Histological chorioamnionitis and pathological stages on very preterm infant outcomes.

AIMS: Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. METHODS: Preterm infants born at ≤ 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. RESULTS: The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). CONCLUSIONS: Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.

Magnetic resonance imaging of the supra-cervical fetal membrane detects an increased risk of prelabor rupture of membranes.

Objective: In 10% of term deliveries and 40% of preterm deliveries, the fetal membrane (FM) ruptures before labor. However, the ability to predict these cases of premature rupture of membranes (PROM) and preterm premature rupture of membranes (PPROM) is very limited. In this paper, our objective was to determine whether a prediction method based on T2 weighted magnetic resonance imaging (MRI) of the supra-cervical FM could predict PROM and PPROM. Methods: This prospective cohort study enrolled 77 women between the 28th and 37th weeks of gestation. Two indicators of fetal membrane defects, including prolapsed depth >5 mm and signal abnormalities, are investigated for our prediction. Fisher's exact test was used to determine whether prolapsed depth >5 mm and/or signal abnormalities were associated with PROM and PPROM. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for prolapsed depth >5 mm, signal abnormalities, and the combination of prolapsed depth >5 mm and signal abnormalities. Result: Among 12 women with PROM (5 preterm and 7 term, prior to labor onset), 9 had membrane prolapse >5 mm and 5 had FM signal abnormalities. Among 65 women with rupture of membranes at term, 2 had membrane prolapse >5 mm and 1 had signal abnormalities. By Fisher's exact test both indicators, membrane prolapse >5 mm and signal abnormalities, were associated with PROM (P<0.001, P<0.001) and PPROM (P=0.001, P<0.001). Additionally, membrane prolapse >5 mm, signal abnormalities, and the combination of the two indicators all demonstrated high specificity for predicting PROM (96.9%, 98.5%, and 100%, respectively) and PPROM (90.3%, 97.2%, and 100%, respectively). Conclusion: MRI can distinguish the supra-cervical fetal membrane in vivo and may be able to identify women at high risk of PPROM.

Risk factors and postnatal biomarkers for acute placental inflammatory lesions and intrauterine infections in preterm infants.

The purpose of this study is to explore risk factors of acute placental inflammatory lesions and the potential postnatal serum biomarkers for predicting the severity of intrauterine infection in preterm infants. We performed a retrospective analysis of premature infants with or without acute placental inflammatory lesions and their mothers by chart review for clinical data and placental histopathology. The preterm infants with acute placental inflammatory lesions had a higher rate of premature rupture of membranes (PROM), a longer duration of PROM, and a higher level of serum sialic acid (SIA) than those of the non-inflammation group (all p < 0.001). According to the different inflammatory histological structures, preterm infants with funisitis had a dominant longer duration of PROM than others (p < 0.05), and their gestational age was youngest among all the infants (p < 0.05). Furthermore, they had the highest content of serum SIA above other groups. The preterm infants in the acute histological chorioamnionitis group showed a similar trend of clinical manifestation and laboratory parameters with the funisitis group. Moreover, the closer the placental lesions were to the fetus, the lower the gestational age of preterm infants was, and the higher the serum SIA content was. CONCLUSION: We utilized a simple and precise anatomically category method of placental inflammatory histopathology for pediatricians to distinguish the extent of fetal inflammatory response for representing early-onset infectious diseases of preterm infants. SIA might be one of the potential early-stage serum biomarkers to reflect the severe intrauterine infections and could guide the postnatal anti-infection treatment. WHAT IS KNOWN: • Acute placental inflammatory lesion contributes to preterm birth and a series of complications in preterm infants. • C-reactive protein and interleukin-6 in neonatal blood can be used as biomarkers for potential early-onset sepsis, but they are influenced by the postnatal physiological changes of preterm infants. WHAT IS NEW: • The value of serum sialic acids of preterm infants within 1-hour afterbirth may be one of the rapid postnatal biomarkers for evaluating the severity of intra-amniotic infection. • The closer the placental lesions are to the fetus, the higher the content of serum sialic acid is.

Chronic abruption-oligohydramnios sequence (CAOS) revisited: possible implication of premature rupture of membranes.

AIM: The pathogenic mechanism of chronic abruption-oligohydramnios sequence (CAOS) remains unknown, and there are no objective standards for diagnosis on imaging or using pathological evidence. We aimed to reconsider and clarify the true pathology of CAOS by integrating clinical, magnetic resonance imaging (MRI) and histopathological findings of the placenta. MATERIAL AND METHODS: This is a case series of patients with CAOS managed at our hospital between 2010 and 2020. The clinical data of the patients, including MRI findings and placental pathology, were reviewed retrospectively. RESULTS: A total of 18 patients were eligible. Preterm birth occurred in 17 (94%) cases; the median gestational age at delivery was 25. Three neonates (17%) died within two years, and 10 neonates (56%) developed chronic lung disease. MRI was performed in 13 cases and clearly showed intrauterine hematoma and hemorrhagic amniotic fluid. Pathologically, in all cases, retroplacental hematoma was not detected, and fetal membranes were extremely fragile and ragged. Shedding and necrosis of the amniotic epithelium was a characteristic finding, which was confirmed in 17 cases (94%). Diffuse chorionic hemosiderosis (DCH) was detected in all cases. CONCLUSIONS: The fundamental cause of CAOS is repeated intrauterine hemorrhage and subsequent subchorionic hematoma, which induces hemorrhagic amniotic fluid and DCH. Consequently, these factors result in the necrosis and weakening of the amnion. Therefore, the true pathology of CAOS is believed to be premature rupture of membranes rather than chronic abruption.

Maternal Plasma and Amniotic Fluid LBP, Pentraxin 3, Resistin, and IGFBP-3: Biomarkers of Microbial Invasion of Amniotic Cavity and/or Intra-amniotic Inflammation in Women with Preterm Premature Rupture of Membranes.

BACKGROUND: We sought to determine whether lipopolysaccharide binding protein (LBP), pentraxin 3, resistin, and insulin-like growth factor binding protein (IGFBP)-3 in plasma and amniotic fluid (AF) can predict microbial invasion of the amniotic cavity (MIAC), intra-amniotic inflammation (IAI), and microbial-associated IAI in women with preterm premature rupture of membranes (PPROM). METHODS: This was a retrospective cohort study involving 168 singleton pregnant women with PPROM. AF obtained via amniocentesis was cultured and assayed for interleukin (IL)-6 to define IAI and for IL-8 to compare with AF biomarkers. Plasma samples were collected at the time of amniocentesis, and C-reactive protein (CRP) levels in serum were compared with plasma biomarkers. The stored plasma and AF samples were assayed for LBP, pentraxin 3 (PTX3), resistin, and IGFBP-3 by ELISA. RESULTS: Multivariate logistic regression analysis revealed that: 1) elevated plasma and AF levels of LBP were independently associated with increased risks of MIAC, IAI, and microbial-associated IAI; 2) elevated AF, but not plasma, PTX3, and resistin levels were independently associated with increased risks of MIAC, IAI, and microbial-associated IAI; 3) decreased IGFBP-3 levels in the plasma were independently associated with only IAI, whereas those in the AF were associated with only microbial-associated IAI. Among the tested biomarkers, AF PTX3 and resistin had the highest predictive performance for MIAC, IAI, and microbial-associated IAI (area under the curves [AUC] = 0.85-0.95), which is similar to the performance of AF IL-8. The AUCs of the plasma LBP and IGFBP-3 were similar to that of serum CRP with respect to IAI. CONCLUSION: Maternal plasma LBP and IGFBP-3 are potential biomarkers for the non-invasive identification of IAI in women with PPROM, with a similar accuracy to the serum CRP level. AF LBP, PTX3, resistin, and IGFBP-3 may be involved in the intra-amniotic inflammatory responses in PPROM complicated by MIAC.

Neonatal Outcomes according to the Latent Period from Membrane Rupture to Delivery among Extremely Preterm Infants Exposed to Preterm Premature Rupture of Membrane: a Nationwide Cohort Study.

BACKGROUND: In accordance with the guidelines for the expectant management of women exposed to previable preterm premature rupture of membrane, we compared neonatal outcomes according to the latent period from membrane rupture to delivery among extremely preterm infants exposed to maternal preterm premature rupture of membrane using the Korean Neonatal Network database. METHODS: Of the 3,305 extremely preterm infants born at 23-27 weeks' gestation between 2014 and 2017 who were registered in the Korean Neonatal Network, 1,464 infants were born to pregnant women who were exposed to preterm premature rupture of membrane. The short latency group was defined as infants born with a latent period between membrane rupture and delivery < 7 days (n = 450), whereas the prolonged latency group was defined as infants born with a latent period of ≥ 7 days (n = 434). Using well-established risk factors for adverse short-term outcomes, multivariate logistic regression analysis was performed to assess a prolonged latent period in preterm premature rupture of membrane as an independent risk factor for neonatal outcomes in extremely preterm infants exposed to preterm premature rupture of membrane. RESULTS: The mean gestational age at membrane rupture in the prolonged latency group was significantly lower than that in the short latency group (22.7 ± 2.5 vs. 25.4 ± 1.3 weeks, P < 0.001). Nevertheless, the mean gestational age at delivery and birth weight were not significantly different between the two groups. The incidence of oligohydramnios and histologic chorioamnionitis in the prolonged latency group was significantly higher than that in the short latency group (38.7 [155/401] vs. 26.1 [105/403], 69.8 [270/384] vs. 61.0 [242/397], respectively, P < 0.05). The survival rate in the prolonged latency group did not differ from that in the short latency group (71.2 [309/434] vs. 73.3 [330/450], P = 0.478). Although the prolonged latency group was not associated with mortality during hospitalization in the multivariate logistic regression analysis, the prolonged latency group's early pulmonary hypertension and bronchopulmonary dysplasia rates were increased by 1.8 and 1.5 times, respectively. CONCLUSION: A prolonged latent period of 7 days or more does not affect the survival rate but increases the risk of bronchopulmonary dysplasia occurrence among extremely preterm infants who are exposed to maternal preterm premature rupture of membrane.

Disorders of placental villous maturation are present in one-third of cases with spontaneous preterm labor.

OBJECTIVES: Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. METHODS: A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. RESULTS: Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). CONCLUSIONS: Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor.

Inflammasome components and ADAMTS4 in premature rupture of membranes.

Inflammation may be responsible for the development of premature rupture of membranes (PROM) including preterm PROM (PPROM) and mature PROM (MPROM). A total of four classic receptor proteins have been confirmed to assemble inflammasomes: NLR family pyrin domain containing (NLRP)1, NLRP3 and NLR family CARD­domain containing 4 (NLRC4) and absent in melanoma 2 (AIM2). The activation and expression of these receptor­modulated inflammasomes in placenta and fetal membrane of PROM pregnancies requires investigation. In addition, a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is a risk factor for PROM, but whether its expression is associated with inflammasome activation remains to be elucidated. In the present study, the placenta and fetal membrane tissues of patients who had suffered PPROM and MPROM and healthy pregnancies were investigated. Reverse transcription­quantitative PCR was used to determine the mRNA expression of inflammasomes and ADAMTS4. Western blotting, immunohistochemistry and ELISA were used to investigate the protein expression levels of inflammasomes and ADAMTS4. The results demonstrated that all four inflammasomes were elevated in placenta and fetal membrane of PPROMs as were mRNA and protein expression levels of IL­18 and IL­1ß (compared with controls). A further increase of inflammasomes and interleukins was observed in MPROMs compared with controls. Similar results were also observed in ADAMTS4 expression in PPROM and MPROM groups. However, immunohistochemistry results revealed no significant difference of inflammasome receptor expression in PPROMs compared with controls. Finally, a general positive correlation between ADAMTS4 and all four inflammasome receptors in placenta and fetal membrane of PPROMs and MPROMs was observed. The present study revealed that NLRP1, NLRP3, AIM2 and NLRC4 inflammasome activation in PROM was increased. Promoted ADAMTS4 level was further observed in PROM group and was significantly correlated with inflammasome expression. Inhibition of inflammasome activation may provide a therapeutic target for clinical PROM treatment.

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.

Pregnancy outcomes associated with chorioamnion membrane separation severity following fetoscopic laser surgery for twin-twin transfusion syndrome.

OBJECTIVE: We tested the hypothesis that increasing severity of chorioamnion membrane separation (CAS) after fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) is associated with worse pregnancy outcomes. METHODS: Prospective cohort of patients undergoing FLS for TTTS between 2011 and 2018. CAS was defined as separation of fetal membranes from the uterine wall on post-operative ultrasound. Patient groups were defined: Group 1: No CAS; Group 2: CAS lower than 50th centile; Group 3: CAS upper than 50th centile or complete CAS. Comparative analysis was performed. RESULTS: Of 387 patients meeting inclusion criteria, 29 (7.5%) had CAS (median 9.8 mm [4.9-30.8 mm]). Group 1 patients were more likely to undergo FLS at later gestational age, had increased recipient maximum vertical pocket, and higher amnioreduction volume than Group 3. Group 3 had higher rates of preterm premature rupture of membrane, delivered earlier and were more likely to terminate than Group 1. Group 2 had fewer neonatal survivors than Group 1. Survival analysis for gestational age at delivery and Cox proportional hazards model indicated increased risk for early delivery in Groups 2 and 3 compared with Group 1. CONCLUSIONS: Patients with CAS ≥9.8 mm or complete CAS after FLS for TTTS had worse obstetric and neonatal outcomes.

MicroRNA Signature of Epithelial-Mesenchymal Transition in Group B Streptococcal Infection of the Placental Chorioamniotic Membranes.

BACKGROUND: Infection-induced preterm birth is a major cause of neonatal mortality and morbidity and leads to preterm premature rupture of placental chorioamniotic membranes. The loss of amniotic epithelial cells and tensile strength preceding membrane rupture is poorly understood. We hypothesized that intrauterine bacterial infection induces changes in microRNA (miRNA) expression, leading to amniotic epithelial cell loss and membrane weakening. METHODS: Ten pregnant pigtail macaques received choriodecidual inoculation of either group B Streptococcus (GBS) or saline (n = 5/group). Placental chorioamniotic membranes were studied using RNA microarray and immunohistochemistry. Chorioamniotic membranes from women with preterm premature rupture of membranes (pPROM) and normal term pregnancies were studied using transmission electron microscopy. RESULTS: In our model, an experimental GBS infection was associated with changes in the miRNA profile in the chorioamniotic membranes consistent with epithelial to mesenchymal transition (EMT) with loss of epithelial (E-cadherin) and gain of mesenchymal (vimentin) markers. Similarly, loss of desmosomes (intercellular junctions) was seen in placental tissues from women with pPROM. CONCLUSIONS: We describe EMT as a novel mechanism for infection-associated chorioamniotic membrane weakening, which may be a common pathway for many etiologies of pPROM. Therapy based on anti-miRNA targeting of EMT may prevent pPROM due to perinatal infection.

Thrombin-Induced Decidual Colony-Stimulating Factor-2 Promotes Abruption-Related Preterm Birth by Weakening Fetal Membranes.

Preterm premature rupture of membranes (PPROM) and thrombin generation by decidual cell-expressed tissue factor often accompany abruptions. Underlying mechanisms remain unclear. We hypothesized that thrombin-induced colony-stimulating factor-2 (CSF-2) in decidual cells triggers paracrine signaling via its receptor (CSF2R) in trophoblasts, promoting fetal membrane weakening and abruption-associated PPROM. Decidua basalis sections from term (n = 10), idiopathic preterm birth (PTB; n = 8), and abruption-complicated pregnancies (n = 8) were immunostained for CSF-2. Real-time quantitative PCR measured CSF2 and CSF2R mRNA levels. Term decidual cell (TDC) monolayers were treated with 10-8 mol/L estradiol ± 10-7 mol/L medroxyprogesterone acetate (MPA) ± 1 IU/mL thrombin pretreatment for 4 hours, washed, and then incubated in control medium with estradiol ± MPA. TDC-derived conditioned media supernatant effects on fetal membrane weakening were analyzed. Immunostaining localized CSF-2 primarily to decidual cell cytoplasm and cytotrophoblast cell membranes. CSF-2 immunoreactivity was higher in abruption-complicated or idiopathic PTB specimens versus normal term specimens (P < 0.001). CSF2 mRNA was higher in TDCs versus cytotrophoblasts (P < 0.05), whereas CSF2R mRNA was 1.3 × 104-fold higher in cytotrophoblasts versus TDCs (P < 0.001). Thrombin enhanced CSF-2 secretion in TDC cultures fourfold (P < 0.05); MPA reduced this effect. Thrombin-pretreated TDC-derived conditioned media supernatant weakened fetal membranes (P < 0.05), which MPA inhibited. TDC-derived CSF-2, acting via trophoblast-expressed CSFR2, contributes to thrombin-induced fetal membrane weakening, eliciting abruption-related PPROM and PTB.

The role of innate immunity in spontaneous preterm labor: A systematic review.

BACKGROUND: Immunoinflammatory response by innate immunity components is a field with increasing interest in understanding the mechanisms behind preterm labor (PTL). OBJECTIVES: Systematic review of the role of innate immunity in spontaneous PTL. STUDY DESIGN: PubMed, Scopus, ClinicalTrials.gov and Web of Science were searched using pregnancy AND innate OR toll-like OR natural-killer OR dendritic AND delivery OR premature OR rupture of membranes. MAIN OUTCOME MEASURES: All article titles and abstracts were evaluated by two individuals, based in strict predefined inclusion criteria. For relevant studies, title, abstract, and full text were assessed to identify PTL and innate immunity studies, excluding multiple pregnancies, cervical insufficiency and indicated PTL. RESULTS: From 894 articles evaluated, 101 full texts articles were assessed independently. For this systematic review 44 studies were finally included. Toll-like receptors 2 and 4 mediated immune dysfunction and inflammation can result in PTL. Moreover, PTL is linked to high levels of CD14+ monocytes; neutrophils seem important in inflammation-associated PTL and in pathological preterm premature rupture of membranes. Besides, decidual natural-killer cells and premature activation of dendritic cells may also participate in the etiology of PTL. Finally, dysregulation of maternal complement might increase the risk of PTL, characterized by high levels of innate lymphoid cells 2 and 3. CONCLUSIONS: Further research is warranted to ascertain the precise role of innate immunity in PTL. Nonetheless, our results indicate that Toll-like receptors, monocytes, natural-killer cells, dendritic cells and complement have significant roles in PTL.

[Pathomorphology of extraplacental membranes in their premature rupture and undifferentiated connectivetissue dysplasia in women]. / Patomorfologiia vneplatsentarnykh obolochek pri ikh prezhdevremennom razryve i nedifferentsirovannoi displazii soedinitel'noi tkani u zhenshchin.

AIM: to investigate the morphological features of the extraplacental membranes (EPM) of the placentas obtained from women with undifferentiated connective tissue dystrophy (UCTD) and premature rupture of the fetal membranes (PROFM). MATERIAL AND METHODS: EPMs of 65 placentas, including 55 from study group women and 10 from control women (having no manifestations of UCTD and PROFM), underwent morphological examination (visual examination, histological and immunohistochemical studies, and electron microscopy). RESULTS: There was subamniotic edema, disorientation and fragmentation of collagen structures in the compact layer, a structural change in the brush border of the amniotic epithelium, and a predominance of vacuolated cytotrophoblast forms in the structure of EPM of the placentas from of women with UCTD. Structural changes were accompanied by the altered function of EPM cells and identified by immunohistochemistry as higher MMP-9 expression by amniocytes and cytotrophoblast cells. PROFM was typified by the proliferation of amniotic epithelium; by the ordered arrangement of collagen fibers, and by large, longitudinally oriented fibroblasts. The structural changes in UCTD and PROFM were also accompanied by the altered function in the EPM cells as higher MMP-9 expression in amniocytes and cytotrophoblast cells. The latter was accompanied by the enhanced proteolysis of the extracellular matrix and can serve as one of the mechanisms, which triggers PROFM. CONCLUSION: Impaired histoarchitectonics and higher MMP-9 expression in the EPM cells should be considered as a manifestation of connective tissue disorganization and may be considered as one of the components in the pathogenesis of PROFM in the presence of UCTD.

Extracellular matrix remodeling effects of serum amyloid A1 in the human amnion: Implications for fetal membrane rupture.

PROBLEM: Rupture of fetal membranes is a crucial event at parturition, which is preceded by extensive extracellular matrix (ECM) remodeling. Our recent studies have demonstrated that the human fetal membranes are capable of de novo synthesis of serum amyloid A1 (SAA1), an acute phase protein, and the abundance of SAA1 in the amnion was increased at parturition. However, the exact role of SAA1 in human parturition remains to be established. METHOD OF STUDY: The effects of SAA1 on the abundance of collagenases and lysyl oxidase, the enzyme that cross-links collagens, were investigated in culture primary human amnion fibroblasts and tissue explants with an aim to examine the involvement of SAA1 in the ECM remodeling in the amnion. RESULTS: Serum amyloid A1 (SAA1) time- and dose-dependently increased the abundance of collagenases MMP-1, MMP-8, and MMP-13, while decreased the abundance of lysyl oxidase-like 1 (LOXL1). These effects of SAA1 were attenuated by siRNA-mediated knockdown of the Toll-like receptor (TLR) 4 and its antagonist CLI-095, but not by siRNA-mediated knockdown of TLR2. Furthermore, the inhibitors for NF-κB (JSH-23) and mitogen-activated protein kinases (MAPKs) p38 (SB203580) and JNK (SP600125) could also attenuate the effects of SAA1, while the inhibitor for MAPK ERK1/2 (PD 98059) could block the effects of SAA1 only on MMP-1, MMP-8, and LOXL1 but not on MMP-13. CONCLUSION: These data highlight a possible role for SAA1 in ECM remodeling preceding membrane rupture by regulating the expression of collagenases MMP-1, MMP-8, MMP-13, and LOXL1 through TLR4-mediated activation of the NF-κB and MAPK pathways in amnion fibroblasts.

Drastic induction of MMP-7 by cortisol in the human amnion: implications for membrane rupture at parturition.

Preterm premature rupture of fetal membranes precedes 30-40% of preterm births. Activation of matrix metalloproteases (MMPs) is the one of the major causes of extracellular matrix (ECM) degradation in membrane rupture. Increased cortisol, regenerated by 11ß-hydroxysteroid dehydrogenase 1 in the amnion at parturition, is known to participate in a number of parturition-pertinent events. However, whether cortisol has a role in the regulation of MMPs in the membranes is not known. Here, we addressed this issue using human amnion tissue, the most tensile layer of the membranes. RNA-sequencing revealed that cortisol induced MMP7 expression dramatically in amnion fibroblasts, which was confirmed by real-time quantitative RT-PCR and Western blotting analysis in cortisol-treated amnion explants and fibroblasts. Measurement of collagen IV α5 chain (COL4A5), a substrate for MMP-7, showed that cortisol reduced its extracellular abundance, which was blocked by an antibody against MMP-7. Moreover, increased MMP-7 but decreased COL4A5 abundance was observed in the amnion tissue following labor-initiated spontaneous rupture of membranes. Mechanistic studies showed that cortisol increased the phosphorylation of c-Jun and the expression of c-Fos, the 2 major components of activated protein 1 (AP-1), respectively. The knocking down of c-Fos or c-Jun significantly attenuated the induction of MMP7 expression by cortisol. Chromatin immunoprecipitation assays showed that cortisol stimulated the enrichment of c-Fos and c-Jun at the AP-1 binding site in the MMP7 promoter. The data suggest that induction of MMP7 by cortisol via AP-1 may be a contributing factor to ECM degradation in membrane rupture at parturition.-Wang, L.-Y., Wang, W.-S., Wang, Y.-W., Lu, J.-W., Lu, Y., Zhang, C.-Y., Li, W.-J., Sun, K., Ying, H. Drastic induction of MMP-7 by cortisol in the human amnion: implications for membrane rupture at parturition.

The impact of time of delivery on gestations complicated by preterm premature rupture of membranes: daytime versus nighttime.

Background: Perinatal death, in particular intrapartum stillbirth and short-term neonatal death, as well as neonatal short-term and long-term morbidity have been associated with the time of day that the birth occurs. Indeed, evening and nighttime deliveries were associated with an increased risk of an adverse perinatal outcome when compared to similar daytime deliveries. Impact of shift change, as well as time of day delivery have been extensively studied in the context of maternal and neonatal complications of cesarean delivery, however, no studies were previously performed on timing of delivery and its effect on the outcome of pregnancies complicated by preterm premature rupture of membranes. Objective: Our objective was to compare obstetric, neonatal as well as long-term outcomes between women delivered in the daytime versus nighttime, in singleton gestations whose pregnancies were complicated by preterm premature rupture of membranes. Study design: This was a secondary analysis of a trial of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network "A Randomized Clinical Trial of the Beneficial Effects of Antenatal Magnesium Sulfate for the Prevention of Cerebral Palsy." For this analysis, the time of delivery was divided into the daytime, from 07:01 to 19:00, and the nighttime, from 19:01 to 07:00. Epidemiological, obstetric characteristics as well as neonatal and long-term outcomes were compared between deliveries occurring during the daytime versus the nighttime periods. Inclusion criteria consisted of singleton gestations diagnosed with preterm premature rupture of membranes (PPROM). Multifetal gestations and pregnancies with preterm labor without preterm premature rupture of membranes were excluded. Results: A total of 1752 patients met inclusion criteria, 881 delivering during the daytime, while 871 during the nighttime. There were no differences in demographic maternal variables. There were no differences in the number of patients receiving steroids and the doses of steroids. Antibiotic prophylaxis was also equal in both groups. Postpartum endometritis, chorioamnionitis, and the latency to delivery were also equivalent between both the groups. Cesarean delivery for distress was the only different outcome, more prevalent in daytime deliveries (157 (44.7%) versus 108 (35.9%) of the nighttime ones p = .02). Neonatal adverse outcomes as well as long-term outcomes were similar between the two groups. Conclusions: In the setting of delivery at a tertiary care center, and in the era of universal use of steroids, and latency antibiotics for the management of preterm premature of membranes, there is no marked difference in pregnancy, neonatal as well as long-term outcomes for infants delivered in the daytime versus nighttime.

Maternal dyslipidemia and risk for preterm birth.

Maternal lipid profiles during pregnancy are associated with risk for preterm birth. This study investigates the association between maternal dyslipidemia and subsequent preterm birth among pregnant women in the state of California. Births were identified from California birth certificate and hospital discharge records from 2007-2012 (N = 2,865,987). Preterm birth was defined as <37 weeks completed gestation and dyslipidemia was defined by diagnostic codes. Subtypes of preterm birth were classified as preterm premature rupture of membranes (PPROM), spontaneous labor, and medically indicated, according to birth certificate data and diagnostic codes. The association between dyslipidemia and preterm birth was tested with logistic regression. Models were adjusted for maternal age at delivery, race/ethnicity, hypertension, pre-pregnancy body mass index, insurance type, and education. Maternal dyslipidemia was significantly associated with increased odds of preterm birth (adjusted OR: 1.49, 95%CI: 1.39, 1.59). This finding was consistent across all subtypes of preterm birth, including PPROM (adjusted OR: 1.54, 95%CI: 1.34, 1.76), spontaneous (adjusted OR: 1.51, 95%CI: 1.39, 1.65), and medically indicated (adjusted OR: 1.454, 95%CI: 1.282, 1.649). This study suggests that maternal dyslipidemia is associated with increased risk for all types of preterm birth.