Fetal Cord Blood Research Articles

Is there an association between the serum zonulin concentration and the occurrence of PPROM?

Aims: The aim is to evaluate the association between intestinal permeability, as assessed by zonulin levels, and preterm premature rupture of membranes (PPROM). Methods: A prospective case-control study was conducted involving 44 pregnant women: 22 with PPROM and 22 matched controls. High-risk pregnancies (gestational diabetes, preeclampsia, multiple pregnancies), chronic diseases, and smoking were exclusion criteria. Demographic and clinical data were collected from medical records. Venous and umbilical cord blood samples were obtained post-delivery, centrifuged at 3000 rpm for 10 min, and stored at -80°C. Results: No significant differences were found between the PPROM and control groups regarding age, body-mass index, gravidity, previous abortions, history of preterm rupture of membrane (PROM), or PPROM. Maternal and cord blood zonulin levels were comparable between groups (p>0.05). In the PPROM group, maternal and fetal cord zonulin levels correlated positively with newborn birthweight (r=0.607, p=0.003; r=0.617, p=0.002, respectively). A strong positive correlation was observed between maternal serum and fetal cord blood zonulin levels (r=0.837, p

Microplastic Particles Detected in Fetal Cord Blood, Placenta, and Meconium: A Pilot Study of Nine Mother-Infant Pairs in South China.

Microplastics (MPs) are emerging environmental pollutants. Pregnancy and infancy are sensitive windows for environmental exposure. However, few studies have investigated the presence of MPs in mother-infant pairs, or the exposure source. In this study, nine mother-infant pairs were recruited, and samples of placenta, cord blood, and meconium were collected. Information about the living environment and dietary habits were collected to determine the source of exposure during pregnancy. Micro-Raman spectroscopy was applied to identify MPs. In total, 9, 4, and 14 types of MPs were identified in the placenta, cord blood, and meconium samples, with particle counts of 34, 14, and 80, respectively. More than 80.47% of MPs detected in samples had a size of 100-400 μm. The abundance of MPs exhibited the order of meconium > placenta > cord blood (Hc = 14.959, p < 0.01). We found that the abundance of MPs in meconium from women who drank tea ≥ 3 times/week during pregnancy was lower than in those who drank less (p = 0.048). Our study presents evidence of MPs transfer via the placenta-cord blood-meconium pathway. We also found that the habit of drinking tea among pregnant women might be related to the abundance of MPs in meconium.

Impact of Fetal Umbilical Cord Blood CD34+ Cells on Breast Cancer Cell Lines: A Mechanism of Fetal Microchimerism

Introduction: Fetal microchimerism could be involved in the regulation of breast cancer oncogenesis. CD34+ cells could be of a particular interest as up to 12% of the CD34+ population in maternal blood are of fetal origin. The aim of this research was to analyze the impact of umbilical cord blood (UCB) CD34+ on MCF-7 and MDA-MB-231 breast cancer cell lines, in order to uncover novel biological mechanisms and suggest novel treatment options for breast cancer. Methods: UCB CD34+ cells were obtained from healthy women at full-term delivery. Direct cultures were grown with MCF-7 and MDA-MB-231 cells. Proliferation, migration, invasion, and transcriptomic analysis of breast cancer cell lines were compared between cultures exposed and nonexposed to UCB CD34+ cells. Interactions between UCB CD34+ and breast cancer cells were analyzed under fluorescent microscopy. Functional analyses were generated with QIAGEN’s Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). Results: Direct contact between UCB CD34+ and breast cancer cell lines induced a reduction in the proliferative capacities of MCF-7 and MDA-MB-231 and diminished the migration abilities of MDA-MB-231 cells. In 3D coculture, UCB CD34+ cells were attracted by tumor spheroids and incorporated into tumor cells. These cell-to-cell interactions were responsible for transcriptome modifications coherent with observed functional modifications. Among the cytokines secreted by UCB CD34+, IFN-γ was identified as a potential upstream regulator responsible for the molecular modifications observed in transcriptomic analysis of MCF-7 breast cancer cells exposed to UCB CD34+ cells, as was IL-17A in MDA-MB-231 cells. Conclusion: Direct cell-to-cell contact induced functional modifications in breast cancer cells. Interactions between UCB CD34+ and breast cancer cells could induce cell fusion and signal transmission via cytokines. Further analysis of direct cell-to-cell interactions should be performed at a molecular level to further understand the potential role of fetal CD34+ cells in breast cancer.

New Marker in the Umbilical Cord Blood of Fetuses with Fetal Growth Restriction: Serum Sortilin-1 Level

Objective: To determine the role of sortilin in the pathogenesis of fetal growth restriction (FGR) by examining serum sortilin levels in fetal cord blood. Methods: This prospective case-control study was conducted at Ankara Etlik City Hospital between July 2023 and January 2024. Group 1 included 44 pregnant women with late FGR; Group 2 included 44 healthy pregnant women as controls. Results: Umbilical cord blood sortilin levels were significantly higher in the FGR group [2.96 (2.43–4.01)] compared to the control group [2.12 (1.74–3.18)] (p = 0.001). Sortilin levels negatively correlated with APGAR scores at 1 min (r=-0.281, p = 0.008) and 5 min (r=-0.292, p = 0.006). A sortilin threshold of 2.58 ng/ml predicted composite adverse neonatal outcomes with 66.7% sensitivity, 53.1% specificity, and an AUC of 0.652 (95% CI: 0.529–0.775, p = 0.031). Conclusion: This study showed that sortilin levels, which are indicators of oxidation, were higher in the cord blood of newborns with late FGR.

Evaluation of Four Humanized NOD-Derived Mouse Models for Dengue Virus-2 Infection.

Dengue is a significant public health problem with no specific viral treatment. One of the main challenges in studying dengue is the lack of adequate animal models recapitulating human immune responses. Most studies on humanized mice use NOD-scid IL2R gamma null (NSG) mice, which exhibit poor hematopoiesis for some cell populations. This study compares three humanized (hu) NOD-derived mouse models for dengue virus-2 (DENV-2) infection in the context of human cytokine expression. Three mouse strains (hu-NSG, hu-EXL, and hu-SGM3) received xenotransplants of human CD34+ fetal cord blood cells from a single donor, and one mouse strain received human peripheral blood mononuclear cells (hu-SGM3-PBMCs). All models exhibited infectious viruses in blood confirmed by plaque assay, but mice expressing human cytokines showed higher viremia compared to conventional NSG mice. The hu-SGM3-PBMCs model developed lethal infections, showing a significant increase in viremia and clinical signs. A detectable human cytokine response was observed in all the DENV-2-infected humanized mouse models. In conclusion, humanized NOD-derived mouse models expressing human cytokines offer a relevant platform for the study of dengue pathogenesis and antiviral therapies.

Fluoride-related changes in the fetal cord blood proteome; a pilot study

BackgroundFluoride exposure during pregnancy has been associated with various effects on offspring, including changes in behavior and IQ. To provide clues to possible mechanisms by which fluoride may affect human fetal development, we completed proteomic analyses of cord blood serum collected from second-trimester pregnant women residing in northern California, USA.ObjectiveTo identify changes in cord blood proteins associated with maternal serum fluoride concentration in pregnant women.MethodsThe proteomes of 19 archived second-trimester cord blood samples from women living in northern California, USA, and having varied serum fluoride concentrations, were analyzed by quantitative mass spectrometry. The 327 proteins that were quantified were characterized by their abundance relative to maternal serum fluoride concentration, and subjected to pathway analyses using PANTHER and Ingenuity Pathway Analysis processes.ResultsPathway analyses showed significant increases in process related to reactive oxygen species and cellular oxidant detoxification, associated with increasing maternal serum fluoride concentrations. Pathways showing significant decreases included complement cascade, suggesting alterations in alterations in process associated with inflammation.ConclusionMaternal fluoride exposure, as measured by serum fluoride concentrations in a small, but representative sample of women from northern California, USA, showed significant changes in the second trimester cord blood proteome relative to maternal serum fluoride concentration.

The Effect of Maternal Blood Glucose on Umbilical Cord Blood Fibrinogen in Women With Gestational Diabetes.

Gestational diabetes mellitus (GDM) is delineated by the presence of glucose intolerance at any level that manifests or is initially identified during pregnancy. Factor I fibrinogen is among the most essential blood coagulation proteins. The concentration of fibrinogen influences platelet aggregation and blood viscosity. This study aimed to determine the correlation between fetal cord blood fibrinogen and plasma fibrinogen in pregnant women with GDM and between fetal cord blood fibrinogen and maternal blood sugar. A cross-sectional study was executed at Al-Elwiya Maternity Teaching Hospital in the obstetrics and gynecology department. The sample included 90 term pregnant women: 45 were confirmed to have GDM, and 45 healthy pregnant women served as control. Estimation of prelabor maternal fasting and random plasma glucose and plasma fibrinogen was performed. During delivery, blood was drawn from the umbilical cord to estimate neonatal plasma glucose and fibrinogen levels. The mean maternal plasma fibrinogen level exhibited a notable increase in women with GDM compared to the control (330.11 ± 56.92 mg/dl versus 254.89 ± 41.01 mg/dl). The infants of diabetic mothers had significantly lower mean cord plasma glucose levels (65.71 ± 14.63 mg/dl versus 77.80 ± 7.81 mg/dl) and higher mean cord plasma fibrinogen levels (269.42 ± 25.91 mg/dl versus 229.69 ± 21.29 mg/dl). Umbilical cord plasma fibrinogen was correlated positively with maternal plasma sugar and fibrinogen. A positive correlation between maternal and fetal cord fibrinogen levels was determined in women with GDM. Monitoring plasma fibrinogen levels in neonates of mothers with GDM could be facilitated by longitudinal, large-scale validation studies enabled by artificial intelligence as a new, evolving technique that contributes to more valuable outcomes. This would shed additional light on the course and function of plasma fibrinogen for a more comprehensive analysis of the fetal clotting system.

Multisite Evaluation and Validation of Optical Genome Mapping for Prenatal Genetic Testing

Prenatal diagnostic testing of amniotic fluid, chorionic villi, or more rarely, fetal cord blood is recommended following a positive or unreportable noninvasive cell-free fetal DNA test, abnormal maternal biochemical serum screen, abnormal ultrasound, or increased genetic risk for a cytogenomic abnormality based on family history. Although chromosomal microarray is recommended as the first-tier prenatal diagnostic test, in practice, multiple assays are often assessed in concert to achieve a final diagnostic result. The use of multiple methodologies is costly, time consuming, and labor intensive. Optical genome mapping (OGM) is an emerging technique with application for prenatal diagnosis because of its ability to detect and resolve, in a single assay, all classes of pathogenic cytogenomic aberrations. In an effort to characterize the potential of OGM as a novel alternative to traditional standard of care (SOC) testing of prenatal samples, OGM was performed on a total of 200 samples representing 123 unique cases, which were previously tested with SOC methods (92/123=74.7% cases tested with at least two SOCs). OGM demonstrated an overall accuracy of 99.6% when compared with SOC methods, a positive predictive value of 100%, and 100% reproducibility between sites, operators, and instruments. The standardized workflow, cost-effectiveness, and high-resolution cytogenomic analysis demonstrate the potential of OGM to serve as a first-tier test for prenatal diagnosis.

Prenatal stress and gestational epigenetic age: No evidence of associations based on a large prospective multi-cohort study.

Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely epigenetic gestational age, using foetal cord-blood DNA-methylation data. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R], n = 1,396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC], n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa], n1 = 1,212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3,928). Measures of epigenetic age acceleration were calculated using three different gestational epigenetic clocks: "Bohlin", "EPIC overlap" and "Knight". Prenatal stress exposure, examined as an overall cumulative score, was not significantly associated with epigenetically-estimated gestational age acceleration or deceleration in any of the clocks, based on the results of the pooled meta-analysis or those of the individual cohorts. No significant associations were identified with specific domains of prenatal stress exposure, including negative life events, contextual (socio-economic) stressors, parental risks (e.g., maternal psychopathology) and interpersonal risks (e.g., family conflict). Further, no significant associations were identified when analyses were stratified by sex. Overall, we find little support that prenatal psychosocial stress is associated with variation in epigenetic age at birth within the general paediatric population.

MYCT1 controls environmental sensing in human haematopoietic stem cells

The processes that govern human haematopoietic stem cell (HSC) self-renewal and engraftment are poorly understood and challenging to recapitulate in culture to reliably expand functional HSCs1–3. Here we identify MYC target 1 (MYCT1; also known as MTLC) as a crucial human HSC regulator that moderates endocytosis and environmental sensing in HSCs. MYCT1 is selectively expressed in undifferentiated human haematopoietic stem and progenitor cells (HSPCs) and endothelial cells but becomes markedly downregulated during HSC culture. Lentivirus-mediated knockdown of MYCT1 prevented human fetal liver and cord blood (CB) HSPC expansion and engraftment. By contrast, restoring MYCT1 expression improved the expansion and engraftment of cultured CB HSPCs. Single-cell RNA sequencing of human CB HSPCs in which MYCT1 was knocked down or overexpressed revealed that MYCT1 governs important regulatory programmes and cellular properties essential for HSC stemness, such as ETS factor expression and low mitochondrial activity. MYCT1 is localized in the endosomal membrane in HSPCs and interacts with vesicle trafficking regulators and signalling machinery. MYCT1 loss in HSPCs led to excessive endocytosis and hyperactive signalling responses, whereas restoring MYCT1 expression balanced culture-induced endocytosis and dysregulated signalling. Moreover, sorting cultured CB HSPCs on the basis of lowest endocytosis rate identified HSPCs with preserved MYCT1 expression and MYCT1-regulated HSC stemness programmes. Our work identifies MYCT1-moderated endocytosis and environmental sensing as essential regulatory mechanisms required to preserve human HSC stemness. Our data also pinpoint silencing of MYCT1 as a cell-culture-induced vulnerability that compromises human HSC expansion.

Anatomical and functional changes of the fetal adrenal gland in intrauterine growth restriction.

The aim of this study was to demonstrate the establishment of adrenal sparing in intrauterine growth restricted (IUGR) human fetuses. IUGR fetuses are a subgroup of small for gestational age (SGA) fetuses that are unable to reach their own growth potential because of chronic hypoxia and undernutrition. We hypothesized that in IUGR fetuses the adrenal gland is relatively larger and secretion of noradrenaline (NA), adrenaline (A), and cortisol is increased. This is a prospective observational study including 65 singleton pregnancies (42 IUGR and 23 controls). Using two-dimensional ultrasound, we measured fetal adrenal diameters and adrenal/abdominal circumference (AD/AC) ratio between 25 and 37 weeks. We considered only one measurement per fetus. In 21 pregnancies we also measured NA, A, and cortisol levels in arterial and venous fetal cord blood collected at the time of delivery. The AD/AC ratio was significantly higher in IUGR fetuses than in controls. Cord NA and A levels were significantly higher in IUGR fetuses than in controls. An increase in cortisol secretion in IUGR fetuses was observed but the difference was not statistically significant. Adrenal sparing correlates with a relative increase in adrenal measurements and function.

Comparative analysis of thiol-disulfide homeostasis dynamics between elective cesarean section and uncomplicated vaginal delivery: insights into perinatal oxidative balance.

Thiols are organic compounds containing sulfhydryl groups that exert antioxidant effects via dynamic thiol-disulfide homeostasis. The shift towards disulfide indicates the presence of an oxidative environment. Different modes of delivery can affect thiol-disulfide homeostasis. Accordingly, we planned this research to evaluate the effects of the mode of delivery on thiol-disulfide homeostasis in both maternal serum and fetal cord blood samples. We conducted a prospective case-control study involving two groups: vaginal delivery (n=50) and elective cesarean section (CS) (n=45). The vaginal delivery group exclusively comprised uncomplicated term deliveries, while the CS group included pregnant individuals with scheduled cesarean deliveries due to the absence of spontaneous labor onset. Maternal serum and fetal cord blood samples were collected, and thiol-disulfide exchanges were analyzed using an automated method capable of measuring both aspects of the thiol-disulfide balance. The levels of native thiol (-SH) and total thiol in both maternal serum and fetal cord blood samples were significantly higher in the vaginal delivery group than those in the CS group. An important discovery of our study was that fetal cord disulfide (-SS) level, which may reflect oxidative stress, was higher in newborns born via vaginal delivery when examined alone. However, in both maternal and fetal cord blood, the combined ratios, SS/SH ratio (%), SS/Total thiol ratio (%), and SH/Total thiol ratio (%) were observed to be similar between the groups in both maternal and fetal cord blood. It was observed that as the mother's weight gained during pregnancy increased, SS/SH and SS/total thiol increased (positive correlation), while SH/total thiol decreased (negative correlation). Our results showed that the dynamic thiol-disulfide homeostasis was greatly influenced by the way of delivery and supported the idea that vaginally-delivered infants may have more oxidative stress.

Comparison of early term results of umbilical cord blood gas sampling among uncomplicated primiparous and multiparous vaginal deliveries and elective cesarean section

Objective: This study aims to investigate the early effects of the mode of delivery on the newborn in cases of non-complicated primiparous and multiparous vaginal deliveries who were admitted to the clinic in active labor, and elective cesarean section by analyzing fetal umbilical cord blood gas. Materials and methods: In this retrospective study, 120 cases were enrolled in the study, including 40 primiparous cases, 40 multiparous cases, and 40 elective cesarean section cases. Age, pregnancy history, medical history, age of gestation at birth, delivery type, fetal Weight, APGAR score, baby gender and fetal blood gas values were statistically analyzed. Results: Statistically significant differences were found between the primiparous vaginal delivery group and the cesarean section and multiparous vaginal delivery groups in the parameters of age, gravidity, parity, and fetal Weight, with primiparous vaginal delivery showing significantly lower parameters. When compared with multiparous and primiparous vaginal delivery, a statistically significant difference was observed in APGAR 1 score, with C/S births having lower scores. In primiparous vaginal delivery, it was found that pH, pH(T), Base(Ecf)c, cHCO3(P)c, cHCO3(p,st)c, cBase(B,ox)c, and cBase(Ecf,ox)c were significantly lower compared to other groups, while only higher levels of pCO2 and mOsmc were observed. In the cesarean section group, lower levels of ctHb, Hctc, cCa, cGlu, and cLac parameters were observed compared to other groups, while the cNa level was significantly higher. Significant differences were found only between primiparous vaginal delivery and cesarean section groups in the parameter cK, with a significantly lower cK value in the C/S group. Conclusion: Primiparous pregnant women exhibited lower birth weight, lower pH in umbilical cord blood, and higher levels of pCO2, while in the cesarean group, lower APGAR score at 1 minute, lower levels of hemoglobin, calcium, glucose, lactate, and potassium were observed.

Effects of paternal and chronological age on BEGAIN methylation and its possible role in autism.

Children from old fathers carry an increased risk for autism spectrum (ASD) and other neurodevelopmental disorders, which may at least partially be mediated by paternal age effects on the sperm epigenome. The brain enriched guanylate kinase associated (BEGAIN) protein is involved in protein-protein interactions at and transmission across synapses. Since several epigenome-wide methylation screens reported a paternal age effect on sperm BEGAIN methylation, here we confirmed a significant negative correlation between BEGAIN promoter methylation and paternal age, using more sensitive bisulfite pyrosequencing and a larger number of sperm samples. Paternal age-associated BEGAIN hypomethylation was also observed in fetal cord blood (FCB) of male but not of female offspring. There was no comparable maternal age effect on FCB methylation. In addition, we found a significant negative correlation between BEGAIN methylation and chronological age (ranging from 1 to 70 years) in peripheral blood samples of male but not of female donors. BEGAIN hypomethylation was more pronounced in male children, adolescents and adults suffering from ASD compared to controls. Both genetic variation (CC genotype of SNP rs7141087) and epigenetic factors may contribute to BEGAIN promoter hypomethylation. The age- and sex-specific BEGAIN methylation trajectories in the male germ line and somatic tissues, in particular the brain, support a role of this gene in ASD development.

MYCT1 Controls Environmental Sensing to Maintain Self-Renewal in Human Hematopoietic Stem Cells

Hematopoietic stem cells (HSC) sustain life-long blood production and have the ability to recapitulate the hematopoietic system upon transplantation. This makes them therapeutically invaluable for the treatment of hematopoietic malignancies and genetic disorders. However, the regulatory processes governing HSC functional competence and engraftment ability are poorly understood and challenging to recapitulate ex vivo, making robust expansion of human HSCs difficult to achieve. We have identified a novel HSC regulatory protein, MYCT1 (MYC target 1), that is highly enriched in self-renewing human HSC but lost during differentiation and culture. Knockdown (KD) experiments in human fetal liver and cord blood revealed a critical requirement for MYCT1 in human HSPC ex vivo expansion and engraftment across HSC ontogeny. Single cell RNAseq of human HSPCs upon MYCT1 KD linked MYCT1 loss in HLF+ HSCs to a profound dysregulation of cellular programs essential for HSC stemness, including mitochondrial activity, proteostasis and splicing. Because MYCT1 becomes drastically downregulated during HSC ex vivo culture, we investigated if restoring MYCT1 expression in culture could improve HSC function. Indeed, maintaining MYCT1 levels during culture via lentiviral expression resulted in improved “stemness” transcriptional signatures, greater expansion of the most undifferentiated EPCR+ITGA3+ human HSPCs, and enhanced engraftment ability upon transplantation. Notably, we also uncovered that the novel albumin free culture conditions reported by Sakurai et al. 2023 to robustly expand human HSCs can also maintain higher levels of MYCT1 expression. This reinforces our findings that the loss of MYCT1 expression is a major contributor to the functional incompetence of human HSCs cultured ex vivo. Nonetheless, the MYCT1 regulated processes and why they are critical for HSC competence are not known. Immunofluorescence and IP-mass spectrometry revealed that MYCT1 localizes in the endosomal membrane and interacts with vesicle trafficking machinery and receptor signaling components essential for HSC function. MYCT1 KD in human HSCs and endothelial cells (EC) led to hyperactive endocytosis and caused exaggerated signaling responses to cytokines in the culture microenvironment. We found that ex vivo culture gradually increased endocytosis specifically in CD34+ EPCR+ HSPCs in parallel with the culture-induced downregulation of MYCT1 in these cells, but not in the more differentiated progeny. On the other hand, restoring MYCT1 expression during HSC culture dampened the excessive endocytosis. Furthermore, maintaining low endocytosis during culture, either by the endocytosis inhibitor chlorpromazine or by sorting HSPCs with lower endocytic internalization of fluorescent dextran, results in the enrichment of immunophenotypic LT-HSCs in culture. Our data show that the moderation of environmental sensing through MYCT1-controlled endocytosis is essential for preserving human HSC self-renewal and engraftment ability. As MYCT1 expression is downregulated in cultured human HSPC, our findings imply that loss of the molecular machinery required for proper sensing of microenvironment signals has far-reaching effects into essential cellular functions required for stemness, and is a key contributor to the functional incompetence of cultured human HSC.

Normal value and changes in CRP values on maternal and fetal umbilical cord blood with the labor and intrapartum interventions

Introduction: C-reactive protein (CRP) is widely used as an inflammatory marker. Since labour is an inflammatory process, CRP values vary during the intrapartum and postpartum period due to multiple factors.Methods: A descriptive-analytical study was carried out at Castle Street Hospital for Women. Mothers who have term singleton pregnancies with uneventful antenatal periods and have undergone vaginal delivery were recruited for the study. Samples were obtained just after admission to the labour ward (S1), 24 hours after the delivery (S2), and the fetal umbilical cord blood (S3). Reference ranges for S2 and S3 were determined using the interquartile range (IQR).Results: Out of 300 mothers recruited for the study, the mean age was 26.73 years (95% Confidence interval 19.5-36.9). There were 266 samples of S1,177 samples of S2, and 173 samples of S3 were collected. The reference range for S2 is 12.70-150.83 mg/dl, and for S3 is 0.1-8.1 mg/dL. The S2 value is significantly associated with duration of labor (r=0.47, p=0.046), number of vaginal examinations (VEs) (p &lt; 0.001), augmentation of labor (AOL) (p=0.001), method of cervical ripening (p=0.014) and intrapartum intervention (p &lt; 0.001). The number of vaginal examinations (p=0.02) and augmentation of labor (p=0.025) are significantly associated with fetal umbilical cord blood (S3).Conclusion: Early postpartum CRP can be risen up to 151 mg/dL after 24 hours of vaginal delivery. It may be associated with prolonged labor, number of VEs performed, AOL, method of cervical ripening, and episiotomy. Fluctuation of normal CRP values during the periods of antenatal, intrapartum, and postpartum needs to be assessed in the Sri Lankan community.

Epigenetically-driven persistence of inflammatory and oxidative phenotypes in adolescents born to women with gestational diabetes

Abstract Background According to the theory of developmental origins of health and disease1, environmental changes during the in-utero period can permanently affect health and vulnerability to diseases later in life. As a matter of fact, the offspring of women with gestational diabetes (GD) exhibit a higher risk for developing obesity, type 2 diabetes (T2D), and atherosclerotic cardiovascular disease (ASCVD) than those individuals with a family history of diabetes2–4. Importantly, epigenetics has emerged as a crucial determinant for this transmission across generations5–8. Mixed Lineage Leukemia 1 (MLL1) histone methyltransferase activates inflammatory and oxidative pathways through trimethylation of histone 3 at lysine 4 amino (H3K4me3)9. Purpose To investigate whether such epigenetic mark regulates genes triggering inflammation and oxidative stress in GD women, and its potential transmission and persistence in their offspring. Methods We isolated peripheral blood mononuclear cells (PBMCs), fetal cord blood mononuclear cells (CBMCs), and umbilical cord vein endothelial cells (HUVECs) from GD and control pregnant women, as well as PBMCs and plasma samples from a retrospective cohort of adolescents (12-16 years old) born to control or GD women. Gene and protein expressions were investigated by RT-PCR, immunoblotting and/or confocal microscopy. H3K4me3 levels on NF-kB p65 and NADPH oxidase isoform 4 (NOX4) promoter regions were assessed by chromatin immunoprecipitation (ChIP) and RT-PCR. Mechanistic studies were performed in control- and GD-HUVECs using the MLL1 inhibitor MM-102 to assess downstream inflammatory mediators and superoxide anion (O2-) generation by electron spin resonance (ESR) spectroscopy. Results Our data showed upregulation of MLL1 and H3K4me3 levels in PBMCs, HUVECs, and CBMCs isolated from GD as compared to control women. ChIP analysis revealed H3K4me3 enrichment in the promoter region of the inflammatory and oxidative master regulatory genes NF-kB p65 and NOX4, respectively, in these cells. We also found an upregulation of NF-kB p65 target genes IL-6, MCP-1, ICAM-1, and VCAM-1, and increased monocyte adhesion and O2- production. The inhibition of MLL1 was able to reduce H3K4me3 levels blunting the inflammatory and oxidative phenotypes in GD-HUVECs. Interestingly enough, we demonstrated a persistent increase of H3K4me3 in the NF-kB p65 promoter region of PBMCs together with an elevation of inflammatory markers in plasma from adolescents born to GD women. Conclusions Our results suggest that GD may induce inflammation and oxidative stress through MLL1-dependent H3K4me3 mechanisms. Such epigenetic mark is transmitted to the offspring and, most importantly, can still be found in adolescence as a pro-inflammatory trigger. These findings pave the way for pharmacological reprogramming of adverse histone modifications to counteract early abnormal phenotypes in GD offspring which may accelerate ASCVD burden.

Use of CFTR modulators in special populations, part 1: Pregnancy and lactation.

Safety and efficacy data regarding cystic fibrosis transmembrane conductance regulator (CFTR) modulator use in the setting of pregnancy or breastfeeding remains lacking due to exclusion from key trials and lack of multicenter prospective and retrospective studies in the post-CFTR modulator era. A scoping review of English articles from the period of January 1, 2012, to July 31, 2023, was conducted utilizing PubMed and EmBase databases with the following terms: "special population (pregnancy, lactation, breastfeeding)" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use." Search results were reviewed by title and abstract for duplications and relevance. Relative to pregnancy or breastfeeding, a total of 18 publications were included for review. Majority of case reports and surveys concluded maternal and infant health were preserved throughout gestation. Likewise, breastfeeding infant case reports show possible changes in liver function and lens opacities, though risk may be increased with both in-utero and breastfeeding exposure. Ivacaftor (IVA) and lumacaftor (LUM) concentrations in fetal cord blood and maternal blood were found to be equivalent. Yet, low concentrations of IVA and LUM were detectable in breastmilk and infant plasma. Current safety data surrounding CFTR modulator use in the setting of pregnancy and lactation is relatively reassuring; however, long-term safety remains unclear, necessitating ongoing observation, and reporting by care teams. As such, treatment decisions should be individualized and coproduced.

Pharmacological blockade of the interleukin-1 receptor suppressed Escherichia coli lipopolysaccharide-induced neuroinflammation in preterm fetal sheep

Intraamniotic inflammation is associated with preterm birth, especially in cases occurring before 32 weeks' gestation, and is causally linked with an increased risk for neonatal mortality and morbidity. Targeted anti-inflammatory interventions may assist in improving the outcomes for pregnancies impacted by intrauterine inflammation. Interleukin-1 is a central upstream mediator of inflammation. Accordingly, interleukin-1 is a promising candidate target for intervention therapies and has been targeted previously using the interleukin-1 receptor antagonist, anakinra. Recent studies have shown that the novel, noncompetitive, allosteric interleukin-1 receptor inhibitor, rytvela, partially resolved inflammation associated with preterm birth and fetal injury. In this study, we used a preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela and anakinra, administered in the amniotic fluid in the setting of intraamniotic Escherichia coli lipopolysaccharide exposure. We hypothesized that both rytvela and anakinra would reduce lipopolysaccharide-induced intrauterine inflammation and protect the fetal brain. Ewes with a singleton fetus at 105 days of gestation (term is ∼150 days) were randomized to one of the following groups: (1) intraamniotic injections of 2 mL saline at time=0 and time=24 hours as a negative control group (saline group, n=12); (2) intraamniotic injection of 10 mg Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 2 mL saline at time=0 hours and time=24 hours as an inflammation positive control group (lipopolysaccharide group, n=11); (3) intraamniotic injection of Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 2.5 mg rytvela at time=0 hours and time=24 hours to test the anti-inflammatory efficacy of rytvela (lipopolysaccharide + rytvela group, n=10); or (4) intraamniotic injection of Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 100 mg anakinra at time=0 hours and time=24 hours to test the anti-inflammatory efficacy of anakinra (lipopolysaccharide + anakinra group, n=12). Amniotic fluid was sampled at time 0, 24, and 48 hours (ie, at each intervention and at delivery). Fetal umbilical cord blood was collected at delivery for differential blood counts and chemical studies. Inflammation was characterized by the analysis of fetal tissue cytokine and chemokine levels using quantitative polymerase chain reaction, enzyme-linked inmmunosorbent assay, and histology. The primary study outcome of interest was the assessment of anakinra and rytvela brain-protective effects in the setting of Escherichia coli lipopolysaccharide-induced intrauterine inflammation. Secondary outcomes of interest were to assess protection from fetal and intrauterine (ie, amniotic fluid, chorioamnion) inflammation. Intraamniotic administration of lipopolysaccharide caused inflammation of the fetal lung, brain, and chorioamnionitis in preterm fetal sheep. Relative to treatment with saline only in the setting of lipopolysaccharide exposure, intraamniotic administration of both rytvela and anakinra both significantly prevented periventricular white matter injury, microglial activation, and histologic chorioamnionitis. Anakinra showed additional efficacy in inhibiting fetal lung myeloperoxidase activity, but its use was associated with metabolic acidaemia and reduced fetal plasma insulin-like growth factor-1 levels at delivery. Intraamniotic administration of rytvela or anakinra significantly inhibited fetal brain inflammation and chorioamnionitis in preterm fetal sheep exposed to intraamniotic lipopolysaccharide. In addition, anakinra treatment was associated with potential negative impacts on the developing fetus.

Clinical Importance of Serum BDNF (Brain-Derived Neurotrophic Factor) Level for the Management of Pregnancies Complicated With Meconium-Stained Amniotic Fluid.

Objective The aim of this study was to investigate the association between poor neonatal outcomes and BDNF (brain-derived neurotrophic factor) levels. We aimed to predict the need for an emergency cesarean and prevent unnecessary interventions in cases complicated with meconium-stained amniotic fluid (MSAF). Methods This study was designed as a case-control study including three groups. Group A included pregnant women who underwent cesarean due to fetal distress. Group B included the women who delivered vaginally. Groups A and B had cases with the presence of meconium in the amniotic fluid. Group C as a control group had clear amniotic fluid. Demographic features, fetal outcomes, and maternal serum and fetal cord blood BDNF levels (Human BDNF ELISA Kit; Synonyms: ANON2, BULN2; Catalog no: E-EL-H0010 96T) were evaluated. Results No significant difference was found between patients with meconium and without meconium in terms of BDNF levels. However, the BDNF level was found to be significantly lowerif fetal distress had occurred with MSAF. Conclusions In conclusion, the study demonstrated that the level of maternal and fetal cord blood BDNF are both significantly lower when fetal distress occurs with the presence of MSAF.