Fetal Umbilical Cord Research Articles

Analysis of the Microbiome Based on 16S rRNA Gene Signature in Women with Preterm versus Term Birth

Abstract Objective: To characterize and compare the microbiome signature in the maternal, intrauterine, and fetal environments and the associated bacterial species in women who experienced preterm birth and term birth. Methods: A total of 140 women with singleton pregnancies were enrolled in this study. Among them, 31 experienced spontaneous preterm delivery (gestational age < 37 weeks), and 28 of them experienced vaginal delivery at term. Maternal peripheral blood, saliva, and vaginal discharge samples and fetal membrane, amniotic fluid, and cord blood samples were collected immediately after delivery under sterile conditions. DNA was isolated from the fetal membrane and umbilical cord blood samples, and the V3-V4 region of the bacterial 16S rRNA gene was sequenced. The sequence data were quality-filtered, chimera-checked, and organized into operational taxonomic units (OTUs) based on phylogeny. Principal coordinate analysis of beta diversity measures was used for visualization. The linear discriminant analysis effect size (LEfSe) algorithm and Wilcoxon test were used to differentiate the microbiomes found in the fetal membranes and cord blood in the cases of preterm birth. Results: OTU analysis based on the 16S rRNA gene showed similar microbiomes in the maternal peripheral blood, amniotic fluid, fetal membranes, and cord blood. However, the LEfSe algorithm revealed significantly different bacterial compositions in the fetal environment between the preterm and term groups, with some of the bacterial species originating from the maternal peripheral blood or saliva. Conclusions: The bacteria in the intrauterine and fetal environments may originate from other body sites through hematogenous transmission, and may cause the occurrence of preterm birth.

Labor dystocia and risk of histological chorioamnionitis and funisitis: a study from a single tertiary referral center

BackgroundIntrauterine inflammation affects short- and long-term neonatal outcomes. Histological chorioamnionitis and funisitis are acute inflammatory responses in the fetal membranes and umbilical cord, respectively. Although labor dystocia includes a potential risk of intrauterine inflammation, the risk of histological chorioamnionitis and funisitis of labor dystocia has not been evaluated yet. This study aimed to examine the association between labor dystocia and risk of histological chorioamnionitis and funisitis.MethodsIn this retrospective cohort study, the cases who underwent histopathological examinations of the placenta and umbilical cord at Fukushima Medical University Hospital, Japan, between 2015 and 2020, were included. From the dataset, the pathological findings of the patients with labor dystocia and spontaneous preterm birth were reviewed. Based on the location of leukocytes, the inflammation in the placenta (histological chorioamnionitis) and umbilical cord (funisitis) was staged as 0–3. Multiple logistic regression analysis was performed to evaluate the risk of histological chorioamnionitis, histological chorioamnionitis stage ≥2, funisitis, and funisitis stage ≥2.ResultOf 317 women who met the study criteria, 83 and 144 women had labor dystocia and spontaneous preterm birth, respectively, and 90 women were included as controls. Labor dystocia was a risk factor for histological chorioamnionitis (adjusted odds ratio, 6.3; 95% confidential interval, 1.9–20.5), histological chorioamnionitis stage ≥2 (adjusted odds ratio, 6.0; 95% confidence interval, 1.7–21.8), funisitis (adjusted odds ratio, 15.4; 95% confidence interval, 2.3–101.3), and funisitis stage ≥2 (adjusted odds ratio, 18.5; 95% confidence interval, 2.5–134.0). Spontaneous preterm birth was also a risk factor for histological chorioamnionitis (adjusted odds ratio, 3.7; 95% confidence interval, 1.7–7.8), histological chorioamnionitis stage ≥2 (adjusted odds ratio, 3.0; 95% confidence interval, 1.2–7.9), and funisitis (adjusted odds ratio, 6.6; 95% confidence interval, 1.4–30.6). However, the adjusted odds ratio was smaller in spontaneous preterm births than in labor dystocia.ConclusionLabor dystocia is a risk factor for severe histological chorioamnionitis and funisitis. Further studies are required to evaluate the effects of histological chorioamnionitis and funisitis on long-term neonatal outcomes.

Fetal biometric based abnormality detection during prenatal development using deep learning techniques

Early in pregnancy, ultrasounds are used to confirm the fetal heartbeat and a uterine pregnancy. Later, ultrasounds screen for fetal growth, placenta location and umbilical cord, as well as the baby's general health and anatomy. Identifying and interpreting fetal standard scan planes during 2-D ultrasound mid-pregnancy examinations are highly complex tasks, which require years of training. Apart from guiding the probe to the correct location, it is equally difficult for a non-expert to identify relevant structures within the image. The procedure requires a sonographer to find the standardized visualization planes with a probe and manually place measurement calipers on the structures of interest. The process is tedious, time consuming, and introduces user variability into the measurements. Automatic image processing can provide tools to help experienced as well as inexperienced operators with these tasks. The proposed method is realized with deep convolutional neural network models to find the region of interest (ROI) of the fetal biometric and organs region in the US image. Based on the ROI, AlexNet, GoogleNet and CNN evaluate the image quality by assessing the goodness of depiction for the key structures of fetal biometrics. In this method both normal and abnormal US data are considered. In addition with that the input sources of the neural network are augmented with the local phase features along with the original US data. These augmented input sources helps to improve the performance of the various Neural Networks. The input sources are trained by AlexNet, GoogleNet and CNN. Then the process of validation is done by performance in proposed Networks for evaluating the accuracy. The performance of proposed work is evaluated with different network configuration. On the dataset of 400 images used in this classification task, proposed work of AlexNet, GoogleNet and CNN achieves accuracy of 90.43%, 88.70%, and 81.25% with reference to expert’s ground truth results respectively.

Ultrasound evaluation of the fetal fat tissue, heart, liver and umbilical cord measurements in pregnancies complicated by gestational and type 1 diabetes mellitus: potential application in the fetal birth-weight estimation and prediction of the fetal macrosomia

BackgroundThe aim of the study was to evaluate the ultrasound-derived measurements of the fetal soft-tissue, heart, liver and umbilical cord in pregnancies complicated by gestational (GDM) and type 1 diabetes mellitus (T1DM), and further to assess their applicability in the estimation of the fetal birth-weight and prediction of fetal macrosomia.MethodsMeasurements were obtained from diet-controlled GDM (GDMG1) (n = 40), insulin-controlled GDM (GDMG2) (n = 40), T1DM (n = 24) and healthy control (n = 40) patients. The following parameters were selected for analysis: fetal sub-scapular fat mass (SSFM), abdominal fat mass (AFM), mid-thigh fat/lean mass (MTFM/MTLM) and inter-ventricular septum (IVS) thicknesses, heart and thorax circumference and area (HeC/HeA; ThC/ThA), liver length (LL), umbilical cord/vein/arteries circumference and area (UmC/UmA; UvC/UvA; UaC/UaA) together with total umbilical vessels (UveA) and Wharton's jelly area (WjA). Regression models were created in order to assess the contribution of selected parameters to fetal birth-weight (FBW) and risk of fetal macrosomia.ResultsMeasurements of the fetal SSFM, AFM, MTFM, MTFM/MTLM ratio, HeC, HeA, IVS, LL, UmC, UmA, UaC, UaA, UveA and WjA were significantly increased among patients with GDMG2/T1DM as compared to GDMG1 and/or control groups (p < .05). The regression analysis revealed that maternal height as well as fetal biparietal diameter, abdominal circumference (AC), AFM and LL measurements were independent predictors of the FBW (p < .05). In addition, increase in the fetal AFM, AC and femur length (FL) was associated with a significant risk of fetal macrosomia occurrence (p < .05). The equation developed for the FBW estimation [FBW(g) = − 2254,942 + 17,204 * FL (mm) + 105,531 * AC (cm) + 131,347 * AFM (mm)] provided significantly lower mean absolute percent error than standard formula in the sub-group of women with T1DM (5.7% vs 9.4%, p < .05). Moreover, new equation including AC, FL and AFM parameters yielded sensitivity of 93.8%, specificity 77.7%, positive predictive value 54.5% and negative predictive value of 97.8% in the prediction of fetal macrosomia.ConclusionsUltrasound measurements of the fetal soft tissue, heart, liver and umbilical cord are significantly increased among women with GDM treated with insulin and T1DM. In addition to standard biometric measurements, parameters, such as AFM, may find application in the management of diabetes-complicated pregnancies.

The effect of nuchal umbilical cord on fetal cardiac and cerebral circulation-cross-sectional study.

The subject of our analysis is the influence of umbilical cord collision around the fetal neck on the fetal heart function and cerebral circulation. Our study was carried out on a group of 115 fetuses from single pregnancies with physiological course, during the 15th to 40th week of pregnancy. In our analysis, we examined the following parameters: Tei index for right ventricle, Tei index for left ventricle with Tei index components: isovolumetric contraction time, isovolumetric relaxation time, ejection time and cardiothoracic area ratio, middle cerebral artery peak systolic velocity (PS MCA), middle cerebral artery pulsatility index (PI MCA). Gestational age in our study was: 28+2±34. The study group of patients with fetal umbilical cord around neck group (fUCAN) included 38 fetuses (20 males, 18 females). The control group of patients with no fetal umbilical cord around neck group (NfUCAN) included 77 fetuses (43 males, 34 females). In our study, we found no significant differences in the values obtained: Tei LV in fUCAN: 0.5±0.1 vs. in NfUCAN: 0.5±0.1; p=0.42), Tei RV in fUCAN: 0.5±0.2 vs. in NfUCAN: 0.4±0.1; (p=0.2). Tricuspid valve regurgitation-TR was observed with the following frequency: fUCAN: 7/38, 18% vs. NfUCAN: 13/77, 17%; p=0.8. MCA PS in study fUCAN group was significantly higher than in NfUCAN (40.2±11.5 vs. 32.5±9.5; p=0.003), although other hemodynamic and clinical variables did not differ between the study and control groups. The fetal nuchal umbilical cord collision did not affect the fetal heart function expressed as Tei index, at the time of fetal heart examination (at mean gestational age 29+4weeks). The fUCAN group presented elevated PS MCA, which was not related to other hemodynamic and clinical variables between the study and control groups.

Amniocele after laparoscopic myomectomy: is expectant management acceptable?

Amniocele after laparoscopic myomectomy: is expectant management acceptable?

Improving Classifiaction Performance of Fetal Umbilical Cord Using Combination of SMOTE Method and Multiclassifier Voting in Imbalanced Data and Small Dataset

Improving Classifiaction Performance of Fetal Umbilical Cord Using Combination of SMOTE Method and Multiclassifier Voting in Imbalanced Data and Small Dataset

The mediation role of insulin-like growth factor 1 in the relationship between prenatal PFBS exposure and adiposity in pre-school girls

Background: Perfluorobutane sulfonate (PFBS), one of the commonly used short-chain per- and polyfluoroalkyl substances (PFAS), has a positive association with adiposity in pre-school girls. However, the exact mechanism of this association remains unknown.Objective: We aimed to investigate whether and the extent to which insulin-like growth factor 1 (IGF1) mediates the association between prenatal exposure to PFBS and female childhood adiposity at 5 years of age.Methods: We conducted a prospective birth cohort study involving 556 pairs of pregnant women-girls from 2012 to 2017 in Shanghai. Fetal umbilical cord blood was collected at birth.A total of 178 girls completed the adiposity measurements using a bioelectrical impedance analysis method. IGF1 and IGFBP3 were measured at 5 years of age, and cord plasma PFAS were tested using LC-MS/MS. Multivariable linear models after adjustment for potential confounders were used to evaluate the associations between PFAS and childhood adiposity. A mediation analysis was used to evaluate the percentage eliminated by IGF1 in the relationship between PFBS exposure and body components at 5 years of age.Results: The median concentration of PFBS in the cord plasma was 0.05 ng/mL. Multivariable linear regression found that PFBS had a significant positive association with waist circumference, fat mass, body fat percentage and waist to height ratio. PFBS also had a significant positive association with IGF1 and IGF1/IGFBP3. Meanwhile, there was a significant positive association between IGF1 and body components. After the mediation analysis, the proportions of the association eliminated by IGF1 was 52.4% for BMI, 35.2% for fat mass, 27.9% for body fat percentage, and 28.4% for waist circumference, respectively. Conclusions: Our findings suggest that IGF1 may play a substantial role in the association between PFBS exposure and adiposity in pre-school girls. These findings provide us a better understanding of the toxicity of PFBS.

Association between prenatal exposure to PFAS and fetal sex hormones: Are the short-chain PFAS safer?

Background: Experimental evidence suggested that per- and polyfluoroalkyl substances (PFAS) may affect the production of reproductive and sex steroid hormones. However, epidemiologic evidence regarding the effects of in utero exposure to PFAS, particularly to short-chained PFAS, on sex hormones in fetus are scarce and inconsistent. Objective: This study aimed to assess the relationship between maternal PFAS exposure and reproductive and sex steroid hormones in the fetal umbilical cord blood. Methods: A total of 752 pregnant women who were recruited in the Shanghai Birth Cohort Study between 2013 and 2016 were selected. We quantified 9 PFAS in early pregnancy (median gestational age at 12 weeks) in maternal blood using HPLC-MS/MS. Dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) were measured in the cord blood using chemiluminescence kits. Both PFAS concentrations and hormones were ln-transformed due to their right skewed distribution. Multiple linear regression was used to evaluate the associations between PFAS and hormones indicators. Results: One ln- unit increase in maternal perfluorobutane sulfonate (PFBS) was related to decreased FSH [-0.093 (95% CI: -0.170, -0.016)] and LH [-0.099 (95% CI: -0.199, -0.001)], and increased SHBG [0.040 (95% CI: 0.007, 0.074)] in cord blood. These associations were larger in girls but non-significant in boys. In girls, FSH (-0.126, 95% CI: -0.244, -0.009), LH (-0.147, 95% CI: -0.301, 0.008) and SHBG (0.062, 95% CI: 0.003, 0.122). No association was found for other 8 PFAS. Conclusions: Prenatal exposure to PFBS was associated with the interruption of fetal reproductive and sex hormone homeostasis in this prospective cohort. These significant associations were limited to girls. Our findings suggested that reproductive toxicity of short-chain PFAS may not be neglected.

MiR-483 is downregulated in pre-eclampsia via targeting insulin-like growth factor 1 (IGF1) and regulates the PI3K/Akt/mTOR pathway of endothelial progenitor cells.

Pre-eclampsia is a serious pregnancy-specific disease with an incidence of 9.4%. MicroRNAs play a key role in regulating factors in pre-eclampsia, but related research is still limited. This study aims to reveal the role and potential mechanisms of miR-483 in pre-eclampsia. miR-483 was detected in venous blood, umbilical cord blood and placental tissue of pre-eclampsia patients by Real-time Quantitative polymerase chain reaction (qRT-PCR). Insulin-like growth factor (IGF1) and miR-483 were detected by qRT-PCR and western blot in endothelial progenitor cells isolated from fetal umbilical cord blood. miR-483 was overexpressed and inhibited to detect changes of IGF1 and PI3K/Akt/mTOR pathway in endothelial progenitor cells by qRT-PCR and western blot. miR-483 was downregulated in venous blood, umbilical cord blood and placental tissue of pre-eclampsia patients. In endothelial progenitor cells, overexpression of miR-483 inhibited the expression of IGF1, and inhibition of miR-483 promoted the expression of IGF1. miR-483 regulates the expression of PI3K, Akt, and mTOR in endothelial progenitor cells. miR-483 is downregulated in pre-eclampsia and regulates endothelial progenitor cells by targeting IGF1. miR-483 is a potential alternative for diagnosing and treating pre-eclampsia.

Characterization of Fetal Thyroid Levels at Delivery among Appalachian Infants.

Thyroid disorders are a frequently encountered issue during pregnancy and a cause of maternal and fetal morbidity. In regions like Appalachia that are particularly susceptible to health disparities, descriptive studies are needed to assist in identifying pathologic derangements. We sought to characterize fetal thyroid hormone levels at delivery and investigate whether or not maternal demographic characteristics affect the prevalence of neonatal thyroid disease. A cross-sectional analysis was conducted on 130 pregnant women recruited from the Tri-State region, incorporating areas of Kentucky, Ohio, and West Virginia. Total triiodothyronine (T3) (p = 0.4799), free T3 (p = 0.6323), T3 uptake (p = 0.0926), total thyroxine (T4) (p = 0.8316), free T4 (p = 0.0566), and Thyroid stimulating hormone (TSH) (p = 0.8745) levels were comparable between urban and rural newborns. We found no effect of hypertension status or nicotine levels on fetal umbilical cord thyroid hormone levels. Maternal diabetic status was associated with lower T4 (p = 0.0099) and free T4 (p = 0.0025) levels. Cotinine affected levels of T4 (p = 0.0339). In regard to maternal Body Mass Index (BMI), there was an increase in total T3 as BMI increased (p = 0.0367) and no significant difference in free T3, T3 uptake, T4, free T4, or TSH. There was a negative correlation between TSH and 1 min Apgar scores (p = 0.0058). Lead and cadmium have been implicated to alter TSH levels, but no correlation was found in our study (r2 = 0.0277). There were no differences in cord blood between urban (37.3 ± 10.3 fmol/ug DNA) and rural (70.5 ± 26.8 fmol/ug DNA) benzo(a)pyrene DNA adducts (p = 0.174). Thyroid disorders present a unique opportunity for the prevention of perinatal morbidity and mortality, since maternal treatment, as well as maternal demographic characteristics, can have direct fetal effects.

A New Self-Healing Hydrogel Containing hucMSC-Derived Exosomes Promotes Bone Regeneration.

BackgroundFractures are a medical disease with a high incidence, and about 5–10% of patients need bone transplantation to fill the defect. In this study, we aimed to synthesize a new type of coralline hydroxyapatite (CHA)/silk fibroin (SF)/glycol chitosan (GCS)/difunctionalized polyethylene glycol (DF-PEG) self-healing hydrogel and to evaluate the therapeutic effects of this novel self-healing hydrogel as a human umbilical cord mesenchymal stem cells (hucMSC)-derived exosome carrier on bone defects in SD rat.MethodsHucMSCs were isolated from fetal umbilical cord tissue and characterized by surface antigen analysis and pluripotent differentiation in vitro. The cell supernatant after ultracentrifugation was collected to isolate exosomes, which were characterized by transmission electron microscopy and western blot analysis. In vitro cell induction experiments were performed to observe the effects of hucMSC-derived exosomes on the biological behavior of mouse osteoblast progenitor cells (mOPCs) and human umbilical vein endothelial cells (HUVECs). The CHA/SF/GCS/DF-PEG hydrogels were prepared using DF-PEG as the gel factor and then structural and physical properties were characterized. HucMSCs-derived exosomes were added to the hydrogel and their effects were evaluated in SD rats with induced femoral condyle defect. These effects were analyzed by X-ray and micro-CT imaging and H&E, Masson and immunohistochemistry staining.ResultsHucMSC-derived exosomes can promote osteogenic differentiation of mOPCs and promote the proliferation and migration of HUVECs. The CHA/SF/GCS/DF-PEG hydrogel has a high self-healing capacity, perfect surface morphology and the precipitated CHA crystals have a small size and low crystallinity similar to natural bone minerals. The MTT results showed that the hydrogel was non-toxic and have a good biocompatibility. The in vivo studies have shown that the hydrogel containing exosomes could effectively promote healing of rat bone defect. The histological analysis revealed more new bone tissue and morphogenetic protein 2 (BMP-2) in the hydrogel-exosome group. In addition, the hydrogel-exosome group had the highest microvessel density.ConclusionA self-healing CHA/SF/GCS/DF-PEG hydrogel was successfully prepared. The hydrogel has excellent comprehensive properties and is expected to become a new type of bone graft material. This hydrogel has the effect of promoting bone repair, which is more significant after the addition of hucMSC-derived exosomes.

Evidence for contamination as the origin for bacteria found in human placenta rather than a microbiota.

Until recently the in utero environment of pregnant women was considered sterile. Recent high-sensitivity molecular techniques and high-throughput sequencing lead to some evidence for a low-biomass microbiome associated with the healthy placenta. Other studies failed to reveal evidence for a consistent presence of bacteria using either culture or molecular based techniques. Comparing conflicting “placental microbiome” studies is complicated by the use of varied and inconsistent protocols. Given this situation, we undertook an evaluation of the in utero environment sterility using several controlled methods, in the same study, to evaluate the presence or absence of bacteria and to explain contradictions present in the literature. Healthy pregnant women (n = 38) were recruited in three maternity wards. Placenta were collected after cesarean section with or without Alexis® and vaginal delivery births. For this study we sampled fetal membranes, umbilical cord and chorionic villi. Bacterial presence was analyzed using bacterial culture and qPCR on 34 fetal membranes, umbilical cord and chorionic villi samples. Shotgun metagenomics was performed on seven chorionic villi samples. We showed that the isolation of meaningful quantities of viable bacteria or bacterial DNA was possible only outside the placenta (fetal membranes and umbilical cords) highlighting the importance of sampling methods in studying the in utero environment. Bacterial communities described by metagenomics analysis were similar in chorionic villi samples and in negative controls and were dependent on the database chosen for the analysis. We conclude that the placenta does not harbor a specific, consistent and functional microbiota.

Maternal obesity alters C19MC microRNAs expression profile in fetal umbilical cord blood

BackgroundTo determine if overweight/obese pregnant women have altered microRNA expression patterns in fetal umbilical cord blood that may affect the development of offspring.MethodsUmbilical cord blood samples were obtained from the fetuses of 34 overweight/obese and 32 normal-weight women after delivery. Next generation sequencing (NGS) analyzed their miRNA expression patterns. miRanda and TargetScan databases were used to predict the miRNAs’ target genes followed by analyses of Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to perform function grouping and pathway analyses. qRT-PCR verified the identity of differentially expressed miRNAs that were revealed in the NGS results.ResultsThere was a positive correlation between newborn body weight and pregestational BMI of pregnant individuals (r = 0.48, P < 0.001). One hundred and eight miRNAs were differentially expressed between the normal and overweight/obese groups, which target genes were enriched in the metabolic pathway. Five C19MC miRNAs (miR-516a-5p, miR-516b-5p, miR-520a-3p, miR-1323, miR-523-5p) were upregulated in the overweight/obese group. Target enrichment analysis suggests their involvement in post-embryonic development, lipid and glucose homeostasis, T cell differentiation and nervous system development.ConclusionsC19MC miRNA expression upregulation in the fetal circulation during the gestation of overweight/obese pregnant women may contribute to altered multisystem metabolic pathway development in their offspring.

Maternal arterial blood gas values during delivery: Effect of mode of delivery, maternal characteristics, obstetric interventions and correlation to fetal umbilical cord blood

Obstetricians routinely use biochemical parameters from non-pregnant women to assess the condition of the laboring mother. However, it is well known that pregnancy leads to significant physiological changes in most organ systems. The aim of this study was to determine normal values for maternal arterial blood gases during vaginal deliveries as compared with control values from planned cesarean sections. We also wanted to elucidate the effect of various maternal characteristics, mode of delivery and obstetric interventions on blood gas values. We carried out a randomly selected, prospective-observational cohort study of 250 women undergoing vaginal delivery and 58 women undergoing planned cesarean section at the Department of Obstetrics and Gynecology, Skåne University Hospital, Malmö, Sweden. We found significant differences for gestational age, parity, umbilical venous blood pH, pCO2 and lactate values between the two study groups (P<.005). Significantly lower pH, pCO2 , pO2 and sO2 were found in mothers delivering vaginally. Higher base deficit, hemoglobin, bilirubin, potassium, glucose and lactate were found in vaginal deliveries than in planned cesarean sections (P<.02). Maternal body mass index (BMI), smoking and hypertension were not significantly correlated to acid base parameters in women with vaginal deliveries. On the other hand, multiple regression showed significant associations for the use of epidural anesthesia on maternal pH (P<.05) and pO2 (P<.01); and synthetic oxytocin on pCO2 (P=.08), glucose (P<.00) and lactate (P<.02) levels in maternal arterial blood. Maternal arterial pH, pCO2 and lactate values correlated significantly to values in venous umbilical cord blood (P<.000). Maternal arterial blood gas parameters varied significantly according to mode of delivery, the use of epidural anesthesia and synthetic oxytocin.

Integration of Placental Transfer in a Fetal-Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus.

Background and ObjectiveAlthough acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal–maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus.MethodsAn acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi®]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations.ResultsTested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N-acetyl-p-benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L.ConclusionThe median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00861-7) contains supplementary material, which is available to authorized users.

Bioinformatics enrichment analysis of genes and pathways related to maternal type 1 diabetes associated with adverse fetal outcomes

Maternal type 1 diabetes mellitus (T1DM) may affect fetal development by altering the gene expression profile of the umbilical cord. The present study aimed to explore the T1DM-induced gene expression changes in the fetal umbilical cord. The raw gene expression profiles (ID: GSE51546) of umbilical cord tissue obtained from six normal mothers (non-diabetic) and six type 1 diabetic mothers were used to identify the differentially expressed genes. Genes that correspond to official gene symbols were selected for protein-protein interaction (PPI) and sub-network construction (combined score > 0.4). Functional annotation for Gene Ontology (GO) and pathway enrichment analysis were performed for genes involved in networking. A total of 110 differentially expressed genes were identified of which 38 were up-regulated while 72 were down-regulated. Only 37 genes were identified to significantly interact with each other. Hub genes including HSPA4, KCTD6, UBE2G1, FBXL19, and EHMT1 were up-regulated while KBTBD7, TRIM32, and NUP were down-regulated. T1DM had a major effect on the expression of genes involved in cellular death and differentiation, cell signaling and communication, protein modification and regulation of GTPase activity. Total 27 pathways were enriched and genes related to Wnt signaling, VEGF signaling, inflammation mediated by chemokine and cytokine signaling pathways, FGF signaling pathways and GnRH receptor pathways were found significantly affected by T1DM. Our results suggest that the T1DM environment seems to alter umbilical cord gene expression involved in the regulation of pathophysiology of the diabetic mother which in turn may lead to long-term consequences in various tissues in infants. This study provides insight into the molecular mechanism underlying the adverse pregnancy outcomes of maternal T1DM.

Analysis of rare thalassemia caused by HS-40 regulatory site deletion

ABSTRACT Objectives: To investigate the effect of HS-40 regulatory site deletion on α-globin gene expression and its clinical significance. Methods: Venous blood samples of subjects were analyzed using a hematology analyzer and high- performance liquid chromatography; fetal cord blood was analyzed by a capillary electrophoresis analyzer. Gap-polymerase chain reaction (PCR), reverse dot blot (RDB), and multiple-link-dependent probe amplification (MLPA) were used for genotyping of thalassemia. Results: The proband was POLR3 K, HS-40 heterozygous deletion; the proband’s wife was –SEA/αα; the fetus was POLR3 K, HS-40 heterozygous deletion combined with –SEA deletion; all of them had microcytic hypochromic anemia. Fetal umbilical cord blood electrophoresis revealed a suspected Hb Bart’s band to be 88.4%, and the fetus was, thus, diagnosed as Hb Bart’s fetus. The red blood cell parameters of the sporadic case showed that he had microcytic hypochromic anemia. Hemoglobin (Hb) electrophoresis analysis showed Hb H to be 5.3%, leading to a diagnosis of Hb H disease. Gap-PCR and RDB identified the genotype to be –α3.7/αα, βA/βA. MLPA detected heterozygous deletion or –α3.7 deletion on one allele and deletion of the HS-40 regulatory site on the other allele. Conclusion: The deletion of HS-40 regulatory site reduced expression of α-globin. HS-40 heterozygous deletion manifested as mild anemia, which was of microcytic hypochromic type. When compounded with –α3.7/αα, it manifested as Hb H disease; and when compounded with –SEA/αɑ, it manifested as Hb Bart’s fetus.

Comparative assessment of fetal blood flow and cardiac system status of pregnant women with mitral valve pathology

Annotation. The aim of this work is to analyze the course of pregnancy in women with mitral pathology, the task is to identify preclinical criteria for worsening cardiovascular pathology that can lead to the development of complications of pregnancy and functioning of the fetal CVS, to evaluate the effectiveness of preventive measures. The article presents the analysis of changes in ultrasound characteristics of fetoplacental blood flow in women with mitral valve prolapse and mitral valve insufficiency, as well as cardiovascular status in these women. Statistical processing was performed by calculating Student coefficients (+) using the Microsoft Excel PC program. Doppler examination of fetal umbilical cord blood flow during pregnancy was studied. The correlation between the level of maternal blood flow compensation and pathological changes in the fetoplacental complex was established. As a result of our work, the prevalence of the disease was estimated. As of 2018, it was found that of the total number of extragenital pathology in 1676 pregnant women with CVSD; respectively for 2017 — 1699, for 2016 — 1925, 2015 — 1857 in the region. Of these, 331 (2018), 313 (2017), 326 (2016), 306 (2015) had mitral valve defects, including prolapse. A retrospective assessment of pregnancy and childbirth indicates the possibility of complications of pregnancy and childbirth. In the group of patients with mitral valve prolapse and mitral valve insufficiency, compared to the control group, they did not show significant changes in the dynamics of the Doppler metrics of cardiovascular pathology, which indicates the compensation of the cardiovascular system against the background of changes in the valve. At the same time, the tendency to decrease of CF in women with mitral valve prolapse and insufficiency of the mitral valve against the background of increasing pregnancy is revealed, indicates a violation of CVD adaptation to changes inherent in pregnancy, which provoke hemic and hemodynamic changes in the body, which will cause pregnancy and fetal status. FPC status in women with mitral valve prolapse and mitral valve insufficiency worsens in the third trimester of pregnancy, especially indicators such as the ratio of systolic volume ratio (SVR) to diastolic volume ratio (DVR) and IR. The administration of 40 mg of ƅ-blockers for a 2-week period improved the FPC, was safe and effective.

The development of preeclampsia in oocyte donation pregnancies is related to the number of fetal-maternal HLA class II mismatches

In oocyte donation (OD) pregnancy, a fetus can be completely allogeneic to the recipient. Consequently, the maternal immune system has to cope with greater immunogenetic dissimilarity compared to naturally conceived pregnancy. Previously, we showed an association between successful OD pregnancy and lower immunogenetic dissimilarity, reflected by the number of fetal-maternal Human Leukocyte Antigen (HLA) mismatches, than expected by chance. In this study we aimed to determine whether the development of preeclampsia in OD pregnancies is related to the number of fetal-maternal HLA mismatches.A retrospective, nested case-control study was performed within a cohort of 76 singleton OD pregnancies. Maternal and fetal umbilical cord blood was typed for HLA-A, -B, -C, -DR and -DQ, and the number of fetal-maternal HLA mismatches was calculated. In addition, the incidence of child-specific HLA antibodies was determined.13 pregnancies were complicated by preeclampsia. To demonstrate an influence of HLA mismatches on the development of preeclampsia, a univariate logistic regression analysis was performed adjusted for maternal age and socio-economic status. A significant association between the number of fetal-maternal HLA class II mismatches and the development of preeclampsia was observed (OR = 3.8, 95 % CI: 1.6–9.0; p = 0.003). This association was not linked to the development of HLA class II antibodies.According to our findings, an increased number of HLA class II mismatches is a risk factor for the development of preeclampsia in OD pregnancies. The effect of HLA class II mismatches might be explained by the induction of a cellular rather than a humoral immune response.