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Yaoyao Chen, Dehua Zhou, Yiyu Tu, Yurong Wang Department of Pediatric, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325200, People’s Republic of ChinaCorrespondence: Dehua Zhou, Email qcyx567@163.comObjective: This study aimed to analyze the risk factors for Preterm Premature Rupture of Membranes (PPROM) and evaluate the impact of the timing of antibiotic administration on maternal and neonatal outcomes.Methods: A retrospective cohort study was conducted involving 480 pregnant women (240 with PPROM and 240 without PPROM) hospitalized between January 2021 and December 2022. Maternal data, genital microbiome profiles, and pregnancy outcomes were collected and compared. Within the PPROM group, patients were subdivided into an Early Treatment group (received intravenous cefuroxime sodium within 12 hours of membrane rupture, n=120) and a Late Treatment group (received antibiotics after 12 hours, n=120). Statistical analyses were performed using SPSS 22.0.Results: Genital infections (73.8% vs 20.4%, p< 0.001) and gestational diabetes mellitus (GDM; 53.3% vs 22.9%, p< 0.001) were significantly more prevalent in the PPROM group and were identified as independent risk factors (Genital infections: OR=3.895; GDM: OR=11.166). The PPROM group had worse outcomes, including a higher cesarean section rate (39.2% vs 25.8%, p=0.002) and higher incidences of neonatal asphyxia (4.2% vs 0.4%, p=0.006) and sepsis (2.5% vs 0%, p=0.040). Compared to the Late Treatment group, the Early Treatment group demonstrated significantly lower rates of intrauterine infection (1.67% vs 7.50%, p< 0.05), cesarean section (30.0% vs 48.3%, p< 0.05), neonatal asphyxia (0.83% vs 7.50%, p< 0.01), and neonatal sepsis (0% vs 5.00%, p< 0.05).Conclusion: Genital tract infections and GDM are significant risk factors for PPROM. Early administration of antibiotics within 12 hours of membrane rupture is associated with substantially improved maternal and neonatal outcomes, underscoring its critical importance in clinical management.Keywords: preterm premature rupture of membranes, PPROM, genital tract infections, timing of antibiotic treatment, maternal and infant outcomes, chorioamnionitis

Pro-pregnancy hormone progesterone (P4) helps to maintain a quiescent status of uterine tissues during gestation. However, P4's functional role in maintaining fetal membrane (amniochorion) integrity remains unclear. P4 functions through its membrane receptors (progesterone receptor membrane components (PGRMCs)) as fetal membrane cells lack nuclear receptors. This study screened the differential expression of PGRMCs in the fetal membranes and tested P4–PGRMC interactions under normal and oxidative stress (OS) conditions expected that can disrupt P4–PGRMC interactions impacting fetal membrane stability resulting in parturition. Human fetal membranes were collected from term and preterm deliveries (N = 5). Immunohistochemistry and western blot localized and determined differential expression of P4 receptors. Primary amnion epithelial, mesenchymal (AMCs), and chorion cell were treated with P4 alone or co-treated (P4 + OS induced by cigarette smoke extract (CSE)). Proximity ligation assay (PLA) documented P4–receptor binding, whereas P4 enzyme-linked immunosorbent assay documented culture supernatant levels. Immunohistology confirmed lack of nuclear progesterone receptors; however, confirmed expressions of PGRMC 1 and 2. Term labor (P = 0.01) and preterm rupture (P = 0.01) are associated with significant downregulation of PGRMC2. OS-induced differential downregulation of PGRMCs in both amnion and chorion cells (all P < 0.05) and downregulates P4 release (AMCs; P = 0.01). The PLA showed preferential receptor–ligand binding in amnion and chorion cells. Co-treatment of P4 + CSE did not reverse CSE-induced effects. In conclusion, P4–PGRMCs interaction maintains fetal membranes' functional integrity throughout pregnancy. Increased OS reduces endogenous P4 production and cell type-dependent downregulation of PGRMCs. These changes can lead to fetal membrane-specific “functional progesterone withdrawal,” contributing to the dysfunctional fetal membrane status seen at term and preterm conditions. Summary sentence Oxidative stress-induces cells type-dependent changes in progesterone receptor membrane component 1 and 2 expression, which could contribute to the disruption of human fetal membranes both at term and preterm labor.

We revisited risk factors and outcomes related to the preterm premature rupture of membranes (PPROM). A total of 7866 pregnant women were recruited during 5 years at their first prenatal visit to the perinatal clinic of the institution. We compared three groups (women without prematurity, women with spontaneous preterm labor with intact membranes (sPL with IM), women with PPROM) regarding 60 criteria about characteristics, lifestyle, medical, gynecological, obstetrical history of mothers, medication during pregnancy, events at delivery, and complications in neonates. Logistic regression analyses adjusting for potential confounding factors were used. Of the 6968 women selected, 189 (2.8%) presented a PPROM, and 225 (3.2%) an sPL with IM. The specific risk factors for PPROM were body mass index (BMI) <18.5 kg/m2 (adjusted odds ratio, aOR: 2.00 (1.09–3.67)), history of PPROM (aOR: 2.75 (1.19–6.36)), nulliparity (aOR: 2.52 (1.77–3.60)), gestational diabetes (aOR: 1.87 (1.16–2.99)), and low level of education (aOR: 2.39 (1.20–4.78)). The complications associated with PPROM were abruption placentae, cesarean, APGAR 5′ <4, birth weight <2500 g, stillbirth, neonatal jaundice, and hospitalization of mother and neonates. All these complications were also associated with sPL with IM. Our study confirms some of the risk factors of PPROM and highlights a new one: gestational diabetes. Outcomes of PPROM are related to prematurity.

Two small leucine-rich proteoglycans (SLRP), decorin and biglycan, play important roles in structural–functional integrity of the placenta and fetal membranes, and their alterations can result in several pregnancy-associated diseases. In this review, we briefly discuss normal placental structure and functions, define and classify SLRPs, and then focus on two SLRPs, decorin (DCN) and biglycan (BGN). We discuss the consequences of deletions/mutations of DCN and BGN. We then summarize DCN and BGN expression in the pregnant uterus, myometrium, decidua, placenta, and fetal membranes. Actions of these SLRPs as ligands are then discussed in the context of multiple binding partners in the extracellular matrix and cell surface (receptors), as well as their alterations in pathological pregnancies, such as preeclampsia, fetal growth restriction, and preterm premature rupture of membranes. Lastly, we raise some unanswered questions as food for thought.

Intrauterine infection is a significant cause of neonatal morbidity and mortality. Ureaplasma parvum is a microorganism commonly isolated from cases of preterm birth and preterm premature rupture of membranes (pPROM). However, the mechanisms of early stage ascending reproductive tract infection remain poorly understood. To examine inflammation in fetal (chorioamnionic) membranes we utilized a non-human primate (NHP) model of choriodecidual U. parvum infection. Eight chronically catheterized pregnant rhesus macaques underwent maternal–fetal catheterization surgery at ∼105–112 days gestation and choriodecidual inoculation with U. parvum (105 CFU/mL, n=4) or sterile media (controls; n= 4) starting at 115–119 days, repeated at 5-day intervals until C-section at 136–140 days (term=167 days). The average inoculation to delivery interval was 21 days, and Ureaplasma infection of the amniotic fluid (AF) was undetectable in all animals. Choriodecidual Ureaplasma infection resulted in increased fetal membrane expression of MMP-9 and PTGS2, but did not result in preterm labor or increased concentrations of AF pro-inflammatory cytokines. However, membrane expression of inflammasome sensors, NLRP3, NLRC4, AIM2, and NOD2, and adaptor ASC (PYCARD) gene expression were significantly increased. Gene expression of IL-1β, IL-18, IL-18R1, CASPASE-1, and pro-CASPASE-1 protein increased with Ureaplasma infection. Downstream inflammatory genes MYD88 and NFκB (Nuclear factor kappa-light-chain-enhancer of activated B cells) were also significantly upregulated. These results demonstrate that choriodecidual Ureaplasma infection, can cause activation of inflammasome complexes and pathways associated with pPROM and preterm labor prior to microbes being detectable in the AF. Summary Sentence Choriodecidual Ureaplasma infection results in activation of inflammasome signaling and pathways associated with preterm labor and pPROM prior to microbial invasion of the amniotic cavity.

Background The rate of preterm birth has been increasing worldwide, including in Brazil. This constitutes a significant public health challenge because of the higher levels of morbidity and mortality and long-term health effects associated with preterm birth. This study describes and quantifies factors affecting spontaneous and provider-initiated preterm birth in Brazil. Methods Data are from the 2011–2012 “Birth in Brazil” study, which used a national population-based sample of 23,940 women. We analyzed the variables following a three-level hierarchical methodology. For each level, we performed non-conditional multiple logistic regression for both spontaneous and provider-initiated preterm birth. Results The rate of preterm birth was 11.5 %, (95 % confidence 10.3 % to 12.9 %) 60.7 % spontaneous - with spontaneous onset of labor or premature preterm rupture of membranes - and 39.3 % provider-initiated, with more than 90 % of the last group being pre-labor cesarean deliveries. Socio-demographic factors associated with spontaneous preterm birth were adolescent pregnancy, low total years of schooling, and inadequate prenatal care. Other risk factors were previous preterm birth (OR 3.74; 95 % CI 2.92–4.79), multiple pregnancy (OR 16.42; 95 % CI 10.56–25.53), abruptio placentae (OR 2.38; 95 % CI 1.27–4.47) and infections (OR 4.89; 95 % CI 1.72–13.88). In contrast, provider-initiated preterm birth was associated with private childbirth healthcare (OR 1.47; 95 % CI 1.09–1.97), advanced-age pregnancy (OR 1.27; 95 % CI 1.01–1.59), two or more prior cesarean deliveries (OR 1.64; 95 % CI 1.19–2.26), multiple pregnancy (OR 20.29; 95 % CI 12.58–32.72) and any maternal or fetal pathology (OR 6.84; 95 % CI 5.56–8.42). Conclusion The high proportion of provider-initiated preterm birth and its association with prior cesarean deliveries and all of the studied maternal/fetal pathologies suggest that a reduction of this type of prematurity may be possible. The association of spontaneous preterm birth with socially-disadvantaged groups reaffirms that the reduction of social and health inequalities should continue to be a national priority.

Preterm premature rupture of membranes, leading to preterm birth, is associated with neonatal and maternal morbidity and mortality. The study aimed to review the existing data on the best predictive value of pregnancy latency for known biomarkers in pregnancies after preterm premature rupture of membranes. The following databases were screened for the purposes of this systematic review: Pubmed/MEDLINE, Web of Science, EMBASE, Scopus, and the Cochrane Library. The study was conducted according to the PRISMA guidelines for systematic reviews. Only a few studies assessed biomarkers predicting pregnancy duration after PPROM. IL-6, IL-8, CRP, IL1RA, s-endoglin, βhCG, AFP, PCT, urea, creatinine, oxygen radical absorbance capacity, MDA, lipocalin-2, endotoxin activity, MMP-8, MMP-9 and S100 A8/A9 were found to have a positive predictive value for delivery timing prediction. Proinflammatory biomarkers, such as IL-6 or CRP, proved to be best correlated with delivery timing, independent of the occurrence of intrauterine infection.

The aim of this study was to elucidate the association between vitamin D (VD) and the risk for preterm birth (PTB) and prelabor rupture of membranes (PROM). This study included two parts, with a cohort study and a case-control study. Plasma 25-hydroxyvitamin vitamin D [25(OH)D] levels in three trimesters in the cohort study and maternal 25(OH)D before delivery in the case-control study were measured. Quantitative real-time PCR was used to detect relative mRNA expression levels of the inflammatory factors associated with pyroptosis in peripheral blood mononuclear cell (PBMC), placenta and fetal membranes. Multinomial logistic regression and the Wilcoxon test were applied to analyze the associations. In the cohort study, 6381 pregnant women were included. We found that VD deficiency in T3 (PTB without PROM: OR = 1.90, 95% CI: 1.02–3.55, Term PROM (TPROM): OR = 0.76, 95% CI: 0.59–0.98) and less change of 25(OH)D between T1 and T3 (PTB without PROM: OR = 2.32, 95% CI: 1.07–5.06, TPROM: OR = 0.73, 95% CI: 0.56–0.96) were associated with the increased risk of PTB without PROM, while there was a decreased risk of TPROM. Neither VD, nor the increase of VD during pregnancy was associated with the premature rupture of membranes preterm delivery (PPROM). In the case-control study, there were no associations between VD during delivery and PTB or PROM (TPROM: OR = 1.33, 95% CI: 0.52–3.44); PTB without PROM: OR = 1.66, 95% CI: 0.33–8.19; PPROM: OR = 1.19, 95% CI: 0.42–3.40). The mRNA expression of NLRP1 (NOD-like receptor thermal protein domain associated protein 1) (p = 0.0165) in PBMC in the TPROM group was higher than that in the term group, and IL-18 (p = 0.0064) was lower than that in the term group. Plasma 25(OH)D in T3 and the increase of 25(OH)D between T1 and T3 were associated with a lower risk for PTB without PROM but a higher risk for TPROM. Further studies are warranted to clarify the association between VD and PTB and PROM and its mechanism.

Plasticizers, particularly phthalates, are widely used to enhance the properties of plastics, yet their harmful effects on human health, especially reproductive health, have raised concerns. This has led governments to promote the use of non-phthalate substitutes. Preterm premature rupture of fetal membranes (PPROM), affecting 3–4% of pregnancies and contributing to 40–50% of preterm births worldwide, has been associated with traditional phthalate exposure. However, no clear link has yet been established between alternative plasticizers and preterm births. Among these substitutes, DINCH (used as a phthalate replacement) and its metabolite, MINCH, appear to be promising options, although their health impacts remain largely unexplored. This study aims to assess the potential effects of DINCH and MINCH on the physiology of fetal membranes, focusing on the nuclear receptor PPARγ, which plays a critical role in pregnancy maintenance. An amniotic epithelial cell model was used to evaluate DINCH and MINCH influence on cytotoxicity, cell viability, and PPARγ activity, including its anti-inflammatory properties. Both exhibited no cytotoxic effects, did not alter PPARγ expression, and did not affect its anti-inflammatory properties. These findings suggest that DINCH and MINCH could serve as safe alternatives to phthalates, potentially reducing the risk of weakening and premature rupture of fetal membranes.

Maternal smoking is a risk factor of preterm prelabor rupture of the fetal membranes (pPROM), which is responsible for 30% of preterm births worldwide. Cigarettes induce oxidative stress and inflammation, mechanisms both implicated in fetal membranes (FM) weakening. We hypothesized that the receptor for advanced glycation end-products (RAGE) and its ligands can result in cigarette-dependent inflammation. FM explants and amniotic epithelial cells (AECs) were treated with cigarette smoke condensate (CSC), combined or not with RAGE antagonist peptide (RAP), an inhibitor of RAGE. Cell suffering was evaluated by measuring lactate dehydrogenase (LDH) medium-release. Extracellular HMGB1 (a RAGE ligand) release by amnion and choriodecidua explants were checked by western blot. NF-κB pathway induction was determined by a luciferase gene reporter assay, and inflammation was evaluated by cytokine RT-qPCR and protein quantification. Gelatinase activity was assessed using a specific assay. CSC induced cell suffering and HMGB1 secretion only in the amnion, which is directly associated with a RAGE-dependent response. CSC also affected AECs by inducing inflammation (cytokine release and NFκB activation) and gelatinase activity through RAGE engagement, which was linked to an increase in extracellular matrix degradation. This RAGE dependent CSC-induced inflammation associated with an increase of gelatinase activity could explain a pathological FM weakening directly linked to pPROM.