The main aim of the study was to determine progranulin levels in amniotic and cervical fluid samples from pregnancies complicated by preterm prelabor rupture of membranes (PPROM) or preterm labor with intact membranes (PTL), with concomitant microbial invasion of the amniotic cavity and/or intra-amniotic inflammation. A total of 104 and 108 women with PPROM and PTL, respectively, were included. Paired amniotic and cervical fluid samples were obtained using transabdominal amniocentesis and Dacron polyester swabs, respectively. Progranulin levels were assessed with an enzyme-linked immunosorbent assay. Women with PPROM and PTL were divided into subgroups based on microbial invasion of the amniotic cavity and/or intra-amniotic inflammation. Differences in progranulin levels among the PPROM and PTL subgroups were found in amniotic fluid: (a) PPROM: intra-amniotic infection: 51.8 pg/mL, sterile intra-amniotic inflammation: 52.8 pg/mL, colonization: 36.4 pg/mL, and negative amniotic fluid: 35.0 pg/mL; p < 0.0001; (b) PTL: intra-amniotic infection: 75.3 pg/mL, sterile intra-amniotic inflammation: 54.0 pg/mL, and negative amniotic fluid: 39.1 pg/mL; p < 0.0001. The corresponding differences were not found in cervical fluid: (a) PPROM: p = 0.14; (b) PTL: p = 0.53. In conclusion, amniotic fluid progranulin levels increased in PPROM and PTL cases with concomitant intra-amniotic inflammation, regardless of whether microbial invasion of the amniotic cavity was present or absent.

• Keywords
• Amniotic fluid, Intra-amniotic inflammation, Invasive sampling, Microbial invasion of the amniotic cavity, Non-invasive sampling, Preterm delivery,
• MeSH
• Amniocentesis MeSH
• Cervix Uteri * metabolism   MeSH
• Chorioamnionitis metabolism   MeSH
• Adult MeSH
• Humans MeSH
• Amniotic Fluid * metabolism   MeSH
• Obstetric Labor, Premature metabolism   MeSH
• Fetal Membranes, Premature Rupture * metabolism   MeSH
• Premature Birth * metabolism   MeSH
• Progranulins * metabolism   MeSH
• Retrospective Studies MeSH
• Pregnancy MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• GRN protein, human MeSH Browser
• Progranulins * MeSH

Preterm prelabour rupture of membranes (PPROM) complicated by intra-amniotic inflammation (IAI) represents a substantial proportion of preterm birth cases. Currently, IAI is frequently defined as amniotic fluid IL-6 concentration above 2,600 pg/mL. However, the amniotic fluid IL-6 concentration was never correlated with the global response of other proinflammatory proteins to the ongoing IAI. In this cross-sectional study, protein quantification was performed using mass spectrometry (MS) analysis followed by target quantification of selected proinflammatory proteins. Levels of amniotic fluid proteins determined by MS were put into the correlation with IL-6 concentration determined by electrochemiluminescence immunoassay method (ECLIA). In total, 925 proteins were efficiently quantified and differential expression analysis revealed 378 proteins upregulated towards IL-6 concentration above 10,000 pg/mL. Four proteins (LCN2, MMP8, MPO, and S100A12) were selected to verify the achieved results and IL-6 concentration of 10,000 pg/mL was determined as the cut-off value for global IAI response.

• MeSH
• Biomarkers metabolism   MeSH
• Chorioamnionitis * metabolism   MeSH
• Adult MeSH
• Interleukin-6 metabolism   MeSH
• Humans MeSH
• Amniotic Fluid * metabolism   MeSH
• Fetal Membranes, Premature Rupture * metabolism   pathology   MeSH
• S100A12 Protein metabolism   MeSH
• Cross-Sectional Studies MeSH
• Pregnancy MeSH
• Inflammation * metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH
• IL6 protein, human MeSH Browser
• Interleukin-6 MeSH
• S100A12 Protein MeSH

INTRODUCTION: The aim of the study was to identify predictive values of the soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) ratio and interleukin (IL)-6, assessed with a clinically available method in a large-volume biochemistry laboratory, in maternal blood, amniotic fluid, and umbilical cord blood for the presence of the placental lesions consistent with maternal vascular malperfusion (MVM) and acute histological chorioamnionitis (HCA), respectively. METHODS: This retrospective study included 92 women with preterm labor with intact membranes (PTL) delivered within 7 days of admission with gestational ages between 22+0 and 34+6 weeks. The sFlt-1/PlGF ratio and IL-6 were assessed in stored samples of maternal serum, amniotic fluid, and umbilical cord serum using Elecsys® sFlt-1, PlGF, and IL-6 immunoassays. RESULTS: Women with MVM had a higher sFlt-1/PlGF ratio in the maternal serum, compared to those without MVM (19.9 vs. 4.6; p < 0.0001), but not in the amniotic fluid or umbilical cord blood. A cut-off value of 8 for the sFlt-1/PlGF ratio in maternal serum was identified as optimal for predicting MVM in patients with PTL. Women with HCA had higher concentrations of IL-6 in maternal serum, compared to those without HCA (11.1 pg/mL vs. 8.4 pg/mL; p = 0.03), amniotic fluid (9,216 pg/mL vs. 1,423 pg/mL; p < 0.0001), and umbilical cord blood (20.7 pg/mL vs. 10.7 pg/mL, p = 0.002). Amniotic-fluid IL-6 showed the highest predictive value. A cut-off value of IL-6 concentration in the amniotic fluid of 5,000 pg/mL was found to be optimal for predicting HCA in PTL. CONCLUSION: Maternal serum sFlt-1/PlGF and amniotic fluid IL-6 concentrations can be used for liquid biopsy to predict placental lesions in women with PTL who deliver within 7 days.

• Keywords
• Amniocentesis, Amniotic fluid, Angiogenic factors, Biomarker, Inflammation, Interleukin-6, PlGF, Preeclampsia, Pregnancy, Preterm birth, Preterm labor with intact membrane, Rapid point-of-care test, Receptor, VEGF, sFlt-1,
• MeSH
• Biomarkers blood   MeSH
• Chorioamnionitis blood   diagnosis   MeSH
• Adult MeSH
• Fetal Blood metabolism   MeSH
• Interleukin-6 * blood   MeSH
• Humans MeSH
• Placenta metabolism   MeSH
• Placenta Growth Factor * blood   MeSH
• Amniotic Fluid metabolism   MeSH
• Obstetric Labor, Premature * blood   MeSH
• Predictive Value of Tests * MeSH
• Vascular Endothelial Growth Factor Receptor-1 * blood   MeSH
• Retrospective Studies MeSH
• Pregnancy MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH
• FLT1 protein, human MeSH Browser
• IL6 protein, human MeSH Browser
• Interleukin-6 * MeSH
• PGF protein, human MeSH Browser
• Placenta Growth Factor * MeSH
• Vascular Endothelial Growth Factor Receptor-1 * MeSH

INTRODUCTION: This study aimed to identify whether microbial invasion of the amniotic cavity and/or intra-amniotic inflammation in women with late preterm prelabor rupture of membranes (PPROM) was associated with changes in concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and its ratio in maternal serum, and whether placental features consistent with maternal vascular malperfusion further affect their concentrations. MATERIAL AND METHODS: This historical study included 154 women with singleton pregnancies complicated by PPROM between gestational ages 34+0 and 36+6 weeks. Transabdominal amniocentesis was performed as part of standard clinical management to evaluate the intra-amniotic environment. Women were categorized into two subgroups based on the presence of microorganisms and/or their nucleic acids in amniotic fluid (determined by culturing and molecular biology method) and intra-amniotic inflammation (by amniotic fluid interleukin-6 concentration evaluation): (1) those with the presence of microorganisms and/or inflammation (at least one present) and (2) those with negative amniotic fluid for infection/inflammation (absence of both). Concentrations of sFlt-1 and PlGF were assessed using the Elecsys® sFlt-1 and Elecsys® PlGF immunoassays and converted into multiples of medians. RESULTS: Women with the presence of microorganisms and/or inflammation in amniotic fluid had lower serum concentrations of sFlt-1 and sFlt-1/PlGF ratios and higher concentrations of PlGF compared with those with negative amniotic fluid. (sFlt-1: presence: median 1.0 multiples of the median (MoM), vs negative: median: 1.5 MoM, P = 0.003; PlGF: presence: median 0.7 MoM, vs negative: median 0.4 MoM, P = 0.02; sFlt-1/PlGF: presence: median 8.9 vs negative 25.0, P = 0.001). Higher serum concentrations of sFlt-1 and sFlt-1/PlGF ratios as well as lower concentrations of PlGF were found in the subsets of women with maternal vascular malperfusion than in those without maternal vascular malperfusion. CONCLUSIONS: Among women experiencing late PPROM, angiogenic imbalance in maternal serum is primarily observed in those without both microbial invasion of the amniotic cavity and intra-amniotic inflammation. Additionally, there is an association between angiogenic imbalance and the presence of maternal vascular malperfusion.

• Keywords
• amniotic fluid, angiogenic factors, inflammation, microorganism, preterm delivery,
• MeSH
• Amniocentesis MeSH
• Biomarkers blood   MeSH
• Chorioamnionitis blood   MeSH
• Adult MeSH
• Gestational Age MeSH
• Humans MeSH
• Placenta Growth Factor * blood   MeSH
• Amniotic Fluid * microbiology   metabolism   MeSH
• Fetal Membranes, Premature Rupture * blood   MeSH
• Vascular Endothelial Growth Factor Receptor-1 * blood   MeSH
• Pregnancy MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• FLT1 protein, human MeSH Browser
• PGF protein, human MeSH Browser

Spontaneous preterm delivery presents one of the most complex challenges in obstetrics and is a leading cause of perinatal morbidity and mortality. Although it is a common endpoint for multiple pathological processes, the mechanisms governing the etiological complexity of spontaneous preterm birth and the placental responses are poorly understood. This study examined placental tissues collected between May 2019 and May 2022 from a well-defined cohort of women who experienced spontaneous preterm birth (n = 72) and healthy full-term deliveries (n = 30). Placental metabolomic profiling of polar metabolites was performed using Ultra-High Performance Liquid Chromatography/Mass Spectrometry (UHPLC/MS) analysis. The resulting data were analyzed using multi- and univariate statistical methods followed by unsupervised clustering. A comprehensive metabolomic evaluation of the placenta revealed that spontaneous preterm birth was associated with significant changes in the levels of 34 polar metabolites involved in intracellular energy metabolism and biochemical activity, including amino acids, purine metabolites, and small organic acids. We found that neither the preterm delivery phenotype nor the inflammatory response explain the reported differential placental metabolome. However, unsupervised clustering revealed two molecular subtypes of placentas from spontaneous preterm pregnancies exhibiting differential enrichment of clinical parameters. We also identified differences between early and late preterm samples, suggesting distinct placental functions in early spontaneous preterm delivery. Altogether, we present evidence that spontaneous preterm birth is associated with significant changes in the level of placental polar metabolites. Dysregulation of the placental metabolome may underpin important (patho)physiological mechanisms involved in preterm birth etiology and long-term neonatal outcomes.

• Keywords
• inflammation, metabolism, metabolomics, placenta, preterm birth,
• Publication type
• Journal Article MeSH

OBJECTIVE: To assess the association between newborn birth weight and the presence of intra-amniotic infection, presence of sterile intra-amniotic inflammation, and absence of intra-amniotic inflammation in pregnancies with preterm labor with intact membranes. METHODS: A total of 69 pregnancies with preterm labor with intact membranes between gestational ages 22 + 0 and 34 + 6 weeks who delivered within seven days of admission were included in this retrospective cohort study. Transabdominal amniocentesis to determine the presence of microorganisms and/or their nucleic acids in amniotic fluid (through culturing and molecular biology methods) and intra-amniotic inflammation (according to amniotic fluid interleukin-6 concentrations) were performed as part of standard clinical management. The participants were further divided into three subgroups: intra-amniotic infection (presence of microorganisms and/or nucleic acids along with intra-amniotic inflammation), sterile intra-amniotic inflammation (intra-amniotic inflammation alone), and without intra-amniotic inflammation. Birth weights of newborns were expressed as percentiles derived from the INTERGROWTH-21st standards for (i) estimated fetal weight and (ii) newborn birth weight. RESULTS: No difference in birth weights, expressed as percentiles derived from the standard for estimated fetal weight, was found among the women with intra-amniotic infection, with sterile intra-amniotic inflammation, and without intra-amniotic inflammation (with infection, median 29; with sterile inflammation, median 54; without inflammation, median 53; p = 0.06). Differences among the subgroups were identified in the birth weight rates, expressed as percentiles derived from the standard for estimated fetal weight, which were less than the 10th percentile (with infection: 20%, with inflammation: 13%, without inflammation: 0%; p = 0.04) and 25th percentile (with infection: 47%, with inflammation: 31%, without inflammation: 9%; p = 0.01). No differences among the subgroups were observed when percentiles of birth weight were derived from the birth weight standard. CONCLUSIONS: The presence of intra-amniotic inflammatory complications in pregnancies with preterm labor with intact membranes prior to the gestational age of 35 weeks was associated with a higher rate of newborns with birth weight less than the 10th and 25th percentile, when percentiles of birth weight were derived from the standard for estimated fetal weight.

• Keywords
• amniocentesis, amniotic fluid, estimated fetal weight, fetal growth, intergrowth, intra-amniotic inflammation, microbial invasion of the amniotic cavity, preterm birth,
• Publication type
• Journal Article MeSH

Objectives: To determine the prevalence and load of Ureaplasma spp. DNA in the cervical fluid of women with singleton pregnancies complicated by preterm prelabor rupture of membranes (PPROM) with respect to intra-amniotic infection, sterile intra-amniotic inflammation, and colonization of the amniotic fluid. Methods: A total of 217 women with PPROM between gestational ages 24 + 0 and 33 + 6 weeks were included in this study. Paired amniotic and cervical fluid samples were collected at the time of admission via transabdominal amniocentesis and using a Dacron polyester swab, respectively. Microbial invasion of the amniotic cavity was diagnosed using a combination of culture and molecular biology methods. Intra-amniotic inflammation was determined based on the concentration of interleukin-6 in the amniotic fluid. Based on the presence or absence of these conditions, the women were stratified into the following subgroups: intra-amniotic infection (with both), sterile intra-amniotic inflammation (with inflammation only), colonization (with microorganisms only), and negative amniotic fluid (without either). The Ureaplasma spp. DNA load in the cervical fluid was assessed using PCR. Results: Ureaplasma spp. DNA in the cervical fluid was found in 61% (133/217) of the women. Women with negative amniotic had similar prevalence of Ureaplasma spp. DNA in cervical fluid (55%) to those with sterile intra-amniotic inflammation (54%) but lower than those with intra-amniotic infection (73%) and colonization (86%; p < 0.0001). Women with negative amniotic fluid had a lower load of Ureaplasma spp. DNA in their cervical fluid (median: 4.7 × 103 copies of DNA/ml) than those with intra-amniotic infection (median: 2.8 × 105 copies DNA/ml), sterile intra-amniotic inflammation (median: 5.3 × 104 copies DNA/ml), and colonization (median: 1.2 × 105 copies DNA/mL; p < 0.0001). Conclusion: In conclusion, in PPROM at <34 weeks, the presence of intra-amniotic infection, sterile intra-amniotic inflammation, or colonization of the amniotic fluid was associated with a higher prevalence and/or load of Ureaplasma spp. DNA in the cervical fluid than the absence of intra-amniotic complications.

• Keywords
• genital mycoplasma, intra-amniotic inflammation, microbial invasion of the amniotic cavity, non-invasive sample, preterm delivery,
• Publication type
• Journal Article MeSH

To determine the main clinical characteristics of preterm prelabor rupture of membranes (PPROM) complicated by colonization of the amniotic cavity (microbial invasion of the amniotic cavity without intra-amniotic inflammation). A total of 302 women with PPROM were included. Transabdominal amniocentesis was performed and amniotic fluid was assessed. Based of microbial invasion of the amniotic cavity and intra-amniotic inflammation (interleukin-6 ≥ 3000 pg/mL), the women were divided into following groups: intra-amniotic infection, sterile intra-amniotic inflammation, colonization of the amniotic cavity, and negative amniotic fluid. Colonization was found in 11% (32/302) of the women. The most common bacteria identified in the amniotic fluid were Ureaplasma spp. with a lower burden than those with intra-amniotic infection (p = 0.03). The intensity of intra-amniotic inflammatory response measured by interleukin-6 was higher in women with colonization than in those with negative amniotic fluid (medians: 961 pg/mL vs. 616 pg/mL; p = 0.04). Women with colonization had higher rates of acute inflammatory placental lesions than those with negative amniotic fluid. In PPROM, colonization, caused mainly by microorganisms from the lower genital tract, might represent an early stage of microbial invasion of the amniotic cavity with a weak intra-amniotic inflammatory response.

• MeSH
• Chorioamnionitis * microbiology   MeSH
• Interleukin-6 MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Placenta MeSH
• Amniotic Fluid microbiology   MeSH
• Fetal Membranes, Premature Rupture MeSH
• Retrospective Studies MeSH
• Pregnancy MeSH
• Inflammation complications   MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Interleukin-6 MeSH

Spontaneous preterm birth is a serious medical condition responsible for substantial perinatal morbidity and mortality. Its phenotypic characteristics, preterm labor with intact membranes (PTL) and preterm premature rupture of the membranes (PPROM), are associated with significantly increased risks of neurological and behavioral alterations in childhood and later life. Recognizing the inflammatory milieu associated with PTL and PPROM, here, we examined expression signatures of placental tryptophan metabolism, an important pathway in prenatal brain development and immunotolerance. The study was performed in a well-characterized clinical cohort of healthy term pregnancies (n = 39) and 167 preterm deliveries (PTL, n = 38 and PPROM, n = 129). Within the preterm group, we then investigated potential mechanistic links between differential placental tryptophan pathway expression, preterm birth and both intra-amniotic markers (such as amniotic fluid interleukin-6) and maternal inflammatory markers (such as maternal serum C-reactive protein and white blood cell count). We show that preterm birth is associated with significant changes in placental tryptophan metabolism. Multifactorial analysis revealed similarities in expression patterns associated with multiple phenotypes of preterm delivery. Subsequent correlation computations and mediation analyses identified links between intra-amniotic and maternal inflammatory markers and placental serotonin and kynurenine pathways of tryptophan catabolism. Collectively, the findings suggest that a hostile inflammatory environment associated with preterm delivery underlies the mechanisms affecting placental endocrine/transport functions and may contribute to disruption of developmental programming of the fetal brain.

• MeSH
• Biomarkers MeSH
• Humans MeSH
• Metabolic Networks and Pathways MeSH
• Disease Susceptibility MeSH
• Placenta metabolism   MeSH
• Premature Birth diagnosis   etiology   metabolism   MeSH
• Gene Expression Regulation MeSH
• Risk Factors MeSH
• Gene Expression Profiling MeSH
• Pregnancy MeSH
• Transcriptome * MeSH
• Tryptophan metabolism   MeSH
• Computational Biology methods   MeSH
• Pregnancy Outcome MeSH
• Inflammation complications   etiology   MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Tryptophan MeSH

To determine the IgGFc-binding protein (FcgammaBP) concentration in amniotic and cervical fluids in preterm prelabor rupture of membranes (PPROM) and preterm labor with intact membranes (PTL) and to assess the diagnostic indices of FcgammaBP to predict intra-amniotic infection (the presence of both microbial invasion of the amniotic cavity and intra-amniotic inflammation). In this study, we included 170 and 79 women with PPROM and PTL, respectively. Paired cervical and amniotic fluid samples were obtained using a Dacron polyester swab and transabdominal amniocentesis, respectively. The FcgammaBP concentrations in the samples were assessed using an enzyme-linked immunosorbent assay. The presence of intra-amniotic infection was associated with elevated FcgammaBP concentrations in pregnancies with PPROM and PTL [PPROM-presence: 86 ng/mL vs. absence: 13 ng/mL, p < 0.0001, area under receiver operating characteristic curve (AUC) = 0.94; PTL-presence: 140 ng/mL vs. absence: 22 ng/mL, p < 0.0001, AUC = 0.86]. In cervical fluid, the concentrations of FcgammaBP were elevated in the presence of intra-amniotic infection in pregnancies with PPROM only (presence: 345 ng/mL vs. absence: 60 ng/mL, p < 0.0001, AUC = 0.93). FcgammaBP in amniotic fluid might be a marker of intra-amniotic infection in women with both PPROM and PTL However, in cervical fluid, it is only observed in women with PPROM.

• MeSH
• Biomarkers metabolism   MeSH
• Adult MeSH
• Pregnancy Complications, Infectious metabolism   MeSH
• Humans MeSH
• Cell Adhesion Molecules metabolism   MeSH
• Amniotic Fluid metabolism   MeSH
• Premature Birth metabolism   MeSH
• Retrospective Studies MeSH
• Pregnancy MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• FCGBP protein, human MeSH Browser
• Cell Adhesion Molecules MeSH