Intravenous immunoglobulins (IVIG) were used in an alternative approach to immunotherapy with allogeneic leukocytes to prevent recurrent spontaneous abortions (RSA). Twenty five women with a history of greater than or equal to 3 unexplained RSA were treated with IVIG during their next pregnancy. An initial dose of 30 g (0.5-0.6 g/kg body weight) was administered at gestational week 5-6. Treatment was continued every 3 weeks with 20 g (0.3-0.4 g/kg) and terminated by week 25. In primary RSA the success rate was 82-85%, which is in the same range as for leukocyte therapy. In contrast, IVIG was successful in only 40% of secondary aborters. We conclude that IVIG can be an effective treatment for prevention of primary RSA. Compared to leukocyte therapy the risks of transmission of infections and of HLA immunization can be avoided.

Due to its strong "immunomodulating" effect in several well established disorders, high-dose intravenous immunoglobulins (IVIG) has been proposed as an alternative for immunotherapy with allogeneic leucocytes in patients with unexplained recurrent spontaneous abortion. This paper is intended to provide an overview on the European experience in this field.Five European pilot studies with a total of 172 patients as well as one controlled double-blind multicenter study including 64 patients were considered. In the latter, 5% human albumin was used as placebo.Success rates of the pilot studies varied from 68 to 87%. In the German controlled study, a significant specific effect of IVIG could not be verified. However, success rates for both IVIG and albumin were in the same range as for allogeneic leucocytes.At present, it is not sufficiently proven that IVIG is an appropriate tool for immunotherapy of recurrent spontaneous abortions. It is suggested that success rates of both IVIG and albumin are due to a placebo effect. However, we cannot exclude that albumin itself provides immunomodulating capacity.

Recurrent spontaneous abortion (RSA) is the cause of childlessness in 2-5% of reproducing couples. Immunological mechanisms have been proposed as an etiology in some cases of RSA. Various forms of immunotherapy have been attempted in individuals thought to have an immunologic mechanism associated with RSA. Intravenous immunoglobulin (IVIG) has been used in a pilot study to successfully treat women with RSA.To evaluate the efficacy of IVIG in the prevention of RSA as prospective randomized, placebo-controlled clinical trial was undertaken. Women experiencing two or more consecutive RSAs receive either IVIG 500 mg/kg/month or placebo (albumin).To date 92 women have been enrolled in the study and 58 pregnancies have been achieved. The outcome of the 58 pregnancies include 20 deliveries, 9 ongoing pregnancies and 29 losses. Fourteen (49%) of the 29 pregnancy losses were blighted ova (empty gestational sacs) and 15 (51%) were intrauterine fetal deaths (IUFD's) occurring in the first trimester of pregnancy. Of 14 blighted ova, 8 were in women receiving IVIG and 6 were receiving placebo. Fifteen IUFD's occurred: 3 (20%) in women receiving IVIG and 12 (80%) placebo. Of 11 pregnancy losses occurring in women receiving IVIG, 8 (73%) were blighted ova and 3 (27%) were IUFD's. Eighteen losses occurred in women receiving placebo: 6 (33%) were blighted ova and 12 (67%) were IUFD's.These preliminary data suggest IVIG may be effective treatment for RSA. Analysis of data from the completed randomized placebo-controlled trial will test this suggestion.

There is no immunological test for the prospective identification of alloimmune causes of miscarriage. We investigated whether activity of natural killer cells was predictive of subsequent abortion in women who had had unexplained recurrent abortions and had received no treatment. 24 women with high preconceptional NK activity, defined as mean plus 1 SD of NK activity of 47 controls, had a significantly higher abortion rate in the next pregnancy than 44 women with normal levels of NK activity (71 vs 20%; relative risk 3.5; 95% CI 1.8-6.5). The preconceptional evaluation of NK activity in women with recurrent miscarriages may thus be predictive of the risk of pregnancy loss at the next conception.

Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage An alloimmune abnormality is believed to be the cause of recurrent miscarriage in couples in whom no other cause can be identified. Because of its immunosuppressive properties, intravenous immunoglobulin (IVIG) is used as a treatment for this disorder. The purpose of this study was to determine whether IVIG improves the chance of successful pregnancy in women with recurrent miscarriage by using individual patient data from efficacy trials. Detailed information on each patient enrolled in these trials was obtained to evaluate the efficacy of IVIG and investigate the effect of clinical variability on pregnancy outcome. Data from 125 patients in the IVIG group and 115 patients in the placebo group were available for analysis. Although the number of previous miscarriages and female age were both negative prognostic factors for successful outcome, there was no significant improvement in successful pregnancy or live birth rate with IVIG. Subgroup analyses indicated that timing of IVIG administration may be important. The results of the present study highlight the importance of stratification for known confounders, so that the role of IVIG can be evaluated in more detail. The collective evidence thus far indicates that IVIG does not have a therapeutic effect that is clinically meaningful.

Background  Intravenous immunoglobulin (IVIG) is a fractionated blood product whose off‐label use for treating a variety of conditions, including spontaneous recurrent miscarriage, has continued to grow in recent years. Its high costs and short supply necessitate improved guidance on its appropriate applications.

To estimate whether intravenous immunoglobulin (IVIG) improves the probability of a live birth in women with unexplained recurrent miscarriage (RM).A computerized search in Medline, Embase, Central, Ovid Medline In-Process, and Other Non-Indexed Citations Databases and randomized controlled trial (RCT) registries was performed. Abstracts of the American Society of Reproductive Medicine and European Society of Human Reproduction and Embryology annual meetings and reference lists of identified reports were searched.None.Women with unexplained primary (without a prior live birth) or secondary (subsequent to a live birth) RM.IVIG or placebo control intervention.Live birth rate per randomized woman.Six relevant RCTs were identified including 272 women with unexplained RM. The overall odds ratio for live birth is 0.92, with a 95% confidence interval of 0.55-1.54, indicating a lack of a treatment effect with IVIG. Similarly, IVIG was not found to be beneficial when women with primary and secondary RM were analyzed separately.A beneficial effect of IVIG in treatment of RM was not observed. Given the absence of a proven mechanism of action, and the lack of a diagnostic algorithm to identify patients who are likely to benefit from such treatment, IVIG administration for treatment of recurrent miscarriage is not justified outside the context of properly designed RCTs.Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

To determine whether infusions with intravenous immunoglobulin (IVIg) during early pregnancy increase live birth rate in women with secondary recurrent miscarriage compared with placebo.

Recurrent pregnancy loss (RPL) affects up to 4% of couples attempting to conceive. RPL is unexplained in over 50% of cases and no effective treatments exist. Due to the immune system's pivotal role during implantation and pregnancy, immune‐mediated RPL may be suspected and immunomodulatory treatments like intravenous immunoglobulin (IVIg) have been administered but remain controversial. The goal of our study was to evaluate our center's 6 year‐outcomes and to develop a framework for IVIg use in RPL.

This study aimed to evaluate changes in natural killer (NK) cell activity and the percentage of monocytes in women with recurrent miscarriage who received medium-dose intravenous immunoglobulin (IVIg) therapy. Fourteen women with a history of six or more recurrent miscarriages of unexplained etiology received 60-g IVIg therapy (20 g daily, for three days) during early gestation. NK cell activity in the peripheral blood decreased to 12% one week after therapy compared with before therapy (median, 22%, P < 0.001) and the percentage of monocytes increased from 5.2% to 7.5% (P < 0.005). Four pregnancies ended in live births of healthy neonates, whereas the other ten pregnancies ended in miscarriages. Excluding one miscarriage with a chromosomal abnormality, the live birth rate was 30.8% (4/13). The rate of reduction of NK cell activity in the success group (-58.8%) tended to be greater than that in the failure group (-14.8%, P = 0.057).Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

We aimed to evaluate the efficacy of IVIG in the treatment with patients with recurrent spontaneous abortion (RSA).

Various causes of recurrent pregnancy loss (RPL) have been identified, but even with a detailed evaluation, almost half of the cases have unidentified etiologies. Immune imbalance is one of the proposed potential etiologies of these idiopathic RPL. To regulate abnormal cellular immunity, intravenous immunoglobulin (IVIG), a type of immunotherapy, is proposed to improve pregnancy outcomes. However, the efficacy of IVIG in RPL is still controversial.

Intravenous immunoglobulin (IVIG) is increasingly used as a treatment for recurrent pregnancy loss (RPL) despite lack of clear evidence on efficacy. Recent data suggest IVIG might be more effective in a subgroup of women with an aberrant immunological profile. Therefore, a systematic review and meta-analysis of studies on the effectiveness of IVIG treatment on pregnancy outcome among women with RPL and underlying immunological conditions (e.g., elevated NK cell percentage, elevated Th1/Th2 ratio, diagnosis with autoimmune disorders) was conducted. Eight non-randomized controlled trials, including 478 women (intervention: 284; control: 194), met eligibility criteria. Meta-analysis showed that treatment with IVIG was associated with a two-fold increase in live birth rate (RR 1.98, 95% CI 1.44–2.73, P < 0.0001). The effect of IVIG was particularly marked in the subgroup of studies including patients based on presence of elevated (> 12%) NK-cell percentage (RR 2.32, 95% CI 1.77–3.02, P < 0.0001) and when starting intervention prior to or during cycle of conception (RR 4.47, 95% CI 1.53–13.05, P = 0.006). In conclusion, treatment with IVIG may improve live birth rate in women with RPL and underlying immune conditions. However, these results should be interpreted with caution as studies are limited by low number of participants and the non-randomized design, which represent seriously biases. Future randomized controlled trials in women with RPL and underlying immune conditions are needed before using IVIG in a clinical setting.

Th17 cells and Treg cells have been proposed as new risk factors for recurrent miscarriage (RM). In this study, we investigated the effect of Intravenous immunoglobulin G (IVIG) on the levels and function of Th17 and Treg cells and pregnancy outcome in women with RM.94 pregnant women with RM were enrolled in this study. Blood was drawn at the time of positive pregnancy. On the same day, IVIG 400mg/kg was administered intravenously for 44 patients. 50 other RM patients were included as no IVIG interfering control group. Following the first administration, IVIG was given every 4 weeks through 32 weeks of gestation. Peripheral blood was drawn after the last administration (32 weeks after pregnancy).IVIG down-regulated Th17 cells population and function and up-regulated Treg cells population and function were significant in the treated group. Pregnancy outcome in IVIG treated subjects was successful in 38 out of 44 RM women (86.3%). However, pregnancy outcome was successful in 21 out of 50 untreated RM women (42%).Administration of IVIG in RM women with cellular immune cells abnormalities during pregnancy influences Th17/Treg ratio in peripheral blood and enhances Treg and decreases Th17 responses.Copyright © 2017. Published by Elsevier B.V.

Th17 cells and Foxp3+ regulatory T (Treg) cells have been proposed as new risk factors for recurrent pregnancy loss (RPL). Intravenous immunoglobulin G (IVIG) was reported to modulate various immune cells. In this study, we investigated the effect of IVIG on the levels of Th17 and Treg cells and pregnancy outcome in women with RPL.

The imbalance in the Th17/Regulatory T (Treg) cell ratio is associated with recurrent pregnancy loss (RPL). This study aimed to determine a cut‐off for the Th17/Treg cell ratio to predict pregnancy outcomes in RPL and evaluate the effectiveness of intravenous immunoglobulin (IVIG) based on this cut‐off value.

Recurrent pregnancy loss has been associated with autoimmune responses to membrane phospholipids and alloimmune reactions against paternally derived molecules on the trophoblast. The problem is psychologically and economically stressful as it undermines the capacity of some couples to reproduce and participate effectively in the day-to-day economic activities. This article reviews the adoption of intravenous immunoglobulin as a form of therapy for the clinical management of recurrent pregnancy loss and of selected autoimmune disorders. Side effects, contraindications and safety of use are discussed.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and adverse pregnancy outcomes, often associated with elevated antiphospholipid antibodies (aPLs). The 2023 ACR/EULAR criteria for APS necessitate persistent medium to high titers of aPLs for laboratory confirmation. However, the impact of persistently low‐titer aPLs in recurrent miscarriage (RM) patients remains controversial. This study aims to analyze the effect of treatment on pregnancy outcomes and maternal–fetal complications in patients with low‐titer aPLs.

Recurrent pregnancy loss (RPL) has an estimated incidence of 1–3% of all couples. The etiology is considered to be multifactorial. Extracellular vesicles (EVs) take part in numerous different physiological processes and their contents show the originating cell and pathophysiological states in different diseases. In pregnancy disorders, changes can be seen in the composition, bioactivity and concentration of placental and non-placental EVs. RPL patients have an increased risk of pregnancy complications. The aim of this prospective study was to examine whether measuring different specific EV markers in plasma before and during pregnancy could be used as predictors of pregnancy loss (PL) in women with RPL. Thirty-one RPL patients were included in this study; 25 had a live birth (LB group) and six had a new PL (PL group). Five blood samples were obtained, one before achieved pregnancy and the others in gestational week 6, 8, 10 and 16. Moreover, some of the patients received intravenous immunoglobulin (IVIG) infusions as part of treatment, and it was also examined whether this treatment influenced the EV levels. Seventeen EV markers specific for the immune system, coagulation, placenta and hypoxia were analyzed in the samples with EV Array, a method able to capture small EVs by using an antibody panel targeting membrane proteins. Comparing the LB and PL groups, one EV marker, CD9, showed a significant increase from before pregnancy to gestational week 6 in the PL group. The changes in the other 16 markers were nonsignificant. One case of late-onset PL showed steeply increasing levels, with sudden decrease after gestational week 10 in nine of 17 markers. Moreover, there was an overall increase of all 17 markers after IVIG treatment in the LB group, which was significant in 15 of the markers. Whether increases in EVs positive for CD9 characterize RPL patients who subsequently miscarry should be investigated in future larger studies.

Recurrent pregnancy loss (RPL), defined as two or more pregnancy losses before the 24th week of gestation, affects 1%–3% of women worldwide. Approximately, 40% of RPL cases are secondary RPL (sRPL), where women have given birth before facing pregnancy losses. The underlying causes of RPL remain unclear, but immune‐related factors may play a role. Previously, a randomised controlled trial using immunoglobulin (IVIG) in sRPL women with a history of four pregnancy losses performed in our RPL unit did not show significant effects of IVIG treatment overall. Yet, some evidence suggests potential benefits for a subset of sRPL patients. In the cohort used for the randomised controlled trial, we examined the role of maternal HLA class II‐presented fetal HLA‐derived epitopes in sRPL using the predicted indirectly recognisable HLA epitopes (PIRCHE‐II) algorithm. In the placebo group, sRPL mothers with an anti‐HLA antibody response had higher PIRCHE‐II scores when having a live birth compared with sRPL women who experienced another pregnancy loss. This difference was not observed in the IVIG‐treated group. Furthermore, as a proxy for T‐cell memory, the number of overlapping peptides between the two paternal haplotypes in couples having live births without treatment displayed a larger number of overlapping peptides. This effect was primarily driven by class II‐derived peptides. These results suggest that specific combinations of sRPL mothers and fathers, particularly those with an anti‐HLA antibody response, may generate higher PIRCHE‐II scores, which could contribute to successful live births. Understanding these immune interactions may provide insights for personalised diagnostic and therapeutic strategies in sRPL.

Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal-foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls.The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls.MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger's test.Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM.The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.