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Background and objective: Pregnancy associated Group B streptococcal infection is a well-established cause of significant neonatal morbidity and mortality. A cross-sectional study was conducted to determine the prevalence of Group B streptococcal infection among women presenting in labor at different ages and gestational ages and its correlation with different risk factors. Methods: Vaginal swab and urine sample for culture from 150 women having risk factors and being in labor and having risk of developing Group B streptococcal infection from 2nd of November 2020 to 2nd of December 2021. Results: The prevalence of Group B streptococcal infection among risky group women during labor in Maternity Teaching Hospital was 8%. The rate of agreement between the vaginal swab results and urine culture results was 92%. There was no significant association between urine culture results with age, parity and prolonged rupture of membrane. A significant high rate of infected urine in culture was found among women with a very extreme preterm gestational age (p value 0.049), and it was also significant among women with pyrexia (p value 0.001). Conclusion: The prevalence of Group B streptococcal infection among high-risk group of women during labor in Maternity Teaching Hospital of Erbil city was 8%.

Abstract Background Preterm labor syndrome is associated with high perinatal morbidity and mortality, and intra-amniotic infection is a cause of preterm labor. The standard identification of causative microorganisms is based on the use of biochemical phenotypes, together with broth dilution-based antibiotic susceptibility from organisms grown in culture. However, such methods could not provide an accurate epidemiological aspect and a genetic basis of antimicrobial resistance leading to an inappropriate antibiotic administration. Hybrid genome assembly is a combination of short- and long-read sequencing, which provides better genomic resolution and completeness for genotypic identification and characterization. Herein, we performed a hybrid whole genome assembly sequencing of a pathogen associated with acute histologic chorioamnionitis in women presenting with PPROM. Results We identified Enterococcus faecium, namely E. faecium strain RAOG174, with several antibiotic resistance genes, including vancomycin and aminoglycoside. Virulence-associated genes and potential bacteriophage were also identified in this genome. Conclusion We report herein the first study demonstrating the use of hybrid genome assembly and genomic analysis to identify E. faecium ST17 as a pathogen associated with acute histologic chorioamnionitis. The analysis provided several antibiotic resistance-associated genes/mutations and mobile genetic elements. The occurrence of E. faecium ST17 raised the awareness of the colonization of clinically relevant E. faecium and the carrying of antibiotic resistance. This finding has brought the advantages of genomic approach in the identification of the bacterial species and antibiotic resistance gene for E. faecium for appropriate antibiotic use to improve maternal and neonatal care.

Nocardioform placentitis (NP) continues to result in episodic outbreaks of abortion and preterm birth in mares and remains a poorly understood disease. The objective of this study was to characterize the transcriptome of the chorioallantois (CA) of mares with NP. The CA were collected from mares with confirmed NP based upon histopathology, microbiological culture and PCR for Amycolatopsis spp. Samples were collected from the margin of the NP lesion (NPL, n = 4) and grossly normal region (NPN, n = 4). Additionally, CA samples were collected from normal postpartum mares (Control; CRL, n = 4). Transcriptome analysis identified 2892 differentially expressed genes (DEGs) in NPL vs. CRL and 2450 DEGs in NPL vs. NPN. Functional genomics analysis elucidated that inflammatory signaling, toll-like receptor signaling, inflammasome activation, chemotaxis, and apoptosis pathways are involved in NP. The increased leukocytic infiltration in NPL was associated with the upregulation of matrix metalloproteinase (MMP1, MMP3, and MMP8) and apoptosis-related genes, such as caspases (CASP3 and CASP7), which could explain placental separation associated with NP. Also, NP was associated with downregulation of several placenta-regulatory genes (ABCG2, GCM1, EPAS1, and NR3C1), angiogenesis-related genes (VEGFA, FLT1, KDR, and ANGPT2), and glucose transporter coding genes (GLUT1, GLUT10, and GLUT12), as well as upregulation of hypoxia-related genes (HIF1A and EGLN3), which could elucidate placental insufficiency accompanying NP. In conclusion, our findings revealed for the first time, the key regulators and mechanisms underlying placental inflammation, separation, and insufficiency during NP, which might lead to the development of efficacious therapies or diagnostic aids by targeting the key molecular pathways.

The objective of this study was to assess the relationship of ACS with neonatal outcomes among very preterm infants born to mothers with clinical chorioamnionitis in China. This was a multicenter retrospective cohort study. Study participants included infants born at

Early-onset neonatal sepsis (EONS), a serious infection in newborns within 3 days, is challenging to diagnose. The current methods often lack accuracy, leading to unnecessary antibiotics or delayed treatment. This study investigates the role of the frozen section examination of placental membranes and umbilical cord (FSMU) to improve EONS diagnosis in the daily lab practice. This retrospective study reviewed data from 59 neonates with EONS risk factors who underwent FSMU according to our institutional protocol. Concordance between the FSMU and the Final Pathological Report (FPR) was assessed. The FSMU demonstrated a high concordance (Kappa = 0.88) for funisitis diagnosis, with excellent accuracy (98.3%). A moderate concordance was observed for chorioamnionitis stage and grade. The FSMU shows promise as a rapid and accurate tool for diagnosing EONS, particularly for funisitis. This study suggests that the FSMU could be a valuable tool for EONS diagnosis, enabling a more judicious antibiotic use and potentially improving outcomes for newborns.

Background: Histological chorioamnionitis (HCA) is a histologic response to intra-uterine inflammation that is usually confirmed by pathology examination after pre-term delivery and characterized by acute granulocyte infiltration into the fetal-maternal or fetal tissues. This study aimed to compare the HCA in pre-term delivery with and without pre-term rupture of membrane for assessment of its role on early neonatal outcomes and fetal heart rate patterns. Materials and Methods: This case-control study was conducted on placenta, chorionamnion, and cord of 100 cases with and without pre-term rupture of membrane between 28 0/7 and 36 6/7 weeks delivered between March 2018 and February 2021. The kind of delivery, gestational age, neonatal intensive care unit admission, a 5 min Apgar score

Female genital tract infections (FGTIs) include vaginal infections (e.g., bacterial vaginosis [BV]), endometritis, pelvic inflammatory disease [PID], and chorioamnionitis [amniotic fluid infection]. They commonly occur in women of reproductive age and are strongly associated with multiple adverse health outcomes including increased risk of HIV/sexually transmitted infection acquisition and transmission, infertility, and adverse birth outcomes such as preterm birth. These FGTIs are characterized by a disruption of the cervicovaginal microbiota which largely affects host immunity through the loss of protective, lactic acid-producing Lactobacillus spp. and the overgrowth of facultative and strict anaerobic bacteria. Prevotella species (spp.), anaerobic Gram-negative rods, are implicated in the pathogenesis of multiple bacterial FGTIs. Specifically, P. bivia, P. amnii, and P. timonensis have unique virulence factors in this setting, including resistance to antibiotics commonly used in treatment. Additionally, evidence suggests that the presence of Prevotella spp. in untreated BV cases can lead to infections of the upper female genital tract by ascension into the uterus. This narrative review aims to explore the most common Prevotella spp. in FGTIs, highlight their important role in the pathogenesis of FGTIs, and propose future research in this area.

Fetal and neonatal exposures to perinatal oxidative stress (OS) are key mediators of bronchopulmonary dysplasia (BPD). To characterize these exposures, adductomics is an exposure science approach that captures electrophilic addition products (adducts) in blood protein. Adducts are bound to the nucleophilic cysteine loci of human serum albumin (HSA), which has a prolonged half-life. We conducted targeted and untargeted adductomics to test the hypothesis that adducts of OS vary with BPD. We studied 205 preterm infants (≤28 weeks) and 51 full-term infants from an ongoing birth cohort. Infant plasma was collected at birth (cord blood), 1-week, 1-month, and 36-weeks postmenstrual age. HSA was isolated from plasma, trypsin digested, and analyzed using high-performance liquid chromatography–mass spectrometry to quantify previously annotated (known) and unknown adducts. We identified 105 adducts in cord and postnatal blood. A total of 51 known adducts (small thiols, direct oxidation products, and reactive aldehydes) were increased with BPD. Postnatally, serial concentrations of several known OS adducts correlated directly with supplemental oxygen exposure. The application of large-scale adductomics elucidated OS-mediated pathways of BPD. This is the first study to investigate the “neonatal–perinatal exposome” and to identify oxidative stress-related exposure biomarkers that may inform antioxidant strategies to protect the health of future generations of infants.

Background: Connexins (Cx) 43 and 40 play a role in leukocytes recruitment in acute inflammation. They are expressed in the endothelial cells. They are also found in the placenta and involved in the placenta development. Acute chorioamnionitis is associated with an increased risk of adverse perinatal outcomes. The aim of this study was to determine the expressions of Cx43 and Cx40 in the placenta of mothers with acute chorioamnionitis, and to correlate their association with the severity of chorioamnionitis and adverse perinatal outcomes. Methods: This study comprised a total of 81 cases, consisting of 39 placenta samples of mothers with acute chorioamnionitis and 42 non-acute chorioamnionitis controls. Cx43 and Cx40 immunohistochemistry were performed on all cases and their expressions were evaluated on cytotrophoblasts, syncytiotrophoblasts, chorionic villi endothelial cells, stem villi endothelial cells, maternal endothelial cells and decidua of the placenta. Results: Primigravida has a significantly higher risk of developing acute chorioamnionitis (p < 0.001). Neonates of mothers with a higher stage of fetal inflammatory response was significantly associated with lung complications (p = 0.041) compared to neonates of mothers with a lower stage. The expression of Cx40 was significantly higher in fetal and maternal vascular endothelial cells in acute chorioamnionitis (p < 0.001 and p = 0.037, respectively) compared to controls. Notably, Cx43 was not expressed in most of the types of cells in the placenta, except for decidua. Both Cx43 and Cx40 expressions did not have correlation with the severity of acute chorioamnionitis and adverse perinatal outcomes. Conclusion: Cx40 was overexpressed in the fetal and maternal vascular endothelial cells in the placenta of mothers with acute chorioamnionitis, and it may have a role in the development of inflammation in placenta.

Abstract Background Chorioamnionitis (CAM) is a common risk factor for preterm births, resulting in several adverse outcomes. The association between infertility treatment and CAM is unclear. Therefore, this study examined the association between infertility treatment and CAM and described subsequent neonatal outcomes. Methods This population-based cohort study used data from the National Vital Statistics System Database. We included women who had a singleton live birth from January 1, 2016 to December 31, 2018. Women-infant pairs were stratified by infertility treatment, and the main outcome was a reported diagnosis of CAM in a checkbox format: clinical CAM or maternal temperature of > 38 °C. Multivariate logistic regression was used to examine the association between infertility treatment and CAM and the effect of infertility treatment on neonatal outcomes in women diagnosed with CAM. Results The final sample comprised 10,900,495 woman-infant pairs, and 1.4% received infertility treatment. Compared with the natural conception group, women receiving infertility treatment had a significantly higher risk of CAM (adjusted odds ratio [aOR] 1.772 [95% confidence interval {CI}, 1.718–1.827]). Furthermore, newborns exposed to CAM had a higher risk of very low birth weight (VLBW) (aOR, 2.083 [95% CI, 1.664–2.606], P

Linas Rovas,1,2 Arturas Razbadauskas,1 Gabriele Slauzgalvyte2 1Klaipeda University, Klaipeda, Lithuania; 2Department of Obstetrics and Gynecology, Klaipeda University Hospital, Klaipeda, LithuaniaCorrespondence: Linas Rovas, Klaipeda University Hospital, Klaipeda University, H. Manto g. 84, Klaipeda, 92294, Lithuania, Tel +37069843875, Email linas.rovas@gmail.comAbstract: Listeriosis is a rare but extremely dangerous infection for both mother and fetus. This pathogen can spread in humans’ bodies by consumption of contaminated food. The main high-risk groups of people for being infected are immunosuppressed and especially pregnant women. We present a case of materno-neonatal listeriosis illustrating that empiric antimicrobial therapy of chorioamnionitis during labor and neonate postpartum can also cover listeriosis which was not diagnosed prior to obtaining cultures.Keywords: listeriosis, chorioamnionitis, pregnancy, neonatal infection, antimicrobial treatment

This aim of this study was to investigate maternal hematological laboratory parameters of term infants before birth diagnosed with asphyxia compared to mothers of healthy term infants and predict asphyxia by these parameters. This study was conducted on 109 and 192 mothers of the fetus with asphyxia and healthy, respectively. Laboratory parameters of complete blood count, including PDW (platelet distribution width), PCT (procalcitonin) and NLR (neutrophil/lymphocyte ratio), were recorded before birth from pregnant women. PDW and basophil counts were significantly higher in the asphyxia group than healthy group (p: .000). The cut-off level of 19.425 accurately predicted the occurrence of asphyxia (AUC = 0.724 (95% confidence interval 0.65–0.78), p = .000). Basophil count could predict asphyxia, especially the cut-off level of> 0.15(10³/μL) (AUC = 0.67) (95% confidence interval 0.60–0.74, p = .000). To predict asphyxia before labor, a cheap and routine test of PDW can be used after more research in this area.IMPACT STATEMENT What is already known on this subject? Asphyxia is still an unsolved problem in neonatal mortality and morbidity, and it is seen in babies of mothers who carry some risks during pregnancy (such as multiple pregnancy, baby of mother with preeclampsia, meconium aspiration, diabetes); however, it is known that it is a subject that is still not fully understood as it can also occur as a result of labor that does not have any risk factors and goes well. What do the results of this study add? In term fetuses without risk factors, it can be predicted to a certain extent whether the fetus will be diagnosed with asphyxia from the hemogram test that can work from the blood of the mother before birth. What are the implications of these findings for clinical practice and/or further research? In clinical practice, asphyxia can be estimated with a cheap and simple test, without any extra examination, by looking at the routine blood tests taken from the mother before going into labor.

BACKGROUND: Maternal sepsis is a leading cause of maternal death in the United States. Approximately two-thirds of maternal deaths because of sepsis are related to delayed recognition or treatment. New early warning systems using a 2-step approach have been developed for the early recognition of sepsis in obstetrics; however, their performance has not been validated. OBJECTIVE: This study aimed to assess the performance of 3 primary screening tools introduced by the Society of Obstetric Medicine Australia and New Zealand and the California Maternal Quality Care Collaborative for use in the first step of their 2-step early warning systems. The obstetrically modified quick Sequential (sepsis-related) Organ Failure Assessment score tool, the obstetrically modified Systemic Inflammatory Response Syndrome tool, and the obstetrically modified Systemic Inflammatory Response Syndrome 1 tool were evaluated for the early detection of sepsis in patients with clinically diagnosed chorioamnionitis. STUDY DESIGN: This was a retrospective cohort study using prospectively collected clinical data at a tertiary care center and an affiliated healthcare system. The electronic health records were searched to identify and verify cases with clinically diagnosed chorioamnionitis between November 2017 and September 2022. The flow sheet for every patient was reviewed to determine when criteria were met for any of the 3 tools. The performance of these tools was analyzed using their sensitivity, specificity, positive and negative predictive values, and receiver operating characteristic curve for the identification of sepsis. RESULTS: There were 545 cases that had the requisite data for inclusion in the analysis. Of note, 11 patients met the criteria for sepsis. Both the obstetrically modified Systemic Inflammatory Response Syndrome and obstetrically modified Systemic Inflammatory Response Syndrome 1 tools had overall similar test characteristics, which were notably different from the obstetrically modified quick Sequential Organ Failure Assessment tool. The screen-positive rate of the obstetrically modified quick Sequential Organ Failure Assessment tool (1.5%; 95% confidence interval, 0.6%–2.9%) was lower than that of the obstetrically modified Systemic Inflammatory Response Syndrome tool (60.0%; 95% confidence interval, 55.7%–64.1%) and the obstetrically modified Systemic Inflammatory Response Syndrome 1 tool (50.0%; 95% confidence interval, 45.8%–54.3%). The sensitivities of the obstetrically modified Systemic Inflammatory Response Syndrome tool (100.0%; 95% confidence interval, 71.5%–100.0%) and the obstetrically modified Systemic Inflammatory Response Syndrome 1 tool (100.0%; 95% confidence interval, 71.5%–100.0%) were higher than that of the obstetrically modified quick Sequential Organ Failure Assessment tool (18.0%; 95% confidence interval, 2.3%–51.8%). All 3 tools had high negative predictive values; however, their positive predictive values were poor. CONCLUSION: This study demonstrated that all 3 tools had limitations in screening for sepsis among patients with a clinical diagnosis of chorioamnionitis. The obstetrically modified quick Sequential Organ Failure Assessment tool missed more than half of the sepsis cases and, thus, had poor performance as a primary screening tool for sepsis. Both the obstetrically modified Systemic Inflammatory Response Syndrome and obstetrically modified Systemic Inflammatory Response Syndrome 1 tools captured all sepsis cases; however, they tended to overdetect sepsis.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm birth survivors characterized by inflammation, impaired alveolarization and dysmorphic vasculature. Activated IL-17A+ lymphocytes are key drivers of inflammation in preterm infants. We have shown that in immature mice chronic airway exposure to lipopolysaccharide (LPS) induces pulmonary inflammation, increased IL-17a expression, and hypoalveolarization, a BPD-like phenotype. The source of IL-17a and contribution to lung pathology is unknown. The natural-killer group 2, member D (NKG2D) receptor mediates activation and IL-17a production in γδ T cells by binding to stress molecules. LPS induces NKG2D ligand expression, including Rae-1 and MULT1. We hypothesized that IL-17a+ γδ T cells and NKG2D signaling mediate neonatal LPS-induced lung injury. Immature C57BL/6J (wild type), Nkg2d-/- or Tcrd-/- (lacking γδ T cells) mice were inoculated with 3ug/10ul of LPS from E. coli O26:B6 or 10ul of PBS intranasally on day of life 3, 5, 7, and 10. Selected mice were treated with neutralizing antibodies against IL-17a, or NKG2D intraperitoneally. Lung immune cells were assessed by flow cytometry and gene expression was analyzed by qPCR. Alveolar growth was assessed by lung morphometry. We established that anti-IL-17a antibody treatment attenuated LPS-induced hypoalveolarization. We found that LPS induced the fraction of IL-17a+NKG2D+ γδ T cells, a major source of IL-17a in the neonatal lung. LPS also induced lung mRNA expression of NKG2D, Rae-1, MULT1, and the DNA damage regulator p53. Anti-NKG2D treatment attenuated the effect of LPS on γδ T cell IL-17a expression, immune cell infiltration and hypoalveolarization. LPS-induced hypoalveolarization was also attenuated in Nkg2d-/- and Tcrd-/- mice. In tracheal aspirates of preterm infants IL-17A and its upstream regulator IL-23 were higher in infants who later developed BPD. Also, human ligands of NKG2D, MICA and MICB were present in the aspirates and MICA correlated with median FiO2. Our novel findings demonstrate a central role for activated IL-17a+ γδ T cells and NKG2D signaling in neonatal LPS-induced lung injury. Future studies will determine the role of NKG2D ligands and effectors, other NKG2D+ cells in early-life endotoxin-induced lung injury and inflammation with a long-term goal to understand how inflammation contributes to BPD pathogenesis. [ABSTRACT FROM AUTHOR]

Global health efforts have increased against infectious diseases, but issues persist with pathogens like Group B Streptococcus (GBS). Preclinical studies have elaborated on the mechanistic process of GBS-induced chorioamnionitis and its impact on the fetal programming of chronic neuropsychiatric diseases. GBS inoculation in rodents demonstrated the following: (i) silent and self-limited placental infection, similar to human chorioamnionitis; (ii) placental expression of chemokines attracting polymorphonuclear (PMN) cells; (iii) in vitro cytokine production; (iv) PMN infiltration in the placenta (histologic hallmark of human chorioamnionitis), linked to neurobehavioral impairments like cerebral palsy and autism spectrum disorders (ASD); (v) upregulation of interleukin-1β (IL-1β) in the placenta and fetal blood, associated with higher ASD risk in humans; (vi) sex-specific effects, with higher IL-1β release and PMN recruitment in male placenta; (vii) male offspring exhibiting ASD-like traits, while female offspring displayed attention deficit and hyperactivity disorder (ADHD)-like traits; (viii) IL-1 and/or NF-kB blockade alleviate placental and fetal inflammation, as well as subsequent neurobehavioral impairments. These findings offer potential therapeutic avenues, including sex-adapted anti-inflammatory treatment (e.g., blocking IL-1; repurposing of FDA-approved IL-1 receptor antagonist (IL-1Ra) treatment). Blocking the IL-1 pathway offers therapeutic potential to alleviate chorioamnionitis-related disabilities, presenting an opportunity for a human phase II RCT that uses IL-1 blockade added to the classic antibiotic treatment of chorioamnionitis. [ABSTRACT FROM AUTHOR]

Introduction: Prelabour rupture of membranes at term affects approximately 10% of women during pregnancy, and it is often associated with a higher risk of infection than when the membranes are intact. In an attempt to control the risk of infection, two main approaches have been used most widely in clinical practice: induction of labour (IOL) soon after the rupture of membranes, also called active management (AM), and watchful waiting for the spontaneous onset of labour, also called expectant management (EM). In addition, previous studies have demonstrated that vaginal examinations increase the risk of chorioamnionitis. However, the effect of vaginal examinations in the context of prelabour rupture of membranes have not been researched to the same extent. Methods: This systematic review analyses and critiques the latest research on the management of term prelabour rupture of membranes, including the effect of vaginal examinations during labour, with a focus on the outcomes of both normal birth, and chorioamnionitis. Due to its complexity, three research questions were identified using the PICO diagram, and subsequently, the results from these searches were combined. The systematic review aimed to identify randomised controlled trials (RCTs) and observational studies that compared active vs expectant management, included number of vaginal examinations and had chorioamnionitis and/or normal birth as outcomes. The following databases were used: MEDLINE, EMBASE, Maternity and Infant care, LILACS, CINAHL and the Cochrane Central Register of Controlled trials. Quality was assessed using a tool developed especifically for this study that included questions from CASP and the Cochrane risk of bias tool. Due to the high degree of heterogeneity meta-analysis was not deemed appropriate. Therefore, simple narrative analysis was carried out. Results: Thirty-two studies met the inclusion criteria, of which 27 were RCTs and 5 observational studies. The overall quality of the studies wasn't high, 15 out of the 32 studies were deemed to be low quality and only 17 out of 32 studies were deemed to be of intermediate quality. The systematic review revealed that the management of term prelabour rupture of membranes continues to be controversial. Previous research has compared active management (Induction of labour shortly after the rupture of membrane) against expectant management (watchful waiting for the spontaneous onset of labour). Although previous studies have demonstrated that vaginal examinations increase the risk of chorioamnionitis, no prospective studies have included an intervention to reduce the number of vaginal examinations. Conclusion: A RCT assessing the consequences of active management and expectant management as well as the effect of vaginal examinations during labour for term prelabour rupture of membranes is necessary. [ABSTRACT FROM AUTHOR]

The aim of this study was to establish the role of thymic stromal lymphopoietin (TSLP) in the intra-amniotic host response of women with spontaneous preterm labor (sPTL) and birth. Amniotic fluid and chorioamniotic membranes (CAM) were collected from women with sPTL who delivered at term (n = 30) or preterm without intra-amniotic inflammation (n = 34), with sterile intra-amniotic inflammation (SIAI, n = 27), or with intra-amniotic infection (IAI, n = 17). Amnion epithelial cells (AEC), Ureaplasma parvum , and Sneathia spp. were also utilized. The expression of TSLP, TSLPR, and IL-7Rα was evaluated in amniotic fluid or CAM by RT-qPCR and/or immunoassays. AEC co-cultured with Ureaplasma parvum or Sneathia spp. were evaluated for TSLP expression by immunofluorescence and/or RT-qPCR. Our data show that TSLP was elevated in amniotic fluid of women with SIAI or IAI and expressed by the CAM. TSLPR and IL-7Rα had detectable gene and protein expression in the CAM; yet, CRLF2 was specifically elevated with IAI. While TSLP localized to all layers of the CAM and increased with SIAI or IAI, TSLPR and IL-7Rα were minimal and became most apparent with IAI. Co-culture experiments indicated that Ureaplasma parvum and Sneathia spp. differentially upregulated TSLP expression in AEC. Together, these findings indicate that TSLP is a central component of the intra-amniotic host response during sPTL. [ABSTRACT FROM AUTHOR]

Previous work has shown that Secretory-IgA (SIgA) binding to the intestinal microbiota is variable and may regulate host inflammatory bowel responses. Nevertheless, the impact of the SIgA functional binding to the microbiota remains largely unknown in preterm infants whose immature epithelial barriers make them particularly susceptible to inflammation. Here, we investigated SIgA binding to intestinal microbiota isolated from stools of preterm infants <33 weeks gestation with various levels of intestinal permeability. We found that SIgA binding to intestinal microbiota attenuates inflammatory reactions in preterm infants. We also observed a significant correlation between SIgA affinity to the microbiota and the infant's intestinal barrier maturation. Still, SIgA affinity was not associated with developing host defenses, such as the production of mucus and inflammatory calprotectin protein, but it depended on the microbiota shifts as the intestinal barrier matures. In conclusion, we reported an association between the SIgA functional binding to the microbiota and the maturity of the preterm infant's intestinal barrier, indicating that the pattern of SIgA coating is altered as the intestinal barrier matures. Mahdally et al. demonstrated the impact of Secretory-IgA functional binding to intestinal microbiota in preterm infants with varying levels of intestinal permeability. The attenuation of inflammatory responses through Secretory-IgA binding to intestinal microbiota was found to be dependent on the changes in microbiota that occur as the intestinal barrier matures. [ABSTRACT FROM AUTHOR]

This study was conducted to determine whether bacteria, fungi, or archaea are detected in the amniotic fluid of patients who underwent midtrimester amniocentesis for clinical indications. Amniotic fluid samples from 692 pregnancies were tested by using a combination of culture and end-point polymerase chain reaction (PCR) techniques. Intra-amniotic inflammation was defined as an interleukin-6 concentration >2,935 pg/mL. Microorganisms were detected in 0.3% (2/692) of cases based on cultivation, 1.73% (12/692) based on broad-range end-point PCR, and 2% (14/692) based on the combination of both methods. However, most (13/14) of these cases did not have evidence of intra-amniotic inflammation and delivered at term. Therefore, a positive culture or end-point PCR in most patients appears to have no apparent clinical significance. Amniotic fluid in the midtrimester of pregnancy generally does not contain bacteria, fungi, or archaea. Interpretation of amniotic fluid culture and molecular microbiologic results is aided by the assessment of the inflammatory state of the amniotic cavity. The presence of microorganisms, as determined by culture or a microbial signal in the absence of intra-amniotic inflammation, appears to be a benign condition. [ABSTRACT FROM AUTHOR]

Preterm delivery can be precipitated by preeclampsia or infection, and preterm infants are at heightened risk of postnatal infection. Little is known about the ontogeny of inflammatory biomarkers in extremely preterm infants. We hypothesized that suspected prenatal infection (clinical chorioamnionitis or spontaneous preterm labor) and clinically diagnosed postnatal infection would be associated with unique biomarker signatures, and those patterns would be influenced by the degree of prematurity. Venous blood was collected daily for the first week and weekly for up to 14 additional weeks from 142 neonates born at 22–32 weeks gestation. A custom array was utilized to measure monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). C-reactive protein (CRP) levels were obtained from the electronic medical record. Independent of gestational age, MCP-1 was significantly increased (p < 0.001) in association with maternal preeclampsia, but MCP-1 was decreased (p < 0.01), and CRP was increased (p < 0.01) in the presence of chorioamnionitis with funisitis. IL-6 and CRP were both increased in infants diagnosed with postnatal infection, with peak levels observed on days 2 and 3, respectively. In conclusion, suspected prenatal and postnatal infections and non-infectious complications of pregnancy are associated with unique biomarker profiles, independent of gestational age, including over a 2-fold increase in MCP-1 among newborns of mothers with preeclampsia. Further, in those clinically diagnosed with a postnatal infection in the absence of antenatal infection concerns, IL-6 increases before CRP, emphasizing a potential role for expanded biomarker screening if antibiotics are initially avoided in infants delivered for maternal indications. [ABSTRACT FROM AUTHOR]

• Removal of cervical cerclage after pPROM significantly decreases the chances of prolongating pregnancy for >48 h and 7 days. • Retention of cerclage significantly increases the risk of chorioamnionitis and Apgar <7 at 5 min. • The rate of stillbirth and of neonatal mortality were similar in the two groups. • Neonatal morbidity with long-term sequalae (i.e., sepsis, NEC) did not differ between the groups. To evaluate maternal and perinatal outcomes of removal versus retention of cervical cerclage after premature preterm rupture of membranes (pPROM). Medline, Embase and Cochrane databases were searched electronically on February 2023 utilizing combinations of the relevant medical subject heading (MeSH) terms, keywords, and word variants that were considered suitable for the topic. Either prospective or retrospective trials were considered suitable for the inclusion. The coprimary outcome of this study were pregnancy latency >7 days from pPROM and pregnancy latency >48 h from pPROM. Random effect head to‐head meta‐analyses were performed to directly compare each outcome, expressing the results as summary odds ratio (OR) for dichotomous outcomes and as mean difference (MD) for continuous outcomes, plus relative 95% confidence interval (CI). Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale. Six studies involving a total of 377 women (169 in the "removal" and 208 in the "retention" group) were included. The rate of pregnancy prolongation >48 h was significantly lower in the removal compared to retention group (OR 0.15, 95% CI 0.07–0.31; p < 0.0001), as well as the rate of pregnancy prolongation >7 days (OR 0.30 95% CI 0.11–0.83; p = 0.02) and pregnancy latency expressed in days (MD −2.84 days, 95% CI −5.40 to −0.29; p = 0.03). The rate of chorioamnionitis was significantly lower in the removal compared to the retention group (OR 0.57 95% CI 0.34–0.96p = 0.03) as was the rate of Apgar score < 7 at 5 min (OR 0.22 95% CI 0.08–0.56; p = 0.002). There was no difference between removal and retention groups for all the other maternal and perinatal outcomes. The decision whether to remove or retain cerclage in case of pPROM should balance the prematurity-related risks with that of infectious complications, thus highlighting the need for tailored management based on gestational age at occurrence of pPROM. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To develop a risk stratification model for severe maternal morbidity (SMM) or mortality after the delivery hospitalization based on information available at the time of hospital discharge. METHODS: This population-based cohort study included all pregnancies among Ohio residents with Medicaid insurance from 2012 to 2017. Pregnant individuals were identified using linked live birth and fetal death records and Medicaid claims data. Inclusion was restricted to those with continuous postpartum Medicaid enrollment and delivery at 20 or more weeks of gestation. The primary outcome of the study was SMM or mortality after the delivery hospitalization and was assessed up to 42 days postpartum and up to 1 year postpartum separately. Variables considered for the model included patient-, obstetric health care professional--, and system-level data available in vital records or Medicaid claims data. Parsimonious models were created with logistic regression and were internally validated. Receiver operating characteristic curves were used to evaluate model performance, and model calibration was assessed. RESULTS: There were 343,842 pregnant individuals who met inclusion criteria with continuous Medicaid enrollment through 42 days postpartum and 287,513 with continuous enrollment through 1 year. After delivery hospitalization discharge, the incidence of SMM or mortality was 140.5 per 10,000 pregnancies through 42 days of delivery and 330.7 per 10,000 pregnancies through 1 year postpartum. The final model predicting SMM or mortality through 42 days postpartum included maternal prepregnancy body mass index, age, gestational age at delivery, mode of delivery, chorioamnionitis, and maternal diagnosis of cardiac disease, preeclampsia or gestational hypertension, or a mental health condition. Similar variables were included in the model predicting SMM or mortality through 365 days with chronic hypertension, pregestational diabetes, and illicit substance use added and chorioamnionitis removed. Both models demonstrated moderate prediction (area under the curve [AUC] 0.77, 95% CI 0.76-0.78 for 42-day model; AUC 0.72, 95% CI 0.71-0.73 for the 1-year model) and good calibration. CONCLUSION: A prediction model for SMM or mortality up to 1 year postpartum was created and internally validated with information available to health care professionals at the time of hospital discharge. The utility of this model for patient counseling and strategies to optimize postpartum care for high-risk individuals will require further evaluation. [ABSTRACT FROM AUTHOR]

Intraventricular hemorrhage (IVH) causes morbidity and mortality in preterm infants and prenatal exposure to inflammation contributes to brain injury. Moreover, prenatal exposure to severe inflammation increases the risk of IVH in preterm neonates. The current study investigated whether intrauterine exposure to inflammation affects cerebral angiogenesis and its underlying mechanisms. Wnt5a, flt1, and vascular endothelial growth factor (VEGF)-A levels in cord blood serum (stored in a bio-bank) of the enrolled patients were measured via enzyme-linked immunosorbent assay. A preterm prenatal inflammation exposure model was established in rats by intraperitoneal injection intraperitoneally during pregnancy. Angiogenesis of cerebral tissue was analyzed using immunohistochemistry. Wnt5a, flt1, and VEGF-A expression levels were measured via immunohistochemistry, immunofluorescence, or western blotting. The correlation between Wnt5a and flt1 expression and the cerebral vessel area was also analyzed. The Wnt5a and flt1 levels in the cord blood serum were significantly higher in the amnionitis group than in the non-amnionitis group. The VEGF-A level in the cord blood serum was significantly lower in the amnionitis group. In the rat model, preterm rats in the prenatal inflammation group exhibited increased microglial cell infiltration and decreased vessel area and diameter in the cerebral tissue compared to the control group. Wnt5a was located in microglial cells, and Wnt5a and flt1 expression in brain tissue significantly increased after prenatal lipopolysaccharide (LPS) exposure. VEGF-A expression declined after prenatal LPS exposure. The cerebral vessel area was negatively correlated with Wnt5a and flt1 expression. Disordered cerebral angiogenesis is associated with increased Wnt5a-Flt1 activation in microglial cells after exposure to intrauterine inflammation. [ABSTRACT FROM AUTHOR]

The incidence of Acinetobacter infections has increased in recent years. Acinetobacter infections are resistant to most antibiotics and can be found in hospitalized patients. Pregnancies complicated by severe sepsis or septic shock are associated with a higher rate of preterm labor and delivery, fetal infection, and operative delivery. This case report describes septic shock due to Acinetobacter lwoffii infection in the 31st week of gestation. A 47-year-old woman, with a gestation of 31 weeks and one day, presented with a fever, and signs of bacterial infection on laboratory tests. Although the patient was started on tazobactam/piperacillin, she went into septic shock, and was transferred to our hospital. Cesarean section was performed at a gestation of 31 weeks and 4 days because of severe maternal pneumonia and non-reassuring fetal status. A. lwoffii was detected in blood cultures collected at the previous hospital, and susceptibility to piperacillin and meropenem to A. lwoffii was confirmed. The pneumonia responded to antibiotic treatment and there were no findings of infection in the neonate. Maternal sepsis is an infrequent but important complication, causing significant maternal and fetal morbidity and fetal and neonatal mortality; therefore, early antibiotic therapy is required to improve the clinical outcome. [ABSTRACT FROM AUTHOR]

Background: Fetal inflammatory response mediated by the influx of immune cells and activation of pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is the major determinant of infection-associated preterm birth (PTB, live births < 37 weeks of gestation). Objective: To reduce the incidence of PTB by minimizing inflammation, extracellular vesicles (EVs) were electroporetically engineered to contain anti-inflammatory cytokine interleukin (IL)-10 (eIL-10), and their efficacy was tested in an ascending model of infection (vaginal administration of E. coli) induced PTB in mouse models. Study design: EVs (size: 30-170 nm) derived from HEK293T cells were electroporated with recombinant IL-10 at 500 volts and 125 Ω, and 6 pulses to generate eIL-10. eIL-10 structural characters (electron microscopy, nanoparticle tracking analysis, ExoView [size and cargo content] and functional properties (co-treatment of macrophage cells with LPS and eIL-10) were assessed. To test efficacy, CD1 mice were vaginally inoculated with E. coli (1010CFU) and subsequently treated with either PBS, eIL-10 (500ng) or Gentamicin (10mg/kg) or a combination of eIL-10+gentamicin. Fetal inflammatory response in maternal and fetal tissues after the infection or treatment were conducted by suspension Cytometer Time of Flight (CyTOF) using a transgenic mouse model that express red fluorescent TdTomato (mT+) in fetal cells. Results: Engineered EVs were structurally and functionally stable and showed reduced proinflammatory cytokine production from LPS challenged macrophage cells in vitro. Maternal administration of eIL-10 (10 µg/kg body weight) crossed feto-maternal barriers to delay E. coli-induced PTB to deliver live pups at term. Delay in PTB was associated with reduced feto-maternal uterine inflammation (immune cell infiltration and histologic chorioamnionitis, NF-κB activation, and proinflammatory cytokine production). Conclusions: eIL-10 administration was safe, stable, specific, delayed PTB by over 72 hrs and delivered live pups. The delivery of drugs using EVs overcomes the limitations of in-utero fetal interventions. Protecting IL-10 in EVs eliminates the need for the amniotic administration of recombinant IL-10 for its efficacy. [ABSTRACT FROM AUTHOR]

Background: The optimal approach to prevent preterm birth (PTB) in twins has not been fully established yet. Recent evidence suggests that placement of cervical cerclage in twin pregnancies with short cervical length at ultrasound or cervical dilatation at physical examination might be associated with a reduced risk of PTB. However, such evidence is based mainly on small studies thus questioning the robustness of these findings. The aim of this systematic review was to determine the role of cervical cerclage in preventing PTB and adverse maternal or perinatal outcomes in twin pregnancies. Methods and findings: Key databases searched and date of last search: MEDLINE, Embase, and CINAHL were searched electronically on 20 April 2023. Eligibility criteria: Inclusion criteria were observational studies assessing the risk of PTB among twin pregnancies undergoing cerclage versus no cerclage and randomized trials in which twin pregnancies were allocated to cerclage for the prevention of PTB or to a control group (e.g., placebo or treatment as usual). The primary outcome was PTB <34 weeks of gestation. The secondary outcomes were PTB <37, 32, 28, 24 weeks of gestation, gestational age at birth, the interval between diagnosis and birth, preterm prelabor rupture of the membranes (pPROM), chorioamnionitis, perinatal loss, and perinatal morbidity. Subgroup analyses according to the indication for cerclage (short cervical length or cervical dilatation) were also performed. Risk of bias assessment: The risk of bias of the included randomized controlled trials (RCTs) was assessed using the Revised Cochrane risk-of-bias tool for randomized trials, while that of the observational studies using the Newcastle–Ottawa scale (NOS). Statistical analysis: Summary risk ratios (RRs) of the likelihood of detecting each categorical outcome in exposed versus unexposed women, and (b) summary mean differences (MDs) between exposed and unexposed women (for each continuous outcome), with their 95% confidence intervals (CIs) were computed using head-to-head meta-analyses. Synthesis of the results: Eighteen studies (1,465 twin pregnancies) were included. Placement of cervical cerclage in women with a twin pregnancy with a short cervix at ultrasound or cervical dilatation at physical examination was associated with a reduced risk of PTB <34 weeks of gestation (RR: 0.73, 95% CI [0.59, 0.91], p = 0.005 corresponding to a 16% difference in the absolute risk, AR), <32 (RR: 0.69, 95% CI [0.57, 0.84], p < 0.001; AR: 16.92%), <28 (RR: 0.54, 95% [CI 0.43, 0.67], 0.001; AR: 18.29%), and <24 (RR: 0.48, 95% CI [0.23, 0.97], p = 0.04; AR: 15.57%) weeks of gestation and a prolonged gestational age at birth (MD: 2.32 weeks, 95% [CI 0.99, 3.66], p < 0.001). Cerclage in twin pregnancy with short cervical length or cervical dilatation was also associated with a reduced risk of perinatal loss (RR: 0.38, 95% CI [0.25, 0.60], p < 0.001; AR: 19.62%) and composite adverse outcome (RR: 0.69, 95% CI [0.53, 0.90], p = 0.007; AR: 11.75%). Cervical cerclage was associated with a reduced risk of PTB <34 weeks both in women with cervical length <15 mm (RR: 0.74, 95% CI [0.58, 0.95], p = 0.02; AR: 29.17%) and in those with cervical dilatation (RR: 0.68, 95% CI [0.57, 0.80], p < 0.001; AR: 35.02%). The association between cerclage and prevention of PTB and adverse perinatal outcomes was exclusively due to the inclusion of observational studies. The quality of retrieved evidence at GRADE assessment was low. Conclusions: Emergency cerclage for cervical dilation or short cervical length <15 mm may be potentially associated with a reduction in PTB and improved perinatal outcomes. However, these findings are mainly based upon observational studies and require confirmation in large and adequately powered RCTs. In a systematic review and meta-analysis, Francesco D'Antonio and colleagues investigate the impact of cervical cerclage on preterm birth in women with twin pregnancy. Author summary: Why was this study done?: Twin pregnancies are at high risk of preterm birth (PTB). Recent evidence suggests that placement of cervical cerclage in twin pregnancies with short cervical length at ultrasound or cervical dilatation at physical examination might be associated with a reduced risk of PTB. However, such evidence is based mainly on small studies thus questioning the robustness of these findings. What did the researchers do and find?: We performed a systematic review and meta-analysis to elucidate whether cervical cerclage in women with twin pregnancy with short cervical length or cervical dilatation may prevent PTB. We included 18 studies. The primary outcome was PTB <34 weeks of gestation. We found that cervical cerclage in women with short cervical length or cervical dilatation was associated with a reduced risk of PTB <34 weeks, gestational age at birth, and adverse neonatal outcome. The strength of association between cerclage and reduced risk of PTB was maintained when considering women with short cervix on ultrasound and those with cervical dilatation at physical examination separately. What do these findings mean?: Cervical cerclage in twin pregnancies with short cervical length or cervical dilatation may be potentially associated with a reduced risk of PTB and improved neonatal outcomes. However, these findings are mainly based on observational studies and, to improve robustness of evidence, confirmation of these outcomes in large and appropriately designed randomized controlled trials (RCTs) is required. [ABSTRACT FROM AUTHOR]

Introduction: Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer from a singular etiology. Most experience cumulative insults from prenatal inflammation, genetic and epigenetic vulnerability, toxins (opioids, other drug exposures, environmental exposure), hypoxia-ischemia, and postnatal stressors such as sepsis and seizures. Accordingly, tailoring of emerging therapeutic regimens with endogenous repair or neuro-immunomodulatory agents for individuals requires a more precise understanding of ligand, receptor-, and non-receptor-mediated regulation of essential developmental hormones. Given the recent clinical focus on neurorepair for PBI, we hypothesized that there would be injury induced changes in erythropoietin (EPO), erythropoietin receptor (EPOR), melatonin receptor (MLTR), NAD-dependent deacetylase sirtuin-1 (SIRT1) signaling, and hypoxia inducible factors (HIF1α, HIF2α). Specifically, we predicted that EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α alterations after chorioamnionitis (CHORIO) would reflect relative changes observed in human preterm infants. Similarly, we expected unique developmental regulation after injury that would reveal potential clues to mechanisms and timing of inflammatory and oxidative injury after CHORIO that could inform future therapeutic development to treat PBI. Methods: To induce CHORIO, a laparotomy was performed on embryonic day 18 (E18) in rats with transient uterine artery occlusion plus intra-amniotic injection of lipopolysaccharide (LPS). Placentae and fetal brains were collected at 24 h. Brains were also collected on postnatal day 2 (P2), P7, and P21. EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α levels were quantified using a clinical electrochemiluminescent biomarker platform, qPCR, and/or RNAscope. MLT levels were quantified with liquid chromatography mass spectrometry Results: Examination of EPO, EPOR, and MLTR1 at 24 h showed that while placental levels of EPO and MLTR1 mRNA were decreased acutely after CHORIO, cerebral levels of EPO, EPOR and MLTR1 mRNA were increased compared to control. Notably, CHORIO brains at P2 were SIRT1 mRNA deficient with increased HIF1α and HIF2α despite normalized levels of EPO, EPOR and MLTR1, and in the presence of elevated serum EPO levels. Uniquely, brain levels of EPO, EPOR and MLTR1 shifted at P7 and P21, with prominent CHORIO-induced changes in mRNA expression. Reductions at P21 were concomitant with increased serum EPO levels in CHORIO rats compared to controls and variable MLT levels. Discussion: These data reveal that commensurate with robust inflammation through the maternal placental-fetal axis, CHORIO impacts EPO, MLT, SIRT1, and HIF signal transduction defined by dynamic changes in EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α mRNA, and EPO protein. Notably, ligand-receptor mismatch, tissue compartment differential regulation, and non-receptormediated signaling highlight the importance, complexity and nuance of neural and immune cell development and provide essential clues to mechanisms of injury in PBI. As the placenta, immune cells, and neural cells share many common, developmentally regulated signal transduction pathways, further studies are needed to clarify the perinatal dynamics of EPO and MLT signaling and to capitalize on therapies that target endogenous neurorepair mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Preterm birth represents the leading cause of neonatal mortality. Pathophysiological pathways, or endotypes, leading to prematurity can be clustered into infection/inflammation and dysfunctional placentation. We aimed to perform a systematic review and meta-analysis exploring the association between these endotypes and risk of mortality during first hospital admission Methods: PROSPERO ID: CRD42020184843. PubMed and Embase were searched for observational studies examining infants with gestational age (GA) ≤34 weeks. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for GA (SGA)/intrauterine growth restriction (IUGR). A random-effects model was used to calculate odds ratios (ORs) and 95% confidence intervals. Heterogeneity was studied using random-effects meta-regression analysis. Results: Of 4,322 potentially relevant studies, 150 (612,580 infants) were included. Meta-analysis showed positive mortality odds for chorioamnionitis (OR: 1.43, 95% confidence interval: 1.25–1.62) and SGA/IUGR (OR: 1.68, 95% confidence interval: 1.38–2.04) but negative mortality odds for HDP (OR 0.74, 95% confidence interval: 0.64–0.86). Chorioamnionitis was associated with a lower GA, while HDP and SGA/IUGR were associated with a higher GA. Meta-regression showed a significant correlation between these differences in GA and mortality odds. Conclusion: Our data suggest that the infectious/inflammatory endotype of prematurity has a greater overall impact on mortality risk as it is the most frequent endotype in the lower GAs. However, when the endotype of placental dysfunction is severe enough to induce growth restriction, it is strongly associated with higher mortality rates even though newborns are more mature. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between clinical and laboratory characteristics of chorioamnionitis in deliveries at term gestation with adverse neonatal outcomes. Design: Retrospective cohort study. Setting: The study is based on data from the Swedish Pregnancy Register, enriched with clinical data extracted from medical charts. Sample: A cohort of 500 term singleton deliveries in Stockholm County with registered diagnosis of chorioamnionitis (based on the assessment of the responsible obstetrician) in the Swedish Pregnancy Register between 2014 and 2020. Methods: Logistic regression was used to estimate odds ratios (ORs) as a measurement of the association between clinical and laboratory characteristics and neonatal complications. Main outcome measures: Neonatal infection and asphyxia‐related complications. Results: The prevalence of neonatal infection and asphyxia‐related complications was 10% and 22%, respectively. First leukocyte count in the second tertile (OR 2.14, 95% CI 1.02–4.49), maximum C‐reactive protein (CRP) level in the third tertile (OR 4.01, 95% Cl 1.66–9.68) and positive cervical culture (OR 2.22, 95% Cl 1.10–4.48) were associated with an increased risk of neonatal infection. Maximum level of CRP in the third tertile (OR 1.93, 95% Cl 1.09–3.41) and fetal tachycardia (OR 1.63, 95% Cl 1.01–2.65) were associated with an increased risk of asphyxia‐related complications. Conclusions: Elevated inflammatory laboratory markers were associated with both neonatal infection and asphyxia‐related complications, and fetal tachycardia was associated with asphyxia‐related complications. Based on these findings, the incorporation of maternal CRP in the management of chorioamnionitis should be considered, and a continuous communication between obstetric and neonatal care extending past the delivery time point endorsed. [ABSTRACT FROM AUTHOR]

Objective: To investigate reliable biomarkers for predicting histological chorioamnionitis (HCA) in women with preterm prelabour rupture of membranes (PPROM). Design: A retrospective study. Setting: A maternity care hospital in Shanghai. Population: Women with PPROM before 34+0/7 weeks of gestation. Methods: Mean values of biomarkers were compared by two‐way analysis of variance (ANOVA). Log‐binomial regression models were used to assess the association between biomarkers and risk of HCA. A stepwise logistic regression model was used to develop a multi‐biomarker prediction model and identify the independent predictors. The area under the receiver operating characteristic curve (AUC) was used to assess prediction performance. Main outcome measures: The ability of the individual biomarker and the combination of multiple biomarkers to predict HCA. Results: In 157 mothers with PPROM, 98 (62.42%) women had HCA and 59 (37.58%) women did not have HCA. No significant differences were observed between the two groups in white blood cell, neutrophil or lymphocyte counts, whereas both high‐sensitivity C‐reactive protein (hsCRP) and procalcitonin (PCT) were significantly higher in the HCA group. HsCRP and PCT were found to be independently associated with the risk of HCA, and PCT had a larger AUC value than hsCRP (p < 0.05). The optimal multi‐biomarker prediction model for HCA (AUC = 93.61%) included hsCRP at 72 hours and PCT at 48 and 72 hours, and PCT had a stronger prediction capacity than hsCRP. Conclusions: PCT could be a reliable biomarker for the early prediction of HCA in women with PPROM within 72 hours of dexamethasone treatment. [ABSTRACT FROM AUTHOR]

The mechanism by which human labor is initiated in the presence of elevated circulating progesterone levels remains unknown. Recent evidence indicates that the progesterone-metabolizing enzyme, 20α-hydroxysteroid dehydrogenase (20α-HSD), encoded by the gene AKR1C1, may contribute to functional progesterone withdrawal. We found that AKR1C1 expression significantly increased with labor onset in term myometrium, but not in preterm myometrium. Among preterm laboring deliveries, clinically diagnosed chorioamnionitis was associated with significantly elevated AKR1C1 expression. AKR1C1 expression positively correlated with BMI before labor and negatively correlated with BMI during labor. Analysis by fetal sex showed that AKR1C1 expression was significantly higher in women who delivered male babies compared to women who delivered female babies at term, but not preterm. Further, in pregnancies where the fetus was female, AKR1C1 expression positively correlated with the mother's age and BMI at the time of delivery. In conclusion, the increase in myometrial AKR1C1 expression with term labor is consistent with 20α-HSD playing a role in local progesterone metabolism to promote birth. Interestingly, this role appears to be specific to term pregnancies where the fetus is male. Upregulated AKR1C1 expression in the myometrium at preterm in-labor with clinical chorioamnionitis suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. The link between AKR1C1 expression and maternal BMI may provide insight into why maternal obesity is often associated with dysfunctional labor. Higher myometrial AKR1C1 expression in male pregnancies may indicate fetal sex-related differences in the mechanisms that precipitate labor onset at term. [ABSTRACT FROM AUTHOR]

Problem: Preterm birth (PTB) remains a leading cause of childhood mortality. Recent studies demonstrate that the risk of spontaneous PTB (sPTB) is increased in individuals with Lactobacillus‐deficient vaginal microbial communities. One proposed mechanism is that vaginal microbes ascend through the cervix, colonize the uterus, and activate inflammatory pathways leading to sPTB. This study assessed whether intrauterine colonization with either Gardnerella vaginalis and Mobiluncus mulieris alone is sufficient to induce maternal‐fetal inflammation and induce sPTB. Method of study: C56/B6J mice, on embryonic day 15, received intrauterine inoculation of saline or 108 colony‐forming units of G. vaginalis (n = 30), M. mulieris (n = 17), or Lactobacillus crispatus (n = 16). Dams were either monitored for maternal morbidity and sPTB or sacrificed 6 h post‐infusion for analysis of bacterial growth and cytokine/chemokine expression in maternal and fetal tissues. Results: Six hours following intrauterine inoculation with G. vaginalis, M. mulieris, or L. crispatus, live bacteria were observed in both blood and amniotic fluid, and a potent immune response was identified in the uterus and maternal serum. In contrast, only a limited immune response was identified in the amniotic fluid and the fetus after intrauterine inoculation. High bacterial load (108 CFU/animal) of G. vaginalis was associated with maternal morbidity and mortality but not sPTB. Intrauterine infusion with L. crispatus or M. mulieris at 108 CFU/animal did not induce sPTB, alter pup viability, litter size, or maternal mortality. Conclusions: Despite inducing an immune response, intrauterine infusion of live G. vaginalis or M. mulieris is not sufficient to induce sPTB in our mouse model. These results suggest that ascension of common vaginal microbes into the uterine cavity alone is not causative for sPTB. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to determine the effectiveness of an alternative method of open fetal surgery to prevent severe unfavorable prenatal events, both for the mother and the fetus. Material and methods: In this study, the previously published results for a cohort of 46 patients, who had undergone intrauterine myelomeningocele repair (IUMR) at our Center by 2014, constituted the retrospective control group (CG). The MOMS protocol had been applied for hysterotomy, with an automatic uterine stapling device. The study group (SG) n = 57 was assembled during a prospective observation. IUMR was performed using an alternative method of hysterotomy, with the typical opening and closure of the uterus, without automatic stapling device, as described by Moron et al. Additionally, our single-center results were compared with the post-MOMS findings of other centers: Children's Hospital of Philadelphia (CHOP) and Vanderbilt University Medical Center (VUMC). Results: No cases of delivery before 30 weeks of gestation (0%, 0/55) were observed in the study group, which is a statistically significant difference (p < 0.05) as compared to controls (15/44). Statistically significantly lower incidence of chorioamniotic separation (5.4% (3/55) vs CHOP 22.9% (22/96), p < 0.001) and contractile activity resulting in preterm labor (16.3% (9/55) vs CHOP 37.5% (36/96), p < 0.05) was found in the study group. Premature rupture of the membranes was statistically significantly less common in the study group as compared to controls, CHOP and VUMC (SG 12.7% (7/55) vs CG 52.2% (24/46), p < 0.001; vs CHOP 32.3% (31/96), p < 0.001; vs VUMC 22% (9/43), p < 0.01, respectively). Conclusions: The presented IUMR method is associated with improved perinatal outcomes, i.e., lower rates of preterm delivery at < 30 weeks of gestation, preterm premature rupture of membranes, and uterine contractility resulting in preterm delivery. That, in turn, results in lower prematurity rates and, consequently, more favorable neonatal outcomes. [ABSTRACT FROM AUTHOR]

The diagnosis of previable preterm pre-labor rupture of membranes (PROM) is known to be associated with poor outcomes for both the mother and the fetus. Following previable preterm PROM, patients are generally offered either active management through the termination of the pregnancy or expectant management to increase the chances of fetal survival. It is difficult to counsel patients because there is a lack of data directly comparing maternal outcomes following active vs. expectant management. Using the data in the current literature, the goal of the present meta-analysis was to determine if there were any differences in terms of maternal risks when active versus elective management was chosen. PubMed, Google Scholar, EMBASE, and Scopus were searched. We found four studies accounting for a total of 506 patients. The risk ratio (RR) of chorioamnionitis in active vs. expectant management was 0.30 (with a 95% confidence interval, CI, of 0.09–1.02). The heterogeneity of the study results was 81% (I2). A sub–analysis of two included studies revealed an RR of postpartum hemorrhage in active vs. expectant management of 0.75 (95% CI 0.27–2.07) and an RR of maternal sepsis of 0.23 (95% CI 0.04–1.28). The heterogeneity of the study results for this sub-analysis was 68% (I2) for postpartum hemorrhage and 0% (I2) for maternal sepsis. Overall, there was no statistically significant difference in the risk of chorioamnionitis, postpartum hemorrhage, or maternal sepsis when active management was chosen over expectant management in previable preterm PROM at <24 weeks. The scarcity and the high heterogeneity of the available data likely contributed to the lack of statistical significance and calls for further work directly comparing maternal outcomes following active vs. expectant management. [ABSTRACT FROM AUTHOR]

We conducted a systematic review and meta-analysis to evaluate the association between gestational diabetes mellitus and infections during pregnancy. We included cross-sectional, case-control, cohort studies and clinical trials, evaluating the frequency of infections in women with and without gestational diabetes mellitus. A search was conducted in Embase, PubMed, and Web of Science electronic databases and by manually searching references, until 23 March 2022, resulting in 16 studies being selected for review, with 111,649 women in the gestational diabetes mellitus group, and 1,429,659 in the controls. Cochrane's Q test of heterogeneity and I² were used to assess heterogeneity. Pooled odds ratio (OR) was calculated. Funnel plots and Egger test were used for assessment of publication bias. The results showed a significant association between gestational diabetes mellitus and infections (pooled-OR 1.3 95% CI [1.2–1.5]). Sub-analyses showed a significant association for urinary tract infections (pooled-OR of 1.2 95% CI [1.1–1.3]), bacterial infections (pooled-OR were 1.2 95% CI [1.1–1.4]), and SARS-CoV-2 (pooled-OR 1.5 95% CI [1.2–2.0]) but not to gingivitis or vaginal candidiasis. The results underscore the significance of acknowledging gestational diabetes mellitus as a risk factor for infections. [ABSTRACT FROM AUTHOR]

Background: Preterm labor syndrome is associated with high perinatal morbidity and mortality, and intra-amniotic infection is a cause of preterm labor. The standard identification of causative microorganisms is based on the use of biochemical phenotypes, together with broth dilution-based antibiotic susceptibility from organisms grown in culture. However, such methods could not provide an accurate epidemiological aspect and a genetic basis of antimicrobial resistance leading to an inappropriate antibiotic administration. Hybrid genome assembly is a combination of short- and long-read sequencing, which provides better genomic resolution and completeness for genotypic identification and characterization. Herein, we performed a hybrid whole genome assembly sequencing of a pathogen associated with acute histologic chorioamnionitis in women presenting with PPROM. Results: We identified Enterococcus faecium, namely E. faecium strain RAOG174, with several antibiotic resistance genes, including vancomycin and aminoglycoside. Virulence-associated genes and potential bacteriophage were also identified in this genome. Conclusion: We report herein the first study demonstrating the use of hybrid genome assembly and genomic analysis to identify E. faecium ST17 as a pathogen associated with acute histologic chorioamnionitis. The analysis provided several antibiotic resistance-associated genes/mutations and mobile genetic elements. The occurrence of E. faecium ST17 raised the awareness of the colonization of clinically relevant E. faecium and the carrying of antibiotic resistance. This finding has brought the advantages of genomic approach in the identification of the bacterial species and antibiotic resistance gene for E. faecium for appropriate antibiotic use to improve maternal and neonatal care. [ABSTRACT FROM AUTHOR]

Introduction: Although different phenotypes of lung disease after preterm birth have recently been described, the underlying mechanisms associated with each phenotype are poorly understood. We, therefore, compared the urinary proteome for different spirometry phenotypes in preterm-born children with preterm- and term-born controls. Methods: Preterm and term-born children aged 7–12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) cohort, underwent spirometry and urine collection. Urine was analysed by Nano-LC Mass-Spectrometry with Tandem-Mass Tag labelling. The preterm-born children were classified into phenotypes of prematurity-associated preserved ratio impaired spirometry (pPRISm, FEV1 < lower limit of normal (LLN), FEV1/FVC ≥ LLN), prematurity-associated obstructive lung disease (POLD, FEV1 < LLN, FEV1/FVC < LLN) and preterm controls (FEV1 ≥ LLN,). Biological relationships between significantly altered protein abundances were analysed using Ingenuity Pathways Analysis software, and receiver operator characteristic curves were calculated. Results: Urine was analysed from 160 preterm-born children and 44 term controls. 27 and 21 were classified into the pPRISm and POLD groups, respectively. A total of 785 proteins were detected. Compared to preterm-born controls, sixteen significantly altered proteins in the pPRISm group were linked to six biological processes related to upregulation of inflammation and T-cell biology. In contrast, four significantly altered proteins in the POLD group were linked with neutrophil accumulation. Four proteins (DNASE1, PGLYRP1, B2M, SERPINA3) in combination had an area under the curve of 0.73 for pPRISm and three combined proteins (S100A8, MMP9 and CTSC) had AUC of 0.76 for POLD. Conclusions: In this exploratory study, we demonstrate differential associations of the urinary proteome with pPRISm and POLD. Trial registration: EudraCT: 2015-003712-20 [ABSTRACT FROM AUTHOR]

Chorioamnionitis, commonly referred to as intrauterine infection or inflammation, is pathologically defined by neutrophil infiltration and inflammation at the maternal-fetal interface. Chorioamnionitis is the common complication during late pregnancy, which lead to a series of serious consequences, such as preterm labor, preterm premature rupture of the fetal membranes, and fetal inflammatory response syndrome. During infection, a large number of neutrophils migrate to the chorio-decidua in response to chemokines. Although neutrophils, a crucial part of innate immune cells, have strong anti-inflammatory properties, over-activating them can harm the body while also eliminating pathogens. This review concentrated on the latest studies on chorioamnionitis-related consequences as well as the function and malfunction of neutrophils. The release of neutrophil extracellular traps, production of reactive oxygen species, and degranulation from neutrophils during intrauterine infection, as well as their pathological roles in complications related to chorioamnionitis, were discussed in detail, offering fresh perspectives on the treatment of chorioamnionitis. [ABSTRACT FROM AUTHOR]

Background: Inflammation of the fetal membranes is an indispensable event of labor onset at both term and preterm birth. Interleukin-33 (IL-33) is known to participate in inflammation via ST2 (suppression of tumorigenicity 2) receptor as an inflammatory cytokine. However, it remains unknown whether IL-33/ST2 axis exists in human fetal membranes to promote inflammatory reactions in parturition. Methods: The presence of IL-33 and ST2 and their changes at parturition were examined with transcriptomic sequencing, quantitative real-time polymerase chain reaction, Western blotting or immunohistochemistry in human amnion obtained from term and preterm birth with or without labor. Cultured primary human amnion fibroblasts were utilized to investigate the regulation and the role of IL-33/ST2 axis in the inflammation reactions. A mouse model was used to further study the role of IL-33 in parturition. Results: Although IL-33 and ST2 expression were detected in both epithelial and fibroblast cells of human amnion, they are more abundant in amnion fibroblasts. Their abundance increased significantly in the amnion at both term and preterm birth with labor. Lipopolysaccharide, serum amyloid A1 and IL-1β, the inflammatory mediators pertinent to labor onset, could all induce IL-33 expression through NF-κB activation in human amnion fibroblasts. In turn, via ST2 receptor, IL-33 induced the production of IL-1β, IL-6 and PGE2 in human amnion fibroblasts via the MAPKs-NF-κB pathway. Moreover, IL-33 administration induced preterm birth in mice. Conclusion: IL-33/ST2 axis is present in human amnion fibroblasts, which is activated in both term and preterm labor. Activation of this axis leads to increased production of inflammatory factors pertinent to parturition, and results in preterm birth. Targeting the IL-33/ST2 axis may have potential value in the treatment of preterm birth. [ABSTRACT FROM AUTHOR]

Introduction: Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes. Methods: Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb. Results: Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased NAMPT expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1–14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAbinduced reductions in inflammatory pathway genes. Discussion: The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPTneutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates. [ABSTRACT FROM AUTHOR]

Acute chorioamnionitis complicates 1–2% of all pregnancies and might increase the prevalence of endometritis that can cause Asherman syndrome or adhesions, but little is known about the direct effects of chorioamnionitis on future fertility. We aimed to evaluate the effect of chorioamnionitis on future fertility and obstetrics complications in patients diagnosed with chorioamnionitis during their pregnancy. We performed an observational, case–control retrospective study of pregnant women aged 18–40 years old, hospitalized with a diagnosis of chorioamnionitis between January 2013 and December 2017. The control group consisted of patients with similar demographic/obstetrics characteristics, matched with a ratio of 1:2 without chorioamnionitis. The prevalence of post gestational diagnostic hysteroscopy was significantly higher in the study group as compared to the control group (22.9% versus 9.0%, respectively; p = 0.005). Moreover, the study group underwent significantly more operative hysteroscopy compared to the control group (10.8% versus 3.6%, respectively; p = 0.04). The patients in the study group had significantly higher prevalence of miscarriages (27% versus 13.2%, respectively; p < 0.01). We conclude that chorioamnionitis may cause endometritis with the consequent impaired fertility, necessitating comprehensive evaluations for secondary infertility, including hysteroscopy aiming to treat intrauterine adhesions that may affect and impair fertility. [ABSTRACT FROM AUTHOR]

Background: Pancreatic stone protein (PSP) is a biochemical serum marker that contains levels that are elevated in various inflammatory and infectious diseases. The role of PSP in the diagnosis of these diseases seems to be more important compared to clinically established biochemical serum markers in discriminating the severity of the same diseases. Standard values for PSP in pregnant women in relation to gestational age have been reported recently. Additionally, increased PSP levels have been observed to be associated with renal dysfunction in pregnant women. The aim of this study is to evaluate the diagnostic role of PSP in pregnancy-related diseases, such as pre-eclampsia (PE), hemolysis-elevated liver enzymes, and low platelet (HELLP) syndrome. In addition, the study aims to assess its diagnostic role in inflammation-triggered diseases as preterm premature rupture of membranes (PPROM) or COVID-19-positive pregnant women. Materials and Methods: In this single-centred prospective study performed at a tertiary university hospital between 2013 and 2021, we included 152 pregnant women who were diagnosed with either PE, HELLP syndrome, or PPROM. In December 2020, in the context of the COVID-19 pandemic, the Independent Ethics Committee (IEC) approved an amendment to the study protocol. Depending on the underlying disease, single or serial-serum PSP measurements were assessed. These PSP values were compared to PSP levels of women with normal pregnancies. Results: Pregnant women diagnosed with pre-eclampsia or HELLP syndrome had significantly increased PSP values (mean 9.8 ng/mL, SD 2.6) compared to healthy singleton pregnant women (mean 7.9 ng/mL, SD 2.6, p ≤ 0.001). There was no difference in serum PSP in pregnant women with PPROM compared to women with uncomplicated singleton pregnancies (mean in PPROM: 7.9 ng/mL; SD 2.9 versus mean in healthy pregnancies: 7.9 ng/mL; SD 2.6, p = 0.98). Furthermore, no difference in the PSP values in women with or without intra-amniotic infection was observed (infection: mean 7.9 ng/mL; SD 2.8 versus no infection: mean 7.8 ng/mL; SD 3, p = 0.85). The mean value of PSP in COVID-19-infected women during pregnancy (8.5 ng/mL, SD 2.3) was comparable to healthy singleton pregnancies (mean 7.9 ng/mL, SD 2.6), p = 0.24. Conclusions: The novel serum biomarker PSP is significantly upregulated in pregnant women with pre-eclampsia and HELLP syndrome. Our observations call for the further evaluation of PSP in randomized controlled clinical trials to demonstrate the actual role of PSP in pregnancy-related diseases and whether it may provide new approaches for the management and discrimination of the severity of these gestational conditions. [ABSTRACT FROM AUTHOR]

Problem: We aimed to determine whether altered levels of various extracellular matrix (ECM)‐related and serine protease proteins in the amniotic fluid (AF) are associated with imminent spontaneous preterm birth (SPTB; ≤7 days) and intra‐amniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) in women with early preterm labor (PTL). Method of study: This retrospective cohort study included 252 women with singleton pregnancies undergoing transabdominal amniocentesis who demonstrated PTL (24–31 weeks). The AF was cultured for microorganism detection to characterize MIAC. IL‐6 concentrations were determined in the AF samples to identify IAI (≥2.6 ng/mL). The following mediators were measured in the AF samples using ELISA: kallistatin, lumican, MMP‐2, SPARC, TGFBI, and uPA. Results: Kallistatin, MMP‐2, TGFBI, and uPA levels were significantly higher and SPARC and lumican levels were significantly lower in the AF of women who spontaneously delivered within 7 days than in the AF of those who delivered after 7 days; the levels of the first five mediators were independent of baseline clinical variables. In the multivariate analysis, elevated levels of kallistatin, MMP‐2, TGFBI, and uPA and low levels of lumican and SPARC in the AF were significantly associated with IAI/MIAC and MIAC, even after adjusting for the gestational age at sampling. The areas under the curves of the aforementioned biomarkers ranged from 0.58 to 0.87 for the diagnoses of each of the corresponding endpoints. Conclusion: ECM‐related (SPARC, TGFBI, lumican, and MMP‐2) and serine protease (kallistatin and uPA) proteins in the AF are involved in preterm parturition and regulation of intra‐amniotic inflammatory/infectious responses in PTL. [ABSTRACT FROM AUTHOR]