Novel Biomarkers: Soluble Urokinase-Type Plasminogen Activator Receptor and Procalcitonin- and Histological Chorioamnionitis after Preterm Premature Rupture of Membranes.

Fetal inflammatory response syndrome or infection after preterm premature rupture of membranes (PPROM) increases neonatal morbidity in preterm deliveries. Biochemical markers from the amniotic fluid (AF) have been used to evaluate possible intra-amniotic infection during the asymptomatic phase after PPROM. This study aimed to describe whether soluble urokinase-type plasminogen activator receptor (suPAR) or procalcitonin (PCT) from AF or maternal sera could reveal fetal inflammatory response or infection after PPROM. AF and maternal serum samples were collected weekly after PPROM (23+ 0 - 34+ 6 gestational weeks) until delivery from twenty women and two women with possible chorioamnionitis with intact membranes. Levels of suPAR, PCT, interleukin-6 (IL-6), glucose, lactate dehydrogenase (LDH), and bacterial PCR were determined from AF and suPAR and PCT and IL-6 from maternal sera. Fetal infection or inflammation response were determined by the histology of the placenta after delivery. AF glucose was significantly lower and AF LDH higher in the fetal site histologic chorioamnionitis (HCA) group, while AF suPAR concentrations tended to be higher in this group. AF suPAR correlated significantly with AF glucose and LDH. Based on receiver operating characteristic (ROC) analysis, AF glucose had the best predictability for fetal site histological chorioamnionitis. The findings of AF PCT were insignificant considering HCA. AF glucose had the highest accuracy in predicting fetal site histologic chorioamnionitis. AF suPAR may be a promising marker; however, our findings were limited by a small study population.

The association of inflammatory changes of the uterus and chorioamniotic membranes with different types of labor activity anomalies.

OBJECTIVE: Aim: To clarify the association between different types of uterine contractility dysfunction and the inflammation of the uterus and chorioamniotic membranes. PATIENTS AND METHODS: Materials and Methods: The association between the inflammation of the uterine layers, chorioamniotic membranes, umbilical cord, and different types of labor activity abnormalities was examined in 382 patients with singleton pregnancies at 28-42 weeks' gestation who underwent Caesarean section (CS) for abnormal uterine contractions and other complications. Statistical analyses included the Mann-Whitney U, Chi-squared test, and logistic regression. RESULTS: Results: In the control group, slight infiltration with polymorphonuclear leukocytes (PMNs) and macrophages of the myometrium and decidua of the lower uterine segment at term pregnancy was found in 59.7% and 73.6% of cases. The main clinical risk factors for placental and decidual membrane inflammation in patients with excessive uterine activity (EUA) were prematurity, multiparity, group B streptococcus (GBS) colonization, and duration of ruptured fetal membranes before the CS. Moderate or marked myometrial inflammation of both uterine segments in the EUA group was diagnosed only in patients with cervical dilation of >6 cm and duration of labor of >8h. In women with hypotonic uterine activity (HUA), decidual and myometrial inflammation was significantly associated with nulliparity and intrapartum factors, such as protracted active first stage of labor, advanced cervical dilation, and number of vaginal examinations. In all cases, inflammation of the myometrium was accompanied by deciduitis. CONCLUSION: Conclusions: Mild inflammation of the decidual membrane and myometrium of the lower segment at term pregnancy is a common physiological phenomenon contributing to labor initiation. Uterine hyperfunction comes as the response of the unaffected myometrium to the release of high concentrations of proinflammatory cytokines produced by the inflamed decidual and chorioamniotic membranes into the bloodstream. Marked myometrial inflammation that occurs in prolonged labor is an additional factor aggravating the hypotonic uterine activity.

Plasma proteomic signature of neonates in the context of placental histological chorioamnionitis.

BACKGROUND: Placental histological chorioamnionitis (HCA) is recognised as a significant risk factor for various adverse neonatal outcomes. This study aims to explore if the inflammatory protein levels in neonates were associated with HCA. METHODS: All women with singleton births from February 2020 to November 2022 were selected and divided into three groups based on maternal placental pathology results: the HCA-stage 1 group (n=24), the HCA-stage 2 group (n=16) and the control group (n=17). Olink Target 96 Inflammation Panel was used to detect the levels of 92 inflammation-related proteins in the plasma of newborns from all three groups within 24 hours after birth. We compared the protein profiles through differential protein expression analysis. RESULTS: A total of six inflammation-related proteins exhibited significant differences between the HCA-stage 1 and the control group. Specifically, TRANCE and CST5 were significantly upregulated (p=0.006, p=0.025, respectively), whereas the expression of IFN-gamma, CXCL9, CXCL10 and CCL19 was significantly downregulated (p=0.040, p=0.046, p=0.007, p=0.006, respectively). HCA-stage 2 newborns had significantly elevated levels of CD5 and CD6 and decreased IFN-gamma, CXCL10 and CCL19 in comparison to controls. These differential proteins were significantly enriched in positive regulation of cytokine activity, leucocyte chemotaxis and positive regulation of T-cell activation pathway-related Gene Ontology terms. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that viral protein interaction with cytokine and cytokine receptor, interleukin-17/NF-kappa B/toll-like receptor/chemokine signalling pathway, and cytokine-cytokine receptor interaction exhibited significant differences. Spearman analysis demonstrated a significant positive connection between the levels of CD6 and CD5 proteins, not only in neonatal leucocytes but also in maternal leucocytes. Additionally, CD6 was found to be associated with neonatal birth weight. CONCLUSIONS: In conclusion, placental histological changes associated with chorioamnionitis appear to influence the expression of inflammatory proteins in offspring. Notably, CD6 and CD5 proteins may potentially contribute to the pathogenesis of HCA-related neonatal diseases.

Changes in Relative Counts of Different Leukocyte Subpopulations in Peripheral and Umbilical Cord Blood of Women With Preterm Prelabor Rupture of Membranes With Respect to Intraamniotic Inflammation and Fetal Inflammatory Response Syndrome.

OBJECTIVE: The aim of this study was to evaluate changes in the relative counts of different leukocyte subsets in peripheral and umbilical cord blood in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) with respect to the presence of intraamniotic inflammation (IAI) and fetal inflammatory response syndrome (FIRS). METHODS: Fifty-two women with singleton pregnancies complicated by PPROM were included in this study. From samples of peripheral and umbilical cord blood, relative counts of these leukocyte subpopulations were determined using multicolor flow cytometry: granulocytes, monocytes, lymphocytes, T cells and their subpopulations, B cells and their subpopulations, and NK cells and their subpopulations. IAI was defined as increased concentrations of interleukin 6 in the amniotic fluid. Amniotic fluid samples were obtained by transabdominal amniocentesis. RESULTS: Women with IAI had higher relative counts of monocytes (p = 0.04) in peripheral blood. There was an increased relative number of granulocytes (p = 0.003) and a decreased number of lymphocytes (p = 0.0048), helper CD4+ T cells (p = 0.019), NK cells (p = 0.0001) within leukocytes, NK cells within lymphocytes (p = 0.003) and CD16+ NK cells within NK cells (p = 0.005) in umbilical cord blood samples of women with FIRS. However, after adjusting the results for gestational age at sampling, all differences disappeared. CONCLUSIONS: The presence of IAI or FIRS is not accompanied by significant changes in the relative counts of immune cells in peripheral blood or umbilical cord blood in pregnancies complicated by PPROM.

Comprehensive morphological study of free radical processes in chronic chorioamnionitis on the background of iron deficiency anemia in pregnancy.

OBJECTIVE: Aim: To establish the features of free radical processes in the endotheliocytes of the chorionic plate of the placenta in chronic chorioamnionitis against the background of iron deficiency anemia of pregnant women using both chemiluminescent and histochemical methods of research. PATIENTS AND METHODS: Materials and Methods: 82 placentas from parturients at 37 - 40 weeks of gestation were studied. Including, for comparison, the placenta during physiological pregnancy and the observation of iron deficiency anemia of pregnant women without inflammation of the placenta. The number of observations in specific study groups is given in the tables. To achieve the objective and solve the tasks set in this study, there were carried out the following histochemical, chemiluminescent, morphometric and statistical methods of material processing. RESULTS: Results: In case of chorionamnionitis against the background of anemia in pregnancy, the R/B ratio (R/B - ratio between amino- (blue) and carboxyl (red) groups of proteins)) in the method with bromophenol blue according to Mikel Calvo was 1.56±0.021, indicators of chemiluminescence of nitroperoxides were 133±4.5, relative optical density units of histochemical staining using the method according to A. Yasuma and T. Ichikawa was - 0.224±0.0015. CONCLUSION: Conclusions: With chronic chorioamnionitis, the intensity of the glow of nitroperoxides, the average indicators of the R/B ratio, and the optical density of histochemical staining for free amino groups of proteins are increased compared to placentas of physiological pregnancy and anemia of pregnant women. Comorbid i anemia of pregnant women causes increasing of the intensity of the glow of nitroperoxides, the average values of the R/B ratio, and the optical density of histochemical staining for free amino groups of proteins comparing to placentas with inflammation without anemia. The key factor in the formation of morphological features of chronic chorioamnionitis with comorbid anemia is the intensification of free radical processes, which is reflected by the increase in the concentration of nitroperoxides in the center of inflammation, with the subsequent intensification of the processes of oxidative modification of proteins, which is followed by the increasing activity of the processes of limited proteolysis.

"Investigation of the potential cellular changes induced by magnesium sulfate and salubrinal in a lipopolysaccharide-induced chorioamnionitis model".

Chorioamnionitis is closely associated with preterm labor and poses a significant public health concern. In this pathological process where inflammation plays a key role, intracellular mechanisms such as endoplasmic reticulum stress are crucial. In this study, we aimed to explore the potential positive outcomes of the combined use of salubrinal (SLB) with magnesium (Mg) treatment in chorioamnionitis. Thirty pregnant rats were divided into 5 groups as: Control, LPS (1 mg/kg), LPS + SLB (1 mg/kg), LPS + Mg (Dhaka protocol), LPS + SLB + Mg. Rats were sacrificed 4 h after LPS administration, then placental and fetal brain tissues were collected. LPS administration enhanced the levels of tumor necrosis factor-alpha, vascular endothelial growth factor, caspase-3 immunoexpressions, BAX, eukaryotic initiation factor 2-alpha, s100, and glial fibrillary acidic protein expressions and lowered BCL2 expressions in the placenta or fetal brains. SLB and Mg treatments were observed to reverse all these findings, and the most significant positive effect was in the LPS + SLB + Mg group. The known anti-inflammatory activity of Mg, when used with SLB, preventing the transition to apoptosis and increasing antioxidant enzyme activity, as identified in this study, can contribute significantly to the literature. However, these results need to be supported by additional molecular studies.

Absolute counts of leukocyte subsets in peripheral blood in pregnancies complicated by preterm prelabour rupture of membranes.

BACKGROUND: This study aimed to assess variations in the absolute counts of various leukocyte subsets in the peripheral blood of women with pregnancies affected by preterm prelabour rupture of membranes (PPROM), in relation to the presence of intra-amniotic inflammation (IAI). METHODS: The study included fifty-two women with singleton pregnancies experiencing PPROM. Absolute counts of different leukocyte subpopulations, such as granulocytes, monocytes, lymphocytes, T cells and their subsets, B cells and their subsets, and NK cells and their subsets, were measured in maternal peripheral blood samples using multicolour flow cytometry. IAI was identified by elevated concentrations of interleukin 6 (IL-6) in the amniotic fluid, which was collected through transabdominal amniocentesis. RESULTS: Women with IAI exhibited higher absolute counts of leukocytes (p = 0.003), granulocytes (p = 0.008), and monocytes (p = 0.009). However, the presence of IAI did not significantly affect the absolute counts of lymphocytes or their subpopulations. CONCLUSIONS: The study found that IAI is associated with changes in the absolute counts of leukocytes from the innate immunity compartment in the peripheral blood of women with pregnancies complicated by PPROM. Conversely, it does not significantly alter the counts of cells from the adaptive immune system. The changes observed may reflect the natural, temporal, and localised characteristics of IAI.

Preterm birth is the most serious complication in contemporary perinatal medicine. Preterm birth, which is defined as a labour before the completion of 37 weeks of pregnancy, is often accompanied by premature rupture of the amniotic membranes and drainage of amniotic fluid. Such a situation is often complicated by inflammation, which adversely affects the health of the foetus. A number of procedures and markers have been developed for the diagnosis of inflammation, but they are determined from hard-to-reach amniotic fluid. It is therefore appropriate to try to find reliable markers of inflammation in the much more accessible maternal peripheral blood. Such a marker can be increased numbers of leukocytes, which have been repeatedly investigated in this context. However, little attention is directed to other leukocyte populations and especially to various lymphocyte subpopulations. This study aimed to test changes in absolute counts of different types of leukocytes and lymphocyte subpopulations in women with premature rupture of membranes with respect to ongoing inflammation. The results of the study showed that inflammation is accompanied by increased numbers of leukocytes, granulocytes and monocytes, however, the results did not show significant changes in the number of lymphocytes and their subpopulations.

Characterization of Inflammation/Immune-, Acute Phase-, Extracellular Matrix-, Adhesion-, and Serine Protease-Related Proteins in the Amniotic Fluid of Women With Early Preterm Prelabor Rupture of Membranes.

PROBLEM: To determine whether altered concentrations of various inflammation/immune-, acute phase-, extracellular matrix-, adhesion-, and serine protease-related proteins in the amniotic fluid (AF) are independently associated with microbial invasion of the amniotic cavity and/or intra-amniotic inflammation (MIAC/IAI), imminent spontaneous preterm delivery (SPTD; ≤7 days), and major neonatal morbidity/mortality (NMM) in women with early preterm prelabor rupture of membranes (PPROM). METHOD OF STUDY: This was a retrospective cohort study involving 111 singleton pregnant women with PPROM (24-31 weeks) undergoing amniocentesis to diagnose MIAC/IAI. The following proteins were measured in stored AF samples by enzyme-linked immunosorbent assay (ELISA): APRIL, DKK-3, Gal-3BP, IGFBP-2, IL-8, VDBP, lumican, MMP-2, MMP-8, SPARC, TGFBI, TGF-ß1, E-selectin, ICAM-5, P-selectin, haptoglobin, hepcidin, SAA1, kallistatin, and uPA. RESULTS: Multivariate logistic regression analyses revealed that (i) elevated APRIL, IL-8, MMP-8, and TGFBI levels in the AF, reduced lumican and SPARC levels in the AF, and high percentages of samples above the lower limit of quantification for AF TGF-ß1 and uPA were significantly associated with MIAC/IAI; (ii) elevated AF levels of IL-8 and MMP-8 were significantly associated with SPTD within 7 days; and (iii) elevated AF IL-6 levels were significantly associated with increased risk for major NMM, when adjusted for baseline covariates. CONCLUSION: ECM (lumican, SPRAC, TGFBI, and TGF-ß1)- and serine protease (uPA)-associated proteins in the AF are involved in the regulation of the host response to infection/inflammation in the amniotic cavity, whereas AF inflammation (IL-8, MMP-8, and IL-6)-associated mediators are implicated in the development of preterm parturition and major NMM in early PPROM.

Maternal chorioamnionitis and the risk for necrotizing enterocolitis in the United States: A national cohort study.

BACKGROUND: Necrotizing enterocolitis (NEC) is a major cause for morbidity and mortality among newborn infants. Chorioamnionitis is a perinatal complication that is associated with preterm delivery. Few reports have studied chorioamnionitis as a possible risk factor for NEC. Further investigation is needed to fully understand this association. OBJECTIVE: To examine the association of chorioamnionitis with NEC in newborn infants. METHODS: We used National Inpatient Sample (NIS) datasets produced by the federal Healthcare Cost and Utilization Project (HCUP). We identified infants born to mothers diagnosed with chorioamnionitis and infants born to mothers who did not have chorioamnionitis. The odds ratios (OR) to develop NEC in infants born to mothers affected by chorioamnionitis were calculated using chi square and Fisher Exact tests in the overall sample and in subgroups of different birthweight (BW) categories. The association was re-evaluated using logistic regression models to control for confounding variables. RESULTS: The study identified 18,973,800 newborn infants admitted during the years 2016-2020. Among infants born to mothers with chorioamnionitis, NEC occurred in 0.9 % compared to 0.1 % in infants born to mothers without chorioamnionitis, (adjusted OR = 1.12, CI:1.02-1.15, p = 0.01). The prevalence of NEC in infants born to mothers with chorioamnionitis varied by the birth weight category, mainly for BW category 2500-4499 g (aOR = 1.61, CI:1.44-1.80, p < 0.001). CONCLUSION: Maternal chorioamnionitis is associated with increased incidence of NEC, particularly in the BW category 2500-4499 g. Further studies are needed to examine the pathophysiological factors underlying this association.

Maternal and perinatal infectious morbidity in term prelabor rupture of membrane according to two induction of labor protocols.

PURPOSE: The optimal labor-induction protocol in women with prelabor rupture of membranes (PROM) is unknown. Whether the management of women with a previous cesarean delivery (CD) with PROM is different remains controversial. We investigated maternal and perinatal outcomes according to two induction protocols of 24 h vs. 12 h. METHODS: In July 2021, our protocol of induction of labor in term-PROM was extended from 12 h to 24 h post-PROM. We compared obstetrical and neonatal outcomes before and after the change. A subgroup analysis of women with previous CD was performed. Results were compared using a univariate analysis. A multivariable model was described to predict neonatal intensive care unit admission (NICU) and clinical chorioamnionitis. RESULTS: The 24 h and 12 h ROM-to-induction protocol groups included 962 and 802 women, respectively. In the 24 h group, a higher proportion of women labored spontaneously (p < 0.001), the rate of chorioamnionitis was higher (p = 0.017), and the CD rate was similar. Admission to the NICU (p = 0.012), antibiotic administration (p = 0.003), and respiratory distress (p = 0.002) were also greater in the 24 h induction group. Among women with a history of CD (n = 143), the need for oxytocin (p = 0.003) and delivery by CD (p = 0.016) were lower in the 24 vs. 12 h group. CONCLUSION: Our results advocate shared decision-making in the expectant management of term-PROM. Women should be informed of the lower chance for induction and the higher risk of infections and neonatal complications with a 24-h induction approach. Longer expectant management in women with a previous CD resulted in significantly lower induction and CD rates.

Duration of Induction of Labor for Second-Trimester Medication Abortion and Adverse Outcomes.

OBJECTIVE: To evaluate the relationship between duration of labor during second-trimester medication abortion and adverse outcomes. METHODS: We conducted a retrospective cohort study including all individuals with a singleton gestation undergoing second-trimester medication abortion without evidence of advanced cervical dilation, rupture of membranes, or preterm labor at four centers. The primary exposure was duration of labor (ie, hours spent from receiving misoprostol to fetal expulsion). The primary outcome was composite morbidity , defined as uterine rupture, need for blood transfusion, clinical chorioamnionitis, intensive care unit admission, or need for readmission. We performed bivariate and multivariate negative binomial analyses. A post hoc subgroup analysis was performed to assess for the risk of the primary outcome by gestational age. We performed tests of homogeneity based on history of uterine scarring and parity. RESULTS: Six hundred eighty-one individuals were included. The median duration of labor was 11 hours (interquartile range 8-17 hours). One hundred thirty-one (19.2%) experienced the primary outcome. When duration of labor was evaluated continuously, a longer duration of labor was associated with an increased frequency of morbidity (adjusted ß=0.68, 95% CI, 0.32-1.04). When duration of labor was evaluated categorically, those experiencing the highest quartile of duration (ie, 17 hours or more) had a statistically higher risk for experiencing morbidity compared with individuals in all other quartiles (adjusted relative risk 1.99, 95% CI, 1.34-2.96). When we focused on components of the composite outcome, clinical chorioamnionitis was significantly different between those experiencing a longer duration and those experiencing a shorter duration of labor (26.2% vs 10.6%, P <.001). On subgroup analysis, gestational age was not associated with the risk of composite morbidity. Tests of homogeneity demonstrated no significant difference in the risk for morbidity among individuals with a history of uterine scarring or based on parity. CONCLUSION: Duration of labor was independently associated with risks for adverse maternal outcomes during second-trimester medication abortion, specifically clinical chorioamnionitis.

Antibiotic Stewardship in Chorioamnionitis Exposed Neonates, A Quality Improvement Project.

BACKGROUND: Rates of neonatal early onset sepsis (EOS) in term infants have recently decreased. The 2018 AAP guidelines for the management of infants at risk for early onset sepsis allows for using a multivariate risk assessment to determine need for empiric antibiotics in infants 35 weeks or greater, including those exposed to chorioamnionitis. METHODS: A quality improvement (QI) project was undertaken to implement use of EOS calculator in chorioamnionitis exposed infants with an aim to safely decrease antibiotic exposure. Multiple Plan-Do-Study-Act (PDSA) cycles occurred to implement the change. Data regarding antibiotics, labs, length of stay and safety metrics were collected. RESULTS: Implementing the EOS calculator's use in chorioamnionitis exposed neonates decreased antibiotic exposure from 100% to 75%, and decreased average duration of antibiotics from 68 to 40 hours. Implementation decreased prolonged courses of antibiotics, lumbar punctures, length of stay and laboratory tests. No cases of early culture confirmed EOS were missed, and none occurred in this well appearing population. CONCLUSIONS: Quality improvement initiatives to implement evidence-based tools can safely and appropriately decrease antibiotic exposure in neonates.

Plasma Kallistatin and Progranulin as Predictive Biomarkers of Intraamniotic Inflammation, Microbial Invasion of the Amniotic Cavity, and Composite Neonatal Morbidity/Mortality in Women With Preterm Premature Rupture of Membranes.

PROBLEM: To explore the clinical utility of nine inflammatory immune-, adhesion-, and extracellular matrix-related mediators in the plasma for predicting intraamniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) and composite neonatal morbidity and/or mortality (CNMM) in women with preterm premature rupture of membranes (PPROM) when used alone or in combination with conventional blood-, ultrasound-, and clinical-based factors. METHODS OF STUDY: This retrospective cohort comprised 173 singleton pregnant women with PPROM (24 + 0 - 33 + 6 weeks), who underwent amniocentesis. Amniotic fluid was cultured for microorganisms and assayed for IL-6 levels. Plasma levels of AFP, CXCL14, E-selectin, Gal-3BP, kallistatin, progranulin, P-selectin, TGFBI, and VDBP were determined by ELISA. Ultrasonographic cervical length (CL) and neutrophil-to-lymphocyte ratio (NLR) were measured. RESULTS: Multivariate logistic regression analyses revealed significant associations between (i) decreased plasma kallistatin levels and IAI/MIAC and (ii) decreased plasma progranulin levels and increased CNMM risk after adjusting for baseline variables (e.g., gestational age at sampling [or delivery] and parity). Using stepwise regression analysis, noninvasive prediction models for IAI/MIAC and CNMM risks were developed, which included plasma progranulin levels, NLR, CL, and gestational age at sampling, and provided a good prediction of the corresponding endpoints (area under the curve: 0.79 and 0.87, respectively). CONCLUSIONS: Kallistatin and progranulin are potentially valuable plasma biomarkers for predicting IAI/MIAC and CNMM in women with PPROM. Particularly, the combination of these plasma biomarkers with conventional blood-, ultrasound-, and clinical-based factors can significantly support the diagnosis of IAI/MIAC and CNMM.

Group B Streptococcus and Intraamniotic Inflammation and Infection.

Intraamniotic inflammation and infection complicate 2% to 5% of term deliveries. Group B Streptococcus (GBS) is a common cause of intraamniotic infection associated with invasive neonatal disease and maternal morbidity. Universal vaginal-rectal screening for GBS colonization is recommended between 36 and 37 weeks. Intrapartum antibiotic prophylaxis is recommended for individuals with positive GBS screens and other risk factors. Intravenous penicillin is the preferred antimicrobial agent. Individuals with penicillin allergies may receive cefazolin for low-risk allergies and either clindamycin or vancomycin for high-risk allergies, depending on their antimicrobial susceptibilities. Clinical trials are underway to evaluate the safety and immunogenicity of maternal anti-GBS vaccine candidates.

Placental chronic inflammatory histopathology and fetal growth in a cohort with universal placental examination.

INTRODUCTION: Chronic placental inflammation is a routinely diagnosed group of placental lesions that reflect immunologic dysfunction of the mother, fetus, or both. METHODS: Complete placental pathology examinations were performed for all term births at New York Presbyterian- Brooklyn Methodist Hospital from January 2010-August 2016. Diagnoses were blinded except to gestational age. CPI lesions were marked as chronic choriodeciduitis, decidual plasma cells, chronic inflammation of basal plate with anchoring villitis, and chronic villitis. RESULTS: In this cohort of term pregnancies, 257 (11.6 %) males and 218 (9.8 %) females had ≥1 CPI lesions. Chronic villitis was the most common (319 or 14 %), with chronic choriodeciduitis, decidual plasma cells, and chronic inflammation of basal plate with anchoring villitis in 94 (4 %), 69 (3 %) and 170 (8 %), respectively. In males, chronic villitis was associated with lower gestational adjusted birthweight and had no association with placental weight. In females, chronic villitis was associated with lower gestational adjusted birthweight, but the effect became nonsignificant after adjustment for placental weight. DISCUSSION: In summary, CPI lesions' incidence and association with birth weight vary by sex. Chronic villitis is associated with lower birthweight in females; this effect is completely mediated by placental weight. Chronic villitis showed a weak direct association of chronic villitis in males, but no association with lower placental weight in males. We suggest that differences between our results and previous publications reflect effects of sampling bias.

The Role of Ureaplasma Species in Prenatal and Postnatal Morbidity of Preterm Infants: Current Concepts.

BACKGROUND: Ureaplasma species are considered commensals of the adult urogenital tract. Yet, in pregnancy, Ureaplasma parvum and Ureaplasma urealyticum have been associated with chorioamnionitis and preterm birth. In preterm infants, Ureaplasma respiratory tract colonization has been correlated with the development of bronchopulmonary dysplasia and has been implicated in the pathogenesis of other complications of prematurity. Controversies on the impact of Ureaplasma exposure on neonatal morbidity, however, remain, and recommendations for screening practices and therapeutic management in preterm infants are missing. SUMMARY: In this review, we outline clinical and experimental evidence of Ureaplasma-driven fetal and neonatal morbidity, critically examining inconsistencies across some of the existing studies. We explore underlying mechanisms of Ureaplasma-associated neonatal morbidity and discuss gaps in the current understanding including the interplay between Ureaplasma and the maternal urogenital tract and the preterm airway microbiome. Ultimately, we highlight the importance of adequate diagnostics and review the potential efficacy of anti-infective therapies. KEY MESSAGES: There is strong evidence that perinatal Ureaplasma exposure is causally related to the development of bronchopulmonary dysplasia, and there are conclusive data of the role of Ureaplasma in the pathogenesis of neonatal central nervous system infection. Observational and experimental findings indicate immunomodulatory capacities that might promote an increased risk of secondary infections. The burden of Ureaplasma exposure is inversely related to gestational age - leaving the tiniest babies at highest risk. A better knowledge of contributing pathogen and host factors and modulating conditions remains paramount to define screening and treatment recommendations allowing early intervention in preterm infants at risk.

Decidual Cells Block Inflammation-Mediated Inhibition of 15-Hydroxyprostaglandin Dehydrogenase in Trophoblasts.

Chorioamnionitis generates prostaglandin (PG) E2 and F2α, promoting fetal membrane rupture, cervical ripening, and uterine contractions. 15-Hydroxyprostaglandin dehydrogenase (HPGD) contributes to pregnancy maintenance by inactivating PGs. Herein, the role of decidual cells in the regulation of HPGD expression at the maternal-fetal interface was investigated. HPGD immunostaining was primarily detected in anchoring villi and choriodecidual extravillous trophoblasts (EVTs) during pregnancy. Chorionic EVTs adjacent to the decidua parietalis exhibited significantly higher HPGD levels than those adjacent to the amnion. HPGD histologic score levels were significantly lower in choriodecidua from chorioamnionitis versus gestational age-matched controls (means ± SEM, 132.6 ± 3.8 versus 31.2 ± 7.9; P < 0.05). Conditioned media supernatant (CMS) from in vitro decidualized term decidual cells (TDCs) up-regulated HPGD levels in differentiated EVTs, primary trophoblasts, and HTR8/SVneo cells. However, CMS from 5 µg/mL lipopolysaccharide or 10 ng/mL IL-1ß pretreated TDC cultures down-regulated HPGD levels in HTR8/SVneo cultures. Similarly, direct treatment of HTR8/SVneo with lipopolysaccharide or IL-1ß significantly reduced HPGD levels versus control (P < 0.05) but not in TDC-CMS pretreated HTR8/SVneo cultures. Collectively, these results uncover a novel decidual cell-mediated paracrine mechanism that stimulates levels of trophoblastic HPGD, whose function is to inactivate labor-inducing PGs, thereby promoting uterine quiescence during pregnancy. However, infectious/inflammatory stimuli in decidual cells cause a paracrine inhibition of trophoblastic HPGD expression, increasing PGE2/PGF2α levels, thereby contributing to preterm birth.

Fetal inflammatory response syndrome predicts early-onset sepsis and cystic periventricular leukomalacia in preterm neonates: A retrospective study.

BACKGROUND: Fetal inflammatory response syndrome (FIRS), the fetal equivalent of chorioamnionitis, is associated with poorer neonatal outcomes. FIRS is diagnosed through placental histology, namely by the identification of funisitis (inflammation of the umbilical cord) and chorionic vasculitis (inflammation of fetal vessels within the chorionic plate). The aim of this study was to identify and evaluate associations between FIRS and neonatal outcomes in preterm neonates. METHODS: We performed a retrospective cohort study at a level III neonatal intensive care unit (NICU), from January 1st 2008 to December 31st 2022, involving all inborn neonates with a gestational age below 30 weeks. We compared preterm neonates based on whether their placental histology described funisitis with chorionic vasculitis (FCV) or not. RESULTS: The study included 113 preterms, 27 (23.9%) of those had FCV and 86 (76.1%) did not. After adjusting to gestational age, prolonged rupture of membranes and preeclampsia, FCV was independently associated with the development of early-onset sepsis (OR = 7.3, p = 0.021) and cystic periventricular leukomalacia (OR = 4.6, p = 0.004). CONCLUSION: The authors identified an association between FIRS and the development of early-onset sepsis and cystic periventricular leukomalacia, highlighting the importance of early detection and management of this condition in order to improve long-term neonatal outcomes.

IL-1 and TNF mediates IL-6 signaling at the maternal-fetal interface during intrauterine inflammation.

Introduction: IL6 signaling plays an important role in triggering labor and IL6 is an established biomarker of intrauterine infection/inflammation (IUI) driven preterm labor (PTL). The biology of IL6 during IUI at the maternal-fetal interface was investigated in samples from human subjects and non-human primates (NHP). Methods: Pregnant women with histologic chorioamnionitis diagnosed by placenta histology were recruited (n=28 term, n=43 for preterm pregnancies from 26-36 completed weeks of gestation). IUI was induced in Rhesus macaque by intraamniotic injection of lipopolysachharide (LPS, n=23). IL1 signaling was blocked using Anakinra (human IL-1 receptor antagonist, n=13), and Tumor necrosis factor (TNF) signaling was blocked by anti TNF-antibody (Adalimumab n=14). The blockers were given before LPS. All animals including controls (intraamniotic injection of saline n=27), were delivered 16h after LPS/saline exposure at about 80% gestation. Results: IUI induced a robust expression of IL6 mRNAs in the fetal membranes (chorion-amnion-decidua tissue) both in humans (term and preterm) and NHP. The major sources of IL6 mRNA expression were the amnion mesenchymal cells (AMC) and decidua stroma cells. Additionally, during IUI in the NHP, ADAM17 (a protease that cleaves membrane bound IL6 receptor (IL6R) to release a soluble form) and IL6R mRNA increased in the fetal membranes, and the ratio of IL6 and soluble forms of IL6R, gp130 increased in the amniotic fluid signifying upregulation of IL6 trans-signaling. Both IL1 and TNF blockade suppressed LPS-induced IL6 mRNAs in the AMC and variably decreased elements of IL6 trans-signaling. Discussion: These data suggest that IL1 and TNF blockers may be useful anti-inflammatory agents via suppression of IL6 signaling at the maternal-fetal interface.