Allogenic Lymphocyte Immunotherapy for Unexplained Recurrent Spontaneous Abortion: A Meta‐Analysis

Allogenic lymphocyte immunotherapy (LIT) as a treatment for unexplained recurrent spontaneous abortion (URSA) is still controversial due to the lack of enough controls to evaluate its effectiveness. Eighteen randomized, placebo‐controlled trials with LIT for URSA were included in the meta‐analysis. Live birth rates for each group were extracted, and the overall odds ratio (OR) for LIT was calculated. The success rate of treatment group was significantly higher (OR 3.74, 95% CI 3.07 ~ 4.57). LIT performed before and during pregnancy had dramatically improved the live birth rate in women with URSA (OR 4.67, 95% CI 3.70 ~ 5.90). The overall OR was 5.25 (95% CI 4.16 ~ 6.64), which supports a low dose of lymphocytes for treating URSA. Our results indicate that LIT provides a significantly beneficial effect over placebo for URSA. LIT given before and during pregnancy is superior to LIT given only before pregnancy, and the lower doses per treatment (less than 100 × 10⁶ lymphocytes or 100 mL peripheral blood) achieved a better outcome.     

The Influence of Intravenous Immunoglobulin Treatment on Maternal Immunity in Women With Unexplained Recurrent Miscarriage

PROBLEM: Recently the protective value of high-dose intravenous immunoglobulin (IVIG) in the treatment of unexplained recurrent miscarriage has been reported to be similar to that of conventional immunotherapy with paternal leukocytes. We examined the effect of IVIG treatment on the cellular and humoral level of maternal immunity to demonstrate the possible mechanism by which IVIG might act to prevent recurrence of pregnancy loss. METHOD: Eight patients were treated with a 20- to 25-g dose of IVIG every 2 to 3 wk during their first-trimester pregnancies. The development of anti-idiotypic autoantibodies against maternal T-cell receptors, maternal anti-paternal lymphocyte antibodies detected by flow cytometric crossmatch, and changes of maternal lymphocyte subpopulations were monitored before pregnancy and then weekly during IVIG treatment. RESULTS: Five of eight patients gave birth successfully after IVIG treatment given during the first trimester of pregnancy (success rate: 62.5%). Although we could not demonstrate a general immunological effect of IVIG on maternal immunity in vivo, a few significant changes of immunological parameters were found in some patients. CONCLUSION: Our results suggest that the effect of IVIG on maternal immunity is not a passive increase of blocking antibody including anti-HLA antibody or modification of maternal T-cell subsets but, more likely, a passive increase of anti-idiotypic antibody against anti-HLA antibody or soluble HLA antigens. However, whether the immunomodulating effect of IVIG is related to its possible mechanism to prevent abortion remains unestablished.     

Clinical Trial of Immunostimulation with a Biological Response Modifier in Unexplained Recurrent Spontaneous Abortion Patients

We determined clinically whether a killed streptococcal preparation (KSP), a biological response modifier, is as effective as paternal lymphocyte immunotherapy for unexplained recurrent pregnancy abortion (RSA) therapy. The success rate of adverse pregnancy in the study group of 23 RSA cases, who were administered low doses of KSP before and during early pregnancy, was statistically compared with that in a control group of 205 women who received paternal lymphocyte immunotherapy. The association of natural killer (NK) cell activity in the peripheral blood with pregnancy outcome was also assessed. The success rate in the study group was 73.9% (17/23), compared to 75.1% (154/ 205) observed for the controls (not significant). Most of the successful cases exhibited low levels of NK cell activity in the peripheral blood. Immunotherapy with low doses of KSP is as effective as that with paternal lymphocytes, providing a simple and safe alternative therapy for unexplained RSA. Suppression of NK cell activity by some immunoregulatory mechanism was also found to have potential benefit in terms of a successful pregnancy outcome.     

High Frequency of Anti‐Protein Z IgM and IgG Autoantibodies in Women with Idiopathic Recurrent Spontaneous Miscarriage

Citation Sater MS, Finan RR, Al‐Hammad SA, Mohammed FA, Issa AA, Almawi WY. High frequency of anti‐protein Z IgM and IgG autoantibodies in women with idiopathic recurrent spontaneous miscarriage. Am J Reprod Immunol 2011; 65: 526–531 Problem Protein Z (PZ) system is an anticoagulant pathway involved in the physiologic regulation of coagulation, and PZ deficiency reportedly enhances prothrombophilic mechanisms, including those implicated with idiopathic recurrent miscarriage (RSM). We investigate plasma anti‐PZ IgM and IgG levels in RSM women and in multiparous control women. Methods Anti‐PZ IgM and IgG levels were measured in 265 RSM women and 283 age‐matched control women by ELISA. Results Elevated anti‐PZ IgG (P < 0.001) and IgM (P < 0.001) titers were seen in patients. The areas under the curves for ROC curve for anti‐PZ IgM (0.898 ± 0.044) and IgG (0.898 ± 0.042) demonstrated no variation in diagnostic capacity. Multivariate analysis confirmed the association of elevated anti‐PZ IgM [adjusted odds ratio, aOR (95% CI) = 6.46 (2.44–17.11)] and IgG [aOR (95% CI) = 7.44 (2.54–21.79)] as independent predictors of RSM after adjusting for confounding covariates and demonstrated a clear gradation of increasing RSM risk associated with increased antibody titers. Conclusion The presence of anti‐PZ IgM and IgG antibodies are risk factors for RSM.     

Decrease in a specific killer cell immunoglobulin-like receptor on peripheral natural killer cells in women with recurrent spontaneous abortion of unexplained etiology

PROBLEM: The aim of this study was to investigate immunophenotypic characteristics of natural killer (NK) cells by assessing specific molecules expressed in women with recurrent spontaneous abortion (RSA) of unexplained etiology. METHOD OF STUDY: Peripheral blood cells were obtained from 20 RSA women and 15 fertile controls. The expression of perforin, CD94, CD161, CD158a, CD158b, and CD244 on CD3- CD56+ NK cells was analyzed by flow cytometry. RESULTS: A significant decrease in CD158a expression was demonstrated in RSA women (mean +/- SD, 22.9 +/- 8.7%) as compared with that in controls (33.6 +/- 15.7%) (P < 0.05). The percentage of NK cells showing dual expression of CD94 and CD161 was relatively higher in RSA women (55.1 +/- 10.2%) than in the controls (47.1 +/- 19.0%), but without statistically significant (P = 0.096). The expression of perforin, CD158b, or CD244 in RSA women did not differ from that in the controls. CONCLUSIONS: A divergence of the specific NK cell repertoire might be related to the etiology of RSA.     

The role of immunity in the pathogenesis and development of pre‐eclampsia

Pre‐eclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality; however, the aetiology of PE still remains unclear. It has been widely accepted that the disease results from insufficient spiral artery remodelling, leading to placental ischaemia and the release of a variety of factors. In recent decades, a large number of studies have observed an abnormal immune response in preeclamptic women and studies of both patients and animal models have shown alterations in the function or the number of immune agents. Thus, researchers believe that alterations in the immune system may contribute to the genesis and pathophysiology of PE. Therefore, identifying the role of the immune system can not only shed light on the nature of PE but also contribute to the development of diagnostic and therapeutic methods for PE. This review focuses on the current knowledge of the immune system including both innate and adaptive immunity and sheds light on their role in PE. Additionally, advances in potential therapeutic measures are discussed.     

MUC1 as a Cell Surface and Secretory Component of Endometrial Epithelium: Reduced Levels in Recurrent Miscarriage

The mucin MUC1 is a large, highly glycosylated, hormonally regulated product of endometrial glandular and luminal epithelium with both cell surface-associated and secreted isoforms. The abundance of mRNA coding for MUC1 increases about sixfold from the proliferative to the early secretory phase (Hey et al., J. Clin. Endocrinol. Metab. 78:337–342, 1994). Immunohistochemical studies show intracellular deposits accumulating in the early secretory phase followed by the release of MUC1 into gland lumens. The apical surface of luminal epithelium is strongly immunopositive in the early secretory phase. We have used a two site ELISA to measure MUC1 in uterine flushings as a function of time after the luteinising hormone (LH) peak. Low levels of secretory MUC1 are observed before day LH+7, while values on days LH+7-LH+13 are much higher. Using semi-quantitative immunohistochemical methods we have shown that in women suffering recurrent spontaneous miscarriage, mid secretory phase levels of MUC1 core protein and mucin-associated glycans are reduced (Serie et al., Fertil. Steril. 62:989–996, 1994). Similarly, lower core protein levels are observed in uterine flushings after day LH+7 in these women. Reduced epithelial secretory function and a resultant change in uterine fluid composition are features of endometrium from recurrent miscarriage patients.