Soluble urokinase plasminogen activator receptor in vaginally collected amniotic fluid predicting fetal inflammatory response syndrome: a prospective cohort study.

BACKGROUND: Improving noninvasive antenatal diagnosis of fetal inflammatory response syndrome (FIRS) can assist in the evaluation of prenatal risk and reduce perinatal outcomes. This study aimed to determine whether soluble urokinase-type plasminogen activator receptor (suPAR) in vaginally collected amniotic fluid is significant in identifying FIRS after preterm premature rupture of membranes before 34 weeks of gestation. METHODS: This was a prospective cohort study of 114 pregnant women and their newborns after preterm premature rupture of membranes at 22-34+6 weeks of gestation. SuPAR was evaluated using an enzyme-linked immunosorbent assay in vaginally collected amniotic fluid. Patients were classified according to the presence or absence of FIRS. FIRS was defined by umbilical cord blood interleukin-6 level > 11 pg/mL or histological funisitis. The data were analyzed using the R package (R-4.0.5). RESULTS: SuPAR was detected in all amniotic fluid samples with a median of 26.23 ng/mL (interquartile range (IQR), 15.19-51.14). The median level of suPAR was higher in the FIRS group than in the non-FIRS group, 32.36 ng/mL (IQR, 17.27-84.16) vs. 20.46 ng/mL (IQR, 11.49-36.63) (P = 0.01), respectively. The presence of histological chorioamnionitis significantly increased the suPAR concentration in the FIRS group (P < 0.001). The areas under the curve for FIRS and FIRS with histological chorioamnionitis were 0.65 and 0.74, respectively, with an optimum cutoff value of 27.60 ng/mL. Controlling for gestational age, the cutoff of suPAR more than 27.60 ng/mL predicted threefold higher odds for FIRS and sixfold higher odds for FIRS with histologic chorioamnionitis. CONCLUSION: Soluble urokinase-type plasminogen activator receptor in vaginally obtained amniotic fluid may assist in evaluating prenatal risk of FIRS in patients after preterm premature rupture of membranes before 34 weeks of gestation.

Causes of preterm birth: Genetic factors in preterm birth and preterm infant phenotypes.

AIM: The aim is to provide an overview of recent research on genetic factors that influence preterm birth in the context of neonatal phenotypic assessment. METHODS: This is a nonsystematic review of the recent scientific literature. RESULTS: Maternal and fetal genetic diversity and rare genome variants are linked with crucial immune response sites. In addition, more frequent in preterm neonates, de novo variants may lead to attention deficits, hyperactivity, autism spectrum disorders, and infertility of both sexes later in life. Environmental factors may also greatly burden fetal, and consequently, neonatal development and neurodevelopment through a failure in the fetal epigenome reprogramming process and even influence the initiation of spontaneous preterm pregnancy termination. Minimally invasive analysis of the transcription factors associated with preterm birth helps elucidate labor mechanisms and predict its timing. We also provide valuable summaries of genomic and transcriptomic factors that contribute to preterm birth. CONCLUSIONS: Investigation of the human genome, epigenome, and transcriptome helps to identify molecular mechanisms linked with preterm delivery and premature newborn clinical appearance in early and late neonatal life and even predict developmental outcomes. Further studies are needed to fully understand the implications of genetic changes in preterm births. These data could be used to develop targeted interventions aimed at selecting the most effective individual treatment and rehabilitation plan.

The significance of TNF-α and MMP-8 concentrations in non-invasively obtained amniotic fluid predicting fetal inflammatory response syndrome.

OBJECTIVE: To determine the significance of tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-8 (MMP-8) in vaginally obtained amniotic fluid predicting fetal inflammatory response syndrome (FIRS) after preterm premature rupture of membranes (PPROM). METHODS: In this prospective case-control study, TNF-α and MMP-8 concentrations were evaluated in vaginally obtained amniotic fluid from women with PPROM at 22-34 weeks of pregnancy. Biomarkers' concentrations were determined using an enzyme-linked immunosorbent assay. Patients were divided into two groups: the FIRS group (cord blood interleukin-6 > 11 pg/ml or histological funisitis) and the non-FIRS group (without these findings). The data were analyzed using R package (R-4.0.5). RESULTS: The median TNF-α and MMP-8 concentrations in amniotic fluid from the 145 women included in the study were higher in the FIRS group than in the non-FIRS group. The area under the curve of TNF-α and MMP-8 was 0.77 and 0.75, respectively. The TNF-α concentration cut-off predicting FIRS was 89.20 pg/ml and was 170.76 pg/ml for MMP-8. In regression analysis, MMP-8 concentration was an independent predictor for FIRS. An MMP-8 concentration greater than 170 ng/ml and a TNF-α concentration greater than 89 pg/ml increased the odds of FIRS 7.62 and 14.92 times, respectively. CONCLUSIONS: MMP-8 and TNF-α concentrations in vaginally obtained amniotic fluid may be good predictors for FIRS after PPROM before 34 weeks of pregnancy. The non-invasive amniotic fluid analysis could be an alternative method to invasive amniocentesis.

Inherited and De Novo Variation in Lithuanian Genomes: Introduction to the Analysis of the Generational Shift.

Most genetic variants are rare and specific to the population, highlighting the importance of characterizing local population genetic diversity. Many countries have initiated population-based whole-genome sequencing (WGS) studies. Genomic variation within Lithuanian families are not available in the public databases. Here, we describe initial findings of a high-coverage (an average of 36.27×) whole genome sequencing for 25 trios of the Lithuanian population. Each genome on average carried approximately 4,701,473 (±28,255) variants, where 80.6% (3,787,626) were single nucleotide polymorphisms (SNPs), and the rest 19.4% were indels. An average of 12.45% was novel according to dbSNP (build 150). The WGS structural variation (SV) analysis identified on average 9133 (±85.10) SVs, of which 95.85% were novel. De novo single nucleotide variation (SNV) analysis identified 4417 variants, where 1.1% de novo SNVs were exonic, 43.9% intronic, 51.9% intergenic, and the rest 3.13% in UTR or downstream sequence. Three potential pathogenic de novo variants in the ZSWIM8, CDC42EP1, and RELA genes were identified. Our findings provide useful information on local human population genomic variation, especially for de novo variants, and will be a valuable resource for further genetic studies, and medical implications.

The Significance of Epidermal Growth Factor in Noninvasively Obtained Amniotic Fluid Predicting Respiratory Outcomes of Preterm Neonates.

Preterm premature rupture of membranes (PPROM) interrupts normal lung development, resulting in neonatal respiratory morbidity. Although post-PPROM risks have been researched, only a few studies have investigated noninvasively obtained amniotic fluid (AF) to predict neonatal outcomes. In this study, we aimed to determine whether epidermal growth factor (EGF) in vaginally-collected AF is a significant predictor of neonatal respiratory outcomes after PPROM. We analyzed EGF in vaginally-obtained AF from 145 women with PPROM at 22−34 weeks of gestation. The following neonatal outcomes were included: respiratory distress syndrome, surfactant need, duration and type of respiratory support, and bronchopulmonary dysplasia. We found that EGF concentration was associated with gestational age, and its medians were lower in neonates with respiratory morbidities than unaffected ones. EGF concentrations gradually declined, the lowest being in the most clinically ill patients. EGF < 35 pg/mL significantly predicted the odds of severe respiratory outcomes. EGF in noninvasively collected AF may be a reliable predictor for respiratory outcomes of preterm neonates with PPROM before 34 weeks of gestation. The results of our study may have implications for further research both in noninvasive amniotic fluid analysis and the management of patients after PPROM.

Neutrophil-lymphocyte ratio for the prediction of histological chorioamnionitis in cases of preterm premature rupture of membranes: a case-control study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is easily calculated blood test parameter, which can be used as marker to predict many inflammatory disorders. The aim of this study was to assess and compare the NLR in maternal blood with the white blood cell (WBC) count and C-reactive protein (CRP) concentration for the prediction of histological chorioamnionitis. METHODS: This was a case-control study of 137 woman with preterm premature rupture of membranes (PPROM) at a gestational age between 22+ 0 and 34+ 6 weeks. Blood samples, collected less than 48 h before delivery and at least 48 h after the administration of corticosteroids, were selected for the analysis. The NLR was calculated by dividing the number of neutrophils by the number of lymphocytes. Chorioamnionitis was diagnosed by the histopathological evaluation of placental membranes and chorionic plate. RESULTS: Patients with diagnosed histological chorioamnionitis (HCA) had significantly higher levels of WBC, CRP and NLR (p-value < 0.001). Levels of WBC, CRP and NLR predicted HCA with an area under the curve (AUC) of 0.81, 0.81 and 0.89, respectively. NLR had statistically significantly higher AUC than WBC, but no significant difference was found between AUCs of NLR and CRP. The cut-off level of NLR was found to be 5,97, which had a sensitivity of 77 % and a specificity of 95 %. CONCLUSION: NLR has a good predictive value for HCA and could be used as an additional diagnostic marker for predicting histological chorioamnionitis in cases with preterm premature rupture of membranes before 34 weeks of gestation.

A value of soluble Toll-like receptor 2 and 4 in vaginally obtained amniotic fluid for the prediction of histological chorioamnionitis.

INTRODUCTION: This study was conducted to evaluate soluble Toll-like receptor 2 (sTLR-2) and soluble Toll-like receptor 4 (sTLR-4) levels in vaginally obtained amniotic fluid and investigate their value in the prediction of histological chorioamnionitis (HCA). MATERIAL AND METHODS: This prospective case-control study included patients who had been diagnosed with preterm premature rupture of membranes before 34 weeks of gestation and were admitted to Vilnius University Hospital Santaros Klinikos. Free leaking amniotic fluid was obtained vaginally using a sterile speculum up to 48 h before delivery. Amniotic fluid levels of sTLR-2 and sTLR-4 were determined using an enzyme-linked immunosorbent assay. The diagnosis of chorioamnionitis was confirmed by histological examination of the placenta and membranes after delivery. RESULTS: The study included 156 patients, 65 with (HCA Group) and 91 without (non-HCA Group) HCA. No statistically significant differences were noted in the concentrations of sTLR-2 and sTLR-4 in vaginally obtained amniotic fluid between patients with and without HCA: the median sTLR-2 level was 0.09 ng/mL in the HCA Group vs 0.1 ng/mL in non-HCA Group, and the median sTLR-4 level was 0.23 ng/mL in the HCA Group vs 0.28 ng/mL in non-HCA Group (p > 0.05). A positive correlation between sTLR-2 and sTLR-4 levels was identified (ρ = 0.57, p < 0.001), but no correlation was found between these markers and gestational age. CONCLUSIONS: Concentrations of sTLR-2 and sTLR-4 in vaginally obtained amniotic fluid do not reflect the presence of HCA in pregnancies complicated by preterm premature rupture of membranes before 34 weeks of gestation.

Comparison of Respiratory Support After Delivery in Infants Born Before 28 Weeks' Gestational Age: The CORSAD Randomized Clinical Trial.

Importance: Establishing stable breathing is a key event for preterm infants after birth. Delivery of pressure-stable continuous positive airway pressure and avoiding face mask use could be of importance in the delivery room. Objective: To determine whether using a new respiratory support system with low imposed work of breathing and short binasal prongs decreases delivery room intubations or death compared with a standard T-piece system with a face mask. Design, Setting, and Participants: In this unblinded randomized clinical trial, mothers threatening preterm delivery before week 28 of gestation were screened. A total of 365 mothers were enrolled, and 250 infants were randomized before birth and 246 liveborn infants were treated. The trial was conducted in 7 neonatal intensive care units in 5 European countries from March 2016 to May 2020. The follow-up period was 72 hours after intervention. Interventions: Infants were randomized to either the new respiratory support system with short binasal prongs (n = 124 infants) or the standard T-piece system with face mask (n = 122 infants). The intervention was providing continuous positive airway pressure for 10 to 30 minutes and positive pressure ventilation, if needed, with the randomized system. Main Outcomes and Measures: The primary outcome was delivery room intubation or death within 30 minutes of birth. Secondary outcomes included respiratory and safety variables. Results: Of 246 liveborn infants treated, the mean (SD) gestational age was 25.9 (1.3) weeks, and 127 (51.6%) were female. A total of 41 infants (33.1%) receiving the new respiratory support system were intubated or died in the delivery room compared with 55 infants (45.1%) receiving standard care. The adjusted odds ratio was statistically significant after adjusting for stratification variables (adjusted odds ratio, 0.53; 95% CI, 0.30-0.94; P = .03). No significant differences were seen in secondary outcomes or safety variables. Conclusions and Relevance: In this study, using the new respiratory support system reduced delivery room intubation in extremely preterm infants. Stabilizing preterm infants with a system that has low imposed work of breathing and binasal prongs as interface is safe and feasible. Trial Registration: ClinicalTrials.gov Identifier: NCT02563717.

Prognostic Markers for Chorioamnionitis: IL-6, TNF-α, and MMP-8 in Vaginally Obtained Amniotic Fluid.

BACKGROUND: Earlier chorioamnionitis diagnosis is crucial to improve maternal and neonatal health outcomes. This study was conducted to evaluate the inlerleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and matrix metalloproteinase 8 (MMP-8) levels in vaginally obtained amniotic fluid to investigate their prognostic value and to determine the most appropriate cut-off values for the prediction of chorioamnionitis. METHODS: This case control study included women who were diagnosed with preterm premature rupture of the membranes before 34 weeks of gestation and were admitted to Vilnius University Hospital Santaros Klinikos. Free-leaking amniotic fluid was obtained vaginally with a sterile speculum less than 48h before delivery. Amniotic fluid IL-6, TNF-α, and MMP-8 levels were determined by the Enzyme Linked Immunosorbent Assay. Diagnosis of chorioamnionitis was confirmed by histological examination of the placenta and membranes after delivery. RESULTS: The study included 156 women, 65 patients in the histological chorioamnionitis group (Group I) and 91 in a group without diagnosed histological chorioamnionitis (Group II). The median concentrations of IL-6, MMP-8, and TNF-α in amniotic fluid were statistically significantly higher in Group I than in Group II (p-value < 0.001). The area under the curve of TNF-α and MMP-8 were higher than the area under the curve of IL-6 (0.91, 0.89, and 0.81, respectively). No statistically significant difference was found when comparing the receiver operating characteristic (ROC) curves of TNF-α and MMP-8. The optimum cut-off values for the prediction of chorioamnionitis were found to be 1389.82 pg/mL for IL-6, 21.17 pg/mL for TNF-α, and 172.53 ng/mL for MMP-8. The sensitivity, specificity, positive prognostic value (PPV), and negative prognostic value (NPV) of the IL-6 cut-off for chorioamnionitis were 88%, 70%, 67%, and 89%, respectively. The sensitivity, specificity, PPV, and NPV of the TNF-α cut-off were 88%, 84%, 79%, and 90%, respectively. The sensitivity, specificity, PPV, and NPV of the MMP-8 cut-off were 80%, 87%, 81%, and 86%, respectively. CONCLUSIONS: The vaginally obtained amniotic fluid IL-6, MMP-8, and TNF-α seem to be good predictors for chorioamnionitis of patients with preterm premature rupture of membranes before 34 weeks of gestation. The noninvasive technique of sampling amniotic fluid could be alternative method to invasive amniocentesis.

Umbilical Blood Levels of IL-6 and TNF-α as Predictors of the Central Nervous System Damage and Retinopathy in Preterm Infants.

OBJECTIVE: The aim was to identify the critical levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor-A in umbilical cord blood that could be used as markers for predicting the central nervous system (CNS) damage and retinopathy of prematurity (ROP) in preterm infants. STUDY DESIGN: A total of 158 preterm infants, born at 22 to 34 weeks of gestation, were evaluated in the first week after birth and at 36 to 37 weeks of postconceptual age. RESULTS: A significant relationship between CNS changes and concentrations of IL-6 (p < 0.001) and TNF-α (p < 0.001) in umbilical cord blood at 22 to 34 weeks of gestation was determined. The concentration of IL-6 >13.0 pg/mL predicts significant CNS damages in 36 to 37-week infants (p = 0.013). ROP was diagnosed in 24.8% infants (n = 149). It was detected that the levels of TNF-α >116.4 pg/mL (p < 0.001) and IL-6 >13.0 pg/mL (p < 0.05) in umbilical cord blood could predict 2 to 3/3 to 4 stages of ROP. CONCLUSION: Critical values of IL-6 and TNF-α in predicting ≥grade III intraventricular hemorrhage in the early adaptation and in predicting marked CNS damages and severe ROP stages in the later adaptation of preterm infants were determined.

Congenital cystic adenomatous malformation: a case report and a literature review.

BACKGROUND: A congenital cystic adenomatoid malformation (CCAM) is a foetal pulmonary development abnormality caused by airway dysgenesis that is characterized by cystic or adenomatous lesions in the terminal bronchioles. The size of the mass, the degree of the mediastinal shift, and the presence of hydrops and polyhydramnios can all affect the severity of a case. Treatment can be initiated at early stages by applying prenatal and postnatal methods. Because CCAM is a rare pathology that is often only accidentally diagnosed during routine ultrasounds, we would like to share our case report to enrich the literature on this pathology and to present a case successfully treated at our hospital. MATERIALS AND METHODS: A patient with her first multiple pregnancy was seen for prenatal care and her first ultrasound at 17 weeks of gestation. One of the twins was diagnosed with a congenital cystic adenomatoid malformation of the left lung. At 20 weeks of gestation, an enlarged left lung with small cysts, a compressed right lung, a compressed and displaced heart, and oligohydramnios were observed. At 28 weeks of gestation, a fetoplacental circulation disorder appeared. At 32 weeks of gestation, due the unstable condition of the affected foetus, the twins were delivered via a C-section. The treatment of the newborn included antibiotics, caffeine citrate, and breathing therapy. RESULTS AND CONCLUSIONS: CCAM are often diagnosed by accident when performing routine pregnancy ultrasound examinations. CT is the most reliable X-ray-based examination method for confirming a diagnosis. When CCAM is suspected in the foetus, amniocentesis and cariotype identification are performed, but chromosomal anomalies related to CCAM are often not identified. Currently, the best treatment results have been achieved by applying combined prenatal therapy and early surgical treatment.

Significance of C-reactive protein in predicting fetal inflammatory response syndrome.

OBJECTIVES: The aim of the study was to identify and evaluate a possible correlation between C-reactive protein (CRP) concentration in maternal blood and the risk of developing fetal inflammatory syndrome (FIRS). MATERIAL AND METHODS: The study included 158 infants born at 22-34 weeks of gestation and their mothers. Umbilical cord blood cytokines were evaluated in immunoassay tests and maternal blood was tested for CRP concentration. RESULTS: The period of gestation was significantly shorter in the FIRS group as compared to the control group (29.5 ± 3.1 vs. 32.2 ± 2.4 weeks, p < 0.001). Gestational age was ≤ 30 weeks for 53.8% of the newborns in the FIRS group and 15.8% of the newborns in the control group (p < 0.001). Maternal CRP before, during and after labor was significantly higher in the FIRS group as compared to the control group (p < 0.001). Our study investigated the correlation between CRP in maternal blood and IL-6 concentration during the entire perinatal period (p < 0.001). CONCLUSION: CRP concentration in the FIRS group was significantly higher than in controls before, during, and after labor. Thus, it seems safe to conclude that changing concentration of inflammatory factors in maternal blood are closely related to FIRS. Elevated CRP in maternal blood might signify a progressing intrauterine infection and herald the development of FIRS.

Leukocytosis as a prognostic marker in the development of fetal inflammatory response syndrome.

OBJECTIVE: To identify and evaluate the correlation between leukocyte count in maternal blood and the risk of developing fetal inflammatory response syndrome (FIRS). PATIENTS AND METHODS: The study involved 158 infants born at 22 - 34 weeks of gestation and their mothers. Umbilical cord blood cytokines were evaluated in immunoassay tests and maternal blood was tested for the leukocyte formula. RESULTS: The period of gestation was significantly shorter in the FIRS group compared to the control group (29.5±3.1 vs. 32.2±2.4 weeks, p<0.001). Gestational age was ≤30 weeks for 53.8% of the newborns in the FIRS group and 15.8% of the newborns in the control group (p<0.001). The number of leukocytes in maternal blood before and during labor was significantly higher in the FIRS group than in the control group (p=0.034 and 0.004, respectively). The study determined the correlation between the total leukocyte count in maternal blood and IL-6 concentration during labor (p=0.05) and tumor necrosis factor (TNF-α) concentration in umbilical cord blood before and during labor (p=0.02 and 0.007, respectively). CONCLUSION: Leukocytosis in the FIRS group was significantly higher than in the control group before and during labor. According to our data, one of the possible indicators of intrauterine infection could be the number of leukocytes in maternal blood.