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Clinical and immunological criteria for the use of intravenous immunoglobulins in women with reproductive failures
Abstract
BACKGROUND:In obstetrics and reproductive medicine, the use of intravenous immunoglobulin remains controversial. There are no clearly developed indications for immunoglobulins therapy. The search for immunological criteria for prescribing this therapy is an urgent task AIM:The aim of this study was to evaluate the effectiveness of the use of intravenous immunoglobulins in the complex therapy of women with multiple reproductive losses associated with changes in the quantitative and functional parameters of natural killer cells. MATERIALS AND METHODS:Group 1 consisted of 61 women with recurrent miscarriage; group 2 involved 40 women with two or morein vitrofertilization failures, while group 3 comprised 27 healthy fertile individuals. The activity of blood natural killer cells was assessed by CD107a expression before and after activation. Patients with altered natural killer cell activity received intravenous immunoglobulins therapy under the control of the dynamics of immunological parameters. RESULTS:The number of natural killer cells that expressed CD107a before and after activation differed between the study groups. In patients receiving intravenous immunoglobulins, gestational complications were observed less frequently, with the incidence of biochemical pregnancy being higher. CONCLUSIONS:In patients with early reproductive failures (such as recurrent miscarriage andin vitrofertilization failures) and immunological abnormalities in the form of altered Natural killer cell activity, the use of intravenous immunoglobulins has an immunomodulatory and clinical effect.
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Recurrent implantation failure (RIF) refers to cases in which women have had three failed in vitro fertilization (IVF) attempts with good quality embryos. The definition should also take advanced maternal age and embryo stage into consideration. The failure of embryo implantation can be a consequence of uterine, male, or embryo factors, or the specific type of IVF protocol. These cases should be investigated to determine the most likely etiologies of the condition, as this is a complex problem with several variables. There are multiple risk factors for recurrent implantation failure including advanced maternal age, smoking status of both parents, elevated body mass index, and stress levels. Immunological factors such as cytokine levels and presence of specific autoantibodies should be examined, as well as any infectious organisms in the uterus leading to chronic endometritis. Uterine pathologies such as polyps and myomas as well as congenital anatomical anomalies should be ruled out. Sperm analysis, pre-implantation genetic screening and endometrial receptivity should be considered and evaluated, and IVF protocols should be tailored to specific patients or patient populations. Treatment approaches should be directed toward individual patient cases. In addition, we suggest considering a new initial step in approach to patients with RIF, individualized planned activities to activate the brain's reward system in attempt to improve immunological balance in the body.
Objective
To study the current evidence on the role of immunotherapy in IVF and in the management of recurrent pregnancy loss (RPL).
Design
Systematic review and meta-analysis.
Setting
A literature search was performed using MEDLINE, PUBMED, CINAHL, and EMBASE until May 2017. Only randomized controlled trials were included, and a meta-analysis was carried out where appropriate.
Patient(s)
Women undergoing IVF treatment with or without a history of recurrent implantation failure and women with idiopathic RPL.
Intervention(s)
Assessment of the efficacy of commonly used immunomodulators such as IV use of [1] immunoglobulin, [2] lymphocyte immunotherapy and [3] intralipid; intrauterine infusion of [4] granulocyte colony-stimulating factor and [5] peripheral blood mononuclear cells; subcutaneous administration of [6] TNF-alpha inhibitors, [7] leukaemia inhibitory factor; and oral administration of [8] glucocorticoids.
Main Outcome Measure(s)
The primary outcomes were live birth rate and miscarriage rate; secondary outcome was clinical pregnancy rate.
Result(s)
Of the 7,226 publications identified, 53 were selected during the initial screening; 30 satisfied the selection criteria and were included in this review.
Conclusion(s)
The available medical literature shows controversial results about the role of immunotherapy when used for improving reproductive outcomes. This study did not show a role for immunotherapy in improving the live birth rate in women undergoing IVF treatment or in the prevention of idiopathic RPL. Currently, immunotherapy should be used in the context of research and should not be used in routine clinical practice to improve reproductive outcomes.
In this study, the authors investigated: (1) whether elevated preconception peripheral blood proportion of CD56+/CD3- lymphocytes (NK cells) was associated with low delivery birthweight in high risk women, and (2) whether intravenous immunoglobulin (IVIg) therapy could be used to improve the delivery outcome in these women.
Materials and methods:
Sixty-six women who had singleton deliveries were divided into four groups. Group 1: 16 women with elevated preconception NK cells (>12%) using IVIg, group 2: eight women with similar elevated preconception NK cells not using IVIg, group 3: 32 women with non-elevated preconception NK cells (≤12%) using IVIg, and group IV: ten women with similar non-elevated preconception NK cells not using IVIg. These groups were similar with regards to patient age, test results, and history.
Results:
Mean gestational age (±cmaz, GSD) of babies at delivery wa± 39.3 ± 1.7± 37.4 ± 3.7± 38.5 ± 1.3, an± 38.7 ± 1.5 weeks, for groups 1, 2, 3 and 4, respectively. Mean birthweight of babies at delivery was± 3,267 373,±2,654 ± 627,±3,129 ± 527, and±3,202 ± 357 grams, respectively. Birthweight was significantly higher for1group I vs. group 2 (p = 0.006) but not for groups 1 vs. group 3. There was no significant difference between the groups for preeclampsia rate, C-section rate or preterm delivery rate.
Conclusion:
In women with elevated preconception peripheral NK cells, mean birthweight at delivery is low without IVIg therapy ±2,654 ± 627 grams) but significantly improved with IVIg therapy ±3,267 ± 373 grams). In high risk wom without preconception NK cell elevation, mean birthweight at delivery is not further-increased with IVIg therapy ±3,202 ± 357 grams with IVIg vs.±3,129 ± 527 grams without IVIg). IVIg may be a treatment option for women with preconception NK elevation at risk of a low birthweight baby. Preconception immune testing may be a tool for determining which patients will benefit from IVIg therapy. Larger repeat studies are needed for confirmation.
Natural killer (NK) cells are a key constituent of the innate immune system, protecting against bacteria, virally infected cells, and cancer. Recognition and protective function against such cells are dictated by activating and inhibitory receptors on the surface of the NK cell, which bind to specific ligands on the surface of target cells. Among the activating receptors is a small class of specialized receptors termed the natural cytotoxicity receptors (NCRs) comprised of NKp30, NKp46, and NKp44. The NCRs are key receptors in the recognition and termination of virally infected and tumor cells. Since their discovery over 10 years ago, ligands corresponding to the NCRs have largely remained elusive. Recent identification of the cellular ligands for NKp44 and NKp30 as exosomal proliferating cell nuclear antigen (PCNA) and HLA-B-associated transcript 3 (BAT3), respectively, implicate that NCRs may function as receptors for damage-associated molecular pattern (DAMP) molecules. In this review, we focus on NKp44, which surprisingly recognizes two distinct ligands resulting in either activation or inhibition of NK cell effector responses in response to tumor cells. The inhibitory function of NKp44 requires further study as it may play a pivotal role in placentation in addition to being exploited by tumors as a mechanism to escape NK cell killing. Finally, we suggest that the NCRs are a class of pattern recognition receptors, which recognize signals of genomic instability and cellular stress via interaction with the c-terminus of DAMP molecules localized to the surface of target cells by various co-ligands.
Decidual natural killer (dNK) cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early pregnancy. However, the mechanism for how the dNK cells play such important roles in successful pregnancy remains undefined. Here, we identified a subtype of dNK cells characterized as having a CD3(-)CD56(bright)CD25(+) phenotype. We found that CD56(bright)CD25(+) NK cells preferentially localize to the maternal/fetal interface during early human pregnancy. CD25(+) dNK cells account for approximately 75% of CD25-expressing decidual immune cells (DICs). However, less than 5% of CD25-positive peripheral blood mononuclear cells are CD25(+) NK cells. Furthermore, CD25(+) and CD25(-) dNK cells exhibit distinct phenotypes: CD25(+) dNK cells display a more activated phenotype and greater cytokine-secreting capacity. Interestingly, coculture of peripheral NK (pNK) cells with primary trophoblasts upregulates the percentage of CD25-expressing pNK cells, resulting in increased expression of activation markers and cytokine production by pNK cells. In addition, we demonstrated that the CXCL12/CXCR4 axis is crucial for the recruitment of CD25(+) dNK cells and contributes to the accumulation of CD3(-)CD56(bright)CD25(+) dNK cells at the maternal/fetal interface. Thus, our data reveal that the crosstalk between trophoblasts and pNK cells leads to the accumulation of CD3(-)CD56(bright)CD25(+) dNK cells, which exert a regulating effect at the maternal/fetal interface.Cellular & Molecular Immunology advance online publication, 5 May 2014; doi:10.1038/cmi.2014.26.
INTRODUCTIONEmbryo implantation is a complex process involving maternal hormonal changes, immune responses and maturational events in the embryo. A pregnancy could fail when these events are not synchronized. It is speculated that in women, an elevation of natural killer (NK) cells may have an effect on reproductive performance, and NK cell levels in blood are currently being used as a diagnostic test to guide the initiation of therapies in patients with infertility.METHODS
We conducted a systematic review to evaluate the (i) levels of NK cells in blood and endometrium in infertile versus fertile women, (ii) association between NK cells and IVF outcome, (iii) levels of NK cells in blood and endometrium in women with recurrent miscarriage (RM) versus controls. The following electronic databases were searched: Medline, EMBASE, Cochrane Library, Web of Science and National Research Register.RESULTSA total of 22 studies were included. Meta-analysis of studies that evaluated peripheral and uterine NK (uNK) cell percentages in infertile versus fertile women showed no significant difference between the two groups [standardized mean difference (SMD) -0.33; 95% confidence intervals (CI) -1.06, 0.4; P = 0.37; SMD -1.82; 95% CI -4.80, 1.17; P = 0.23 respectively]. Pooling of studies that reported peripheral NK cells as numbers showed significantly higher NK cell numbers in infertile women compared with fertile controls (SMD 3.16; 95% CI 1.07, 5.24; P = 0.003). Meta-analysis of studies that evaluated the role of NK cells in IVF outcome showed no significant difference in live birth rates in women with elevated NK cells or NK cell activity compared with women without elevated peripheral NK cells or NK cell activity (NK activity assessed using a cytotoxicity assay) (relative risk 0.57; 95% CI 0.06, 5.22; P = 0.62). Meta-analysis of studies that evaluated peripheral NK cell percentages in women with RM versus controls showed significantly higher NK cell percentages in women with RM (SMD 1.36; 95% CI 0.04, 2.69; P = 0.04). Meta-analysis of studies that evaluated peripheral NK cell numbers showed significantly higher NK cell numbers in women with RM compared with controls (SMD 0.81; 95% CI 0.47, 1.16; P < 0.00001). Meta-analysis of studies that evaluated uNK cells showed no significant difference in women with RM compared with controls (SMD 0.40; 95% CI -1.24, 2.04; P = 0.63).CONCLUSIONS
Further research is needed before NK cell assessment can be recommended as a diagnostic tool in the context of female infertility or RM. There is no clear explanation as to why the results differ when data for NK cells are expressed as numbers or a percentage. On the basis of current evidence, NK cell analysis and immune therapy should be offered only in the context of clinical research.
Natural killer cells constitute 50-90% of lymphocytes in human uterine decidua in early pregnancy. Here, CD56(bright) uterine decidual NK (dNK) cells were compared with the CD56(bright) and CD56(dim) peripheral NK cell subsets by microarray analysis, with verification of results by flow cytometry and RT-PCR. Among the approximately 10,000 genes studied, 278 genes showed at least a threefold change with P < or = 0.001 when comparing the dNK and peripheral NK cell subsets, most displaying increased expression in dNK cells. The largest number of these encoded surface proteins, including the unusual lectinlike receptors NKG2E and Ly-49L, several killer cell Ig-like receptors, the integrin subunits alpha(D), alpha(X), beta1, and beta5, and multiple tetraspanins (CD9, CD151, CD53, CD63, and TSPAN-5). Additionally, two secreted proteins, galectin-1 and progestagen-associated protein 14, known to have immunomodulatory functions, were selectively expressed in dNK cells.
Peripheral natural killer (pNK) and uterine NK (uNK) cells have been associated with reproductive failure. We systematically reviewed the literature to assess whether numbers or activity of pNK or uNK cells predicted subsequent pregnancy and outcome.
We searched the electronic MEDLINE database from 1950 to April 2010 for relevant publications by using MeSH terms 'natural killer cells', 'reproduction' and 'pregnancy complications'. We included studies that measured pre-pregnancy pNK and uNK cell numbers or activity in women with recurrent miscarriage (RM) or infertility, and reported subsequent pregnancy outcomes of miscarriage or failure to conceive after assisted reproductive technology (ART).
The search identified 783 publications and 12 fulfilled the inclusion criteria. There were too few women entered into the observational studies to assess whether high pNK cell percentages or activity predicted subsequent miscarriage in women with idiopathic RM (numbers: n = 32, OR 17, 95% CI 0.82-350.6, activity: n = 92, OR 2.51, 95% CI 0.16-40.29), or implantation failure (n = 203, OR 1.35, 95% CI 0.28-6.46), or miscarriage in infertile women after ART (n = 79, OR 2.48, 95% CI 0.50-12.32). Similarly, the studies of uNK cells were not large enough to assess whether abnormal uNK cell density predicted subsequent miscarriage in women with idiopathic RM (n = 72, OR 1.33, 95% CI 0.16-11.11). None of the uNK cell studies in women with infertility reported pregnancy outcomes dichotomized for uNK cell numbers.
The prognostic value of measuring pNK or uNK cell parameters remains uncertain. More studies are needed to confirm or refute the role of NK cell assessments as a predictive test for screening women who may benefit from immunotherapy.
Inflammatory mediators play important roles in the development and progression of cancer. Cellular stress, damage, inflammation, and necrotic cell death cause release of endogenous damage-associated molecular pattern (DAMP) molecules or alarmins, which alert the host of danger by triggering immune responses and activating repair mechanisms through their interaction with pattern recognition receptors. Recent studies show that abnormal persistence of these molecules in chronic inflammation and in tumor microenvironments underlies carcinogenesis and tumor progression, indicating that DAMP molecules and their receptors could provide novel targets for therapy. This review focuses on the role of DAMP molecules high-mobility group box 1 and S100 proteins in inflammation, tumor growth, and early metastatic events.
Extravillous trophoblast cell (EVT) invasion of decidua and inner third of the myometrium is critical for a successful pregnancy. Many decidual factors are likely to play a role in regulating this process, including uterine natural killer (uNK) cell-derived cytokines.
1) uNK cells are a major source of IFN gamma (IFN-gamma) and 2) IFN-gamma inhibits EVT invasion via an increase in EVT apoptosis and/or a decrease in active protease levels.
Total decidual and uNK cells from 8-10 wk and 12-14 wk gestational age were cultured. IFN-gamma mRNA (real-time RT-polymerase chain reaction) and protein levels (FastQuant multicytokine analysis) were determined. EVT invasion in the presence of IFN-gamma or anti-IFN-gamma-neutralizing antibodies was assessed. Trophoblast apoptosis and proliferation was assessed in explants by immunohistochemistry for M30 and Ki67. Substrate zymography was performed to determine levels of secreted MMP2, MMP9, and uPA.
mRNA and protein for IFN-gamma was detected in both total decidual and uNK cell fractions. Trophoblast invasion was inhibited by IFN-gamma. The level of M30-positive EVT was increased in the presence of IFN-gamma whereas levels of secreted MMP2 were decreased.
uNK cells are a source of IFN-gamma within early human pregnancy decidua. Mechanisms of IFN-gamma inhibition of EVT invasion include both increased EVT apoptosis and reduced levels of active proteases.
No data regarding phenotypic assets of circulating lymphocytes in anti-phospholipid syndrome (APS) are reported in the literature. Role of anti-phospholipid antibodies (aPL) in recurrent spontaneous abortion (RSA) remains uncertain, while natural killer (NK)-cells are involved in RSA pathogenesis. In this study, patients affected with APS without RSA, APS with RSA and RSA without aPL were studied for NK-cell subpopulation to evaluate its role in abortive events typical of APS.
NK-cell levels in peripheral blood of APS patients without RSA (n = 28) and in APS-RSA patients (n = 25) were evaluated by means of flow cytofluorimetry. NK-cells levels were evaluated also in RSA without aPL associated with either endocrine (n = 86), anatomic (n = 30) or idiopathic (n = 77) conditions and in 42 healthy women.
High NK levels were found in 14/25 (56%) APS-RSA patients. Among these patients, all except one aborted before the 10th gestational week (GW), while among the remaining patients all except one aborted after the 10th GW. NK mean levels were significantly higher in APS-RSA than in all the other conditions studied, including healthy subjects, except idiopathic RSA.
Our results demonstrate that the numbers and proportions of NK-cells are significantly higher in patients with RSA with APS than in APS without RSA. Increased numbers of NK-cells correlate with reduced gestational age at abortion in patients with APS-RSA. These data lead to a hypothesis that NK-cells contribute to the development of RSA in patients with APS. NK-cells might precipitate damage initiated by aPL or they might cause pathology in RSA independent of aPL.
Over the last few decades, the advancement in reproductive technologies and protocols to improve embryo quality through culture techniques and genetic testing to eliminate chromosomally abnormal embryos resulted in better pregnancy rates and outcomes after fertility treatments. Unfortunately, some patients still struggle with recurrent implantation failures (RIF) and recurrent pregnancy losses (RPL). Immune aetiologies have been attributed to play an important role in some of those patients. Maintaining a preconceptional anti‐inflammatory environment for implantation and pregnancy continuation yields superior results. Intravenous immunoglobulin G (IVIG) treatment has been reported to enhance reproductive outcome in patients with RIF and RPL with immune dysregulations. In this systemic review, we analyzed outcomes of IVIG trials for RIF and RPL, its mechanism of action, dosing, administration, side effects, and evidence for its use in women with RIF and RPL.
The term placental bed was coined to describe the maternal-fetal interface (ie, the area in which the placenta attaches itself to the uterus). Appropriate vascularization of this area is of vital importance for the development of the fetus; this is why systematic investigations of this area have now been carried out. Initially, the challenge was the identification and classification of the various successive branching of uterine arteries in this area. These vessels have a unique importance because failure of their physiological transformation is considered to be the anatomical basis for reduced perfusion to the intervillous space in women with preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, abruptio placentae, and fetal death. To investigate in depth the pathophysiology of the placental bed, some 60 years ago, a large number of placental bed biopsies, as well as of cesarean hysterectomy specimens with placenta in situ, from both early and late normotensive and hypertensive pregnancies, were carefully dissected and analyzed. Thanks to the presence of a series of specific physiological changes, characterized by the invasion and substitution of the arterial intima by trophoblast, this material allowed the identification in the placental bed of normal pregnancies of the main vessels, the uteroplacental arteries. It was then discovered that preeclampsia is associated with defective or absent transformation of the myometrial segment of the uteroplacental arteries. In addition, in severe hypertensive disease, atherosclerotic lesions were also found in the defective myometrial segment. Finally, in the basal decidua, a unique vascular lesion, coined acute atherosis, was also identified This disorder of deep placentation, coined defective deep placentation, has been associated with the great obstetrical syndromes, grouping together preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. More recently, simplified techniques of tissue sampling have been also introduced: decidual suction allows to obtain a large number of decidual arteries, although their origin in the placental bed cannot be determined. Biopsies parallel to the surface of the basal plate have been more interesting, making possible to identify the vessels' region (central, paracentral, or peripheral) of origin in the placental bed and providing decidual material for immunohistochemical studies. Finally, histochemical and electron microscopy investigations have now clarified the pathology and pathogenetic mechanisms underlying the impairment of the physiological vascular changes.
Background
Recurrent miscarriage (RM) has a multifactorial etiology mainly due to chromosomal abnormalities and immunological factors. Treating RM has remained to be a challenging issue and the role of intravenous immunoglobulin (IVIG) in treating RM is still controversial.
Materials and Methods
This study aimed to evaluate the changes in natural killer (NK) cells’ frequency and cytotoxicity in patients with RM who received the IVIG therapy. A total of 78 women with a history of three or more recurrent miscarriages were included and their peripheral blood was drawn in case of positive pregnancy test. On the same date, 400 mg/kg of IVIG was administrated intravenously in 38 women and it continued every four weeks through weeks 30–32 of gestation. The remaining 40 patients with RM were included to be the untreated control group. Then, the effects of IVIG on NK cell frequency, cytotoxic activity, and the expression of inhibitory and activating receptors in the patients with RM, pre and posttreatment were assessed.
Results
NK cells percentage and cytotoxicity were significantly reduced in the IVIG‐treated patients after 32 weeks of gestation (p < 0.0001). Expression levels of inhibitory receptors was increased, however, the expression levels of activating receptors were significantly decreased after the IVIG therapy. Pregnancy outcome after the treatment was significantly higher (86.8%) in the IVIG‐treated patients than controls (45%; p = 0.0006).
Conclusion
Our results suggested that women with RM may benefit from IVIG as a therapeutic approach and the frequency and functional status of peripheral NK cells may serve as a valuable predictive factor of therapy response.
This book focuses on uterine endometrial function and receptivity from multiple perspectives. The chapters cover a variety of topics including the role of estrogen and progesterone, animal models, parameters for assessing endometrial receptivity, the mechanism of angiogenesis, epigenetic regulation, and stem/progenitor cells. Despite nearly 35 years of experience with in vitro fertilization, the rate of successful implantations remains low. Abnormal endometrial receptivity has been proposed as one of the factors contributing to reduced reproductive potential in women, but our understanding of it is limited. Endometrial receptivity results from an orchestrated interplay between the embryo and the maternal endometrium, and the receptive status, known as the window of implantation, is reached only briefly in the mid-luteal phase. This book provides a comprehensive overview of the latest advances in endometrial function and paves the way for innovative treatments and drug development for infertility. This work will appeal to a wide readership, from researchers on endometrial function and assisted reproductive technology (ART) to clinicians and technicians in the field of gynecology.
Providing the latest evidence-based information on etiology, evaluation and treatment, this unique text provides an in-depth, comprehensive discussion of the epidemiology, genetic and endocrinologic factors and medical and surgical management of recurrent pregnancy loss (RPL). Taking a multidisciplinary approach including psychological treatment and patient perspectives, all aspects of current RPL prevention and treatment are elucidated. Detailed chapters provide real-world illustrative material and cover the set-up and management of RPL clinics and databases, containing practical tips. Recurrent Pregnancy Loss will be an excellent resource for OB-GYN specialists, general and reproductive endocrinologists, radiologists, hematologists, psychiatrists, psychologists, and any other investigators or clinicians treating patients confronted with this emotionally and physically trying condition.
Recurrent implantation failure refers to failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40years. The failure to implant may be a consequence of embryo or uterine factors. Thorough investigations should be carried out to ascertain whether there is any underlying cause of the condition. Ovarian function should be assessed by measurement of antral follicle count, FSH and anti-Müllerian hormone. Increased sperm DNA fragmentation may be a contributory cause. Various uterine pathology including fibroids, endometrial polyps, congenital anomalies and intrauterine adhesions should be excluded by ultrasonography and hysteroscopy. Hydrosalpinges are a recognized cause of implantation failure and should be excluded by hysterosalpingogram; if necessary, laparoscopy should be performed to confirm or refute the diagnosis. Treatment offered should be evidence based, aimed at improving embryo quality or endometrial receptivity. Gamete donation or surrogacy may be necessary if there is no realistic chance of success with further IVF attempts. Recurrent implantation failure is an important cause of repeated IVF failure. It is estimated that approximately 10% of women seeking IVF treatment will experience this particular problem. It is a distressing condition for patients and frustrating for clinicians and scientists. In this review, we have discussed the definition and management of the possible underlying causes of recurrent implantation failure.
Before effective treatment for reproductive failure can be instituted, the cause of the failure must be determined. A search of PubMed was made to identify the published data regarding diagnosis and treatment of reproductive failure. Results were compared with the frequency of antiphospholipid antibodies (APA) in 2995 women with histories of unexplained infertility, recurrent implantation failure, recurrent pregnancy loss, and fertile women. In addition, pregnancy outcomes among 442 women experiencing reproductive failure and elevated NK cell activity after treatment with intravenous immunoglobulin (IVIg) (N = 242) or intralipids (N = 200) were compared. The prevalence of APA was the same among women with the diagnosis of unexplained infertility, recurrent implantation failure, and recurrent miscarriage. Heparin and aspirin are successful in the treatment of elevated APA among women with recurrent miscarriage but not with recurrent implantation failure. IVIg has been successful in the treatment of recurrent miscarriage and recurrent implantation failure among women with elevated APA and/or NK cell activity. When the pregnancy outcomes of women with a history of reproductive failure and elevated NK cell cytotoxicity treated with intralipid were compared with women treated with IVIg, no differences were seen. Immunotherapy for treatment of reproductive failure enhances live birth but only in those women displaying abnormal immunologic risk factors.
To analyse the peripheral blood NK cells in women with repeated IVF failure (RIF) and a fertile control group to determine which parameters best differentiate the two populations.
Peripheral blood from the luteal phase of 171 women with RIF and 33 fertile controls was analysed by four-colour flow cytometry for NK cell concentration, subset differentiation and the activation marker CD69.
Women with RIF had significantly increased NK cell numbers as determined by concentration (P < 0.05) and percentage of lymphocytes (P < 0.001), increased concentration of the CD56(dim) subtype (P < 0.05), and increased concentration of activated CD56(dim) CD69(+) cells (P = 0.0001). There was no correlation between any NK cell parameters with the length of infertility or number of embryo transfer cycles.
Peripheral blood NK cell activity is significantly higher in women with RIF than in fertile controls. Future trials of immune therapy in women undergoing IVF should target those with high NK activity.
Aspects of the immunological relationship between mother and conceptus still remain a mystery, although the recent advances in molecular biology have enlightened some of the parameters that participate in fetomaternal cross-talk during implantation. The atypical expression of major histocompatibility complex (MHC), the specific role of some hormones and cytokines, as well as the temporal and spatial distributions of uterine natural killer cells, represent substantive parameters of fetomaternal immunotolerance during implantation. Although human maternal and fetal immunology is difficult to investigate, aberrant immune responses and an imbalanced cytokine network may be related to infertility, implantation failures after IVF and recurrent pregnancy losses. In this review, immunological and interacting factors involved in human reproductive failure are summarized and critically evaluated.
In summary (1) Nonpregnant women with RSAs of unknown etiology have higher levels of CD56+ lymphocytes when compared to normal controls; (2) The levels of CD19+, CD56+, and CD56+/CD16+ PBL of pregnant women with RSA are significantly higher than those of multiparous pregnant normal controls; (3) Women with autoantibodies to phospholipids have significantly higher levels of elevated CD56+ and CD56+/CD16+ lymphocytes when compared to women without antiphospholipid antibodies; (4) Women with autoantibodies to nuclear components demonstrate higher numbers of CD19+/CD5+ cells compared to women without autoantibodies to nuclear components; (5) Idiopathic infertile women with multiple prior IVF failures demonstrate significantly higher levels of CD56+ pBL than normal fertile controls and the conception rate is much higher in those with CD56+ levels less than 12%; (6) Elevations of CD56+ lymphocytes to over 18% during a pregnancy is a good prognostic indicator of impending pregnancy loss. We have not seen a liveborn infant in women with levels of 18% or higher without IVIg therapy; and (7) Infertile and RSA women who fail alloimmune and autoimmune therapy have significant alterations in cellular and humoral immunity involving NK cells and CD19+/CD5+ B cells.
To evaluate the effect of intravenous immunoglobulin (IVIG) on pregnancy outcome in couples with repeated unexplained in vitro fertilization (IVF) failure.
Prospective, randomized, double blind, placebo-controlled clinical trial.
A university-based and a free-standing IVF program.
Fifty-one couples with a history of repeated unexplained IVF failure who were preparing for another fresh IVF cycle or replacement of cryopreserved embryos.
Eligible women underwent a standard IVF stimulation using a long luteal phase GnRH analog protocol. Cryopreserved embryos were replaced after endometrial preparation with oral micronized estradiol and subsequent vaginal progesterone. The women were randomly selected to receive IVIG (500 mg/kg) or an equivalent volume of normal saline. The first infusion was given on the day of embryo transfer or during the preceding 72 hours. The second infusion was given 4 weeks later if a clinical pregnancy was confirmed by ultrasound.
Live-birth rates.
Overall, the live-birth rates were 4/26 (15%) for the IVIG group and 3/25 (12%) for the placebo group (P=0. 52). There were 39 fresh IVF cycles, which yielded a clinical pregnancy rate of 28%, with live-birth rates of 4/21 (19%) for the IVIG group and 3/18 (17%) for the placebo group (P=0.59).
In this randomized clinical trial, IVIG did not improve the live-birth rate in couples with repeated unexplained IVF failure, stringently defined by known determinants of IVF outcome.
The way by which intravenous immunoglobulin (IvIg) acts to prevent immunlogically mediated recurrent spontaneous abortions (RSA) has not been clarified. In the present study, a possible effect of IvIg on the T helper cell (Th1/Th2) balance was investigated in abortions of either alloimmune or autoimmune abnormalities.
The study included 21 women treated with IvIg before conception because of a history of RSA characterized by alloimmune abnormalities (n = 15) or associated with anti-phospholipid antibodies (APA) (n = 6). Peripheral blood samples, collected before and 5 days after the first IvIg infusion, were stimulated, and Th1 and Th2 cells were detected by flow-cytometric analysis using a combination of monoclonal antibodies against T-cell surface markers and intracellular interferon (IFN)-gamma and interleukin (IL)-4. The percentage of IFN-gamma-producing (Th1) and IL-4-producing (Th2) cells and the Th1/Th2 ratio were compared between pre- and post-infusion samples.
A decrease of Th1 percentage in 66.6% of the cases and a concurrent Th2 percentage increase (47.61%) resulted in a decrease in the Th1/Th2 ratio in most of the cases (76.1%) (p < 0.01). Similar results were found in Group A (Th1/Th2 decreased in 60% of the cases, p < 0.05), while in Group B the effect of IvIg was not clear (Th1/Th2 increased in three and decreased in another three cases).
Our finding suggests that IvIg administration in women with alloimmune RSA enhances Th2 polarization. This is not always the case with APA-associated abortions.
Because immunological aberrations might be the cause of miscarriage in some women, several immunotherapies have been used to treat women with otherwise unexplained recurrent pregnancy loss.
The objective of this review was to assess the effects of any immunotherapy, including paternal leukocyte immunization and intravenous immune globulin on the live birth rate in women with previous unexplained recurrent miscarriages.
We searched the Cochrane Pregnancy and Childbirth Group Trials Register (December 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2004, Issue 3), MEDLINE (1966 to September 2004) and EMBASE (1980 to September 2004).
Randomized trials of immunotherapies used to treat women with three or more prior miscarriages and no more than one live birth after, in whom all recognised non-immunologic causes of recurrent miscarriage had been ruled out and no simultaneous treatment was given.
The review author and the two co-authors independently extracted data and assessed study quality for all studies considered for this review.
Twenty trials of high quality were included. The various forms of immunotherapy did not show significant differences between treatment and control groups in terms of subsequent live births: paternal cell immunization (12 trials, 641 women), Peto odds ratio (Peto OR) 1.23, 95% confidence interval (CI) 0.89 to 1.70; third party donor cell immunization (three trials, 156 women), Peto OR 1.39, 95% CI 0.68 to 2.82; trophoblast membrane infusion (one trial, 37 women), Peto OR 0.40, 95% CI 0.11 to 1.45; intravenous immune globulin, Peto OR 0.98, 95% CI 0.61 to 1.58.
Paternal cell immunization, third party donor leukocytes, trophoblast membranes, and intravenous immune globulin provide no significant beneficial effect over placebo in improving the live birth rate.
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.
We conducted a systematic review of randomised controlled trials evaluating IVIG for treatment of spontaneous recurrent miscarriage.
A systematic search strategy was applied to Medline (1966 to June 2005) and the Cochrane Register of Controlled Trials (June 2005).
We included all randomised controlled trials comparing all dosages of IVIG to placebo or an active control.
Two investigators independently extracted data using a standardised data collection form. Measures of effect were derived for each trial independently, and studies were pooled based on clinical and methodologic appropriateness.
We identified eight trials involving 442 women that evaluated IVIG therapy used to treat recurrent miscarriage. Overall, IVIG did not significantly increase the odds ratio (OR) of live birth when compared with placebo for treatment of recurrent miscarriage (OR 1.28, 95% CI 0.78-2.10). There was, however, a significant increase in live births following IVIG use in women with secondary recurrent miscarriage (OR 2.71, 95% CI 1.09-6.73), while those with primary miscarriage did not experience the same benefit (OR 0.66, 95% CI 0.35-1.26).
IVIG increased the rates of live birth in secondary recurrent miscarriage, but there was insufficient evidence for its use in primary recurrent miscarriage.
A problem in the unregulated use of intravenous immunoglobulin in obstetrics
- E A Ushkalova
- E M Shifman
The influence of immunomodulating therapy on clinical and laboratory results in pregnant women with antiphopholipid syndrome and recurrent pregnancy loss
- A A Chugunova
- M S Zainulina
- A V Selutin