Relationship Between Anatomic Features of the Placenta, the Type of Abnormal Placental Cord Insertion and Adverse Pregnancy Outcomes in Singleton Pregnancies: A Prospective Observational Study.

INTRODUCTION: This study aimed to evaluate the potential value of placental anatomic features and various types of normal and abnormal cord insertion types in predicting adverse maternal-fetal outcomes in singleton pregnancies. We also tried to assess the association between these outcomes and various types of placental cord insertion. METHOD: This prospective observational study was performed on singleton pregnancies. For each patient placental features including diameter, thickness, type of cord insertion, and the shortest distance between the cord insertion point and placental edge were recorded. The relationship between these factors and the development of multiple adverse pregnancy outcomes including preterm labor, intrauterine fetal death (IUFD), and the rate of neonatal intensive care unit (NICU) admissions were evaluated and reported. RESULTS: Overall 308 patients were enrolled in the study. Smoker mothers had significantly smaller placentas (P-value = .008), and those with lower diameter placentas were more likely to suffer from IUFD (P-value = .0001). Shorter placental cord insertion distances led to more episodes of preterm labor (P-value = .057). Eccentric-type placental cord insertion was significantly associated with the development of preeclampsia (P-value = .006). DISCUSSION: Abnormalities in placental diameter and cord insertion can lead to significant maternal-fetal complications including preterm labor, IUFD, and preeclampsia.

MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL FEATURES OF PLACENTAL DAMAGE DUE TO THE INCORPORATION OF 137Cs. / MORFOLOGIChNI TA IMUNO-GISTOKhIMIChNI OSOBLYVOSTI POShKODZhENNIa PLATsENTY VNASLIDOK INKORPORUVANNIa 137Cs.

OBJECTIVE: to investigate the morphological and immunohistochemical features of placental damage due to theincorporation of 137Cs depending on the scenario of pregnancy completion. MATERIALS AND METHODS: The study material consisted of placentas from 60 women with reproductive losses inanamnesis and signs of termination of the current pregnancy (first group) and placental samples from 30 women with an uncomplicated gestation and an unencumbered anamnesis (control group). The detailed study required the distribution of placental samples from the first group into subgroups. Subgroup 1a included 38 placentas from women who gave birth at 37-40 weeks, despite signs of termination of the current pregnancy. Subgroup 1b - placentas of 13 women who gave birth at a gestation period of 28-36 weeks + 6 days. Subgroup 1c - 9 placental samples from women who gave birth at a gestation period of 22-27 weeks + 6 days. The volumetric activity of the 137Cs in the placentas was measured using ß-spectrometer. The histology of the placenta was studied using a standard technique. The following expressions were studied in placenta: CD31 / PECAM-1, CD45 / T200 / LCA, CD56 / NCAM-1, CEA / CD66e Ab-2, Vimentin, using indirect streptavidin peroxidase detection method. RESULTS: Placentas accumulate 137Cs. The different volumetric activity of the isotope correlates with scenarios of pregnancy. Due to the action of incorporated 137Cs with a specific mass of more than 1.1 Bq/kg, placental dysfunction develops. The consequences of placental dysfunction depend on the volumetric activity of the 137Cs and the preservation of adaptive and compensatory reactions in the placenta. Morphological and immunohistochemical features of placental damage to incorporated 137Cs were established, depending on the scenario of completion of pregnancy. A marker of unfavorable completion of pregnancy is the expression of a carcinoembryonic antigen (CEA) in the placenta. CONCLUSIONS: Premature termination of pregnancy (PTP) is a multifactorial pathology associated with pathological changes in immune and neuroendocrine regulation and hereditary, infectious, and environmental factors that disrupt the adaptation mechanisms in the mother-placenta-fetus system. Intraplacental irradiation of 137Cs is one of the factors in the multifactorial nature of reproductive losses. As a result of intraplacental irradiation of 137Cs, the architecture of the placenta is disturbed, the activity of pro-inflammatory cytokines CD45 and CD56 increases, and the coagulation cascade is activated. Extreme effects depend on the volumetric activity of the isotope incorporated in the placenta and the organ's compensatory capacity. Accumulation of up to 1.0 Bq/kg 137Cs does not affect the course of gestation. Internal irradiation with an activity of 4.5-10.4 Bq/kg 137Cs triggers late preterm labor. The nature of the damages corresponds to the category of «lesion of the maternal stroma¼ of the placenta. The volumetric activity of 137Cs over 10.4 Bq/kg is a probable cause of early preterm labor and antenatal fetal death. At the same time, the maternal and fetal structures of the placenta suffer damage. Expression of vimentin is a marker of placental destruction due to internal irradiation of 137Cs with a specific gravity of more than 4.5 Bq/kg. Expression of CEA in the structures of the placenta of women with PTP is a unique find and marker of premature birth and antenatal fetal death with intraplacental irradiation of 137Cs with an activity of more than 4.5 Bq/kg.

Chronic Deciduitis With Plasma Cells: A Quantitative and Clinicopathological Analysis Concerning Different Trimesters.

Background: Chronic deciduitis is a chronic inflammatory placental disease. It is associated with severe perinatal complications, especially recurrent miscarriage, preterm birth, preterm labor, and preterm prelabor rupture of membranes.Methods: This study presents a detailed quantification of plasma cells and lymphocytes, and regards clinicopathological associations concerning different trimesters in 99 cases displaying chronic deciduitis with plasma cells (CD), 23 cases from the second trimester and 76 cases from the third trimester, respectively. The control group without CD consisted of matched placentas concerning the gestational weeks.Results: In every instance lymphocytes were more numerous than plasma cells. The mean value/highest score in ten high power fields were 50/321 for plasma cells, and 460/995 for lymphocytes, respectively. In the second trimester the scores for plasma cells were significantly higher than in the third trimester. In the third trimester preterm labor occurred significantly more often in cases with chronic deciduitis related to the control group (P < .05).Conclusion: In chronic deciduitis the plasma cell count is usually higher in the second compared to the third trimester. A brisk infiltration of the decidua with plasma cells could probably point to a more severe clinical manifestation and a higher risk for preterm labor and preterm birth.

The induction of preterm labor in rhesus macaques is determined by the strength of immune response to intrauterine infection.

Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed rhesus macaque models of IUI driven by lipopolysaccharide (LPS) or live Escherichia coli. PTL did not occur in LPS challenged rhesus macaques, while E. coli-infected animals frequently delivered preterm. Although LPS and live E. coli both caused immune cell infiltration, E. coli-infected animals showed higher levels of inflammatory mediators, particularly interleukin 6 (IL-6) and prostaglandins, in the chorioamnion-decidua and amniotic fluid (AF). Neutrophil infiltration in the chorio-decidua was a common feature to both LPS and E. coli. However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E. coli. RNA sequencing (RNA-seq) analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon (IFN) response, chemotaxis, sumoylation, and iron homeostasis were up-regulated in the E. coli group compared to the LPS group. Our data suggest that the intensity of the host immune response to IUI may determine susceptibility to PTL.

Trophoblasts Modulate the Ca2+ Oscillation and Contraction of Myometrial Smooth Muscle Cells by Small Extracellular Vesicle- (sEV-) Mediated Exporting of miR-25-3p during Premature Labor.

The placenta could transmit information to the maternal circulation via the secretion of small extracellular vesicles (sEVs), but little is known about whether and how these sEVs participate in premature labor (PTL). We speculate that miRNA plays an important role in sEV-mediated fetal-maternal information transmission. The present study was aimed at investigating whether the placenta can regulate the contraction of the maternal myometrium via sEV-mediated transmit of miR-25-3p during PTL. The expression of miR-25-3p and its targets Cav3.2 and SERCA2a in clinical samples, cells, and animal specimens was detected. The role of miR-25-3p was observed in the LPS-induced preterm labor mouse model. The sEVs from HTR-8/SVneo cells were characterized by transmission electron microscopy and nanoparticle tracking analysis. The Ca2+ oscillation in HMSMs was analyzed by an intracellular Ca2+ change tracking assay on a confocal microscope. The contraction of HMSMs was detected by a collagen matrix contraction assay. We found that miR-25-3p can directly bind to the 3'UTR of Cav3.2 and SERCA2a. The miR-25-3p level was decreased, and the expression of its targets Cav3.2 and SERCA2a was increased in the placenta and myometrium tissues of PTL patients. Forced upregulation of miR-25-3p reduced the oxidative stress and inflammation responses and the incidence of PTL in LPS-treated mice. The expression of miR-25-3p was not changed in LPS-stimulated human myometrial smooth muscle cells (HMSMs) but was strongly reduced in the trophoblast cell and its sEVs. Additionally, the trophoblast cell line HTR-8/SVneo could transmit miR-25-3p into HMSMs via sEVs. The sEVs derived from LPS-stimulated trophoblasts upregulated the expression of Cav3.2 and SERCA2a and triggered Ca2+ oscillation as well as the contraction of HMSMs; these effects were partially reversed by the overexpression of miR-25-3p in the trophoblasts. Further, the upregulation of miR-25-3p induced changes of Ca2+ oscillation and contraction of HMSMs mediated by sEVs which were also abrogated by the knockdown of miR-25-3p in HMSMs. The results demonstrated that miR-25-3p plays a crucial role in PTL via Cav3.2- and SERCA2a-mediated Ca2+ oscillation and contraction of HMSMs. PTL seems to be related to the decreased exosomal miR-25-3p content transmitted by the trophoblasts under inflammatory conditions.

Identification and validation of DNA methylation changes in pre-eclampsia.

INTRODUCTION: Pre-eclampsia (PE) is a dangerous placental condition that can lead to premature labour, seizures and death of mother and infant. Several studies have identified altered placental DNA methylation in PE; however, there is widespread inconsistency between studies and most findings have not been replicated. This study aimed to identify and validate consistent differences in methylation across multiple PE cohorts. METHODS: Seven publicly available 450K methylation array datasets were analysed to identify consistent differentially methylated positions (DMPs) in PE. DMPs were identified based on methylation difference (≥10%) and significance (p-value ≤ 1 × 10-7). Targeted deep bisulfite sequencing was then performed to validate a subset of DMPs in an additional independent PE cohort. RESULTS: Stringent analysis of the seven 450K datasets identified 25 DMPs (associated with 11 genes) in only one dataset. Using more relaxed criteria confirmed 19 of the stringent 25 DMPs in at least four of the remaining six datasets. Targeted deep bisulfite sequencing of eight DMPs (associated with three genes; CMIP, ST3GAL1 and DAPK3) in an independent PE cohort validated two DMPs in the CMIP gene. Seven additional CpG sites in CMIP were found to be significantly differentially methylated in PE. DISCUSSION: The identification and validation of significant differential methylation in CMIP suggests that the altered DNA methylation of this gene may be associated with the pathogenesis of PE, and may have the potential to serve as diagnostic biomarkers for this dangerous condition of pregnancy.

Change in cervical length after arrested preterm labor and risk of preterm birth.

OBJECTIVE: To assess the association between preterm birth and cervical length after arrested preterm labor in high-risk pregnant women. METHODS: In this post-hoc analysis of a randomized clinical trial, transvaginal cervical length was measured in women whose contractions had ceased 48 h after admission for threatened preterm labor. At admission, women were defined as having a high risk of preterm birth based on a cervical length of < 15 mm or a cervical length of 15-30 mm with a positive fetal fibronectin test. Logistic regression analysis was used to investigate the association of cervical length measured at least 48 h after admission and of the change in cervical length between admission and at least 48 h later, with preterm birth before 34 weeks' gestation and delivery within 7 days after admission. RESULTS: A total of 164 women were included in the analysis. Women whose cervical length increased between admission for threatened preterm labor and 48 h later (32%; n = 53) were found to have a lower risk of preterm birth before 34 weeks compared with women whose cervical length did not change (adjusted odds ratio (aOR), 0.24 (95% CI, 0.09-0.69)). The risk in women with a decrease in cervical length between the two timepoints was not different from that in women with no change in cervical length (aOR, 1.45 (95% CI, 0.62-3.41)). Moreover, greater absolute cervical length after 48 h was associated with a lower risk of preterm birth before 34 weeks (aOR, 0.90 (95% CI, 0.84-0.96)) and delivery within 7 days after admission (aOR, 0.91 (95% CI, 0.82-1.02)). Sensitivity analysis in women randomized to receive no intervention showed comparable results. CONCLUSION: Our study suggests that the risk of preterm birth before 34 weeks is lower in women whose cervical length increases between admission for threatened preterm labor and at least 48 h later when contractions had ceased compared with women in whom cervical length does not change or decreases. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The Relationship Between Matrix Metalloproteinase-8 in After Birth Oral Fluid and Acute Histologic Chorioamnionitis in Preterm Delivery.

Elevated concentration of matrix metalloproteinase-8 (MMP-8) in amniotic fluid is a known predictor of intra-amniotic inflammation and infection. The aim of this study was to determine the nature of the association between MMP-8 levels in oral fluid obtained immediately after birth and acute histologic chorioamnionitis (HCA) in preterm delivery. Oral fluid was collected from 93 consecutive preterm birth newborns between gestational weeks of 24 + 0 and 36 + 6. Concentrations of MMP-8 and interleukin-8 (IL-8) in after birth oral fluid were measured by ELISA. Acute HCA was defined as the presence of neutrophils infiltration into chorioamnionic membranes. Logistic regression analysis was used for the statistical analysis. MMP-8 concentrations in after birth oral fluid were significantly higher for women with acute HCA than for those without (median [range]; 68.3 ng/mL [0.06-12,479.6] vs. 10.2 ng/mL [0.06-1808.2], p = 0.002). A strong association was observed between MMP-8 and IL-8 levels (γ2 = 0.87, p < 0.01). The cutoff level of MMP-8 in after birth oral fluid for acute HCA was 39.7 ng/mL (sensitivity of 63.2%, specificity of 81.1%). Multivariable logistic regression analysis showed MMP-8 in after birth oral fluid had an odds ratio of 4.17 for acute HCA (95% confidence interval [CI] = 1.08-16.17, p = 0.03). An elevated MMP-8 level in after birth oral fluid is associated with acute HCA in preterm birth. Newborn oral fluid immediately after birth might provide another source for information of intra-amniotic condition just before birth.

Relationship between histologic chorioamnionitis and genital tract cultures in pre term labour.

The objective was to determine the relationship of histological chorioamnionitis (HCA) with genital tract cultures in preterm birth. Among two hundred women recruited for the study, 100 were taken as cases with gestational age between ≥28 and <37 weeks and 100 women with gestational age >37 weeks were taken as controls. Vaginal swabs were taken for culture sensitivity and vaginal smears were made for performing whiff test and heat dry gram stained smear was examined for growth of microorganisms. Histopathologic examination of the placenta was done after delivery. 49 cases and 26 controls had evidence of histological chorioamnionitis. A significant difference was observed in relation to the presence of E. coli, presence of clue cells, positive whiff test and occurrence of bacterial vaginosis in subjects with and without histological chorioamnionitis. Thus, we conclude that the presence of histological chorioamnionitis is closely related to the presence of pathogenic microorganisms in the cervicovaginal region.IMPACT STATEMENTWhat is already known on the subject? Histologic chorioamnionitis has been regarded to reflect amniotic fluid infection and there are studies showing an association between histologic chorioamnionitis, amniotic fluid, and subchorionic plate cultures. Nevertheless, studies of the correlation of the cervical swab cultures with intrauterine infection in preterm birth remain inconclusive.What do the results of this study add? Histologic chorioamnionitis is closely related to the presence of pathogenic microorganisms in the cervicovaginal region.What are the implications of these findings for clinical practice and/or further research? High vaginal swab cultures and gram staining of vaginal smear is useful in detecting antenatal patients who are at a higher risk for preterm labour. After detection, early intervention may be done to avoid preterm deliveries in these high-risk pregnancies.

Fetal inflammatory response is positively correlated with the progress of inflammation in chorionic plate.

INTRODUCTION: No information exists about the relationship among the progress of inflammation in chorionic-plate, fetal inflammatory response (FIR), funisitis, amnionitis and early-onset neonatal sepsis (EONS) in patients with either preterm labor or preterm premature rupture of membranes (preterm-PROM). The objective of current study is to examine this issue. METHODS: Study population included 247 singleton preterm gestations (21.6 weeks ≤ gestational age at delivery≤36 weeks) who had either preterm-labor or preterm-PROM with acute placental inflammation. We examined the intensity of FIR, and the frequency of fetal inflammatory response syndrome (FIRS), funisitis, amnionitis and proven or suspected EONS according to the progress of inflammation in chorionic-plate. The intensity of FIR was measured with umbilical cord plasma (UCP)-CRP concentration (ng/ml) at birth, and FIRS was defined as an elevated UCP-CRP concentration (≥200 ng/ml). The progress of inflammation in chorionic-plate was divided with a slight modification from previously reported-criteria as follows: stage-0, inflammation-free chorionic-plate; stage-1, inflammation restricted to subchorionic fibrin (SCF); stage-2, inflammation in the connective tissue (CT) of chorionic-plate without chorionic vasculitis; stage-3, chorionic vasculitis. RESULTS: 1) Stage-0, stage-1, stage-2 and stage-3 of inflammation in chorionic-plate were present in 36.8% (91/247), 29.6% (73/247), 25.5% (63/247), and 8.1% (20/247) of cases; 2) UCP-CRP concentration at birth was significantly and positively correlated with the progress of inflammation in chorionic-plate (Spearman's rank correlation test, P < .000001, γ = 0.391 and Kruskal-Wallis test, P < .001); 3) Moreover, FIRS, funisitis, amnionitis, and EONS were significantly more frequent as a function of the progress of inflammation in chorionic-plate. DISCUSSION: The intensity of FIR and the frequency of FIRS were positively correlated with the progress of inflammation in chorionic-plate in patients with either PTL or preterm-PROM. This suggests chorionic-plate may be an independent compartment for the analysis of inflammation.

Synergic interaction between ritodrine and magnesium sulfate on the occurrence of critical neonatal hyperkalemia: A Japanese nationwide retrospective cohort study.

Our aim was to evaluate the association between ritodrine and magnesium sulfate (MgSO4) and the occurrence of neonatal hyperkalemia or hypoglycemia among late preterm infants in a retrospective cohort study. We used a nationwide obstetrical database from 2014. A total of 4,622 live preterm infants born at 32-36 gestational weeks participated. Fourteen risk factors based on both clinical relevance and univariate analysis were adjusted in multivariable logistic regression analyses. Neonatal hyperkalemia and hypoglycemia occurred in 7.6% (284/3,732) and 32.4% (1,458/4,501), respectively. Occurrence of hyperkalemia was associated with concomitant usage of ritodrine and MgSO4 compared with no usage (adjusted odds ratio [aOR] 1.53, 95% confidence interval [CI] 1.09-2.15). Occurrence of hypoglycemia was associated with ritodrine alone (aOR 2.58 [CI 2.21-3.01]) and with concomitant usage of ritodrine and MgSO4 (aOR 2.59 [CI 2.13-3.15]), compared with no usage, and was associated with long-term usage (≥ 48 hours) of ritodrine and cessation directly before delivery. In conclusion, in late preterm infants, usage of ritodrine together with MgSO4 was associated with occurrence of critical neonatal hyperkalemia, and long-term usage of ritodrine and cessation directly before delivery were associated with neonatal hypoglycemia.

Associations Between Placental Corticotropin-Releasing Hormone, Maternal Cortisol, and Birth Outcomes, Based on Placental Histopathology.

Preterm birth remains the leading cause of neonatal morbidity and mortality, with complex biochemical pathways requiring continued understanding and assessment. The objective of this study is to assess the associations between maternal cortisol and placental corticotropin-releasing hormone (placental CRH) concentrations with birth outcomes when stratified by placental histopathology. We conducted an analysis of 112 singleton pregnancies who received betamethasone between 23 and 34 weeks' gestation. Maternal blood and saliva were collected prior to betamethasone administration and samples assayed for plasma cortisol (pCort), salivary cortisol (sCort), and placental CRH levels. Placental findings were characterized as inflammatory, maternal vascular underperfusion (MVU), or no pathology, and compared for the outcomes of placental CRH, pCort, and sCort levels, gestational age at birth (GAB), and birthweight percentiles (BWP). Thirty-six subjects were characterized as inflammatory, 38 as MVU, and 38 without placental abnormalities. Histopathology groups differed significantly on placental CRH levels, GAB, and BWP. Post hoc tests suggested that the MVU group had higher placental CRH than the inflammatory or no pathology groups, and despite delivering earlier than the other two groups, the inflammatory group had infants with significantly higher BWP. No differences existed between groups in terms of mean plasma or sCort levels. Higher placental CRH and pCort levels were associated with earlier GAB in the overall sample, but when split by group, these associations remained significant only among the MVU group. Higher placental CRH was also associated with lower BWP in the overall sample but did not remain significant when split by group. Higher sCort was associated with lower BWP only in the MVU group. There is differentiation of placental CRH, cortisol, and birth outcomes when evaluated by placental histopathology. This highlights the importance of evaluating birth outcomes within the context of placental histopathology.

Compartmentalized profiling of amniotic fluid cytokines in women with preterm labor.

OBJECTIVE: Amniotic fluid cytokines have been implicated in the mechanisms of preterm labor and birth. Cytokines can be packaged within or on the surface of extracellular vesicles. The main aim of this study was to test whether the protein abundance internal to and on the surface of extracellular vesicles changes in the presence of sterile intra-amniotic inflammation and proven intra-amniotic infection in women with preterm labor as compared to the women with preterm labor without either intra-amniotic inflammation or proven intra-amniotic infection. STUDY DESIGN: Women who had an episode of preterm labor and underwent an amniocentesis for the diagnosis of intra-amniotic infection or intra-amniotic inflammation were classified into three groups: 1) preterm labor without either intra-amniotic inflammation or proven intra-amniotic infection, 2) preterm labor with sterile intra-amniotic inflammation, and 3) preterm labor with intra-amniotic infection. The concentrations of 38 proteins were determined on the extracellular vesicle surface, within the vesicles, and in the soluble fraction of amniotic fluid. RESULTS: 1) Intra-amniotic inflammation, regardless of detected microbes, was associated with an increased abundance of amniotic fluid cytokines on the extracellular vesicle surface, within vesicles, and in the soluble fraction. These changes were most prominent in women with proven intra-amniotic infection. 2) Cytokine changes on the surface of extracellular vesicles were correlated with those determined in the soluble fraction; yet the magnitude of the increase was significantly different between these compartments. 3) The performance of prediction models of early preterm delivery based on measurements on the extracellular vesicle surface was equivalent to those based on the soluble fraction. CONCLUSIONS: Differential packaging of amniotic fluid cytokines in extracellular vesicles during preterm labor with sterile intra-amniotic inflammation or proven intra-amniotic infection is reported herein for the first time. The current study provides insights into the biology of the intra-amniotic fluid ad may aid in the development of biomarkers for obstetrical disease.

The orphan nuclear receptor Nr4a1 mediates perinatal neuroinflammation in a murine model of preterm labor.

Prematurity is associated with perinatal neuroinflammation and injury. Screening for genetic modulators in an LPS murine model of preterm birth revealed the upregulation of Nr4a1, an orphan nuclear transcription factor that is normally absent or limited in embryonic brains. Concurrently, Nr4a1 was downregulated with magnesium sulfate (MgSO4) and betamethasone (BMTZ) treatments administered to LPS exposed dams. To understand the role of Nr4a1 in perinatal brain injury, we compared the preterm neuroinflammatory response in Nr4a1 knockout (KO) versus wild type (wt) mice. Key inflammatory factors Il1b, Il6 and Tnf, and Iba1+ microglia were significantly lower in Nr4a1 KO versus wt brains exposed to LPS in utero. Treatment with MgSO4/BMTZ mitigated the neuroinflammatory process in wt but not Nr4a1 KO brains. These results correspond with a reduction in cerebral hemorrhage in wt but not mutant embryos from dams given MgSO4/BMTZ. Further analysis with Nr4a1-GFP-Cre × tdTomato loxP reporter mice revealed that the upregulation of Nr4a1 with perinatal neuroinflammation occurs in the cerebral vasculature. Altogether, this study implicates Nr4a1 in the developing vasculature as a potent mediator of neuroinflammatory brain injury that occurs with preterm birth. It is also possible that MgSO4/BMTZ mitigates this process by direct or indirect inhibition of Nr4a1.

Cellular immune responses in amniotic fluid of women with preterm clinical chorioamnionitis.

OBJECTIVE: Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Some preterm births are associated with clinical chorioamnionitis; yet, this condition has been poorly investigated. Herein, we characterized the amniotic fluid cellular immune responses in women with preterm clinical chorioamnionitis. METHODS AND SUBJECTS: Amniotic fluid samples were obtained from women with preterm clinical chorioamnionitis and a positive or negative microbiological culture (n = 17). The cellular composition of amniotic fluid was evaluated using fluorescence microscopy, scanning and transmission electron microscopy, and flow cytometry. Women without preterm clinical chorioamnionitis were also examined (n = 10). RESULTS: Amniotic fluid from women with preterm clinical chorioamnionitis and a positive culture had: (1) abundant neutrophils associated with viable and non-viable bacteria, (2) neutrophils performing phagocytosis, (3) neutrophils forming NETs, (4) increased numbers of neutrophils, monocytes/macrophages, and CD4+ T cells, and (5) high expression of IL-1ß by neutrophils and monocytes/macrophages. Amniotic fluid from women with preterm clinical chorioamnionitis and proven infection tended to have fewer monocytes/macrophages and CD4+ T cells compared to those without chorioamnionitis. CONCLUSION: We provide the first morphologic and phenotypic characterization of the cellular immune responses in the amniotic cavity of women with preterm clinical chorioamnionitis, a condition associated with adverse neonatal outcomes.

Association of amniotic fluid sludge with preterm labor and histologic chorioamnionitis in pregnant Japanese women with intact membranes: A retrospective study.

AIM: The presence of amniotic fluid sludge has been identified as a risk factor for preterm birth. We sought to validate the clinical characteristics of amniotic fluid sludge in Japanese pregnant women with preterm labor and intact membranes. METHODS: This was a retrospective study of 54 patients. The presence of amniotic fluid sludge was confirmed using transvaginal ultrasonography data during pregnancy. The following data were collected: gestational age, the presence of histologic chorioamnionitis, time from the diagnosis of threatened premature labor to delivery, oncofetal fibronectin (onfFN) levels, C-reactive protein peak value levels, cervical length at the time of onset of threatened premature labor and types of neonatal complications. RESULTS: Significant differences (P = 0.03) were observed in the age at delivery in relation to the presence of amniotic sludge: delivery occurred at 28.3 ± 4.5 weeks and 31.7 ± 4.3 weeks in sludge positive patients and sludge-negative patients, respectively. Presence of sludge in patients diagnosed with histological chorioamnionitis at <37 weeks of gestation differed significantly (P = 0.01): sludge-positive, 81.8%; sludge-negative, 20.9%. Among the sludge-positive patients, 100% were positive for serum onfFN (≥50 ng/mL), whereas only 54% of sludge-negative patients were positive for serum onfFN (P = 0.03). Presence of amniotic fluid sludge did not significantly affect neonatal complications. CONCLUSION: Our results confirmed previous findings that amniotic fluid sludge is a self-determining risk factor for preterm birth and chorioamnionitis in pregnant Japanese women.

Characterization of vaginal microbiota in women with preterm labor with intra-amniotic inflammation.

This study aims to investigate the relation between vaginal microbiota and exposition to intra-amniotic inflammation (IAI). We conducted a prospective cohort study in women with preterm labor <34 weeks who had undergone amniocentesis to rule out IAI. Vaginal samples were collected after amniocentesis. Women with IAI included those with positive amniotic fluid (AF) for a microorganism identified by specific culture media and Sanger sequencing 16S ribosomal RNA gene and/or high AF interleukin (IL)-6 levels. Vaginal microbiota was characterized by 16S ribosomal RNA gene amplicon sequencing. Specific quantitative PCR targeted to Lactobacillus spp. was also performed. Regression models were used to evaluate associations between vaginal microbiota and exposition to IAI. Concerning our results, 64 women were included. We observed an inverse association between AF IL-6 levels and load of Lactobacillus spp. Depletion in Lactobacillus spp. load was significantly associated with an early gestational age at delivery and a short latency to delivery. Microbial-diversity was found to be a risk factor for the subsequent occurrence of clinical chorioamnionitis. To the contrary, higher Lactobacillus spp. load had a protective role. In conclusion, the study identifies reduced bacterial load of Lactobacillus spp. in women exposed to IAI and found microbial-diversity and Lactobacillus spp. depletion to be associated with a worse perinatal outcome.

A mystery mass on the placenta.

Chorioangioma or chorangioma is a benign placental tumour which occurs in 1% of the pregnancies. Large lesions of more than 4-5 cm in size, also known as giant chorangiomas, are rare with the incidence of 1:3500 and 1:9000 birth. Unlike small tumours, the giant chorangiomas are highly associated with pregnancy complications. We report a case of multiple large chorangiomas resulting in an extremely preterm delivery. A 24-year-old primigravida presented at 25 weeks of gestation for threatened preterm labour. Transabdominal ultrasound revealed an echogenic mass on the placenta measuring 8.7 × 4.4 cm. Following a successful tocolysis and administration of a course of antenatal corticosteroids, she was discharged home. At 27 weeks of gestation, she developed a second episode of preterm contractions. Besides, the foetus was found to be small for gestational age. In the second episode of preterm contractions, intravenous magnesium sulfate infusion was commenced for foetal neuroprotection. Tocolysis was commenced for severe prematurity. She went into spontaneous preterm labour. Placenta examination revealed multiple solid masses with fleshy and congested dark red surface. A histopathological examination of the placenta confirmed the diagnosis of chorangiomas. The baby was discharged in good condition at 5 months of age. Placental chorangiomas, notably when they are multiple and large in size, are associated with adverse pregnancy outcomes. Therefore, close antenatal surveillance is necessary to allow timely recognition and intervention of pregnancy complications. Our case portrays an unexpected favourable neonatal outcome associated with a giant chorangiomas.

Fetal T Cell Activation in the Amniotic Cavity during Preterm Labor: A Potential Mechanism for a Subset of Idiopathic Preterm Birth.

Prematurity is the leading cause of perinatal morbidity and mortality worldwide. In most cases, preterm birth is preceded by spontaneous preterm labor, a syndrome that is associated with intra-amniotic inflammation, the most studied etiology. However, the remaining etiologies of preterm labor are poorly understood; therefore, most preterm births are categorized as idiopathic. In this study, we provide evidence showing that the fetal immune system undergoes premature activation in women with preterm labor without intra-amniotic inflammation, providing a potential new mechanism of disease for some cases of idiopathic preterm birth. First, we showed that fetal T cells are a predominant leukocyte population in amniotic fluid during preterm gestations. Interestingly, only fetal CD4+ T cells were increased in amniotic fluid of women who underwent idiopathic preterm labor and birth. This increase in fetal CD4+ T cells was accompanied by elevated amniotic fluid concentrations of T cell cytokines such as IL-2, IL-4, and IL-13, which are produced by these cells upon in vitro stimulation, but was not associated with the prototypical cytokine profile observed in women with intra-amniotic inflammation. Also, we found that cord blood T cells, mainly CD4+ T cells, obtained from women with idiopathic preterm labor and birth displayed enhanced ex vivo activation, which is similar to that observed in women with intra-amniotic inflammation. Finally, we showed that the intra-amniotic administration of activated neonatal CD4+ T cells induces preterm birth in mice. Collectively, these findings provide evidence suggesting that fetal T cell activation is implicated in the pathogenesis of idiopathic preterm labor and birth.

Dysregulation of placental ABC transporters in a murine model of malaria-induced preterm labor.

Malaria in Pregnancy (MiP) is characterized by placental accumulation of Plasmodium-infected erythrocytes, intrauterine growth restriction (IUGR) and preterm delivery (PTD). Placental ATP-binding cassette (ABC) transporters mediate the efflux of nutrients, cytokines and xenobiotics. The expression and activity of these transporters are highly responsive to infection. We hypothesized that MiP would perturb the expression of placental ABC transporters, promoting PTD. Peripheral blood, spleens, livers and placentas of pregnant mice, infected with Plasmodium berghei ANKA on gestational day (GD) 13.5, were collected and analyzed on GD18.5. The primary consequences of human MiP, including IUGR, PTD (20%) and placental inflammation, were recapitulated in our mouse model. Electron microscopy revealed attenuated presence of labyrinthine microvilli and dilated spongiotrophoblasts -granular endoplasmic reticulum cisternae. Additionally, a decrease in placental Abca1 (ABCA1), Abcb1b (P-glycoprotein), Abcb9 and Abcg2 (BCRP) expression was observed in MiP mice. In conclusion, MiP associated with PTD impairs placental ABC transporters' expression, potentially modulating placental nutrient, environmental toxin and xenobiotic biodistribution within the fetal compartment, and may, at some degree, be involved with pregnancy outcome in MiP.