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Human Reproduction Update Jun 2022Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal-foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls.
OBJECTIVE AND RATIONALE
The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls.
SEARCH METHODS
MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger's test.
OUTCOMES
Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM.
WIDER IMPLICATIONS
The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.
Topics: Abortion, Habitual; Cytokines; Embryo Implantation; Endometrium; Female; Humans; Killer Cells, Natural; Placenta; Pregnancy; Uterus
PubMed: 35265977
DOI: 10.1093/humupd/dmac006 -
Frontiers in Immunology 2022Recurrent spontaneous abortion (RSA) is defined as two or more pregnancy loss, affecting the happiness index of fertility couples. The mechanisms involved in the...
Recurrent spontaneous abortion (RSA) is defined as two or more pregnancy loss, affecting the happiness index of fertility couples. The mechanisms involved in the occurrence of RSA are not clear to date. The primary problem for the maternal immune system is how to establish and maintain the immune tolerance to the semi-allogeneic fetuses. During the pregnancy, decidual macrophages mainly play an important role in the immunologic dialogue. The purpose of this study is to explore decidual macrophages, and to understand whether there is a connection between these cells and RSA by analyzing their phenotypes and functions. Pubmed, Web of Science and Embase were searched. The eligibility criterion for this review was evaluating the literature about the pregnancy and macrophages. Any disagreement between the authors was resolved upon discussion and if required by the judgment of the corresponding author. We summarized the latest views on the phenotype, function and dysfunction of decidual macrophages to illuminate its relationship with RSA.
Topics: Pregnancy; Humans; Female; Decidua; Abortion, Habitual; Macrophages; Abortion, Induced
PubMed: 36569856
DOI: 10.3389/fimmu.2022.994888 -
BMC Medical Genomics Jun 2015Preterm birth (PTB), or birth before 37 weeks of gestation, is the leading cause of newborn death worldwide. PTB is a critical area of scientific study not only due to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preterm birth (PTB), or birth before 37 weeks of gestation, is the leading cause of newborn death worldwide. PTB is a critical area of scientific study not only due to its worldwide toll on human lives and economies, but also due to our limited understanding of its pathogenesis and, therefore, its prevention. This systematic review and meta-analysis synthesizes the landscape of PTB transcriptomics research to further our understanding of the genes and pathways involved in PTB subtypes.
METHODS
We evaluated published genome-wide pregnancy studies across gestational tissues and pathologies, including those that focus on PTB, by performing a targeted PubMed MeSH search and systematically reviewing all relevant studies.
RESULTS
Our search yielded 2,361 studies on gestational tissues including placenta, decidua, myometrium, maternal blood, cervix, fetal membranes (chorion and amnion), umbilical cord, fetal blood, and basal plate. Selecting only those original research studies that measured transcription on a genome-wide scale and reported lists of expressed genetic elements identified 93 gene expression, 21 microRNA, and 20 methylation studies. Although 30 % of all PTB cases are due to medical indications, 76 % of the preterm studies focused on them. In contrast, only 18 % of the preterm studies focused on spontaneous onset of labor, which is responsible for 45 % of all PTB cases. Furthermore, only 23 of the 10,993 unique genetic elements reported to be transcriptionally active were recovered 10 or more times in these 134 studies. Meta-analysis of the 93 gene expression studies across 9 distinct gestational tissues and 29 clinical phenotypes showed limited overlap of genes identified as differentially expressed across studies.
CONCLUSIONS
Overall, profiles of differentially expressed genes were highly heterogeneous both between as well as within clinical subtypes and tissues as well as between studies of the same clinical subtype and tissue. These results suggest that large gaps still exist in the transcriptomic study of specific clinical subtypes as well in the generation of the transcriptional profile of well-studied clinical subtypes; understanding the complex landscape of prematurity will require large-scale, systematic genome-wide analyses of human gestational tissues on both understudied and well-studied subtypes alike.
Topics: DNA Methylation; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genome-Wide Association Study; Humans; Phenotype; Placenta; Pregnancy; Premature Birth; Risk Factors; Term Birth; Transcriptome
PubMed: 26044726
DOI: 10.1186/s12920-015-0099-8 -
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 -
Frontiers in Immunology 2021Several studies report the role of Regulatory T-cells (Tregs) in the pathophysiology of pregnancy adverse outcomes. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several studies report the role of Regulatory T-cells (Tregs) in the pathophysiology of pregnancy adverse outcomes.
OBJECTIVE
The aim of this systematic review and meta-analysis was to determine whether there is an association between regulatory T cell levels and pregnancy adverse outcomes (PAOs), including pre-eclampsia and preterm birth (PTB).
METHOD
Literature searches were conducted in PubMed/MEDLINE, Embase, and Cochrane CENTRAL databases. Inclusion criteria were original articles (clinical trials, case-control studies and cohort studies) comparing Tregs, sampled from the decidua or maternal blood, in healthy pregnant women women with pre-eclampsia or PTB. The outcome was standardised mean difference (SMD) in Treg numbers. The tau-squared (Tau²), inconsistency index (I²), and chi-squared (χ²) test quantified heterogeneity among different studies. Analyses were performed in RevMan software V.5.4.0 for Mac using a random-effects model with outcome data reported with 95% confidence intervals (CI). This study was prospectively registered with PROSPERO (CRD42020205469). PRISMA guidelines were followed.
RESULTS
From 4,085 unique studies identified, 36 were included in qualitative synthesis, and 34 were included in quantitative synthesis (meta-analysis). In total, there were 1,783 participants in these studies: healthy controls=964, pre-eclampsia=759, PTB=60. Thirty-two studies compared Tregs in healthy pregnant women and women with pre-eclampsia, and 30 of these sampled Tregs from peripheral blood showing significantly higher Treg numbers in healthy pregnancies (SMD; 1.46; 95% CI, 1.03-1.88; I²=92%). Four studies sampled Tregs from the maternal decidua showing higher Tregs in healthy pregnancies (SMD, 0.76; 95% CI, -0.13-1.65; I²=84%). No difference was found in the number of Tregs between early late pre-eclampsia (SMD,-1.17; 95% CI, -2.79-0.44; I²=94%). For PTB, two studies compared Tregs sampled from the peripheral blood with a tendency for higher Tregs in healthy pregnancies but this did not reach significance (SMD, 2.18; 95% CI, -1.34-5.70; I²=96%). Subcohort analysis using Treg analysis (flow cytometry qPCR immunofluorescence tissue staining) showed similar associations.
CONCLUSION
Lower Tregs in pregnancy, sampled from the maternal peripheral blood, are associated with pre-eclampsia. There is a need for further studies to confirm a relationship between low Tregs and PTB. As the precise mechanisms by which Tregs may mediate pre-eclampsia and PTB remain unclear, further fundamental research is necessary to elucidate the underlying processes and highlight the causative link.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, identifier CRD42020205469.
Topics: Adult; CD4 Lymphocyte Count; Female; Humans; Phenotype; Predictive Value of Tests; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk Assessment; Risk Factors; T-Lymphocytes, Regulatory
PubMed: 34777347
DOI: 10.3389/fimmu.2021.737862 -
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 -
Journal of Trace Elements in Medicine... Jul 2024Contamination with heavy metals (HM) has great environmental consequences in the environment due to lack of biodegradation, in addition, accumulation in living beings... (Review)
Review
STATEMENT OF PROBLEM
Contamination with heavy metals (HM) has great environmental consequences in the environment due to lack of biodegradation, in addition, accumulation in living beings causes defects in tissues and organs, deteriorating their function and inducing a wide spectrum of diseases. Human biomonitoring consists of the periodic measurement of a certain chemical substance or metabolite in a particular population, using matrices that can be acute or chronic. Teeth are chronic matrices that have great characteristics of resistance and chronological storage of information. This review aims to identify the mechanisms, spatial location, and affinity of HM within teeth, along with understanding its applicability as a chronological record matrix in the face of HM contamination.
MATERIAL AND METHODS
A systematic search review was performed using the PubMed/Medline, Web of Science, and Scopus metasearch engines, and the terms "teeth" OR "dental" OR "tooth" AND "heavy metals" were intersected. Complete articles are included in Spanish, English and Portuguese without time restrictions, involving studies in humans or in vitro; Letters to the editor, editorials and those that did not refer to information on the incorporation and relationship of HM with the teeth were excluded.
RESULTS
837 published articles were detected, 91 were adjusted to the search objective, and 6 were manually included. Teeth are structures with a great capacity for information retention in the face of HM contamination due to low physiological turnover and their long processes of marked formations by developmental biorhythm milestones such as the neonatal line (temporal reference indicator). The contamination mechanisms inside the tooth are linked to the affinity of hydroxyapatite for HM; this incorporation can be in the soft matrix during the apposition phase or as part of the chemical exchanges between hydroxyapatite and the elements of the environment.
CONCLUSION
The teeth present unique characteristics of great resistance and affinity for HM, as well as a chronological biomarker for human biomonitoring, so they can be used as means of expertise or evidence to confirm or rule out a fact of environmental characteristics in the legal field.
Topics: Humans; Biomarkers; Metals, Heavy; Tooth, Deciduous; Dentition, Permanent
PubMed: 38547726
DOI: 10.1016/j.jtemb.2024.127435 -
Ultrasound in Obstetrics & Gynecology :... Aug 2015To evaluate the diagnostic accuracy of ultrasound in predicting the location of an intrauterine pregnancy before visualization of the yolk sac is possible. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To evaluate the diagnostic accuracy of ultrasound in predicting the location of an intrauterine pregnancy before visualization of the yolk sac is possible.
METHODS
This was a systematic review conducted in accordance with the PRISMA statement and registered with PROSPERO. We searched MEDLINE, EMBASE and The Cochrane Library for relevant citations. Studies were selected in a two-stage process and their data extracted by two reviewers. Accuracy measures were calculated for each ultrasound sign, i.e. gestational sac, double decidual sac sign, intradecidual sign, chorionic rim sign and yolk sac. Individual study estimates were plotted in summary receiver-operating characteristics curves and forest plots for examination of heterogeneity. The quality of included studies was assessed.
RESULTS
Seventeen studies including 2564 women were selected from 19 959 potential papers. Following meta-analysis, the presence of a gestational sac on ultrasound examination was found to predict an intrauterine pregnancy with a sensitivity of 52.8% (95% CI, 38.2-66.9%) and specificity of 97.6% (95% CI, 94.3-99.0%). The corresponding performance of the double decidual sac sign, intradecidual sign, chorionic rim sign and yolk sac were: 81.8% (95% CI, 68.1-90.4%) and 97.3% (95% CI, 76.1-99.8%); 66.1% (95% CI, 58.9-72.8%) and 100% (95% CI, 91.0-100%); 79.9% (95% CI, 73.0-85.7%) and 97.1% (95% CI, 89.9-99.6%); and 42.2% (95% CI, 27.7-57.9%) and 100% (95% CI, 54.1-100%), respectively.
CONCLUSION
Visualization of a gestational sac, double decidual sac sign, intradecidual sign or chorionic rim sign increases the probability of an intrauterine pregnancy but is not as accurate for diagnosis as the detection of the yolk sac. However, the findings were limited by the small number and poor quality of the studies included and heterogeneity in the index test and reference standard.
Topics: Decidua; Female; Gestational Sac; Humans; Pregnancy; Pregnancy Trimester, First; Pregnancy, Ectopic; Ultrasonography, Prenatal; Yolk Sac
PubMed: 25393076
DOI: 10.1002/uog.14725 -
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 -
Expert Review of Clinical Immunology 2016Regulatory T-cells (Tregs) are key players in successful pregnancy and their deficiencies are implicated in pregnancy complications such as preeclampsia (PE), but the... (Review)
Review
Regulatory T-cells (Tregs) are key players in successful pregnancy and their deficiencies are implicated in pregnancy complications such as preeclampsia (PE), but the results are inconsistent among studies. This study aims to compile an overview of the studies about the associations of Tregs and PE risk and to provide recommendations for future research. A sensitive search of three databases including PubMed, Scopus and Google scholar (from 1995 to January 9, 2015) identified 636 unique titles. An accurate process of study selection, data extraction and method qualification were independently conducted by authors on retrieved papers. Seventeen papers met the inclusion criteria and were included in quality assessment. Regarding the source of Tregs, 14 studies assessed Tregs in peripheral blood, 2 studies in peripheral blood and decidua and one study in peripheral blood and umbilical cord blood. Despite variation in the combinations of markers and other aspects of the studies designs, remarkable constancy in the results of studies that measured Tregs as CD4+FoxP3+ or CD4+CD25+FoxP3+ cells (but not CD4+CD25(high/low)FoxP3+ markers) was found, which in broad terms showed a shift towards fewer Treg cells in PE. This review revealed an association between lower percentage of circulating CD4+FoxP3+ or CD4+CD25+FoxP3+ Tregs and the risk of PE. Given the above issue and regarding the high consistency of studies on reduction of suppressive activity of Tregs in PE, we have proposed a model in which the Tregs deficiency is a reflection of immune endocrine imbalance, which reverses maternal tolerance and results in development of preeclampsia.
Topics: Female; Forkhead Transcription Factors; Humans; Immune Tolerance; Interleukin-2 Receptor alpha Subunit; Lymphocyte Count; Pre-Eclampsia; Pregnancy; T-Lymphocytes, Regulatory
PubMed: 26580672
DOI: 10.1586/1744666X.2016.1105740