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The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis

Published:September 16, 2016DOI:https://doi.org/10.1016/j.rbmo.2016.08.025

      Abstract

      The aim of this study was to investigate the effect of passive immunotherapy using intravenous immunoglobulin (IVIG) on unexplained recurrent spontaneous abortion (RSA). Live birth rates were analysed and binary data were calculated using risk ratio and 95% confidence interval. Meta-analysis of 11 studies showed that the difference in the live birth rate between the IVIG treatment and placebo groups was on the margin of significance (RR = 1.25, 95% CI 1.00 to 1.56, P = 0.05). Both cumulative and trial sequential meta-analyses indicated potential beneficial effect of IVIG but the evidence was inconclusive. Subgroup analysis showed that the live birth rate in primary (RR = 0.88, 95% CI 0.71 to 1.07) and secondary (RR = 1.26, 95% CI 0.99 to 1.61) RSA patients was not significantly different between the IVIG and placebo groups. Live birth rate was significantly different when IVIG was administered before conception (RR = 1.67, 95% CI 1.30 to 2.14, P < 0.0001) but not after implantation (RR = 1.10, 95% CI 0.93 to 1.29). Evidence is insufficient to support the beneficial effects of IVIG on an unexplained RSA. Further high quality studies are needed to elucidate the effectiveness of IVIG.

      Keywords

      Introduction

      Recurrent spontaneous abortion (RSA) is defined as two or more spontaneous abortions (with the same partner) before 20th gestational week of pregnancy or loss of pregnancy when fetal weight is less than 500 g. It is further categorized into primary RSA and secondary RSA. Primary RSA refers to a series of spontaneous abortions without a previous live birth; and secondary RSA refers to a series of spontaneous abortions ensuing a live birth or stillbirth. Between 1 and 5% of all women are affected by RSA during childbearing years (
      • Kuon R.
      • Wallwiener L.
      • Germeyer A.
      • Strowitzki T.
      • Daniel V.
      • Toth B.
      Establishment of a standardized immunological diagnostic procedure in RM patients.
      ). The risk of subsequent spontaneous abortion in women who have experienced RSA also increases with the number of previous spontaneous abortions. This risk can reach as high as 50% after two pregnancy losses. Clinically, it is crucial to prevent RSA by certain interventions when possible (
      • Xiao S.-J.
      • Zhao A.-M.
      The new progress in the etiology of recurrent miscarriage.
      ). Various factors contribute to the occurrence of RSA, including chromosome abnormalities, genital anatomic abnormality, endocrine disturbances, autoimmune disturbance, infectious disease and pro-thrombophilic status. Some patients, however, experience unexplained RSA, which may be related to alloimmunity (
      • Cohen M.
      • Bischof P.
      Factors regulating trophoblast invasion.
      ), including elevated compatibility in human leukocyte antigen (HLA), phenotypic changes in immune cell subsets, Th1/Th2 cytokine imbalance, and deficiencies in generation of blocking (protective) antibodies (
      • Lin Q.
      Basic and clinical research progress of unexplained recurrent miscarriage.
      ).
      Immunological disturbances were reported to play an important role in RSA. High levels of natural killer cell subsets, autoantibodies and inflammatory cytokines were found in the peripheral blood of patients who had experienced RSA. Activated leukocyte and certain specific natural killer cells that were beyond normal level were also found in the decidua of these patients (
      • Hill J.A.
      • Polgar K.
      • Anderson D.J.
      T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion.
      ,
      • Kruse C.
      • Steffensen R.
      • Varming K.
      • Christiansen O.B.
      A study of HLA-DR and -DQ alleles in 588 patients and 562 controls confirms that HLA-DRB1*03 is associated with recurrent miscarriage.
      ,
      • Quack K.C.
      • Vassiliadou N.
      • Pudney J.
      • Anderson D.J.
      • Hill J.A.
      Leukocyte activation in the decidua of chromosomally normal and abnormal fetuses from women with recurrent abortion.
      ,
      • Xu L.
      • Chang V.
      • Murphy A.
      • Rock J.A.
      • Damewood M.
      • Schlaff W.
      • Zacur H.A.
      Antinuclear antibodies in sera of patients with recurrent pregnancy wastage.
      ). Further evidence indicated that secondary RSA showed worse immune rejection than that of primary RSA, particularly in immunological disturbances of white blood cell heterogeneity. Additionally, gene expressions of HLA-DR3 and HLA-G were higher in secondary RSA compared with primary RSA and control groups (
      • Christiansen O.B.
      • Kolte A.M.
      • Dahl M.
      • Larsen E.C.
      • Steffensen R.
      • Nielsen H.S.
      • Hviid T.V.
      Maternal homozygocity for a 14 base pair insertion in exon 8 of the HLA-G gene and carriage of HLA class II alleles restricting HY immunity predispose to unexplained secondary recurrent miscarriage and low birth weight in children born to these patients.
      ). A previous study also showed that the risk of RSA was higher in those with a firstborn boy compared with a firstborn girl, owing to the reaction of male-specific (H-Y) antigens to the immune system (
      • Nielsen H.S.
      • Steffensen R.
      • Lund M.
      • Egestad L.
      • Mortensen L.H.
      • Andersen A.M.
      • Lidegaard O.
      • Christiansen O.B.
      Frequency and impact of obstetric complications prior and subsequent to unexplained secondary recurrent miscarriage.
      ).
      In the late 1980s, passive immunization with intravenous immunoglobulin (IVIG) was used to treat RSA, and was reported to have beneficial effects. The underlying mechanism might be associated with neutralization of autoantibodies in the circulatory system, inhibition of natural killer cell, attenuation of complement-mediated cytotoxicity and release of regulatory T lymphocytes (
      • Schwab I.
      • Nimmerjahn F.
      Intravenous immunoglobulin therapy: how does IgG modulate the immune system?.
      ). Today, unexplained RSA is commonly treated off-label with IVIG in a clinical setting (
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      ). Immunoglobulin is extracted from normal blood donors, and therefore might pose some potential risks to receivers including allergies and infectious diseases, such as HIV, hepatitis and prions. Although, IVIG is generally well tolerated, common adverse reactions (headaches, myalgia, fevers, chills, dizziness, nausea, and vomiting) occur in less than 5% of the patients. In addition, IVIG therapy does not increase the risk of premature birth (
      • Schwab I.
      • Nimmerjahn F.
      Intravenous immunoglobulin therapy: how does IgG modulate the immune system?.
      ).
      The effectiveness of IVIG treatment on unexplained RSA has been controversial.
      • Coulam C.B.
      • Krysa L.
      • Stern J.J.
      • Bustillo M.
      Intravenous immunoglobulin for treatment of recurrent pregnancy loss.
      and
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      both suggested that passive immunization with IVIG improved or showed trend of improving the live birth rate in women who had experienced RSA women relative to treatment with placebo. Randomized controlled trials also demonstrated otherwise (
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      ,
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      ,
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ,
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      ). Recently, diverging results suggest that, although the effect of IVIG treatment observed in patients with primary RSA is not beneficial, women with secondary RSA have a higher live birth rate (
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      ,
      • Christiansen O.B.
      • Nielsen H.S.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage: does it work?.
      ,
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      ,
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ). These observations, however, need to be confirmed, as each study was limited by the relatively low number of participants.
      Therefore, our present study aimed to review the currently available randomized controlled trials to determine the effectiveness of IVIG in improving the chance of live birth in unexplained RSA patients, which included studies on the Chinese population, and to further identify the efficacy of IVIG in different subgroups.

      Materials and methods

      Inclusion criteria and participants

      Primary RSA is defined as two or more spontaneous abortions occuring before the 20th gestational week of pregnancy without a history of live birth. Secondary RSA is defined as three or more spontaneous abortions occuring before the 20th gestational week of pregnancy subsequent to a live birth or stillbirth. Women at any age who have the following conditions were excluded: chromosomal abnormality in either couple, chromosomal abnormality in abortion specimen, abnormality in family genetic histories, maternal reproductive tract abnormalities, uterine malformations, maternal endocrine abnormalities, acquired or inherited thrombophilia, environmental factors and other unexplained recurrent abortions.

      Intervention

      The treatment group received IVIG before pregnancy or during the first trimester of pregnancy. The control group received a placebo.

      Studies outcomes

      The primary outcomes are the live birth rates, the number of achieved pregnancies and the number of live births.

      Types of studies

      Studies were selected from both Chinese and English languages. Publications with randomized, randomized-controlled, or randomized-allocated trials were included irrespective of the blinding methods.

      Exclusion criteria

      The exclusion criteria were as follows: studies that did not report clear diagnosis and criteria of inclusion and exclusion on participants' selection; studies that were involved in other treatments beyond IVIG; studies that reported inaccurate or incomplete data and were unable to provide outcomes; and studies that were duplicated.

      Literature search

      Electronic databases

      The relevant published literatures searches were conducted in the following databases: PubMed (1966–2016), EMBASE (1980–2016), ScienceDirect (1980–2016), MEDLINE (1980–2016), OVID (1980–2016), Chinese journals full-text database (CNKI) (1980–2016), VIP Chinese scientific and technical journals database (VIP), 1989–2016), and articles electronic journals database (1998–2016). The last update was May 2016.

      Keywords searches

      ‘Abortion’, ‘habitual’, ‘habitual hbortion’, ‘recurrent abortion’, ‘miscarriage’, ‘recurrent’, ‘abortion’, ‘immunoglobulins’, ‘intravenous’, ‘IVIG’, ‘passive immunity’, ‘allocation’, ‘random’, ‘randomization’, ‘controlled clinical trials’, ‘randomized’, ‘clinical trials’, ‘trials’, ‘randomized clinical’.

      PubMed search strategy

      (((((((randomization) OR allocation, random) OR trials, randomized clinical) OR clinical trials, randomized) OR controlled clinical trials, randomized)) AND (((((‘immunoglobulins, intravenous’[Mesh]) OR IVIG) OR passive immunity) OR ‘immunoglobulins’[Mesh]) OR immunoglobulin)) AND (((‘abortion, habitual’[Mesh]) OR habitual abortion) OR (((miscarriage, recurrent) OR recurrent abortion) OR abortion, recurrent)).

      Selection of studies

      Articles were imported into EndNote X4 to record important information and the most complete and best bibliographies were saved. Articles were evaluated on the basis of volume, issue, completeness in abstracts and if the articles were accessible. Articles were screened by reading the full-text. Eligible articles were labelled ‘to be included’ in the notes column of EndNote X4 whereas others were labelled as ‘to be determined’ or ‘to be excluded (with reasons specified)’. Pending literatures were further evaluated by checking references.

      Quality assessment of included studies

      The quality of each included study was evaluated on the basis of the randomized controlled trail risk of bias assessment recommended by Cochrane Centre (Cochrane handbook version 5.1.0). Evaluation of the entries included the following seven aspects: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. Each entry was then classified as low risk, unclear risk, or high risk.

      Data extraction

      The data extraction form was self-designed. The following information was recorded: first author, publication year, inclusion criteria of participants, types of spontaneous abortion, therapeutic strategy, baseline compatibility, intervention in treatment and placebo groups, sample size of intervention and outcomes in both treatment and placebo groups. Two reviewers worked independently on literature screening, quality assessment and data extraction. Disagreement was discussed for consensus or determined by the assistance of a third reviewer.

      Primary outcome measurement

      Live birth rate (number of live births/number of achieved pregnancies).

      Statistical analysis

      Binary data outcomes were calculated using risk ratio and 95% confidence interval through Cochrane RevMan 5.2 software provided by Cochrane Centre.
      The chi-squared method was used to assess heterogeneity, and the degree of heterogeneity was assessed with I2 statistic. If no significant difference in heterogeneity was detected between groups (P > 0.1, I2 ≤ 50%), fixed-effect model was used for analysis. If a significant difference in heterogeneity was detected between groups (P ≤ 0.1, I2 > 50%), subgroups of interventional strategy was used to analyse the source of clinical heterogeneity. Random-effect model was used for combined analysis when sources of heterogeneity were uncertain.
      Cumulative meta-analysis was performed using STATA 13.1 (StataCorp LP, USA). Outcomes were accrued according to the year of publication. The cumulative effect size and trends were analysed to evaluate the effectiveness of IVIG, to assess the effect of an individual study on the overall effect size, and to determine whether additional studies are required.
      Trial sequential analysis (TSA) was carried outo to minimize the risk of false positive errors (type I errors) produced by random errors due to sparse data and repetitive testing in meta-analysis. The required information size refers to the required number of participants to produce statistically significant result in meta-analysis. We estimated a diversity-adjusted required information size in accordance with the diversity in the intervention effect estimates among the included trials. Diversity-adjusted required information size was estimated using two-sided αv = 5%, β = 20%, the control event proportions calculated from the placebo group, and the relative risk reduction of 20% in outcomes. Although meta-analysis aims to detect the efficacy of an intervention as early as possible, TSA with monitoring boundaries are used to decide whether trials should be terminated early to prevent wastage of medical and research resources.
      Sensitivity analysis was carried out by removing one study at a time to determine if the effect size were dependent on a certain single study.
      If more than 10 studies were included, a funnel plot was used to assess for publication bias. An asymmetry indicated existence of publication bias. Harbord's modified and Egger's linear regression tests were further used to assess funnel plot asymmetry. P < 0.05 was considered to be significant.

      Results

      Study selection

      A preliminary search yielded 175 relevant citations, with 23 citations eliminated because they included duplicated studies. A total of 119 citations did not meet the screening criteria and were excluded. The remaining 33 articles were retrieved for detailed evaluation and, of these, 22 articles were excluded for the following reasons: not a randomized controlled study (n = 4), did not fulfill inclusion criteria (n = 7), did not meet intervention strategy (n = 2), control group did not meet intervention strategy (n = 5) and insufficient data report (n = 4). Only 11 articles met the inclusion criteria and were included in this meta-analysis (Figure 1) (
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      ,
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      ,
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Coulam C.B.
      • Krysa L.
      • Stern J.J.
      • Bustillo M.
      Intravenous immunoglobulin for treatment of recurrent pregnancy loss.
      ,
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      ,
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      ,
      • Lin L.
      • Li J.
      The analysis of recurrent miscarriage: etiology, immunotherapy and observation.
      ,
      • Liu T.
      • Chen H.
      Comparison of different methods for treating unexplained recurrent miscarriage efficacy.
      ,
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ).

      Quality assessment

      The methodology of each included trial was evaluated using the risk of bias assessment tool. Overall, the 11 citations included trials that were considered as low-risk studies. Six studies were classified as low risk whereas the other five had uncertain risk of biases in the following aspects: random sequence generation, allocation concealment, blinding of participants and intervention providers, and other source of bias. The quality assessment for each study is shown in Table 1, Figure 2 and Figure 3.
      Table 1Quality assessment of each included study.
      AuthorRandom sequence generationAllocation concealmentBlinding of participants and personnelBlinding of outcome assessmentIncomplete outcome dataSelective reportingOther bias
      German RSA/IVIG (
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      )
      Low risk (random digital packet by computer)Unclear risk (not described)Low risk (blinding of participants and obstetricians)Low riskLow riskLow riskUnclear risk (insufficient information on baseline compatibility; no evidence on sample size estimation)
      • Coulam C.B.
      • Krysa L.
      • Stern J.J.
      • Bustillo M.
      Intravenous immunoglobulin for treatment of recurrent pregnancy loss.
      Low risk (random digital packet by computer)Unclear risk (not described)Low risk (blinding of participants and obstetricians)Low riskLow riskLow riskLow risk
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      Low risk (random digital packet by computer)Low risk (digital encoding)Low risk (blinding of participants and obstetricians)Low riskLow riskLow riskLow risk
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      Low risk (random digital packet by computer)Low risk (digital encoding)Low risk (double blind)Low riskLow riskLow riskUnclear risk (no evidence on sample) size estimation)
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      Low riskLow risk (digital encoding)Low risk (blinding of participants, obstetricians, and personnel)Low riskLow riskLow riskLow risk
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      Low risk (centralized distribution)Low risk (opaque sealed envelope method)Low risk (blinding of participants and Obstetricians)Low riskLow riskLow riskLow risk
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      Low risk (random digital packet by computer)Low risk (digital encoding)Low risk (blinding of participants and obstetricians)Low riskLow riskLow riskLow risk
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      Low risk (random digital packet by computer)Low riskLow risk (blinding of participants, Obstetricians, and personnel)Low riskLow riskLow riskLow risk
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      Low risk (random digital packet by computer)Low risk (digital encoding)Low risk (blinding of participants and obstetricians)Low riskLow riskLow riskLow risk
      • Liu T.
      • Chen H.
      Comparison of different methods for treating unexplained recurrent miscarriage efficacy.
      Unclear risk (randomization not described)Unclear risk (not described)Unclear risk (not described)Low riskLow riskLow riskUnclear risk (insufficient information on baseline compatibility, no evidence on sample size estimation)
      • Lin L.
      • Li J.
      The analysis of recurrent miscarriage: etiology, immunotherapy and observation.
      Unclear risk (randomization not described)Unclear risk (not described)Unclear risk (not described)Low riskLow riskLow riskUnclear risk (no evidence on sample size estimation)
      Figure 2
      Figure 2Risk of bias assessment summary for each included study. + = low risk of bias; ? = unclear risk of bias.
      Figure 3
      Figure 3Risk of bias assessment for all included studies.

      Characteristics of included studies

      The characteristics of the 11 included studies are presented in Table 2. These studies were reported between 1994 and 2015. All of the studies recruited women who had experienced at least two or more spontaneous abortions. A total of 582 patients achieved pregnancy; 297 patients were in the IVIG treatment group for RSA and 285 patients were in the placebo group. A total of 202 live births occurred in the IVIG group and 151 in placebo groups. In the primary RSA subgroup, 57 out of 93 women treated with IVIG and 63 out of 90 women treated with placebo achieved a live birth. Meanwhile in the secondary RSA subgroup, of the 112 women treated with IVIG, 69 achieved a live birth and of the 108 treated with placebo, 53 achieved a live birth. All of the studies were randomized and double-blinded. The age of participants, dosage and timing of IVIG administration, however, as well as the placebo used varied among studies.
      Table 2Details of trials and pregnancy outcomes comparing intravenous immunoglobulin treatment and placebo for women who have experienced recurrent spontaneous abotion.
      Included studiesParticipantsPregnancy confirmationTherapeutic strategy
      German RSA/IVIG 1994 (
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      )
      Women aged <40 years who had three or more spontaneous abortions at <16 weeks of gestation and no live children.Positive beta-HCG test (≥75 IU/l)30 g of IVIG or 5% albumin (control) initiated at <8 weeks of gestation and 20 g given every 3 weeks until 25 weeks of gestation
      • Coulam C.B.
      • Krysa L.
      • Stern J.J.
      • Bustillo M.
      Intravenous immunoglobulin for treatment of recurrent pregnancy loss.
      Women aged 18–45 years who had two or more consecutive RSA and no other cause found for spontaneous abortionThe presence of embryonic cardiac activity by ultrasonography500 mg/kg IVIG versus 0.5% albumin given during follicular phase and every 28 days until pregnancy was achieved and then continued until 28–32 weeks of gestation.
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      Three or more spontaneous abortions and no more than one live birth or one fetal death after 14 weeks of gestation, and no other cause found for spontaneous abortion.The presence of embryonic cardiac activity by ultrasonographyIVIG or human albumin given at weeks 5–8, then every other week. IVIG was adjusted according to weight: 60–80 kg: 35 g in week 5–6; 25 g in week 7–26; 30 g in week 28, 30, 32 and 34; >80 kg: 5 g more at each infusion
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      Women aged <42 years who had three or more consecutive RSA with the same partner in the first trimester and had no live birthAn appropriate cranio-caudal length and the presence of embryonic cardiac activity by ultrasonographyIVIG 25 g/day for two consecutive days and 25 g administered 3 weeks later with ultrasound confirmation of viable pregnancy or saline solution with 5% human albumin (control)
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      Two or more documented consecutive RSA under 20 weeks of gestation and no other cause found for spontaneous abortion.Levels of serum beta-HCG and the presence of embryonic cardiac activity by endovaginal ultrasonography.IVIG 500 mg/kg (or normal saline). Infusions were given initially at a rate of 60 ml/h and gradually increased to 180 ml/h. If conception did not occur within six menstrual cycles, participation ended. With documentation of pregnancy, the participant received the same infusion every 4 weeks until 18 weeks of gestation.
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      Three or more consecutive RSA under 20 weeks of gestation and no other cause found for spontaneous abortion (primary RSA or secondary were included).The presence of embryonic cardiac activity by ultrasonography.Women received IVIG (20 g Gammonativ 400 ml) or placebo (saline 400 ml) every 3 weeks on five occasions if a viable pregnancy was confirmed by ultrasound before each treatment. By error, one patient with a successful outcome of pregnancy in the IVIG group received only four infusions.
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      Four or more spontaneous abortions at <26 weeks of gestation and no other cause found for spontaneous abortion.Levels of serum beta-HCG and the presence of embryonic cardiac activity by endovaginal ultrasonographyWeekly IVIG or human albumin given at week 5 until week 10. Infusions were subsequently carried out every second week until the 26th week of gestation. Until the 20th gestational week, a total of 0.8 g of study drug per kg body weight was administered. From gestational week 20 to 26, 1.0 g of study drug per kg body weight was given.
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      Women aged 18–45 years who had experiencedthree or more idiopathic secondary spontaneous abortions with their present partner and in whom the most recent conception took place less than 1 year agoLevels of serum berta-HCG and the presence of embryonic cardiac activity by ultrasonographyIVIG 500 mg/kg (or normal saline). Participants were administered 14–21 days from the projected next menstrual period. The infusion rate was 60 ml/h for the first hour, then increased to a maximum of 180 ml/h. If conception did not occur within six menstrual cycles, participation ended. With documentation of pregnancy, the participant received the same infusion every 4 weeks until 18–20 weeks of gestation, with adjustment for weight based on her prior visit.
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      Women aged 18–45 years who had four or more confirmed spontaneous abortions before gestational week 14 and at least one birth occurring after gestational week 28; ≥3 of the spotnaneous abortions should be consecutive after the last birth and be fathered by the present partner.Levels of serum beta-HCG and the presence of embryonic cardiac activity by ultrasonographyA total of eight IVIG or human albumin was given until gestational weeks 14–15. Infusions were given over 3–4 h on an outpatient basis. The second infusion was given 3–6 days after the first and subsequently three infusions were given at intervals of 6–8 days and three infusions at intervals of 12–16 days. The normal active drug was immunoglobulin human CSL Behring 120 mg/ml (number 41, Privigen CSL Behring 100 mg/ml). At each infusion, participants weighing <75 kg before pregnancy were given 24 g (25 g), and for those weighing ≥75 kg, 36 g (35 g). In the placebo group, 200 ml or 300 ml of human albumin CSL Behring 5% was given at each infusion according to weight respectively.
      • Liu T.
      • Chen H.
      Comparison of different methods for treating unexplained recurrent miscarriage efficacy.
      Three or or more RSAThe presence of embryonic cardiac activity by ultrasonographyAdministered IVIG gamma type before pregnancy with 20 g every 3 weeks on four occasions. Then participants were infused with same treatments twice after pregnancy. Prevention of spontaneous abortion was given once a visible pregnancy was confirmed.
      • Lin L.
      • Li J.
      The analysis of recurrent miscarriage: etiology, immunotherapy and observation.
      Three or more RSA with the same partnerThe presence of embryonic cardiac activity by ultrasonographyOnce pregnant, participants received 5 g of gamma albumin (2.5 g/vial by Yuhualan pharmaceutical) per day for 7 days or 10 g/day for 3 days. The therapeutic strategy was given every 3 weeks until 12 weeks of gestation.
      Included studiesTreatment groupControl groupStudy design
      InterventionNumber of live birthsNumber of achieved pregnanciesInterventionNumber of live birthsNumber of achieved pregnancies
      German RSA/IVIG 1994 (
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      )
      IVIGPrimary RSA 20335% albuminPrimary RSA 2131Multi-centre;

      randomized;

      double blind;

      centralized distribution
      • Coulam C.B.
      • Krysa L.
      • Stern J.J.
      • Bustillo M.
      Intravenous immunoglobulin for treatment of recurrent pregnancy loss.
      IVIGTotal RSA 18290.5% albuminTotal RSA 1132Multi-centre;

      Randomized;

      double blind
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      IVIGSecondary RSA 914Human albuminSecondary RSA 210Multi-centre;

      randomized;

      double blind
      Recurrent late spontaneous abortions3Recurrent late spontaneous abortions 37
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      IVIGPrimary RSA 16225% human albuminPrimary RSA 2024Multi-centre;randomized,

      double blind,

      centralized distribution
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      IVIGPrimary RSA 510Normal salinePrimary RSA 410Randomized;

      double blind;

      centralized distribution
      Secondary RSA 710Secondary RSA 611
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      IVIGPrimary RSA 911Normal salinePrimary RSA 89Multi-centre;

      randomized;

      double blind
      Secondary RSA 811Secondary RSA 710
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      IVIGPrimary RSA 717Human albuminPrimary RSA 1016Randomized;

      double blind
      Secondary RSA 612Secondary RSA 313
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      IVIGSecondary RSA 1623Normal salineSecondary RSA 1524Multi-centre,

      randomized;

      double blind
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      IVIGSecondary RSA 2342Human albuminSecondary RSA 2040Multi-centre;

      randomized;

      double blind
      • Liu T.
      • Chen H.
      Comparison of different methods for treating unexplained recurrent miscarriage efficacy.
      IVIGTotal RSA 3435HCGTotal RSA 1129
      • Lin L.
      • Li J.
      The analysis of recurrent miscarriage: etiology, immunotherapy and observation.
      IVIGTotal RSA 2425Regular spontaneous abortion preventionTotal RSA 1019
      Total RSA: a series of two or more spontaneous abortions before 20th gestational week of pregnancy with the same partner, including primary and secondary RSA.
      Primary RSA: a series of two or more spontaneous abortions before 20th gestational week of pregnancy without a history of live birth.
      Secondary RSA: aseries of three or more spontaneous abortions before 20th gestational week of pregnancy subsequent to a live birth or stillbirth.
      Recurrent late spontaneous abortions: ≥1 second trimester sponaneous abortion.
      IVIG, intravenous immunoglobulin; RSA, recurrent spontaneous abortion.

      Data analysis of IVIG passive immunotherapy on unexplained RSA

      Comparison of live birth rate between IVIG-treated and placebo groups

      As shown in Figure 4, there was strong heterogeneity between the studies (P = 0.003, I2 = 62%). Therefore, a random-effects model was used to produce an overall summary. Our random-effects analyses showed that the difference in the live birth rates between IVIG treatment and placebo groups was on the margin of significance (RR = 1.25, 95% CI 1.00 to 1.56; P = 0.05) (Figure 4). Our cumulative meta-analysis showed that, after the inclusion of studies, the point estimates for relative risk and the confidence interval became stable, with a trend favouring the treatment of IVIG (Figure 5). We noted a marginal significance (RR = 1.25, 95% CI 1.00 to 1.56; P = 0.05) after the inclusion of
      • Lin L.
      • Li J.
      The analysis of recurrent miscarriage: etiology, immunotherapy and observation.
      study. The clinical trial conducted by Lin et al. was comprised of a small sample size and therefore had little effect on the overall effect size. This significant observation after the inclusion of Lin et al. study is therefore not sufficiently convincing. Further trials are required to validate this observation. Our TSA showed thatthe cumulative Z-curve was marginally at the conventional boundary for benefit but had not crossed the trial sequential monitoring boundary for benefit. The number of participants had not reached the required information size, suggesting that the conventional meta-analysis might yield false positive conclusion (Figure 6). More trials are required to conclude the effectiveness of IVIG.
      Figure 4
      Figure 4Live birth rate between intravenous immunoglobulin treatment and placebo groups in patients who have experienced recurrent spontaneous abortion.
      Figure 5
      Figure 5Cumulative meta-analysis of randomized trials comparing intravenous immunoglobulin with placebo in patientw who have experienced unexplained recurrent spontaneous abortion. IVIG, intravenous immumoglobulin; RR, relative risk.
      Figure 6
      Figure 6Trial sequential analysis of all included studies on the effect of intravenous immunoglobulin on live birth rate in unexplained recurrent spontaneous abortion patients. A diversity-adjusted required information size of 1848 patients was calculated on the basis of a live birth rate of 52.98% in the control group, relative risk reduction of 20%, α = 5% (two-sided), and β = 20%. The cumulative Z-curve did not cross the trial sequential monitoring boundaries for benefits, harms, or futility, and the required information size was not reached.

      Analysis of RSA subgroups

      RSA can be divided into primary and secondary RSA. Five studies were identified that enrolled patients with primary RSA (
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      ,
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      ,
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ). Among the 93 RSA patients in the IVIG treatment group who became pregnant, 57 patients successfully delivered live birth, whereas the placebo group showed that 63 out of 90 RSA patients successfully delivered live birth. Meta-analysis showed little heterogeneity between studies (I2 = 0%). Fixed-effect meta-analysis showed no significant difference in the live birth rate between the IVIG treatment and placebo groups (RR = 0.88, 95% CI 0.71 to 1.07). On the other hand, six studies involved secondary RSA (
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      ,
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      ,
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ,
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      ). A total of 112 RSA patients in the IVIG group were pregnant and 69 of them successfully delivered live birth. In the placebo group, a total of 108 pregnancies occurred, in which 53 patients successfully delivered live birth. Meta-analysis showed little heterogeneity between placebo and treatment groups (I2 = 0%) and fixed-effect analyses showed marginal insignificant difference in the live birth rates between the two groups (RR = 1.26, 95% CI 0.99 to 1.61) (Figure 7). Further cumulative and TSA meta-analyses were carried out on the secondary RSA subgroup. Cumulative meta-analysis showed that after inclusion of studies, the point estimates for RR and the CI became stable, and no significant difference was observed in the live birth rate between IVIG treatment and placebo groups (Figure 8). The TSA analysis showed that the cumulative Z-curve was marginally at the conventional boundary for benefit and had not reached the trial sequential monitoring boundary for benefit (Figure 9). The number of participants had not reached the required information size. Our data suggest that the clinical benefit of IVIG is not significant. More studies are required to validate the efficacy of IVIG in secondary RSA patients.
      Figure 7
      Figure 7Comparison of primary and secondary recurrent spontaneous abortion in intravenous immunoglobulin treated and placebo groups.
      Figure 8
      Figure 8Cumulative meta-analysis of randomized trials comparing intravenous immunoglobulin with placebo in secondary recurrent spontaneous abortion patients.
      Figure 9
      Figure 9Trial sequential analysis of the effect of intravenous immunoglobulin on live birth rate in secondary recurrent spontaneous abortion patients. A diversity-adjusted required information size of 811 patients was calculated on the basis of a live birth rate of 58.59% in the control group, relative risk reduction of 20%, α = 5% (two-sided), and β = 20%. The cumulative Z-curve did not cross the trial sequential monitoring boundaries for benefits, harms, or futility, and the required information size was not reached. IVIG, intravenous immunoglobulin.

      Analysis of IVIG administration timing

      The effect of IVIG administered before conception or after implantation on the live birth rate was also analysed. Four studies were identified (
      • Coulam C.B.
      • Krysa L.
      • Stern J.J.
      • Bustillo M.
      Intravenous immunoglobulin for treatment of recurrent pregnancy loss.
      ,
      • Liu T.
      • Chen H.
      Comparison of different methods for treating unexplained recurrent miscarriage efficacy.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ,
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      ), with a total of 213 women who had experienced RSA who started treatment with either IVIG or placebo before conception and seven studies (
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      ;
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      ,
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      ,
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      ,
      • Lin L.
      • Li J.
      The analysis of recurrent miscarriage: etiology, immunotherapy and observation.
      ,
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      ) with 369 RSA patients treated with IVIG or placebo after confirmation of pregnancy. Meta-analysis for administration of IVIG before conception showed a significant difference in the live birth rate between IVIG treatment and placebo groups (RR = 1.67, 95% CI 1.30 to 2.14; P < 0.0001). Meta-analysis for administration of IVIG after embryo implantation showed no significant difference in the live birth rate between IVIG treatment and placebo groups (RR = 1.10, 95% CI 0.93 to 1.29 (Figure 10). Our data suggest that women with RSA may benefit from IVIG administered before conception.
      Figure 10
      Figure 10Comparison of live birth rate between pre-conception and post-implantation intravenous immunoglobulin administration. CI, confidence interval.

      Sensitivity analysis and publication bias

      A sensitivity analysis was conducted to evaluate the robustness of our findings. Each study was removed one at a time and the effect size was recalculated. Our leave-one-out sensitivity analysis showed similar, consistent results, indicating that no individual study significantly affected the overall effect size (Figure 11).
      Figure 11
      Figure 11Sensitivity analysis for all included studies.
      A funnel plot was used to check for the existence of publication bias. Our funnel plot showed asymmetry and indicated potential publication bias (Figure 12). Accordingly, we carried out Harbord's modified and Egger's linear regression tests, in which no evidence of publication bias were found.
      Figure 12
      Figure 12Assessment of publication biases. RR, relative risk; SE, standard error.

      Discussion

      Cliically, IVIG has been widely used to treat unexplained RSA, although its efficacy has not yet been clinically proven (
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      ). The high cost for this immunotherapy, its limited supply as well as its potential side-effects call for a guideline for appropriate applications (
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      ). A total of 175 relevant published literatures were searched between 1966 and 2016 in PubMed, EMBASE, CNKI, VIP, articles electronic journals database, ScienceDirect, MEDLINE, and OVID. Eleven randomized-controlled studies were included in the meta-analysis after screening (
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      ,
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      ,
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Coulam C.B.
      • Krysa L.
      • Stern J.J.
      • Bustillo M.
      Intravenous immunoglobulin for treatment of recurrent pregnancy loss.
      ,
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      ,
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      ,
      • Lin L.
      • Li J.
      The analysis of recurrent miscarriage: etiology, immunotherapy and observation.
      ,
      • Liu T.
      • Chen H.
      Comparison of different methods for treating unexplained recurrent miscarriage efficacy.
      ,
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ,
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      ). The 11 included studies were high-quality trials with low risk of biases. Of the 582 women who achieved pregnancy, 353 had live births. Our analysis showed that IVIG might be of beneficial value to treat unexplained RSA. Cumulative and TSA indicated the need for more clinical trials to validate the effectiveness of IVIG as its therapeutic value is still inconclusive.
      As
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      demonstrated that IVIG was more effective in secondary RSA than in primary RSA, RSA was divided into primary or secondary RSA for further meta-analysis in this review. From the 11 included studies, five studies enrolled primary RSA patients (
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Group T.G.R.I.
      Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
      ,
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      ,
      • Perino A.
      • Vassiliadis A.
      • Vucetich A.
      • Colacurci N.
      • Menato G.
      • Cignitti M.
      • Semprini A.E.
      Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ), and six studies recruited secondary RSA patients (
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      ,
      • Christiansen O.B.
      • Mathiesen O.
      • Husth M.
      • Rasmussen K.L.
      • Ingerslev H.J.
      • Lauritsen J.G.
      • Grunnet N.
      Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
      ,
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ,
      • Jablonowska B.
      • Selbing A.
      • Palfi M.
      • Ernerudh J.
      • Kjellberg S.
      • Lindton B.
      Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
      ,
      • Stephenson M.D.
      • Dreher K.
      • Houlihan E.
      • Wu V.
      Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
      ,
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      ). Following the review by
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      , our present meta-analysis included additional two high-quality, randomized controlled studies published in 2010 and 2014, composed of large sample sizes (
      • Christiansen O.B.
      Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
      ,
      • Stephenson M.D.
      • Kutteh W.H.
      • Purkiss S.
      • Librach C.
      • Schultz P.
      • Houlihan E.
      • Liao C.
      Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
      ). Our results, however, did not support the clinical benefit of IVIG on secondary RSA patients, which contradicted the conclusion made by
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      . Cumulative meta-analysis and TSA analyses indicate that present studies are not conclusive and further trials are warranted.
      The present meta-analysis observed heterogeneity among included studies. Leave-one-out sensitivity analysis showed no individual study which significantly affected the overall effect size. The heterogeneity may be associated with the inconsistency of the study design, especially in terms of the selection of participants and control group, interventional strategy, and therapeutic regimen. Age and number of previous spontaneous abortions varied among patient populations. As age increased, fertility declined and the chance for spontaneous abortion also increased (
      • Daya S.
      • Gunby J.
      • Porter F.
      • Scott J.
      • Clark D.A.
      Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage.
      ).
      • Daya S.
      • Gunby J.
      • Porter F.
      • Scott J.
      • Clark D.A.
      Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage.
      demonstrated that the success rate for pregnancy (≥20 weeks of gestation) declined with age and the number of previous spontaneous abortions (
      • Daya S.
      • Gunby J.
      • Porter F.
      • Scott J.
      • Clark D.A.
      Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage.
      ). Moreover, the immunological characteristics of an individual could also vary among patients. For instance, high levels of peripheral natural killer cells have been correlated with poor pregnancy outcomes (
      • Seshadri S.
      • Sunkara S.K.
      Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis.
      ). Multiple reports have indicated that the treatment of IVIG suppresses the peripheral levels and activities of natural killer cells (
      • Kwak J.Y.
      • Kwak F.M.
      • Ainbinder S.W.
      • Ruiz A.M.
      • Beer A.E.
      Elevated peripheral blood natural killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions.
      ,
      • Morikawa M.
      • Yamada H.
      • Kato E.H.
      • Shimada S.
      • Kishi T.
      • Yamada T.
      • Kobashi G.
      • Fujimoto S.
      Massive intravenous immunoglobulin treatment in women with four or more recurrent spontaneous abortions of unexplained etiology: down-regulation of NK cell activity and subsets.
      ,
      • Rigal D.
      • Vermot-Desroches C.
      • Heitz S.
      • Bernaud J.
      • Alfonsi F.
      • Monier J.C.
      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.
      ,
      • Roussev R.G.
      • Ng S.C.
      • Coulam C.B.
      Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G.
      ,
      • Ruiz J.E.
      • Kwak J.Y.
      • Baum L.
      • Gilman-Sachs A.
      • Beaman K.D.
      • Kim Y.B.
      • Beer A.E.
      Effect of intravenous immunoglobulin G on natural killer cell cytotoxicity in vitro in women with recurrent spontaneous abortion.
      ,
      • Szereday L.
      • Spath P.
      • Szekeres-Bartho J.
      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.
      ,
      • Yamada H.
      • Deguchi M.
      • Maesawa Y.
      • Nakajima Y.
      • Nishino Y.
      • Tanimura K.
      • Ebina Y.
      Medium-dose intravenous immunoglobulin therapy for women with six or more recurrent miscarriages.
      ), improving reproductive outcomes in RSA patients (
      • Cohen B.M.
      • Machupalli S.
      Use of gammaglobulin to lower elevated natural killer cells in patients with recurrent miscarriage.
      ,
      • Moraru M.
      • Carbone J.
      • Alecsandru D.
      • Castillo-Rama M.
      • Garcia-Segovia A.
      • Gil J.
      • Alonso B.
      • Aguaron A.
      • Ramos-Medina R.
      • Martinez de Maria J.
      • Oliver-Minarro D.
      • Rodriguez-Mahou M.
      • Ortega V.
      • Caballero P.
      • Melia E.
      • Vidal J.
      • Cianchetta-Sivori M.
      • Esteban C.
      • Vargas-Henny L.
      • Dale J.
      • Ortiz-Quintana L.
      • Fernandez-Cruz E.
      • Sanchez-Ramon S.
      Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells.
      ,
      • Perricone R.
      • Di Muzio G.
      • Perricone C.
      • Giacomelli R.
      • De Nardo D.
      • Fontana L.
      • De Carolis C.
      High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins.
      ,
      • Ramos-Medina R.
      • Garcia-Segovia A.
      • Gil J.
      • Carbone J.
      • Aguaron de la Cruz A.
      • Seyfferth A.
      • Alonso B.
      • Alonso J.
      • Leon J.A.
      • Alecsandru D.
      • Melia E.
      • Carrillo de Albornoz E.
      • Ordonez D.
      • Santillan I.
      • Verdu V.
      • Garcia Ruiz de Morales J.M.
      • Lopez-Hoyos M.
      • Lopez Larios A.
      • Sampalo A.
      • Caballero P.
      • Ortiz Quintana L.
      • Fernandez-Cruz E.
      • Sanchez-Ramon S.
      Experience in IVIg therapy for selected women with recurrent reproductive failure and NK cell expansion.
      ,
      • Shimada S.
      • Takeda M.
      • Nishihira J.
      • Kaneuchi M.
      • Sakuragi N.
      • Minakami H.
      • Yamada H.
      A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion.
      ,
      • van den Heuvel M.J.
      • Peralta C.G.
      • Hatta K.
      • Han V.K.
      • Clark D.A.
      Decline in number of elevated blood CD3(+) CD56(+) NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy.
      ). Therefore, patients with higher peripheral nautral killer cell levels may benefit from IVIG treatment compared with those with lower levels. These variables were not considered during the recruitment of participants, which might thus affect the outcomes of the studies.
      Variation in the intervention method, for example, the timing of IVIG administration, either during pre-conception or post-implantation, might also affect the outcome.
      • Sapir T.
      • Carp H.
      • Shoenfeld Y.
      [Intravenous immunoglobulin (IVIG) as treatment for recurrent pregnancy loss (RPL)].
      reported that IVIG administration before conception increased chance of live delivery in primary RSA women, whereas in secondary RSA women, IVIG given after embryo implantation had a higher success rate.
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      , however, showed that IVIG infusion given to RSA women before ovulation was not as effective compared with those who were given administration after confirmation of pregnancy (
      • Hutton B.
      • Sharma R.
      • Fergusson D.
      • Tinmouth A.
      • Hebert P.
      • Jamieson J.
      • Walker M.
      Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
      ). These diverging reports affecting interventional strategy necessitate an analysis for determining the optimal administration timing. Interestingly, our meta-analysis showed that IVIG treatment given before pregnancy would increase the rate of live birth in RSA patients.
      To date, the optimal dose for IVIG administration in RSA women remains unknown (
      • Daya S.
      • Gunby J.
      • Porter F.
      • Scott J.
      • Clark D.A.
      Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage.
      ). In most of the published trials, the IVIG doses administered were relatively low compared with autoimmune diseases that could hinder a possible treatment effect (
      • Christiansen O.B.
      • Pedersen B.
      • Rosgaard A.
      • Husth M.
      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.
      ). No dose-response study has ever been conducted to identify the optimal dose. The placebo given in each trial also varied and might have potential influence on the outcome. Reports suggested that albumin, which was used as placebo in trials, had been associated with ovarian hormone regulation and therefore might have led to beneficial effects in the patients (
      • Asch R.H.
      • Ivery G.
      • Goldsman M.
      • Frederick J.L.
      • Stone S.C.
      • Balmaceda J.P.
      The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome.
      ).
      Over time, we have gained a deeper understanding of RSA and its complications. Recent studies have revealed multiple new contributors in RSA, including genetic polymorphisms, circulating microparticles, glycoproteins, as well as novel immunologic risk factors (
      • Alijotas-Reig J.
      • Garrido-Gimenez C.
      Current concepts and new trends in the diagnosis and management of recurrent miscarriage.
      ). These factors were not known beforehand, and therefore trials as early as 1994 did not consider these factors when recruiting RSA participants. Certain sub-populations with unexplained RSA but not all may benefit from IVIG populations. Limited knowledge of RSA, therefore, hampers the effort to design a well-controlled clinical trial to validate the effectiveness of IVIG.
      In addition, double-blinded, randomized trials are difficult to execute. The unwillingness of participants to be randomized to the placebo groups (
      • Silver R.M.
      Intravenous immune globulin: another disappointing treatment for recurrent pregnancy loss.
      ), and the invasive nature of the treatment itself, are some of the reasons for the low number of participants in a trial. The high cost of treatment involved also prevents the initiation of clinical studies and limits the recruitment of participants and therefore, hinders the determination of an optimal dose and duration of IVIG. Apart from that, differences in treatment protocol among studies may also generate variations in outcomes. For instance, the conventional treatment protocols include: administration of IVIG at 400–500 mg/kg per day for 1–3 days with an interval of 3–4 weeks, and given until week 26–32; administration of IVIG at low dose (200 mg/kg per day) once in 4 weeks until week 26–32; continuous administration of IVIG at a single high dose (20–30 g/day) after pregnancy for 5 days; administration of IVIG (400–500 mg/kg per day) in combination with heparin (5000 IU subcutaneous, twice a day) and aspirin (75 mg/day, oral) continuously for 1–3 days with an interval of 3–4 months. Therefore, these variations call for standardization of protocol for optimal IVIG administration.
      From our 11 high-quality, low-risk, randomized controlled trials, we conclude that, although IVIG treatment does not benefit primary RSA patients, the overall effect of IVIG in RSA patients, or in women with secondary RSA, is still inconclusive. Further high-quality studies with adequate number of participants and rigorous study designs are warranted. Future trials should include efforts to address the following issues which may influence the outcome: trials should be double-blinded and randomized to reduce bias; participants should be controlled in age, history of spontaneous abortion, endocrine status, genetic polymorphisms, and immunological characteristics; to identify the best timing for IVIG administration (pre-conception versus post-implantation); and to ascertain the most effective and optimal dosage for treatment.

      References

        • Alijotas-Reig J.
        • Garrido-Gimenez C.
        Current concepts and new trends in the diagnosis and management of recurrent miscarriage.
        Obstet. Gynecol. Surv. 2013; 68: 445-466
        • Asch R.H.
        • Ivery G.
        • Goldsman M.
        • Frederick J.L.
        • Stone S.C.
        • Balmaceda J.P.
        The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome.
        Hum. Reprod. 1993; 8: 1015-1020
        • Christiansen O.B.
        Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics.
        Clin. Exp. Immunol. 2014; 178: 120-122
        • Christiansen O.B.
        • Nielsen H.S.
        Intravenous immunoglobulin in the prevention of recurrent miscarriage: does it work?.
        Chem. Immunol. Allergy. 2005; 88: 117-127
        • Christiansen O.B.
        • Mathiesen O.
        • Husth M.
        • Rasmussen K.L.
        • Ingerslev H.J.
        • Lauritsen J.G.
        • Grunnet N.
        Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.
        Hum. Reprod. 1995; 10: 2690-2695
        • Christiansen O.B.
        • Pedersen B.
        • Rosgaard A.
        • Husth M.
        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.
        Hum. Reprod. 2002; 17: 809-816
        • Christiansen O.B.
        • Kolte A.M.
        • Dahl M.
        • Larsen E.C.
        • Steffensen R.
        • Nielsen H.S.
        • Hviid T.V.
        Maternal homozygocity for a 14 base pair insertion in exon 8 of the HLA-G gene and carriage of HLA class II alleles restricting HY immunity predispose to unexplained secondary recurrent miscarriage and low birth weight in children born to these patients.
        Hum. Immunol. 2012; 73: 699-705
        • Cohen B.M.
        • Machupalli S.
        Use of gammaglobulin to lower elevated natural killer cells in patients with recurrent miscarriage.
        J. Reprod. Med. 2015; 60: 294-300
        • Cohen M.
        • Bischof P.
        Factors regulating trophoblast invasion.
        Gynecol. Obstet. Invest. 2007; 64: 126-130
        • Coulam C.B.
        • Krysa L.
        • Stern J.J.
        • Bustillo M.
        Intravenous immunoglobulin for treatment of recurrent pregnancy loss.
        Am. J. Reprod. Immunol. 1995; 34: 333-337
        • Daya S.
        • Gunby J.
        • Porter F.
        • Scott J.
        • Clark D.A.
        Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage.
        Hum. Reprod. Update. 1999; 5: 475-482
        • Group T.G.R.I.
        Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group.
        Br. J. Obstet. Gynaecol. 1994; 101: 1072-1077
        • Hill J.A.
        • Polgar K.
        • Anderson D.J.
        T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion.
        JAMA. 1995; 273: 1933-1936
        • Hutton B.
        • Sharma R.
        • Fergusson D.
        • Tinmouth A.
        • Hebert P.
        • Jamieson J.
        • Walker M.
        Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review.
        BJOG. 2007; 114: 134-142
        • Jablonowska B.
        • Selbing A.
        • Palfi M.
        • Ernerudh J.
        • Kjellberg S.
        • Lindton B.
        Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.
        Hum. Reprod. 1999; 14: 838-841
        • Kruse C.
        • Steffensen R.
        • Varming K.
        • Christiansen O.B.
        A study of HLA-DR and -DQ alleles in 588 patients and 562 controls confirms that HLA-DRB1*03 is associated with recurrent miscarriage.
        Hum. Reprod. 2004; 19: 1215-1221
        • Kuon R.
        • Wallwiener L.
        • Germeyer A.
        • Strowitzki T.
        • Daniel V.
        • Toth B.
        Establishment of a standardized immunological diagnostic procedure in RM patients.
        J. Reprod. Immunol. 2012; 94: 55
        • Kwak J.Y.
        • Kwak F.M.
        • Ainbinder S.W.
        • Ruiz A.M.
        • Beer A.E.
        Elevated peripheral blood natural killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions.
        Am. J. Reprod. Immunol. 1996; 35: 363-369
        • Lin L.
        • Li J.
        The analysis of recurrent miscarriage: etiology, immunotherapy and observation.
        Jilin Med. J. 2015; : 2733-2734
        • Lin Q.
        Basic and clinical research progress of unexplained recurrent miscarriage.
        Chin. J. Obstet. Gynecol. 2003; 38: 481-483
        • Liu T.
        • Chen H.
        Comparison of different methods for treating unexplained recurrent miscarriage efficacy.
        Guide China Med. 2010; : 36-37
        • Moraru M.
        • Carbone J.
        • Alecsandru D.
        • Castillo-Rama M.
        • Garcia-Segovia A.
        • Gil J.
        • Alonso B.
        • Aguaron A.
        • Ramos-Medina R.
        • Martinez de Maria J.
        • Oliver-Minarro D.
        • Rodriguez-Mahou M.
        • Ortega V.
        • Caballero P.
        • Melia E.
        • Vidal J.
        • Cianchetta-Sivori M.
        • Esteban C.
        • Vargas-Henny L.
        • Dale J.
        • Ortiz-Quintana L.
        • Fernandez-Cruz E.
        • Sanchez-Ramon S.
        Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells.
        Am. J. Reprod. Immunol. 2012; 68: 75-84
        • Morikawa M.
        • Yamada H.
        • Kato E.H.
        • Shimada S.
        • Kishi T.
        • Yamada T.
        • Kobashi G.
        • Fujimoto S.
        Massive intravenous immunoglobulin treatment in women with four or more recurrent spontaneous abortions of unexplained etiology: down-regulation of NK cell activity and subsets.
        Am. J. Reprod. Immunol. 2001; 46: 399-404
        • Nielsen H.S.
        • Steffensen R.
        • Lund M.
        • Egestad L.
        • Mortensen L.H.
        • Andersen A.M.
        • Lidegaard O.
        • Christiansen O.B.
        Frequency and impact of obstetric complications prior and subsequent to unexplained secondary recurrent miscarriage.
        Hum. Reprod. 2010; 25: 1543-1552
        • Perino A.
        • Vassiliadis A.
        • Vucetich A.
        • Colacurci N.
        • Menato G.
        • Cignitti M.
        • Semprini A.E.
        Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
        Hum. Reprod. 1997; 12: 2388-2392
        • Perricone R.
        • Di Muzio G.
        • Perricone C.
        • Giacomelli R.
        • De Nardo D.
        • Fontana L.
        • De Carolis C.
        High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins.
        Am. J. Reprod. Immunol. 2006; 55: 232-239
        • Quack K.C.
        • Vassiliadou N.
        • Pudney J.
        • Anderson D.J.
        • Hill J.A.
        Leukocyte activation in the decidua of chromosomally normal and abnormal fetuses from women with recurrent abortion.
        Hum. Reprod. 2001; 16: 949-955
        • Ramos-Medina R.
        • Garcia-Segovia A.
        • Gil J.
        • Carbone J.
        • Aguaron de la Cruz A.
        • Seyfferth A.
        • Alonso B.
        • Alonso J.
        • Leon J.A.
        • Alecsandru D.
        • Melia E.
        • Carrillo de Albornoz E.
        • Ordonez D.
        • Santillan I.
        • Verdu V.
        • Garcia Ruiz de Morales J.M.
        • Lopez-Hoyos M.
        • Lopez Larios A.
        • Sampalo A.
        • Caballero P.
        • Ortiz Quintana L.
        • Fernandez-Cruz E.
        • Sanchez-Ramon S.
        Experience in IVIg therapy for selected women with recurrent reproductive failure and NK cell expansion.
        Am. J. Reprod. Immunol. 2014; 71: 458-466
        • Rigal D.
        • Vermot-Desroches C.
        • Heitz S.
        • Bernaud J.
        • Alfonsi F.
        • Monier J.C.
        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.
        Clin. Immunol. Immunopathol. 1994; 71: 309-314
        • Roussev R.G.
        • Ng S.C.
        • Coulam C.B.
        Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G.
        Am. J. Reprod. Immunol. 2007; 57: 262-269
        • Ruiz J.E.
        • Kwak J.Y.
        • Baum L.
        • Gilman-Sachs A.
        • Beaman K.D.
        • Kim Y.B.
        • Beer A.E.
        Effect of intravenous immunoglobulin G on natural killer cell cytotoxicity in vitro in women with recurrent spontaneous abortion.
        J. Reprod. Immunol. 1996; 31: 125-141
        • Sapir T.
        • Carp H.
        • Shoenfeld Y.
        [Intravenous immunoglobulin (IVIG) as treatment for recurrent pregnancy loss (RPL)].
        Harefuah. 2005; 144 (454, 453): 415-420
        • Schwab I.
        • Nimmerjahn F.
        Intravenous immunoglobulin therapy: how does IgG modulate the immune system?.
        Nat. Rev. Immunol. 2013; 13: 176-189
        • Seshadri S.
        • Sunkara S.K.
        Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis.
        Hum. Reprod. Update. 2014; 20: 429-438
        • Shimada S.
        • Takeda M.
        • Nishihira J.
        • Kaneuchi M.
        • Sakuragi N.
        • Minakami H.
        • Yamada H.
        A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion.
        Am. J. Reprod. Immunol. 2009; 62: 301-307
        • Silver R.M.
        Intravenous immune globulin: another disappointing treatment for recurrent pregnancy loss.
        BJOG. 2015; 122: 509
        • Stephenson M.D.
        • Dreher K.
        • Houlihan E.
        • Wu V.
        Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.
        Am. J. Reprod. Immunol. 1998; 39: 82-88
        • Stephenson M.D.
        • Kutteh W.H.
        • Purkiss S.
        • Librach C.
        • Schultz P.
        • Houlihan E.
        • Liao C.
        Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial.
        Hum. Reprod. 2010; 25: 2203-2209
        • Szereday L.
        • Spath P.
        • Szekeres-Bartho J.
        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.
        Am. J. Reprod. Immunol. 1999; 42: 282-287
        • van den Heuvel M.J.
        • Peralta C.G.
        • Hatta K.
        • Han V.K.
        • Clark D.A.
        Decline in number of elevated blood CD3(+) CD56(+) NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy.
        Am. J. Reprod. Immunol. 2007; 58: 447-459
        • Xiao S.-J.
        • Zhao A.-M.
        The new progress in the etiology of recurrent miscarriage.
        Chin. J. Pract. Gynecol. Obstet. 2014; 30: 41-45
        • Xu L.
        • Chang V.
        • Murphy A.
        • Rock J.A.
        • Damewood M.
        • Schlaff W.
        • Zacur H.A.
        Antinuclear antibodies in sera of patients with recurrent pregnancy wastage.
        Am. J. Obstet. Gynecol. 1990; 163: 1493-1497
        • Yamada H.
        • Deguchi M.
        • Maesawa Y.
        • Nakajima Y.
        • Nishino Y.
        • Tanimura K.
        • Ebina Y.
        Medium-dose intravenous immunoglobulin therapy for women with six or more recurrent miscarriages.
        J. Reprod. Immunol. 2015; 109: 48-51

      Biography

      Song-Yang Zhong, is a Director at the Department of Pharmacy, The People's Hospital of Quzhou, Quzhou, Zhejiang, China. His current research interests are evidence-based medicine and fundamental pharmaceutical research, which includes the area of human reproductive system.