cell adhesion to extracellular matrix in women with a history of recurrent spontaneous abortions,” American Journal of Reproductive Immunology, vol. 44, no. 6, pp. 336–341, 2000.
View at: Publisher Site | Google Scholar
M. Ahmadi, S. Abdolmohammadi-Vahid, M. Ghaebi et al., “Effect of intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL),” Biomedicine & Pharmacotherapy, vol. 92, pp. 1095–1102, 2017.
View at: Publisher Site | Google Scholar
O. Graphou, A. Chioti, A. Pantazi et al., “Effect of intravenous immunoglobulin treatment on the Th1/Th2 balance in women with recurrent spontaneous abortions,” American Journal of Reproductive Immunology, vol. 49, no. 1, pp. 21–29, 2003.
View at: Publisher Site | Google Scholar
A. Ephrem, S. Chamat, C. Miquel et al., “Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis,” Blood, vol. 111, no. 2, pp. 715–722, 2008.
View at: Publisher Site | Google Scholar
A. Kessel, H. Ammuri, R. Peri et al., “Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function,” Journal of Immunology, vol. 179, no. 8, pp. 5571–5575, 2007.
View at: Publisher Site | Google Scholar
J. Kwekkeboom, “Modulation of dendritic cells and regulatory T cells by naturally occurring antibodies,” Advances in Experimental Medicine and Biology, vol. 750, pp. 133–144, 2012.
View at: Publisher Site | Google Scholar
D. A. Somerset, Y. Zheng, M. D. Kilby, D. M. Sansom, and M. T. Drayson, “Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset,” Immunology, vol. 112, no. 1, pp. 38–43, 2004.
View at: Publisher Site | Google Scholar
A. Schumacher, K. Heinze, J. Witte et al., “Human chorionic gonadotropin as a central regulator of pregnancy immune tolerance,” Journal of Immunology, vol. 190, no. 6, pp. 2650–2658, 2013.
View at: Publisher Site | Google Scholar
M. S. Maddur, M. Sharma, P. Hegde, S. Lacroix-Desmazes, S. V. Kaveri, and J. Bayry, “Inhibitory effect of IVIG on IL-17 production by Th17 cells is independent of anti-IL-17 antibodies in the immunoglobulin preparations,” Journal of Clinical Immunology, vol. 33, Supplement 1, pp. S62–S66, 2013.
View at: Google Scholar
M. S. Maddur, S. V. Kaveri, and J. Bayry, “Comparison of different IVIg preparations on IL-17 production by human Th17 cells,” Autoimmunity Reviews, vol. 10, no. 12, pp. 809-810, 2011.
View at: Publisher Site | Google Scholar
M. S. Maddur, J. Vani, P. Hegde, S. Lacroix-Desmazes, S. V. Kaveri, and J. Bayry, “Inhibition of differentiation, amplification, and function of human T_H17 cells by intravenous immunoglobulin,” Journal of Allergy and Clinical Immunology, vol. 127, no. 3, pp. 823–830.e7, 2011.
View at: Publisher Site | Google Scholar
J. Sha, F. Liu, J. Zhai, X. Liu, Q. Zhang, and B. Zhang, “Alteration of Th17 and Foxp3(+) regulatory T cells in patients with unexplained recurrent spontaneous abortion before and after the therapy of hCG combined with immunoglobulin,” Experimental and Therapeutic Medicine, vol. 14, no. 2, pp. 1114–1118, 2017.
View at: Publisher Site | Google Scholar
S. Othy, P. Hegde, S. Topçu et al., “Intravenous gammaglobulin inhibits encephalitogenic potential of pathogenic T cells and interferes with their trafficking to the central nervous system, implicating sphingosine-1 phosphate receptor 1-mammalian target of rapamycin axis,” Journal of Immunology, vol. 190, no. 9, pp. 4535–4541, 2013.
View at: Publisher Site | Google Scholar
D. J. Kim, S. K. Lee, J. Y. Kim et al., “Intravenous immunoglobulin G modulates peripheral blood Th17 and Foxp3(+) regulatory T cells in pregnant women with recurrent pregnancy loss,” American Journal of Reproductive Immunology, vol. 71, no. 5, pp. 441–450, 2014.
View at: Publisher Site | Google Scholar
M. Ahmadi, S. A. Aghdam, M. Nouri et al., “Intravenous immunoglobulin (IVIG) treatment modulates peripheral blood Th17 and regulatory T cells in recurrent miscarriage patients: non randomized, open-label clinical trial,” Immunology Letters, vol. 192, pp. 12–19, 2017.
View at: Publisher Site | Google Scholar
S. Jafarzadeh, M. Ahmadi, S. Dolati et al., “Intravenous immunoglobulin G treatment increases live birth rate in women with recurrent miscarriage and modulates regulatory and exhausted regulatory T cells frequency and function,” Journal of Cellular Biochemistry, vol. 120, no. 4, pp. 5424–5434, 2019.
View at: Publisher Site | Google Scholar
J. Bayry, L. Mouthon, and S. V. Kaveri, “Intravenous immunoglobulin expands regulatory T cells in autoimmune rheumatic disease,” The Journal of Rheumatology, vol. 39, no. 2, pp. 450-451, 2012.
View at: Publisher Site | Google Scholar
B. Olivito, A. Taddio, G. Simonini et al., “Defective FOXP3 expression in patients with acute Kawasaki disease and restoration by intravenous immunoglobulin therapy,” Clinical and Experimental Rheumatology, vol. 28, no. 1, pp. 93–97, 2010.
View at: Google Scholar
N. Tsurikisawa, H. Saito, C. Oshikata, T. Tsuburai, and K. Akiyama, “High-dose intravenous immunoglobulin treatment increases regulatory T cells in patients with eosinophilic granulomatosis with polyangiitis,” The Journal of Rheumatology, vol. 39, no. 5, pp. 1019–1025, 2012.
View at: Publisher Site | Google Scholar
A. H. Massoud, J. Guay, K. H. Shalaby et al., “Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3-positive regulatory T cells,” Journal of Allergy and Clinical Immunology, vol. 129, no. 6, pp. 1656–1665.e3, 2012.
View at: Publisher Site | Google Scholar
J. Trinath, P. Hegde, M. Sharma et al., “Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2-dependent prostaglandin E2 in human dendritic cells,” Blood, vol. 122, no. 8, pp. 1419–1427, 2013.
View at: Google Scholar
R. Aslam, Y. Hu, S. Gebremeskel et al., “Thymic retention of CD4+CD25+FoxP3+ T regulatory cells is associated with their peripheral deficiency and thrombocytopenia in a murine model of immune thrombocytopenia,” Blood, vol. 120, no. 10, pp. 2127–2132, 2012.
View at: Publisher Site | Google Scholar
S. Y. Lee, Y. O. Jung, J. G. Ryu et al., “Intravenous immunoglobulin attenuates experimental autoimmune arthritis by inducing reciprocal regulation of Th17 and Treg cells in an interleukin-10-dependent manner,” Arthritis & Rhematology, vol. 66, no. 7, pp. 1768–1778, 2014.
View at: Publisher Site | Google Scholar
J. Y. Kwak, F. M. Kwak, S. W. Ainbinder, A. M. Ruiz, and A. E. Beer, “Elevated peripheral blood natural killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions,” American Journal of Reproductive Immunology, vol. 35, no. 4, pp. 363–369, 1996.
View at: Publisher Site | Google Scholar
R. Perricone, G. Di Muzio, C. Perricone et al., “High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins,” American Journal of Reproductive Immunology, vol. 55, no. 3, pp. 232–239, 2006.
View at: Google Scholar
D. Rigal, C. Vermot-Desroches, S. Heitz, J. Bernaud, F. Alfonsi, and J. C. Monier, “Effects of intravenous immunoglobulins (IVIG) on peripheral blood B, NK, and T cell subpopulations in women with recurrent spontaneous abortions: specific effects on LFA-1 and CD56 molecules,” Clinical Immunology and Immunopathology, vol. 71, no. 3, pp. 309–314, 1994.
View at: Publisher Site | Google Scholar
R. G. Roussev, S. C. Ng, and C. B. Coulam, “Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G,” American Journal of Reproductive Immunology, vol. 57, no. 4, pp. 262–269, 2007.
View at: Google Scholar
J. E. Ruiz, J. Y. Kwak, L. Baum et al., “Intravenous immunoglobulin inhibits natural killer cell activity in vivo in women with recurrent spontaneous abortion,” American Journal of Reproductive Immunology, vol. 35, no. 4, pp. 370–375, 1996.
View at: Publisher Site | Google Scholar
L. Heilmann, M. Schorsch, and T. Hahn, “CD3-CD56+CD16+ natural killer cells and improvement of pregnancy outcome in IVF/ICSI failure after additional IVIG-treatment,” American Journal of Reproductive Immunology, vol. 63, no. 3, pp. 263–265, 2010.
View at: Google Scholar
F. Mahmoud, M. Diejomaoh, A. Omu, H. Abul, and D. Haines, “Effect of IgG therapy on lymphocyte subpopulations in the peripheral blood of Kuwaiti women experiencing recurrent pregnancy loss,” Gynecologic and Obstetric Investigation, vol. 58, no. 2, pp. 77–83, 2004.
View at: Publisher Site | Google Scholar
B. M. Cohen and S. Machupalli, “Use of gammaglobulin to lower elevated natural killer cells in patients with recurrent miscarriage,” The Journal of Reproductive Medicine, vol. 60, no. 7-8, pp. 294–300, 2015.
View at: Google Scholar
R. Ramos-Medina, A. García-Segovia, J. Gil et al., “Experience in IVIg therapy for selected women with recurrent reproductive failure and NK cell expansion,” American Journal of Reproductive Immunology, vol. 71, no. 5, pp. 458–466, 2014.
View at: Publisher Site | Google Scholar
J. Tanaka, A. Kitashoji, Y. Fukunaga, J. Kashihara, A. Nakano, and A. Kamizono, “Intravenous immunoglobulin suppresses abortion relates to an increase in the CD44bright NK subset in recurrent pregnancy loss model mice,” Biology of Reproduction, vol. 95, no. 2, p. 37, 2016.
View at: Google Scholar
S. Shimada, M. Takeda, J. Nishihira et al., “A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion,” American Journal of Reproductive Immunology, vol. 62, no. 5, pp. 301–307, 2009.
View at: Publisher Site | Google Scholar
D. A. Clark, K. Wong, D. Banwatt et al., “CD200-dependent and nonCD200-dependent pathways of NK cell suppression by human IVIG,” Journal of Assisted Reproduction and Genetics, vol. 25, no. 2-3, pp. 67–72, 2008.
View at: Publisher Site | Google Scholar
D. A. Clark and G. Chaouat, “Loss of surface CD200 on stored allogeneic leukocytes may impair anti-abortive effect in vivo,” American Journal of Reproductive Immunology, vol. 53, no. 1, pp. 13–20, 2005.
View at: Publisher Site | Google Scholar
G. J. Wright, H. Cherwinski, M. Foster-Cuevas et al., “Characterization of the CD200 receptor family in mice and humans and their interactions with CD200,” Journal of Immunology, vol. 171, no. 6, pp. 3034–3046, 2003.
View at: Publisher Site | Google Scholar
V. R. Aluvihare, M. Kallikourdis, and A. G. Betz, “Regulatory T cells mediate maternal tolerance to the fetus,” Nature Immunology, vol. 5, no. 3, pp. 266–271, 2004.
View at: Publisher Site | Google Scholar
M. Morikawa, H. Yamada, E. H. Kato et al., “Massive intravenous immunoglobulin treatment in women with four or more recurrent spontaneous abortions of unexplained etiology: down-regulation of NK cell activity and subsets,” American Journal of Reproductive Immunology, vol. 46, no. 6, pp. 399–404, 2001.
View at: Publisher Site | Google Scholar
H. Yamada, M. Deguchi, Y. Maesawa et al., “Medium-dose intravenous immunoglobulin therapy for women with six or more recurrent miscarriages,” Journal of Reproductive Immunology, vol. 109, pp. 48–51, 2015.
View at: Publisher Site | Google Scholar
M. Ahmadi, M. Ghaebi, S. Abdolmohammadi-Vahid et al., “NK cell frequency and cytotoxicity in correlation to pregnancy outcome and response to IVIG therapy among women with recurrent pregnancy loss,” Journal of Cellular Physiology, vol. 234, no. 6, pp. 9428–9437, 2018.
View at: Google Scholar
Y. Uemura, M. Suzuki, T. Y. Liu et al., “Role of human non-invariant NKT lymphocytes in the maintenance of type 2 T helper environment during pregnancy,” International Immunology, vol. 20, no. 3, pp. 405–412, 2008.
View at: Publisher Site | Google Scholar
D. A. Clark, C. B. Coulam, and R. B. Stricker, “Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF),” Journal of Assisted Reproduction and Genetics, vol. 23, no. 1, pp. 1–13, 2006.
View at: Publisher Site | Google Scholar
D. Oliver-Miñarro, J. Gil, A. Aguaron, M. Rodríguez-Mahou, E. Fernandez-Cruz, and S. Sanchez-Ramon, “NK cell expansion in obstetrical antiphospholipid syndrome: guilty by association?” European Journal of Obstetrics & Gynecology and Reproductive Biology, vol. 145, no. 2, p. 227, 2009.
View at: Google Scholar
M. J. van den Heuvel, C. G. Peralta, K. Hatta, V. K. Han, and D. A. Clark, “Decline in number of elevated blood CD3(+) CD56(+) NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy,” American Journal of Reproductive Immunology, vol. 58, no. 5, pp. 447–459, 2007.
View at: Publisher Site | Google Scholar
A. E. Beer, J. Y. Kwak, and J. E. Ruiz, “Immunophenotypic profiles of peripheral blood lymphocytes in women with recurrent pregnancy losses and in infertile women with multiple failed in vitro fertilization cycles,” American Journal of Reproductive Immunology, vol. 35, no. 4, pp. 376–382, 1996.
View at: Publisher Site | Google Scholar
K. King, S. Smith, M. Chapman, and G. Sacks, “Detailed analysis of peripheral blood natural killer (NK) cells in women with recurrent miscarriage,” Human Reproduction, vol. 25, no. 1, pp. 52–58, 2009.
View at: Google Scholar
J. Y. Kwak, A. Gilman-Sachs, M. Moretti, K. D. Beaman, and A. E. Beer, “Natural killer cell cytotoxicity and paternal lymphocyte immunization in women with recurrent spontaneous abortions,” American Journal of Reproductive Immunology, vol. 40, no. 5, pp. 352–358, 1998.
View at: Publisher Site | Google Scholar
E. E. Winger, J. L. Reed, S. Ashoush, T. El-Toukhy, S. Ahuja, and M. Taranissi, “Elevated preconception CD56+16+ and/or Th1:Th2 levels predict benefit from IVIG therapy in subfertile women undergoing IVF,” American Journal of Reproductive Immunology, vol. 66, no. 5, pp. 394–403, 2011.
View at: Publisher Site | Google Scholar
H. Karasuyama, K. Miyake, S. Yoshikawa, and Y. Yamanishi, “Multifaceted roles of basophils in health and disease,” The Journal of Allergy and Clinical Immunology, vol. 142, no. 2, pp. 370–380, 2018.
View at: Publisher Site | Google Scholar
D. Voehringer, “Protective and pathological roles of mast cells and basophils,” Nature Reviews. Immunology, vol. 13, no. 5, pp. 362–375, 2013.
View at: Publisher Site | Google Scholar
H. Karasuyama, K. Obata, T. Wada, Y. Tsujimura, and K. Mukai, “Newly appreciated roles for basophils in allergy and protective immunity,” Allergy, vol. 66, no. 9, pp. 1133–1141, 2011.
View at: Publisher Site | Google Scholar
Y. Ito, T. Satoh, K. Takayama, C. Miyagishi, A. F. Walls, and H. Yokozeki, “Basophil recruitment and activation in inflammatory skin diseases,” Allergy, vol. 66, no. 8, pp. 1107–1113, 2011.
View at: Publisher Site | Google Scholar
A. L. Thompson, “Caesarean delivery, immune function and inflammation in early life among Ecuadorian infants and young children,” Journal of Developmental Origins of Health and Disease, vol. 10, no. 5, pp. 555–562, 2019.
View at: Google Scholar
J. Eckl-Dorna, A. Ellinger, K. Blatt et al., “Basophils are not the key antigen-presenting cells in allergic patients,” Allergy, vol. 67, no. 5, pp. 601–608, 2012.
View at: Publisher Site | Google Scholar
C. Kitzmüller, B. Nagl, S. Deifl et al., “Human blood basophils do not act as antigen-presenting cells for the major birch pollen allergen bet v 1,” Allergy, vol. 67, no. 5, pp. 593–600, 2012.
View at: Publisher Site | Google Scholar
M. Sharma, P. Hegde, V. Aimanianda et al., “Circulating human basophils lack the features of professional antigen presenting cells,” Scientific Reports, vol. 3, no. 1, p. 1188, 2013.
View at: Publisher Site | Google Scholar
K. Miyake, N. Shiozawa, T. Nagao, S. Yoshikawa, Y. Yamanishi, and H. Karasuyama, “Trogocytosis of peptide-MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils,” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 5, pp. 1111–1116, 2017.
View at: Publisher Site | Google Scholar
E. Stephen-Victor, M. Das, M. Sharma et al., “Demystification of enigma on antigen-presenting cell features of human basophils: data from secondary lymphoid organs,” Haematologica, vol. 102, no. 6, pp. e233–e237, 2017.
View at: Publisher Site | Google Scholar
D. Voehringer, “Basophil modulation by cytokine instruction,” European Journal of Immunology, vol. 42, no. 10, pp. 2544–2550, 2012.
View at: Publisher Site | Google Scholar
M. C. Siracusa, S. A. Saenz, D. A. Hill et al., “TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation,” Nature, vol. 477, no. 7363, pp. 229–233, 2011.
View at: Publisher Site | Google Scholar
J. M. Leyva-Castillo, P. Hener, P. Michea et al., “Skin thymic stromal lymphopoietin initiates Th2 responses through an orchestrated immune cascade,” Nature Communications, vol. 4, no. 1, p. 2847, 2013.
View at: Publisher Site | Google Scholar
M. Sharma, M. Das, E. Stephen-Victor et al., “Regulatory T cells induce activation rather than suppression of human basophils,” Science Immunology, vol. 3, no. 23, p. eaan0829, 2018.
View at: Publisher Site | Google Scholar
D. Jiao, C. K. Wong, H. N. Qiu et al., “NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation,” Cellular & Molecular Immunology, vol. 13, no. 4, pp. 535–550, 2016.
View at: Publisher Site | Google Scholar
J. Suurmond, J. N. Stoop, F. Rivellese, A. M. Bakker, T. W. Huizinga, and R. E. Toes, “Activation of human basophils by combined toll-like receptor- and FcεRI-triggering can promote Th2 skewing of naive T helper cells,” European Journal of Immunology, vol. 44, no. 2, pp. 386–396, 2013.
View at: Google Scholar
C. Galeotti, E. Stephen-Victor, A. Karnam et al., “Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE,” The Journal of Allergy and Clinical Immunology, vol. 144, no. 2, pp. 524–535.e8, 2019.
View at: Publisher Site | Google Scholar
C. Galeotti, A. Karnam, J. D. Dimitrov, A. Chevailler, S. V. Kaveri, and J. Bayry, “Anti-IgE IgG autoantibodies isolated from therapeutic normal IgG intravenous immunoglobulin induce basophil activation,” Cellular & Molecular Immunology, vol. 17, no. 4, pp. 426–429, 2020.
View at: Publisher Site | Google Scholar
C. Galeotti, S. V. Kaveri, and J. Bayry, “IVIG-mediated effector functions in autoimmune and inflammatory diseases,” International Immunology, vol. 29, no. 11, pp. 491–498, 2017.
View at: Publisher Site | Google Scholar
R. M. Anthony, T. Kobayashi, F. Wermeling, and J. V. Ravetch, “Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway,” Nature, vol. 475, no. 7354, pp. 110–113, 2011.
View at: Google Scholar
S. Fulda and D. Kögel, “Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy,” Oncogene, vol. 34, no. 40, pp. 5105–5113, 2015.
View at: Publisher Site | Google Scholar
T. T. Kanninen, B. R. de Andrade Ramos, and S. S. Witkin, “The role of autophagy in reproduction from gametogenesis to parturition,” European Journal of Obstetrics, Gynecology, and Reproductive Biology, vol. 171, no. 1, pp. 3–8, 2013.
View at: Google Scholar
Y. Su, J. Wu, J. He et al., “High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process,” Endocrine Journal, vol. 64, no. 6, pp. 613–621, 2017.
View at: Publisher Site | Google Scholar
J. E. Lee, H. A. Oh, H. Song et al., “Autophagy regulates embryonic survival during delayed implantation,” Endocrinology, vol. 152, no. 5, pp. 2067–2075, 2011.
View at: Publisher Site | Google Scholar
J. S. Rhee, J. L. Saben, A. L. Mayer et al., “Diet-induced obesity impairs endometrial stromal cell decidualization: a potential role for impaired autophagy,” Human Reproduction, vol. 31, no. 6, pp. 1315–1326, 2016.
View at: Publisher Site | Google Scholar
M. J. Mulla, I. C. Weel, J. A. Potter et al., “Antiphospholipid antibodies inhibit trophoblast toll-like receptor and inflammasome negative regulators,” Arthritis & Rhematology, vol. 70, no. 6, pp. 891–902, 2018.
View at: Google Scholar
H. X. Tan, S. L. Yang, M. Q. Li, and H. Y. Wang, “Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion,” Cell Communication and Signaling, vol. 18, no. 1, p. 73, 2020.
View at: Publisher Site | Google Scholar
M. Das, A. Karnam, E. Stephen-Victor et al., “Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy,” Cell Death & Disease, vol. 11, no. 1, p. 50, 2020.
View at: Publisher Site | Google Scholar
R. H. Asch, G. Ivery, M. Goldsman, J. L. Frederick, S. C. Stone, and J. P. Balmaceda, “The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome,” Human Reproduction, vol. 8, no. 7, pp. 1015–1020, 1993.
View at: Publisher Site | Google Scholar
D. Winkelhorst, M. F. Murphy, A. Greinacher et al., “Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review,” Blood, vol. 129, no. 11, pp. 1538–1547, 2017.
View at: Publisher Site | Google Scholar
American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, “Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation,” Pediatrics, vol. 114, no. 1, pp. 297–316, 2004.
View at: Publisher Site | Google Scholar
J. B. Bussel, R. L. Berkowitz, J. G. McFarland, L. Lynch, and U. Chitkara, “Antenatal treatment of neonatal alloimmune thrombocytopenia,” The New England Journal of Medicine, vol. 319, no. 21, pp. 1374–1378, 1988.
View at: Publisher Site | Google Scholar
J. B. Bussel, R. P. Kimberly, R. D. Inman et al., “Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura,” Blood, vol. 62, no. 2, pp. 480–486, 1983.
View at: Google Scholar
T. Hara, S. Miyazaki, N. Yoshida, and N. Goya, “High doses of gamma globulin and methylprednisolone therapy for idiopathic thrombocytopenic purpura in children,” European Journal of Pediatrics, vol. 144, no. 3, pp. 240–242, 1985.
View at: Publisher Site | Google Scholar
A. C. Newland, M. A. Boots, and K. G. Patterson, “Intravenous IgG for autoimmune thrombocytopenia in pregnancy,” The New England Journal of Medicine, vol. 310, no. 4, pp. 261-262, 1984.
View at: Publisher Site | Google Scholar
Ş. Özsoylu and P. Merlob, “Intravenous immunoglobulin for neonatal isoimmune thrombocytopenia,” European Journal of Pediatrics, vol. 150, no. 1, pp. 72-73, 1990.
View at: Publisher Site | Google Scholar
D. Sidiropoulos and B. Straume, “The treatment of neonatal isoimmune thrombocytopenia with intravenous immunoglobin (IgG i.v.),” Blut, vol. 48, no. 6, pp. 383–386, 1984.
View at: Publisher Site | Google Scholar
N. P. Paridaans, M. M. Kamphuis, A. Taune Wikman et al., “Low-dose versus standard-dose intravenous immunoglobulin to prevent fetal intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia: a randomized trial,” Fetal Diagnosis and Therapy, vol. 38, no. 2, pp. 147–153, 2015.
View at: Publisher Site | Google Scholar
N. M. Van Der Lugt, M. M. Kamphuis, N. P. Paridaans et al., “Neonatal outcome in alloimmune thrombocytopenia after maternal treatment with intravenous immunoglobulin,” Blood Transfusion, vol. 13, no. 1, pp. 66–71, 2015.
View at: Google Scholar
J. B. Bussel, R. L. Berkowitz, C. Hung et al., “Intracranial hemorrhage in alloimmune thrombocytopenia: stratified management to prevent recurrence in the subsequent affected fetus,” American Journal of Obstetrics and Gynecology, vol. 203, no. 2, pp. 135.e1–135.e14, 2010.
View at: Google Scholar
R. L. Berkowitz, M. L. Lesser, J. G. McFarland et al., “Antepartum treatment without early cordocentesis for standard-risk alloimmune Thrombocytopenia,” Obstetrics and Gynecology, vol. 110, Part 1, no. 2, pp. 249–255, 2007.
View at: Publisher Site | Google Scholar
T. Sapir, H. Carp, and Y. Shoenfeld, “Intravenous immunoglobulin (IVIG) as treatment for recurrent pregnancy loss (RPL),” Harefuah, vol. 144, no. 6, pp. 415–420, 2005.
View at: Google Scholar
R. M. Gorczynski, S. Hadidi, G. Yu, and D. A. Clark, “The same immunoregulatory molecules contribute to successful pregnancy and transplantation,” American Journal of Reproductive Immunology, vol. 48, no. 1, pp. 18–26, 2002.
View at: Publisher Site | Google Scholar
B. Nosslin, “Analysis of disappearance time-curves after single injection of labelled proteins,” Ciba Foundation Symposium, vol. 9, pp. 113–130, 1972.
View at: Google Scholar
E. D. Lobo, R. J. Hansen, and J. P. Balthasar, “Antibody pharmacokinetics and pharmacodynamics,” Journal of Pharmaceutical Sciences, vol. 93, no. 11, pp. 2645–2668, 2004.
View at: Publisher Site | Google Scholar
M. H. Ensom and M. D. Stephenson, “A two-center study on the pharmacokinetics of intravenous immunoglobulin before and during pregnancy in healthy women with poor obstetrical histories,” Human Reproduction, vol. 26, no. 9, pp. 2283–2288, 2011.
View at: Publisher Site | Google Scholar
A. W. Burks, H. A. Sampson, and R. H. Buckley, “Anaphylactic reactions after gamma globulin administration in patients with Hypogammaglobulinemia,” The New England Journal of Medicine, vol. 314, no. 9, pp. 560–564, 1986.
View at: Publisher Site | Google Scholar
R. Rachid and F. A. Bonilla, “The role of anti-IgA antibodies in causing adverse reactions to gamma globulin infusion in immunodeficient patients: a comprehensive review of the literature,” The Journal of Allergy and Clinical Immunology, vol. 129, no. 3, pp. 628–634, 2012.
View at: Publisher Site | Google Scholar
R. Zhang and H. M. Szerlip, “Reemergence of sucrose nephropathy: acute renal failure caused by high-dose intravenous immune globulin therapy,” Southern Medical Journal, vol. 93, no. 9, pp. 901–904, 2000.
View at: Google Scholar
J. Kinney, L. Mundorf, C. Gleason et al., “Efficacy and pharmacokinetics of intravenous immune globulin administration to high-risk neonates,” American Journal of Diseases of Children, vol. 145, no. 11, pp. 1233–1238, 1991.
View at: Google Scholar
C. M. Radder, D. L. Roelen, E. M. van de Meer-Prins, F. H. Claas, H. H. Kanhai, and A. Brand, “The immunologic profile of infants born after maternal immunoglobulin treatment and intrauterine platelet transfusions for fetal/neonatal alloimmune thrombocytopenia,” American Journal of Obstetrics and Gynecology, vol. 191, no. 3, pp. 815–820, 2004.
View at: Publisher Site | Google Scholar
Y. Sherer, Y. Levy, and Y. Shoenfeld, “IVIG in autoimmunity and cancer--efficacy versus safety,” Expert Opinion on Drug Safety, vol. 1, no. 2, pp. 153–158, 2002.
View at: Google Scholar
M. C. Dalakas, “Intravenous immune globulin therapy for neurologic diseases,” Annals of Internal Medicine, vol. 126, no. 9, pp. 721–730, 1997.
View at: Google Scholar
“Intravenous immunoglobulin (IVIG) and recurrent spontaneous pregnancy loss,” Fertility and Sterility, vol. 82, Supplement 1, pp. S199–S200, 2004.
View at: Google Scholar
E. Ramirez, J. A. Romero-Garrido, E. Lopez-Granados et al., “Symptomatic thromboembolic events in patients treated with intravenous- immunoglobulins: Results from a retrospective cohort study,” Thrombosis Research, vol. 133, no. 6, pp. 1045–1051, 2014.
View at: Publisher Site | Google Scholar
E. Rasmark Roepke, M. Hellgren, R. Hjertberg et al., “Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses,” Acta Obstetricia et Gynecologica Scandinavica, vol. 97, no. 8, pp. 921–941, 2018.
View at: Publisher Site | Google Scholar

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Copyright © 2020 Xiuhua Yang and Tao Meng. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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