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International Journal of Molecular... Jun 2021Placental abruption is the separation of the placenta from the lining of the uterus before childbirth. It is an infrequent perinatal complication with serious...
Placental abruption is the separation of the placenta from the lining of the uterus before childbirth. It is an infrequent perinatal complication with serious after-effects and a marked risk of maternal and fetal mortality. Despite the fact that numerous placental abruption risk factors are known, the pathophysiology of this issue is multifactorial and not entirely clear. The aim of this review was to examine the current state of knowledge concerning the molecular changes on the maternal-fetal interface occurring in placental abruption. Only original research articles describing studies published in English until the 15 March 2021 were considered eligible. Reviews, book chapters, case studies, conference papers and opinions were excluded. The systematic literature search of PubMed/MEDLINE and Scopus databases identified 708 articles, 22 of which were analyzed. The available evidence indicates that the disruption of the immunological processes on the maternal-fetal interface plays a crucial role in the pathophysiology of placental abruption. The features of chronic non-infectious inflammation and augmented immunological cytotoxic response were found to be present in placental abruption samples in the reviewed studies. Various molecules participate in this process, with only a few being examined. More advanced research is needed to fully explain this complicated process.
Topics: Abruptio Placentae; Female; Humans; Placenta; Pregnancy; Thrombin
PubMed: 34205566
DOI: 10.3390/ijms22126612 -
Frontiers in Immunology 2021The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the...
The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal-fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell-cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts-DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal-fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal-fetal immune tolerance mediated by trophoblasts-DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.
Topics: Abortion, Habitual; Animals; Decidua; Female; Humans; Immune Privilege; Immunotherapy; Pregnancy; Trophoblasts
PubMed: 33717198
DOI: 10.3389/fimmu.2021.642392 -
Journal of Assisted Reproduction and... Dec 2020Chronic endometritis (CE) is a frequent hysteroscopic and histological finding which affects embryo transfer implantation during IVF-ICSI cycles. In particular, CE...
PURPOSE
Chronic endometritis (CE) is a frequent hysteroscopic and histological finding which affects embryo transfer implantation during IVF-ICSI cycles. In particular, CE impairs proper decidualization and, subsequently, implantation. Although this correlation has been clearly clarified, a pathophysiological explanation assembling all the studies performed has not been elucidated yet. For this reason, we have structured a systematic review considering all the original articles that evaluated a pathological element involved in CE and implantation impairment.
METHODS
The authors searched electronic databases and, after screening, collected 15 original articles. These were fully scanned and used to create a summary pathway.
RESULTS
CE is primarily caused by infections, which lead to a specific cytokine and leukocyte pattern in order to prepare the uterus to fight the noxa. In particular, the immunosuppression requested for a proper semi-allogenic embryo transfer implantation is converted into an immunoreaction, which hampers correct embryo implantation. Moreover, endometrial vascularization is affected and both irregular vessel density and luminal thickening and thrombosis reduce what we have first identified as endometrial flow reserve. Finally, incorrect uterine wave propagation could affect embryo contact with decidua.
CONCLUSION
This is the first summary of evidence on CE pathophysiology and its relationship with infertility. Understanding the CE pathophysiology could improve our knowledge in embryo transfer success.
Topics: Chronic Disease; Embryo Implantation; Endometritis; Female; Fertilization in Vitro; Humans; Infertility, Female; Pregnancy; Pregnancy Rate
PubMed: 33025403
DOI: 10.1007/s10815-020-01955-8 -
BioMed Research International 2020Preeclampsia (PE) is termed as a systemic disease that involves multiple organs; however, the exact etiology is still quite unclear. It is believed that the poor...
Preeclampsia (PE) is termed as a systemic disease that involves multiple organs; however, the exact etiology is still quite unclear. It is believed that the poor remodeling of uterine spiral arteries triggers PE, thereby causing failed placentation and producing inflammatory factors. The decline of blood flow results in lowering the nutrients and oxygen received by the fetus and augmenting the placental pressure in PE. Decidual immune cells, especially uterine natural killer (uNK) cells, are involved in the process of placentation. Decidual NK (dNK) cells significantly contribute to the vascular remodeling through the secretion of cytokines and angiogenic mediators in normal placental development. The abnormal activation of NK cells in both the peripheral blood and the decidua was counted among the causes leading to PE. The correlation existing between maternal killer cell immunoglobulin-like receptor (KIR) and HLA-C in trophoblast cells constitutes a robust evidence for the genetic etiology of PE. The combinations of the two kinds of gene systems, together with the KIR genotype in the mother and the HLA-C group in her fetus, are likely to exactly decide the pregnancy outcome. The women, who have the inappropriate match of KIR/HLA-C, are likely to be prone to the augmented risk of PE. However, the combinations of KIR/HLA-C in PE undergo ethnic changes. The extensive prospective research works in Europe, Asia, and Africa are required for providing more findings in PE patients.
Topics: Animals; Female; Fetus; Genotype; HLA-C Antigens; Humans; Killer Cells, Natural; Pre-Eclampsia; Pregnancy; Receptors, KIR; Trophoblasts; Uterine Artery; Uterus
PubMed: 32309433
DOI: 10.1155/2020/4808072 -
Journal of Reproductive Immunology Jun 2020Regulatory T cells (Tregs) are essential in tolerizing the maternal immune system toward the semi-allogeneic embryo. In this systematic review, we evaluated the...
Regulatory T cells (Tregs) are essential in tolerizing the maternal immune system toward the semi-allogeneic embryo. In this systematic review, we evaluated the association of levels and function of Tregs in peripheral blood and decidua with recurrent miscarriage (RM), defined as two unexplained miscarriages. We included 18 studies. Ten studies showed a significantly decreased level of Tregs in peripheral blood of non-pregnant women with RM, compared to controls (p < 0.05). In pregnant women with RM, levels of Tregs in the peripheral blood were significantly lower compared to control groups (p = 0.0004), as shown in nine studies. Moreover, seven studies described a decrease of Treg levels in the placenta of pregnant women with RM (p < 0.0001) compared to controls. Accordingly, the median of the relative changes (MRC) between cases and controls in the non-pregnant group (peripheral blood), and the two pregnant groups (peripheral blood and decidua) were -0.18 (-0.27-0), -0.26 (-0.35 to -0.17), and -0.52 (0.63--0.31), respectively. In addition to the assessment of Tregs by phenotype, six out of the 18 included studies investigated the functionality of these cells. These studies showed a lower inhibitory effect of Tregs cells on the proliferation of effector T cells of women with RM compared to fertile women. Also, the expression of IL-10 and TGF-beta was diminished. This systematic review shows that Treg levels and their function are significantly decreased in peripheral blood and decidua of pregnant and non-pregnant women with RM. This underlines the hypothesis that Tregs play a role in the pathogenesis of RM.
Topics: Abortion, Habitual; Female; Forkhead Transcription Factors; Humans; Immune Tolerance; Interleukin-10; Placenta; Pregnancy; T-Lymphocytes, Regulatory; Transforming Growth Factor beta
PubMed: 32199194
DOI: 10.1016/j.jri.2020.103105 -
Journal of Reproductive Immunology Nov 2019Immunoinflammatory response by innate immunity components is a field with increasing interest in understanding the mechanisms behind preterm labor (PTL).
BACKGROUND
Immunoinflammatory response by innate immunity components is a field with increasing interest in understanding the mechanisms behind preterm labor (PTL).
OBJECTIVES
Systematic review of the role of innate immunity in spontaneous PTL.
STUDY DESIGN
PubMed, Scopus, ClinicalTrials.gov and Web of Science were searched using pregnancy AND innate OR toll-like OR natural-killer OR dendritic AND delivery OR premature OR rupture of membranes.
MAIN OUTCOME MEASURES
All article titles and abstracts were evaluated by two individuals, based in strict predefined inclusion criteria. For relevant studies, title, abstract, and full text were assessed to identify PTL and innate immunity studies, excluding multiple pregnancies, cervical insufficiency and indicated PTL.
RESULTS
From 894 articles evaluated, 101 full texts articles were assessed independently. For this systematic review 44 studies were finally included. Toll-like receptors 2 and 4 mediated immune dysfunction and inflammation can result in PTL. Moreover, PTL is linked to high levels of CD14 monocytes; neutrophils seem important in inflammation-associated PTL and in pathological preterm premature rupture of membranes. Besides, decidual natural-killer cells and premature activation of dendritic cells may also participate in the etiology of PTL. Finally, dysregulation of maternal complement might increase the risk of PTL, characterized by high levels of innate lymphoid cells 2 and 3.
CONCLUSIONS
Further research is warranted to ascertain the precise role of innate immunity in PTL. Nonetheless, our results indicate that Toll-like receptors, monocytes, natural-killer cells, dendritic cells and complement have significant roles in PTL.
Topics: Decidua; Female; Fetal Membranes, Premature Rupture; Humans; Immunity, Innate; Inflammation; Pregnancy; Premature Birth
PubMed: 31581042
DOI: 10.1016/j.jri.2019.102616 -
The Cochrane Database of Systematic... Jul 2019Fetal fibronectin (FFN) is an extracellular matrix glycoprotein localized at the maternal-fetal interface of the amniotic membranes, between chorion and decidua, where...
BACKGROUND
Fetal fibronectin (FFN) is an extracellular matrix glycoprotein localized at the maternal-fetal interface of the amniotic membranes, between chorion and decidua, where it is concentrated in this area between decidua and trophoblast. In normal conditions, FFN is found at very low levels in cervicovaginal secretions. Levels greater than or equal to 50 ng/mL at or after 22 weeks have been associated with an increased risk of spontaneous preterm birth. In fact, FFN is one of the best predictors of preterm birth in all populations studied so far, and can help in selecting which women are at significant risk for preterm birth. This is an update of a review first published in 2008.
OBJECTIVES
To assess the effectiveness of management based on knowledge of FFN testing results for preventing preterm birth.
SEARCH METHODS
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register (7 September 2018), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 September 2018), and reference lists of retrieved studies.
SELECTION CRITERIA
Randomized controlled trials of pregnant women screened with FFN for risk of preterm birth. Studies included are based exclusively on knowledge of FFN results versus no such knowledge, and we have excluded studies including women with only positive or only negative FFN results.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach.
MAIN RESULTS
We identified 16 trials, of which six were eligible for inclusion. The six included studies randomized 546 women with singleton gestations and threatened preterm labor (PTL) at 23 0/7 to 34 6/7 weeks. A total of 277 women were randomized to knowledge and 269 to no knowledge of FFN. No trials were identified on asymptomatic women or multiple gestations.The risk of bias of included studies was mixed. For selected important outcomes, preterm birth before 37, 34, and 32 weeks, and maternal hospitalization, we graded the quality of the evidence and created a 'Summary of findings' table. For these outcomes, the evidence was graded as mainly low quality due to the imprecision of effect estimates.Management based on knowledge of FFN results may reduce preterm birth before 37 weeks (21.6%) versus controls without such knowledge (29.2%) (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.52 to 1.01; 4 trials; 357 women; low-quality evidence). However, management based on knowledge of FFN results may make little or no difference to preterm birth before 34 (RR 1.09, 95% CI 0.54 to 2.18; 4 trials; 357 women; low-quality evidence) or maternal hospitalization (RR 1.06, 95% CI 0.79 to 1.43; 5 trials; 441 women; low-quality evidence). The evidence for preterm birth before 32 weeks is uncertain because the quality was found to be very low (average RR 0.79, 95% CI 0.16 to 3.96; 4 trials; 357 women; very low-quality evidence).For all other outcomes, for which there were available data (preterm birth less than 28 weeks; gestational age at delivery (weeks); birthweight less than 2500 g; perinatal death; tocolysis; steroids for fetal lung maturity; time to evaluate; respiratory distress syndrome; neonatal intensive care unit (NICU) admission; and NICU days), knowledge of FFN results may make little or no difference to the outcomes.
AUTHORS' CONCLUSIONS
The evidence from this review suggests that management based on knowledge of FFN results may reduce preterm birth before 37 weeks. However, our confidence in this result is limited as the evidence was found to be of low quality. Effects on other substantive outcomes are uncertain due to serious concerns in study design, inconsistency, and imprecision of effect estimates. No trials were identified on asymptomatic women, or multiple gestations.Future studies are needed that include specific populations (e.g. singleton gestations with symptoms of preterm labor), a study group managed with a protocol based on the FFN results, and that report not only maternal but also important perinatal outcomes. Cost-effectiveness analyses are also needed.
Topics: Biomarkers; Female; Fibronectins; Gestational Age; Humans; Infant, Newborn; Obstetric Labor, Premature; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome, Newborn
PubMed: 31356681
DOI: 10.1002/14651858.CD006843.pub3 -
The Journal of Maternal-fetal &... Jun 2020Multiple factors and pathways have been reported as critical machineries for cell differentiation and survival during pregnancy; a number of them involve glycogen...
Multiple factors and pathways have been reported as critical machineries for cell differentiation and survival during pregnancy; a number of them involve glycogen synthase kinase (GSK) 3a/β. Several reports on GSK3's functional role exist; however, the specific role of GSK3 in reproductive tissues and its contribution to normal or abnormal parturition are still unclear. To fill this knowledge gap, a systematic review of literature was conducted to better understand the functional role of GSK3 in various intrauterine tissues during implantation, pregnancy, and parturition. We conducted a systematic review of literature on GSK3's expression and function reported between 1980 and 2017 in reproductive tissues during pregnancy using three electronic databases (Web of Science, Medline, and ClinicalTrials.gov). Study selection, data extraction, quality assessment and analyses were performed in duplicate by two independent reviewers. A total of 738 citations were identified; 80 were selected for full text evaluation and 25 were included for final review. GSK3's regulation and function were mostly studied in tissues and cells from placentas (12), fetuses (8), uteruses (6), and ovaries (2). GSK3 is primarily reported as a downstream responder of protein kinase B (AKT)-, Wnt-, and reactive oxygen species (ROS)-related pathways where it plays a critical role in cell survival and growth in reproductive tissues. Though GSK3 has been functionally linked to a number of biological processes in reproductive tissues, it has primarily been studied as a secondary signaler of various conserved cell signaling pathways. Lack of scientific rigor in studying GSK3's role in reproductive tissues makes this molecule's function still obscure. No studies have reported GSK3 in the cervix, and very few reports exist in myometrium and decidua. This systematic review suggests more functional and mechanistic studies focusing on GSK3 need to be conducted in reproductive biology.
Topics: Biomarkers; Female; Glycogen Synthase Kinase 3; Humans; Parturition; Pregnancy
PubMed: 30278798
DOI: 10.1080/14767058.2018.1531843 -
American Journal of Reproductive... Dec 2018Oxidative stress (OS) plays a role in uterine tissue remodeling during pregnancy and parturition. While p38 MAPK is an OS-response kinase, a precise functional role is...
Oxidative stress (OS) plays a role in uterine tissue remodeling during pregnancy and parturition. While p38 MAPK is an OS-response kinase, a precise functional role is unknown. Therefore, we conducted a systematic review of literature on p38 MAPK expression, activation, and function in reproductive tissues throughout pregnancy and parturition, published between January 1980 and August 2017, using four electronic databases (Web of Science, PubMed, Medline, and CoCHRANE). We identified 418 reports; 108 were selected for full-text evaluation and 74 were included in final review. p38 MAPK was investigated using feto-maternal primary or immortalized cells, tissue explants, and animal models. Western blot was most commonly used to report phosphorylated (active) p38 MAPK. Human placenta (27), chorioamniotic membranes (14), myometrium (13), decidua (8), and cervix (1) were the studied tissues. p38 MAPK's functions were tissue and gestational age dependent. Isoform specificity was hardly reported. p38 MAPK activity was induced by ROS or proinflammatory cytokines to promote cell signaling linked to cell fate, primed uterus, ripened cervix, and proinflammatory cytokine/chemokine production. In 35 years, reports on p38 MAPK's role during pregnancy and parturition are scarce and current literature is insufficient to provide a comprehensive description of p38 MAPK's mechanistic role during pregnancy and parturition.
Topics: Animals; Disease Models, Animal; Female; Gene Expression Regulation; Genitalia, Female; Humans; Inflammation; Oxidative Stress; Parturition; Pregnancy; Reproduction; Signal Transduction; p38 Mitogen-Activated Protein Kinases
PubMed: 30178469
DOI: 10.1111/aji.13047 -
The Journal of Maternal-fetal &... Feb 2020The identification of women at risk for preterm birth should allow interventions which could improve neonatal outcome. Fetal fibronectin, a glycoprotein which acts... (Meta-Analysis)
Meta-Analysis
The identification of women at risk for preterm birth should allow interventions which could improve neonatal outcome. Fetal fibronectin, a glycoprotein which acts normally as glue between decidua and amniotic membranes could be a good marker of impending labour when its concentration in cervicovaginal secretions between 22 and 36 weeks of gestation is ≥50 ng/mL. Many authors worldwide have tested this marker with many different methodologies and clinical settings, but conclusions about its clinical use are mixed. It is time for a comprehensive update through a systematic review and meta-analysis. We searched PubMed, Cochrane Library, and Embase, supplemented by manual search of bibliographies of known primary and review articles, international conference papers, and contact with experts from 1-1990 to 2-2018. We have selected all type of studies involving fetal fibronectin test accuracy for preterm delivery. Two authors independently extracted data about study characteristics and quality from identified publications. Contingency tables were constructed. Reference standards were preterm delivery before 37, 36, 35, 34, and 32 weeks, within 28, 21, 14, or 7 d and within 48 h. Data were pooled to produce summary likelihood ratios for positive and negative tests results. One hundred and ninety-three primary studies were identified allowing analysis of 53 subgroups. In all settings, none of the summary likelihood ratios were >10 or <0.1, thus indicating moderate prediction, particularly in asymptomatic women and in multiple gestations. The fetal fibronectin test should not be used as a screening test for asymptomatic women. For high-risk asymptomatic women, and especially for women with multiple pregnancies, the performance of the fetal fibronectin test was also too low to be clinically relevant. Consensual use as a diagnostic tool for women with suspected preterm labor, the best use policy probably still depends on local contingencies, future cost-effectiveness analysis, and comparison with other more recent available biochemical markers.
Topics: Female; Fibronectins; Humans; Obstetric Labor, Premature; Pregnancy
PubMed: 29914277
DOI: 10.1080/14767058.2018.1491031