Recent Advances in Immunotherapeutic Approaches for Recurrent Reproductive Failure

Human reproduction is an insufficient process, disturbed by various factors, such as immunologic aberrations of mother. Immunologic abnormalities, including cellular and humoral immunity imbalance, cause dysregulated immune responses against embryo, fetus, and associated components and lack of maternal immunotolerance, which compromise the maintenance of pregnancy. Therefore, evaluation of immunologic parameters, including cellular and humoral immunity assessment (T and B lymphocyte, T helper subtypes, NK cells, cytokines, and autoantibodies), especially in women with a history of pregnancy loss or implantation failure, would help clinicians to manage the disorder and prevent next unfavorable pregnancy outcomes. Moreover, several immunomodulatory approaches have been introduced to modulate the abnormal immunologic responses in patients who experience reproduction failure, especially those diagnosed with immunologic basis. Anticoagulants, corticosteroids, intravenous immunoglobulin, immunosuppressive medications used in inhibition of graft rejection, such as calcineurin inhibitors, recombinant cytokines, and cell therapy approaches, are among these modalities. Here, we discuss the proposed mechanisms of immunologic abnormalities involved in the etiopathogenesis of reproduction disorders, besides the suggested immunologic tests and immunotherapeutic approaches which may be helpful in management of these disorders

A Comparison of 4- and 24-Hour Urine Samples for the Diagnosis of Proteinuria in Pregnancy

Background: Preeclampsia is a serious complication of pregnancy, and it is vital to diagnosis the condition as early as possible. Proteinuria is an important symptom of preeclampsia, and repeated urine analysis to screen for the condition is part of the standard antenatal care. The purpose of this study was to determine the correlation between 4- and 24-hour urine total protein values to examine whether the 4-hour urine samples could be used for the diagnosis of proteinuria in hypertensive disorders of pregnancy. Methods: A cross-sectional study was performed on 110 pregnant (after gestational week 20 of pregnancy) patients who were hypertensive (blood pressure ≥140/90 mmHg) and had proteinuria as defined by positive urinary protein of at least 1+ in dipstick. Patients' urine samples were collected over 24 hours; the first 4 hours were collected separately from the next 20-hours. Patients, who did not collect the 24-hour urine, were excluded from the study. One hundred patients met the criteria, and were included in the study. The urine volume, total protein and creatinine levels of 4- and 24-hours samples were measured. The correlation between 4-hour and 24-hour samples was examined using Pearson correlation test. Results: Of the 100 patients, 42 had no proteinuria, 44 had mild proteinuria, and 14 had severe proteinuria. The urine protein values of 4-hour samples correlated with those of the 24-hours samples for patients with mild and severe forms of the disease (P<0.001, r=0.86). Conclusion: This study showed there was a correlation between 4-hour and 24-hour urine proteins. The finding indicates that a random 4-hour sample might be used for the initial assessment of proteinuri

Downregulation of Circulating miR-23a-3p, miR-101-3p And miR-let-7c In Women With Idiopathic Recurrent Pregnancy Loss

Abstract Recently, circulating microRNAs have attracted much attention because they can serve as reliable non-invasive diagnostic and prognostic biomarkers for pregnancy-related complications. So, this study aimed to quantify miR-23a-3p, miR-101-3p and miR-let-7c expression levels in plasma of patients with idiopathic recurrent pregnancy loss (iRPL) and healthy subjects and to evaluate their potential diagnostic value in iRPL patients. A total of 120 plasma samples were obtained from sixty women with a history of at least two consecutive iRPL and sixty healthy women without a history of miscarriage to evaluate the expression levels of the circulating miR-23a-3p, miR-101-3p and miR-let-7c by quantitative real-time polymerase chain reaction (qPCR) technique. The correlation between studied miRNAs and clinicopathological parameters was also assessed. Receiver operating characteristic (ROC) curve was plotted to determine the diagnostic accuracy of miR-23a-3p, miR-101-3p and miR-let-7c in iRPL. Our results showed that the miR-23a-3p expression level in plasma of iRPL patients was lower than those in healthy controls but without a statistically significant difference (P = 0.113). The expression levels of miR-101-3p and miR-let-7c were significantly downregulated in iRPL patients compared with healthy subjects (P &lt; 0.05). The expression levels of miR-23a-3p and miR-let-7c was negatively correlated with number of abortions in iRPL patients. We observed statistically significant positive correlation between miR-23a-3p and miR-101-3p (r = 0.478, P = 0.001), miR-23a-3p and miR-let-7c (r = 0.561, P = 0.0001), miR-101-3p and miR-let-7c (r = 0.533, P = 0.0001) in patients with iRPL. The current study provides evidence indicating that downregulation of miR-23a-3p, miR-101-3p and miR-let-7c may be associated with iRPL.</jats:p

Embryo-maternal cross-talk: key players in successful implantation and live birth rates

Abstract A successful pregnancy requires that the embryo and the endometrium undergo regulated alterations during the preimplantation phase, which can have positive effects on each other due to these adaptations. The focus of this review is to study the alterations in both the immune system and gene expression within the endometrium, along with exploring the embryonic surface and secretory markers crucial for successful implantation. Innate and adaptive immune cells in the endometrium phenotypically differ from immune cells in other human tissues. Research has demonstrated the significance of the communication network among these cells, as well as the involvement of cytokines and chemokines in the implantation process. In addition to immune cells, changes in endometrial gene expression, such as adhesion molecules, homeobox (HOX) genes, and progestagen-associated endometrial protein (PAEP), lead to developing a receptive endometrial phenotype. The embryo is another key actor in the implantation process, and its interaction with the endometrium relies on the expression of surface and secretory components before implantation. There are many surface factors, such as integrins, which contribute to establishing physical connections. In contrast, secretory factors, such as preimplantation factor (PIF) with paracrine and autocrine effects, are crucial in embryonic development and the preparation of the uterine environment

The Role of Heparin in Embryo Implantation in Women with Recurrent Implantation Failure in the Cycles of Assisted Reproductive Techniques (Without History of Thrombophilia).

Objective:Several studies have shown the improving effect of heparin on the outcomes of ART. Moreover, it has been reported that adding heparin in non-thrombophilia patients with RIF is useful.The aim of this study was to evaluate the beneficial effects of heparin on ART outcomes in women with history of recurrent implantation failure (RIF) and without history of congenital or acquired thrombophilia in a randomized, controlled clinical trial (RCT). Materials and methods:In this study, 100 patients with a history of two or more failures in implantation in cycles of ART were randomly subdivided into two groups of study and control. Patients of the control group just received the luteal phase support. In the patients of study group, in addition to the routine support of luteal phase following in vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI), 5000 units of subcutaneous heparin was administered for 15 days from the day of oocyte pick up. Pregnancy test (β-HCG) was done for patient of two groups 15 days after IVF.In the study group, pregnancy test was positive in 16 (32%) patients and negative in 34 (68%) patients. Results:In the control group, pregnancy test was positive in 15 (30%) patients and negative in 35 (70%) patients. There was no significant difference between two groups for the role of heparin in the pregnancy rate (p = 0.5).Although the effect of heparin on pregnancy was not statistically significant in this study, with regard to the numerous benefits of this agent, it is recommended to study its effects in further studies with lager sample size

The association of Treg and Th17 cells development factors and anti-TPO autoantibodies in patients with recurrent pregnancy loss

Abstract Objectives Thyroid autoimmunity is considered as the most prevalent autoimmune condition in women in fertility age. There are different clinical evidences indicating the association between thyroid autoimmunity and increased risk of RPL. This study aimed to analyze the association of Tregs and Th17 cells development factors and anti–thyroid peroxidase (anti-TPO) antibodies in RPL patients. Healthy controls (n = 36), TPO + controls (n = 25) and TPO + RPL (n = 32) participated in this study. After blood sampling, the frequency of Th17 and Tregs was evaluated using flow cytometry. Real-time PCR and ELISA was used to assess the status of Tregs and Th17 related transcription factors and cytokines in mRNA and protein level, respectively. Results TPO + RPL group showed a higher Th17 frequency compared to healthy controls and TPO + controls groups (p = 0.0002 and p = 0.04, respectively). Additionally, mRNA expression levels of RORγT and IL-17 were significantly higher in TPO + RPL compared to healthy controls and TPO + controls groups. In contrast, Foxp3 and TGFβ expression was lower in TPO + RPL. ELISA findings also indicated a significantly higher IL-17 and lower TGFβ secretion in TPO + RPL compared to healthy controls and TPO + controls. Thyroid autoimmunity should intensely be controlled specially in patients with RPL history