Type and Location of Adenomyosis in Women with Recurrent Pregnancy Loss: A Transvaginal Ultrasonographic Assessment.

The current knowledge on adenomyosis as a risk factor for RPL is very scant. Overall 120 women were included in this retrospective observational study. They were divided in three groups each of which consisted of 40 subjects: Group 1: women with RPL who were diagnosed to have adenomyosis on transvaginal ultrasound (TVS); Group 2: patients with RPL without ultrasonographic findings of adenomyosis; Group 3: patients with ultrasound diagnosis of adenomyosis without RPL and at least one live birth pregnancy. The copresence of endometriosis was also investigated. Among women with RPL, patients with adenomyosis (Group 1) had higher number of pregnancy losses (p = 0.03) and lower age at first pregnancy loss (p = 0.03) than women without adenomyosis (Group 2). Moreover, they had more frequently primary RPL (p = 0.008). Adenomyosis of the inner myometrium was found more frequently (p = 0.04) in patients of Group 1 than in patients of Group 3 in which adenomyosis was mainly in the outer myometrium (p= 0.02). No differences were found in the severity of adenomyosis between these two groups of women. TVS findings for endometriosis were observed more frequently in women with adenomyosis without RPL (Group 3) than in the other two groups of patients. Adenomyosis can be a factor involved in RPL. Differences in adenomyosis localization are associated with different risks for RPL. Patients with RPL should be investigated for the presence of adenomyosis and also for the type and localization of the disease in the different myometrial layers.

When the Embryo Meets the Endometrium: Identifying the Features Required for Successful Embryo Implantation.

Evaluation of the optimal number of embryos, their quality, and the precise timing for transfer are critical determinants in reproductive success, although still remaining one of the main challenges in assisted reproduction technologies (ART). Indeed, the success of in vitro fertilization (IVF) treatments relies on a multitude of events and factors involving both the endometrium and the embryo. Despite concerted efforts on both fronts, the overall success rates of IVF techniques continue to range between 25% and 30%. The role of the endometrium in implantation has been recently recognized, leading to the hypothesis that both the "soil" and the "seed" play a central role in a successful pregnancy. In this respect, identification of the molecular signature of endometrial receptivity together with the selection of the best embryo for transfer become crucial in ART. Currently, efforts have been made to develop accurate, predictive, and personalized tests to identify the window of implantation and the best quality embryo. However, the value of these tests is still debated, as conflicting results are reported in the literature. The purpose of this review is to summarize and critically report the available criteria to optimize the success of embryo transfer and to better understand current limitations and potential areas for improvement.

High mobility group box 1 in women with unexplained recurrent pregnancy loss.

OBJECTIVES: To investigate whether high mobility group box 1 (HMGB1) is involved in unexplained recurrent pregnancy loss (uRPL). METHODS: Plasma levels of HMGB1 were measured by ELISA in non-pregnant women with (n=44) and without (n=53 controls) uRPL. Their platelets and plasma-derived microvesicles (MVs) were also assayed for HMGB1. Endometrial biopsies were taken in selected uRPL (n=5) and control women (n=5) and the tissue expression of HMGB1 was determined by western blot and immunohistochemistry (IHC). RESULTS: plasma levels of HMGB1 were significantly higher in women with uRPL than in control women. HMGB1 content in platelets and MVs obtained from women with uRPL was significantly higher than that obtained from control women. HMGB1 expression in endometrium was higher in tissues obtained from women with uRPL than in tissues obtained from control women. IHC analysis revealed that HMGB1 is expressed in endometrium with different patterns between uRPL and control women. CONCLUSIONS: HMGB1 could be involved in uRPL.

Diagnostic factors for recurrent pregnancy loss: an expanded workup.

PURPOSE: There is limited information on the risk factors for recurrent pregnancy loss (RPL). METHODS: In this study, a patient-based approach was used to investigate the possible involvement and relative relevance of a large number of diagnostic factors in 843 women with RPL who underwent an extensive diagnostic workup including 44 diagnostic factors divided into 7 major categories. RESULTS: The rates of abnormalities found were: (1) genital infections: 11.74%; (2) uterine anatomic defects: 23.72%; (3) endocrine disorders: 29.42%; (4) thrombophilias: 62%; (5) autoimmune abnormalities: 39.2%; (6) parental karyotype abnormalities 2.25%; (7) clinical factors: 87.78%. Six hundred and fifty-nine out of eight hundred and forty-three women (78.17%) had more than one abnormality. The mean number of pregnancy losses increased by increasing the number of the abnormalities found (r = 0.86949, P < 0.02). The factors associated with the highest mean number of pregnancy losses were cervical isthmic incompetence, anti-beta-2-glycoprotein-1 antibodies, unicornuate uterus, anti-prothrombin A antibodies, protein C deficiency, and lupus anticoagulant. The majority of the considered abnormalities had similar, non-significant prevalence between women with 2 versus ≥ 3 pregnancy losses with the exception of age ≥ 35 years and MTHFR A1298C heterozygote mutation. No difference was found between women with primary and secondary RPL stratified according to the number of abnormalities detected (Chi-square: 8.55, P = 0.07). In these women, the only factors found to be present with statistically different rates were age ≥ 35 years, cigarette smoking, and genital infection by Ureaplasma. CONCLUSION: A patient-based diagnostic approach in women with RPL could be clinically useful and could represent a basis for future research.

HLA-G and Recurrent Pregnancy Loss.

Placentation is an immunological compromise where maternal immune system cells and trophoblastic cells interact to reach an equilibrium condition. Although the cross talk between the two systems is complex and not completely understood, Human Leukocyte Antigen G (HLA-G), expressed on trophoblastic cell surfaces, seems to be one of the main molecules involved in the modulation of both local and systemic maternal immune response. The prevalence of recurrent pregnancy loss (RPL), probably underestimated, is 5% of all women who achieve pregnancy, and about 40-60% percent of RPL cases are unexplained. There is an immunological analogy between allograft rejection and miscarriage, and the purpose of this review is to describe how the HLA-G pathway alterations are involved in disrupting the immunologic balance and in increasing the risk of recurrent pregnancy loss.

Antinuclear antibodies positivity in women in reproductive age: From infertility to adverse obstetrical outcomes - A meta-analysis.

This systematic review and meta-analysis were designed to identify possible correlations between isolated serum antinuclear antibody (ANA) and (i) infertility in the context of in-vitro fertilization (IVF), (ii) idiopathic recurrent pregnancy losses (RPL), and (iii) second/ third trimester pregnancy complications. We performed a systematic review and meta-analysis of the literature in PubMed Library database from inception to March 2022 following PRISMA guidelines. Our pooled results showed a lower pregnancy rate among ANA-positive women undergoing IVF/ICSI compared to ANA-negative women undergoing the same procedures (279/908 versus 1136/2347, random effect, odds ratio -OR- 0.50, 95% confidence interval -CI- 0.38-0.67, p 0.00001, I2 = 58%). We also reported a higher miscarriage rate among ANA-positive compared to ANA-negative women (48/223 versus 109/999, random effect, OR: 3.25 95% CI: 1.57-6.76, p = 0.002, I2 = 61%) and a lower implantation rate (320/1489 versus 1437/4205, random effect, OR: 0.51, 95% CI: 0.36-0.72, p = 0.0001, I2 = 78%). Regarding RPL, pooled results demonstrated a higher prevalence of ANA-positivity in RPL women compared to controls (698/2947 versus 240/3145, random effect, OR: 3.22, 95% CI: 2.12-4.88, p 0.00001, I2 77%), either using > 2 or > 3 pregnancy losses threshold for defining RPL. Heterogeneity of reporting outcome did not allow a quantitative analysis and led to no clear demonstration of an effect of serum ANA on the incidence of stillbirth, preeclampsia and hypertensive disorders. In conclusion, the unfavorable effect of serum ANA was observed in women following IVF. Similarly, ANA were associated with the risk of RPL, while data were unconclusive in terms of late pregnancy complications.

Clinical significance of endometrial abnormalities: an observational study on 1020 women undergoing hysteroscopic surgery.

BACKGROUND: The overall clinical significance of the finding of endometrial abnormalities in predicting premalignant/malignant endometrial lesions is still incompletely determined. For this reason the management, surgical or expectant, of women in which an endometrial abnormality has been detected is debated. METHODS: This retrospective study was carried out on 1020 consecutive women, 403 premenopausal and 617 postmenopausal, who underwent operative hysteroscopy in a University Hospital for suspected endometrial abnormalities, which were detected by transvaginal ultrasound (TVS) and/or office hysteroscopy. In these women, the clinical characteristics and findings at TVS and hysteroscopy were evaluated in relation to the presence/absence of premalignant/malignant endometrial lesions at pathology report. RESULTS: The clinical characteristics considered were significantly different when the study women were compared according to their menopausal status. Premalignant/malignant lesions were found in 34/1020 (3.33%) women. Complex hyperplasia with atypia and endometrial cancer were detected in 22 (2.15%) and 12 (1.17%) cases, respectively. The postmenopausal women had a significantly higher risk of premalignant/malignant lesions than premenopausal women (O.R. = 5.098 [95% C.I.: 1.782-14.582], P < 0.005). This risk was even higher when abnormal uterine bleeding (AUB) was present (O.R. = 5.20 [95% C.I.: 2.38-11.35], P < 0.0001). The most significant associations with premalignant/malignant endometrial lesions were BMI, AUB in postmenopause, overall polyp size, atypical aspect of endometrial polyps at hysteroscopy, postmenopausal status, diabetes mellitus and patient age. CONCLUSIONS: The results of the present study suggest that the proper, aggressive or expectant, management of endometrial abnormalities should take into account both ultrasonographic and hysteroscopic findings together with the specific clinical characteristics of the patients.

α-Lipoic Acid and its Role on Female Reproduction.

α-lipoic Acid (ALA), also known as thioctic acid, is a biological thiol present in all types of prokaryotic and eukaryotic cells. It has been shown that ALA or its reduced form, DHLA, has several positive effects on human health, acting as a biological antioxidant, metal chelator and detoxifying agent. It is able to reduce the oxidation of several antioxidant agents like glutathione, vitamins C and E, and modulate insulin and NF-kB signaling pathways. ALA's pharmacological effects are not only related to its antioxidant properties but it shows an anti-inflammatory action. In particular, ALA is able to reduce inflammasome activity, the pro-inflammatory cytokine levels, such as TNF-α, IL-1ß, IL-6, IL-18 and IL-17, interferon (INF)-γ as well as the production of Vascular and Intercellular cell adhesion protein (VCAM-1 and ICAM-1). In recent papers, ALA has been indicated as a possible therapeutic approach to several endocrine or inflammatory disorders affecting female reproduction. Aim of the current review was to assess whether ALA has an evidence- based beneficial role on gynecological and obstetrical diseases such as polycystic ovary syndrome (PCOS), endometriosis, and miscarriage.

Clinical consequences of defective decidualization.

Decidualization is characterized by a series of genetic, metabolic, morphological, biochemical, vascular and immune changes occurring in the endometrial stroma in response to the implanting embryo or even before conception and involves the stromal cells of the endometrium. It is a fundamental reproductive event occurring in mammalian species with hemochorial placentation. A growing body of experimental and clinical evidence strongly suggests that defective or disrupted decidualization contributes to the establishment of an inappropriate maternal-fetal interface. This has relevant clinical consequences, ranging from recurrent implantation failure and recurrent pregnancy loss in early pregnancy to several significant complications of advanced gestation. Moreover, recent evidence indicates that selected diseases of the endometrium, such as chronic endometritis and endometriosis, can have a detrimental impact on the decidualization response in the endometrium and may help explain some aspects of the reduced reproductive outcome associated with these conditions. Further research efforts are needed to fully understand the biomolecular mechanisms ans events underlying an abnormal decidualization response. This will permit the development of new diagnostic and therapeutic strategies aimed to improve the likelihood of achieveing a successful pregnancy.

Erratum to "Uterine Tumor Resembling Ovarian Sex Cord Tumors Type II with Vaginal Vault Recurrence".

[This corrects the article DOI: 10.1155/2019/5231219.].

Pregnancy-Related Complications in Women with Recurrent Pregnancy Loss: A Prospective Cohort Study.

The aim of this prospective cohort study was to determine whether women with recurrent pregnancy loss (RPL) have an increased risk of pregnancy complications compared to normal pregnant women. A total of 1092 singleton pregnancies were followed, 431 in women with RPL and 661 in normal healthy women. The prevalence of the following complications was observed: threatened miscarriage, miscarriage, cervical insufficiency, chromosomal/genetic abnormalities, fetal anomalies, oligohydramnios, polyhydramnios, fetal growth restriction, intrauterine fetal death, gestational diabetes mellitus (GDM), preeclampsia, placenta previa, abruptio placentae, pregnancy-related liver disorders, and preterm premature rupture of the membranes. The odds ratio and 95% CI for each pregnancy complication considered were determined by comparing women with RPL and normal healthy women. Women with RPL had an overall rate of pregnancy complications higher than normal women (OR = 4.37; 95% CI: 3.353-5.714; p < 0.0001). Their risk was increased for nearly all the conditions considered. They also had an increased risk of multiple concomitant pregnancy complications (OR = 4.64; 95% CI: 3.10-6.94, p < 0.0001). Considering only women with RPL, women with ≥3 losses had a higher risk of pregnancy complications than women with two losses (OR = 1.269; 95% CI: 1.112-2.386, p < 0.02). No differences were found in the overall risk of pregnancy complications according to the type, explained or unexplained, of RPL. Women with secondary RPL had an increased risk of GDM than women with primary RPL. Pregnancy in women with RPL should be considered at high risk.

A rare case of vulvar superficial myofibroblastoma associated with ambigous and unusual differential diagnosis.

•Superficial myofibroblastoma of the Labia Majora.•Differential diagnosis between vulvar superficial myofibroblastoma and cyst/hydrocele of Nuck duct.•Differential diagnosis between vulvar superficial myofibroblastoma and inguinal/crural hernia.

First-trimester trophoblasts obtained by chorionic villus sampling maintain tolerogenic and proteomic features in successful pregnancies despite a history of unexplained recurrent pregnancy loss.

PROBLEM: While there are several known causes for recurrent pregnancy loss (RPL), about 50% are unexplained (uRPL), and in these cases, an aberrant immune regulation seems to be involved. Although fetally derived trophoblast cells have a key role in immune regulation, it is difficult to study their immune function during pregnancy, and it is not known whether trophoblast function may be an inherent aberration in uRPL or whether it is associated with the outcome of the current pregnancy. METHOD OF STUDY: Chorionic villus sampling (CVS) was performed for clinical indications at 12 weeks of gestation. Superfluous materials, divided in small explants, were cultured for 20-24 hours, and supernatants (conditioned medium) were collected from 36 women with singleton normal pregnancies, of whom 9 women had a history of RPL. The secreted immune protein profile was measured by proximity extension assay, and the conditioned medium was further used in functional ex vivo models to assess ability to polarize blood monocytes and CD4+ T cells into immune regulatory phenotypes, as detected by flow cytometry. RESULTS: Conditioned medium from chorionic villi, human fetally derived placental tissue, was able to induce a decidual-type of M2-like macrophages, as well as an expansion of Treg cells ex vivo, both in women with uRPL and in control women. The preserved immunological properties were confirmed by a maintained immune protein profile in RPL compared with controls. CONCLUSION: Trophoblasts in an ex vivo model maintain tolerogenic and proteomic profile features in successful pregnancies, despite a previous history of RPL.

Time-to-Pregnancy in Women with Unexplained Recurrent Pregnancy Loss: A Controlled Study.

To determine whether differences are present in the time-to-pregnancy (TTP) between women with unexplained recurrent pregnancy loss (uRPL) and control women, in this case-control, retrospective study, carried out in tertiary university hospitals, the TTP, defined as the months needed to reach pregnancy from when the woman started to try to conceive, was determined in 512 women, 207 of which were diagnosed as having uRPL and 305 were normal healthy control women. The specific TTPs for each pregnancy, stratified by order of pregnancy occurrence, were also determined. Pregnancy rates by time were calculated by using the Kaplan-Meier method to construct the survival curves. The age at which the pregnancies occurred was determined. Comparisons were carried out between women with uRPL and controls. Overall, 1192 pregnancies occurred and were analyzed. Mean TTP in uRPL women was shorter than in controls (P < 0.001) when all the pregnancies were considered. Similarly, it was shorter in the first, second, third, and fifth pregnancy. The pregnancy rates of uRPL women were shorter than that of control women for the first three pregnancies, for which the numbers of subjects allowed the comparisons to be made. These findings were observed despite maternal age of uRPL women was higher than that of control women. TTP is shorter in uRPL than in normal women. This finding clinically supports to the hypothesis that women with uRPL could be, at least in early stages of pregnancy, more fertile or receptive toward the implanting embryo than healthy women.

Uterine and placental blood flow indexes and antinuclear autoantibodies in unexplained recurrent pregnancy loss: should they be investigated in pregnancy as correlated potential factors? A retrospective study.

BACKGROUND: The potential role of antinuclear antibodies (ANA) in recurrent pregnancy loss (RPL) pathogenesis is still debated, although some evidences suggest that they could affect pregnancy outcome, leading to a higher miscarriage rate in these patients. A hypothesized mechanism is through changes in uterine flow in pre-conceptional stage, by modifying endometrial receptivity in RPL. However, scant data are available, in pregnancy, about their role in RPL placental perfusion, also in relation to its potential treatments, such as low molecular weight heparin (LMWH). The aim of this study is to retrospectively further investigate the correlation between two-dimensional (2D) and three-dimensional (3D) uterine and placental flow indexes and the presence or the absence of ANA in women with unexplained RPL (uRPL), treated or not treated with LMWH. METHODS: 2D Doppler measurement of pulsatility index (PI) of the uterine arteries and 3D ultrasonography determination of vascularization index (VI), flow index (FI) and vascularization flow index (VFI) was carried out with the aid of the virtual organ computer-aided analysis (VOCAL) technique in LMWH treated (n 24) and not treated-uRPL patients (n 20) and in the relative control group (n 27), each group divided in ANA+ and ANA- subgroups. Serum assay for the presence of ANA was performed in all women. RESULTS: No differences were found in PI, VFI and VI values, by comparing the different groups. A difference in VI values was found for ANA- patients between RPL women not treated with LMWH and the treated ones (p = 0,01), which have lower VI values and similar to controls. By considering only ANA- treated and not treated RPL patients, the ROC curve shows an area of 0,80 and at the VI cut-off of 11,08 a sensitivity of 85% and a specificity of 67%. CONCLUSIONS: LMWH could exert a potential beneficial effect in restoring the physiological blood flow supply in terms of VI in uRPL ANA- status, suggesting to include ANA and VI investigations in the RPL diagnostic algorithm in a research context, since further studies are needed to clarify this challenging hypothesis in order to try to ameliorate ANA and abnormal placental vascularization negative influence on RPL pregnancy outcome .

Effect of chorionic villus sampling on placental volume and vascularization in the first trimester of pregnancy.

Objective: To evaluate the effects of chorionic villus sampling (CVS) on placental volume (PV), perfusion, and vasculature in the first trimester of pregnancy.Method: Uterine artery pulsatility index (PI), PV, vascularization index (VI), flow index (FI), and Vascularization Flow Index (VFI) were serially measured in 38 pregnant women who underwent CVS. Thirty-eight women who did not undergo invasive prenatal diagnosis were recruited as controls.Results: CVS was associated with a mild reduction of PI, a reduction of placental VI, FI, and VFI and with an increase in PV detected one week after the procedure. The outcome of pregnancy was similar between women of the two groups.Conclusion: Our findings showed that CVS is associated with mild placental vascular and morphological changes. However, these changes do not seem to be associated with adverse outcome.

Longitudinal Changes of Subpubic Arch Angle throughout Pregnancy.

OBJECTIVE: The objective of this study is to assess whether the subpubic arch angle (SPA) changes throughout pregnancy. MATERIALS AND METHODS: We recruited a group of nulliparous women in the first trimester of pregnancy. Each woman was assessed 3 times throughout pregnancy, once per each trimester, by measuring SPA using a recently described highly reproducible three-dimensional transperineal ultrasound (linear reconstruction with contrast enhancement technique; OmniView-volume contrast imaging). Repeated measures analysis of variance was used to study SPA changes during pregnancy. RESULTS: Overall, 97 women were included in the final analysis. SPA increased progressively and significantly (F = 27.824, p < 0.001) from the first to the second trimester (121.8 ± 8.7 vs. 123.5 ± 8.4°, p = 0.01) and from the second to the third trimester (123.5 ± 8.4 vs. 125.3 ± 8.1°, p = 0.01). CONCLUSION: SPA width increases progressively but slightly during pregnancy. Although this finding is interesting, the extremely small difference detected is unlikely to be clinically significant.

The pathogenic role of autoantibodies in recurrent pregnancy loss.

In the present manuscript, we review the recent research investigating the pathogenic association between most studied autoantibodies and recurrent pregnancy loss. Pregnancy loss represents a common obstetric complication occurring in about 15%-25% of all clinically recognized pregnancies. The recurrence of pregnancy loss identifies a distinct clinical entity, that is recurrent pregnancy loss (RPL), affecting about 2%-4% of couples. Several factors, including age, chromosomal abnormalities, uterine anomalies, thrombophilic disorders, endocrinopathies, hormonal and metabolic disorders, infections, sperm quality, and lifestyle issues, are involved in RPL. The role of autoantibodies in RPL is only partially determined. In some cases (antiphospholipid antibodies [aPL]), their involvement is well established. In other cases (anti-thyroid autoantibodies, antinuclear, anti-transglutaminase, and anti-endomysial antibodies), it is still debated, despite multiple, although not fully conclusive, evidences strongly suggest a possible involvement in RPL. Further extensive research is needed to definitively confirm or exclude their actual role.

Molecular Signaling Regulating Endometrium-Blastocyst Crosstalk.

Implantation of the embryo into the uterine endometrium is one of the most finely-regulated processes that leads to the establishment of a successful pregnancy. A plethora of factors are released in a time-specific fashion to synchronize the differentiation program of both the embryo and the endometrium. Indeed, blastocyst implantation in the uterus occurs in a limited time frame called the "window of implantation" (WOI), during which the maternal endometrium undergoes dramatic changes, collectively called "decidualization". Decidualization is guided not just by maternal factors (e.g., estrogen, progesterone, thyroid hormone), but also by molecules secreted by the embryo, such as chorionic gonadotropin (CG) and interleukin-1ß (IL-1 ß), just to cite few. Once reached the uterine cavity, the embryo orients correctly toward the uterine epithelium, interacts with specialized structures, called pinopodes, and begins the process of adhesion and invasion. All these events are guided by factors secreted by both the endometrium and the embryo, such as leukemia inhibitory factor (LIF), integrins and their ligands, adhesion molecules, Notch family members, and metalloproteinases and their inhibitors. The aim of this review is to give an overview of the factors and mechanisms regulating implantation, with a focus on those involved in the complex crosstalk between the blastocyst and the endometrium.

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal-fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.