Fetoplacental Unit Research Articles

Fetal Maturation and Intrauterine Survival in Asian American Women by Ethnicity.

Although there are multiple ethnic subgroups of the Asian race, this population is usually treated as homogenous in public health research and practice. There is a dearth of information on fetal maturation and perinatal outcomes among Asian American women compared with their non-Hispanic (NH) White counterparts. This study aimed to determine whether fetal maturation, as captured by gestational age periods, influences the risk of stillbirth in Asian American fetuses, in general, as well as within different ethnic subgroups: Asian Indian, Korean, Chinese, Vietnamese, Japanese, and Filipino, using NH Whites as referent. We included singleton births within 37 to 44 gestational weeks occurring in Asian American and NH White mothers from 2014 to 2017. Adjusted logistic regression models were used to quantify the association between mother's race/ethnicity and risk of stillbirth by gestational age phenotypes: early-term, full-term, late-term, and postterm. Compared with NH Whites, Asian Americans had 35% (adjusted odds ratio 0.65, 95% confidence interval 0.53-0.76) and 28% (adjusted odds ratio 0.72, 95% confidence interval 0.59-0.85) lower risk of early-term and full-term stillbirths, respectively. Our study suggests the existence of differential maturation of the fetoplacental unit as explanation for the decline in intrauterine survival advantage with advancing gestational age among Asian American subgroups.

Roles of natural resistance-associated macrophage protein-1 in modulating bacterial distribution and immune responses during Salmonella enterica serovar Typhimurium infection in murine pregnancy.

Salmonella enterica serovar Typhimurium (S.Tm) infection in Nramp1+/+ mice during pregnancy can lead to profound bacterial growth in the feto-placental unit and adverse pregnancy outcomes, including fetal loss, maternal illness and death. The kinetics and mechanisms by which S.Tm gains entry within individual feto-placental unit, and disseminates through tissues leading to placental resorption and fetal demise remain unclear. Mice were systemically infected with S.Tm. Bacterial burden within spleen and individual placentas, and placental/fetal resorptions were quantified. Flow cytometric analysis of immune cell types in the spleen and individual placentas was performed. Cytokine expression in maternal serum was determined through cytometric bead array. Systemic infection with S.Tm resulted in preferential bacterial proliferation in placentas compared to the spleen in Nramp1+/+ mice.At 24 h post-infection, the mean infection rate of individual placentas per mouse was ∼50%, increasing to >75% by 72 h post-infection, suggesting that initial infection in few sites progresses to rapid spread of infection through the uterine milieu. This correlated with a steady increase in placental/fetal resorption rates.Placental infection was associated with local increased neutrophil percentages, whereas numbers and percentages in the spleen remained unchanged, suggesting dichotomous modulation of inflammation between the systemic compartment and the feto-maternal interface. Reduced survival rates of pregnant mice during infection correlated with decreased serum IFN-γ but increased IL-10 levels relative to non-pregnant controls. Pregnancy compromises host resistance conferred by Nramp1 against S.Tm through compartment-specific regulation of maternal and placental cellular responses, and modulation of systemic cytokine expression.

Placental protein 13 dilation of pregnant rat uterine vein is endothelium dependent and involves nitric oxide/calcium activated potassium channels signals

IntroductionAccumulating evidence demonstrates the importance of the galectin protein Placental Protein 13 (PP13) in predicting Preeclampsia (PE), a gestational disorder that has no cure and is associated with a compromised uterine vascular adaptation to pregnancy. Uterine vasculature undergoes significant remodeling (growth in length and in circumference) during normal pregnancy to accommodate the increased blood volume to the feto-placental unit. The aim of this study was to demonstrate the role of PP13 on the uterine veins (UVs). MethodsPP13 was tested on UVs isolated from rat by using a pressurized myograph. The PP13 investigation was carried out in the presence of: a) nitric oxide synthases inhibitors (l-NAME + L-NNA, 2 x 10−4 M); b) small conductance Ca2+-activated K+ channels (SKca) inhibitor (Apamin, 10−7 M); c) intermediate conductance Ca2+-activated K+ channels (IKca) inhibitor (TRAM-34, 10−5 M); d) big conductance Ca2+-activated K+ channels (BKca) inhibitor (Paxilline, 10−5 M) and in the absence of endothelium. ResultsOur results showed that in late pregnancy, PP13 induced a significant dilation of UVs that is endothelium dependent. Further, PP13-dilation is mediated by the SKca – NO – BKca pathway.Discussion: For the first time, this study provides evidence that in pregnancy, the UVs are dilated by PP13 and suggests SKCa as a potential target for treatments aimed at restoring pregnancy complication associated with deficiency in uterine adaptation.

UMBILICAL COILING INDEX AND ITS RELATIONSHIP WITH PERINATAL OUTCOMES

Aim: To evaluate any adverse perinatal outcomes associated with abnormal coiling of umbilical cord. Introduction:The primary objective of antenatal and intrapartum fetal surveillance both in early and late pregnancy is to prevent fetal death. One of the most important parts of the fetoplacental unit is the umbilical cord. It is now being studied in predicting the perinatal outcome. Materials and methods: This prospective study was conducted in Obstetrics and gynaecology department of a tertiary care hospital in Smt. Kashibai navale medical college and general hospital Narhe, Pune.Three hundred and fifty (350) umbilical cords of babies delivered either by vaginally or by lower segment caesarian section were examined. The umbilical coiling index was calculated by dividing the total number of coils by the length of the cord in cms. Subjects with umbilical coiling index below 10th percentile, between 10th and 90th percentile and above 90th percentile were defined as hypocoiled, normocoiled and hypercoiled respectively. It was then correlated with the following pregnancy outcomes: mode of delivery, preterm delivery, birth weight, meconium staining, Apgar score at 1 and 5 minutes, and neonatal intensive care unit (NICU) admissions. Hypocoiled cords were those having umbilical cord coiling index (UCI) less than 10th percentile and hypercoiled cords were those having UCI >90th percentile Statistical analysis was done . The results were statistically analysed by chi-square test. The p value ≤ 0.05 was considered statistically significant for all the analyses. Result: The mean UCI was 0.61 ± 0.16. The hypocoiled umbilical cords (UCI < 10th percentile) were significantly associated with low birth weight, meconium staining, low Apgar score at 1 minute, and increased NICU admissions with a p-value < 0.05. Conclusion:Abnormall UCI(hypocoiling) are significantly associated with adverse perinatal outcome.

Endocrine Autoimmunity in Pregnancy.

Human gestation leads to a number of physiological alterations which peak at the development of placentta known for, among many other functions, being a transient but highly potent endocrine organ. Hormonal activity of placenta is marked by its ability to continuously produce and secrete high levels of progesterone. Progesterone guards the well-being of the fetoplacental unit throughout the gestation and one of the proposed mechanisms of this principle involves the development of local and systemic immune tolerance mainly due to impediment of CD4+ lymphocyte activation. However, though these alterations are present and well-established, autoimmunity is not entirely rare and a wide spectrum of diseases can continue, or develop de novo, throughout the gestation or even after the delivery. Up-to-date data supports the existence of a relationship between the clinical course of chosen autoimmune diseases and levels of circulating sex steroids.The most common autoimmune endocrinopathies in pregnant women are Hashimoto’s disease, Graves’ disease, and, more rarely, primary adrenal insufficiency in the form of Addison’s disease. Gestation can influence the clinical course of these endocrinopathies in patients who were diagnosed before conception. Multiple particles, like TSH-receptor stimulating antibodies, thyroid hormones, glucocorticoids, and anti-thyroid medications, can cross the placental barrier and evoke biological action in fetal tissues. Thyroid pathology in the form of postpartum thyroiditis is particularly prevalent in patients with positive anti-thyroperoxidase and anti-thyroglobulin antibodies. Certain populations are more at risk of developing numerous gestational complications and require regular follow-up. In our paper, we would like to address physiological, physiopathological, and clinical aspects of endocrine autoimmunity throughout human gestation, as well as special circumstances to consider in pregnant women.

Impact of Metformin Treatment on Human Placental Energy Production and Oxidative Stress.

Metformin is increasingly prescribed in pregnancy, with beneficial maternal effects. However, it is not known how metformin-treatment impacts metabolism and energy production in the developing feto-placental unit. We assessed the human placental response to metformin using both in vivo and in vitro treated samples. trophoblasts were derived from placentas collected from non-laboured Caesarean deliveries at term, then treated in vitro with metformin (0.01 mM, 0.1 mM or vehicle). Metformin-concentrations were measured using liquid-chromatography mass-spectrometry. Oxygen consumption in cultured-trophoblasts was measured using a Seahorse-XF Mito Stress Test. Markers of oxidative-stress were assayed using qRT-PCR. Metformin-transporter mRNA and protein-levels were determined by quantitative RT-PCR and Western-blotting respectively. Metformin concentrations were also measured in sample trios (maternal plasma/fetal plasma/placental tissue) from pregnancies exposed to metformin on clinical-grounds. Maternal and fetal metformin concentrations in vivo were highly correlated over a range of concentrations (R2 = 0.76, p < 0.001; average fetal:maternal ratio 1.5; range 0.8–2.1). Basal respiration in trophoblasts was reduced by metformin treatment (0.01 mM metformin; p < 0.05, 0.1 mM metformin; p < 0.001). Mitochondrial-dependent ATP production and proton leak were reduced after treatment with metformin (p < 0.001). Oxidative stress markers were significantly reduced in primary-trophoblast-cultures following treatment with metformin. There is a close linear relationship between placental, fetal, and maternal metformin concentrations. Primary-trophoblast cultures exposed to clinically-relevant metformin concentrations have reduced mitochondrial-respiration, mitochondrial-dependent ATP-production, and reduced markers of oxidative-stress. Given the crucial role of placental energy-production in supporting fetal growth and well-being during pregnancy, the implications of these findings are concerning for intrauterine fetal growth and longer-term metabolic programming in metformin-exposed pregnancies.

Fetoplacental Unit Ultrasonography and Immunoreactive Steroid Concentrations in Jennies Experiencing Late-Term Pregnancy Loss

This study aimed to compare ultrasonographic features and steroid concentrations of jennies undergoing late-term pregnancy loss (n = 5) with gestationally age-matched health controls (n = 5). Transrectal ultrasonography of the combined thickness of uterus and placenta (CTUP) and fetal eyeball diameter was carried out at 15-day-intervals. Fetal heartbeat, aortic, and thorax diameters were determined by transabdominal ultrasonography at 30-day-intervals. Blood samples were collected simultaneous with each transrectal ultrasonography to determine progestogen and estradiol concentrations. Data were assessed for normality with Shapiro-Wilks. Data were log-transformed and analyzed with a mix model. Non-normally distributed data were analyzed with Kruskal-Wallis. Post-hoc analyzes were performed with Sidák's or Dunn's tests based on distribution. Gestational length between groups was compared with a t-test. Statistical significance was set at P < .05. The gestational length was shorter in jennies experiencing pregnancy loss (345 ± 32.3 vs. 365.4 ± 10.4 d P = .0009). Increasing gestational age (P < .0001) and pregnancy loss group (P = .004) had greater CTUP measurements with an interaction between them (P = .01). Fetal eyeball diameter increased with gestational age (P < .0001) but did not vary with group (P = .26), and there was no interaction between gestational age and group (P = .71). Fetal aortic and thorax diameters increased with gestational age (P < .0001), but an interaction between gestational age and group was only present with thorax diameter (P = .01). No effect of group was found for aortic (P = .78) or thorax (P = .86) diameters. Group (P = .06) and gestational age (P = .07) tended to be associated with an increased fetal heartbeat, but there was no interaction between them (P = .98). There was no effect of gestational age (P = .31), group (P = .19), or interaction between them for progestogens concentrations (P = .21). Estradiol concentration was not affected by gestational age (P = .76) or group (P = .51). In conclusion, late-term pregnancy loss was associated with increased CTUP measurements in donkeys.

Syncytin-1 nonfusogenic activities modulate inflammation and contribute to preeclampsia pathogenesis.

Maternal cellular and humoral immune responses to the allogeneic fetoplacental unit are a normal part of pregnancy adaptation. Overactive or dysregulated immune responses that often manifest as inflammation are considered a key element for the development of preeclampsia. Infiltration and activation of macrophages, nature killer cells, and T lymphocytes are frequently observed in the decidua and placenta associated with preeclampsia. In addition to local inflammation, systemic inflammatory changes including increased levels of TNF-α and interleukins (ILs) are detected in the maternal circulation. Syncytin-1 is an endogenous retroviral envelope protein that mediates the fusion of trophoblasts to form syncytiotrophoblasts, a cellular component carrying out most of placental barrier, exchange, and endocrine functions. In addition to these well-defined fusogenic functions that are known for their close association with preeclampsia, multiple studies indicated that syncytin-1 possesses nonfusogenic activities such as those for cell cycle and apoptosis regulation. Moreover, syncytin-1 expressed by trophoblasts and various types of immune cells may participate in regulation of inflammation in preeclamptic placenta and decidua. This review concentrates on the triangular relationship among inflammation, syncytin-1 nonfusogenic functions, and preeclampsia pathogenesis. Data regarding the reciprocal modulations of inflammation and poor vascularization/hypoxia are summarized. The impacts of syncytin-A (the mouse counterpart of human syncytin-1) gene knockout on placental vascularization and their implications for preeclampsia are discussed. Syncytin-1 expression in immune cells and its significance for inflammation are analyzed in the context of preeclampsia development. Finally, the involvements of syncytin-1 nonfusogenic activities in neuroinflammation and multiple sclerosis are compared to findings from preeclampsia.

Fetal Zone Steroids Show Discrete Effects on Hyperoxia-Induced Attenuation of Migration in Cultured Oligodendrocyte Progenitor Cells.

Cerebral oxygenation disturbances contribute to the pathogenesis of brain lesions in preterm infants with white matter damage. These children are at risk of developing long-term neurodevelopmental disabilities. Preterm birth is associated with sudden hormonal changes along with an untimely increase in oxygen tissue tension. There is a persistent high postnatal production of fetal zone steroids (FZS), which serve in the fetoplacental unit as precursors for placental estrogen synthesis during pregnancy. The role of FZS in events associated with oxygenation differences and their impact on the developing white matter is not well understood. Therefore, we investigated the effect of hyperoxia (80% O2) and subsequent administration of FZS on the protein composition and migration capabilities of immature oligodendrocytes using the OLN93 (rat-derived OPC) cell line as an experimental model. We tested the effect of the FZS, dehydroepiandrosterone (DHEA), 16α-OH-DHEA, and adiol (5-androstene-3β, 17β-diol). After 24-hour exposure to hyperoxia, we monitored the changes in the proteome profile following treatment and observed significant alterations in pathways regulating cytoskeletal remodelling, cell migration, and cell survival. Additionally, hyperoxia leads to impaired migration of the OLN93 cells in culture. Administration of the FZS showed positive effects on the migration process under normoxic conditions in general. However, under hyperoxic conditions, the trend was less prominent. The observed effects could be related to changes in levels of cofilin/LIMK pathway-associated proteins. Adiol had a negative effect when administered together with estradiol, and the proteomic data reveal the activation of ephrin receptor signalling that might be responsible for the attenuation of migration. The results suggest that FZS can differentially regulate pathways involved in the migration of OLN93 cells. A deeper insight into the precise role of endogenous FZS would be an essential prerequisite for developing new treatment strategies including supplementation of estradiol and other steroids in preterm infants.

Progesterone prolongs time to delivery and attenuates blood pressure possibly by improving inflammation and endothelial function in response to preeclampsia

Preeclampsia (PE), new onset hypertension during pregnancy, affects 5‐7% of all pregnancies in the U.S. and is associated with reduced fetal weight, increased inflammation, vascular endothelial dysfunction (increased endothelin‐1 (ET‐1) and decreased nitric oxide (NO)) and hypertension. To date the best treatment remains early delivery of the feto‐placental unit. Activated lymphocytes during normal pregnancy (NP) express progesterone receptors, which stimulate a protein called Progesterone Induced Blocking Factor (PIBF) that is reduces during hypertensive pregnancy disorders. Therefore, this study was designed to test the hypothesis that progesterone, in the form of 17‐hydroxyprogesterone caproate (17‐OHPC), reduces inflammation, markers of endothelial dysfunction while reducing blood pressure and prolong time to delivery in PE women. In our ongoing clinical trial, PE participants received 17‐OHPC (250 mg, I.M.) with blood draws before and after injection. Placentas were collected at delivery. PIBF was 18.6 +/‐1.0 pg/mL in NT (n=4), 14.53 +/‐ 1.0 pg/mL in PE (n=10, p&lt;0.05), and 15.78 +/‐0.85 in PE+17‐OHPC (n=6). Placental CD4+ T cells were 6.5+/‐ 2.7 in PE (n=3), 4.6+/‐ 2.0 in PE +17‐OHPC (n=4). Circulating CD4+ T cells were 18.23 +/‐4.8 in PE (n=4), 14.4+/‐1.2 % gate in PE+17‐OHPC (n=5). Placental TH2 cells were 81.7+/‐10.6% gate in PE and 84.7+/‐11.0 in PE+17‐OHPC. Placental and circulating NK cells were 20.84 +/‐ 6.8 % gate, 7.2 +/‐ 2.0 in PE which reduced to 4.7+/‐1.03, 5.3 +/‐ 1.5 % gate in PE+17‐OHPC. Circulating TNF‐alpha was 32.0 +/‐ 3.4 pg/mL in PE (n=8), which decreased to 21.1+/‐5.5 in PE+17OHPC (n=4). Circulating ET‐1 was 2.53+/‐ 0.4 pg/mL in healthy normal pregnant (NP, n=5), 6.7 +/‐ 1.4 in PE (n=18, p&lt;0.05) and 4.9 +/‐ 1.3 in PE+17‐OHPC. Placenta preproendothelin ‐1 (PPET‐1) increased 1.5 fold change in PE (n=4) compared to NP, which was reduced to 0.96 in PE+17‐OHPC (n=4). Importantly, endotheling‐1 measured in HUVECS media treated with PE sera was 68 +/‐ 22 pg/mg of protein in PE which reduced to 57 +/‐19 in PE+17OHPC (n=6). Moreover, circulation nitrate‐nitrite was 50 +/‐ 9 uM in PE and significantly increased to 94 +/‐14 in PE+17‐OHPC. 17‐OHPC prolonged time of delivery beyond 72h on average and average systolic blood pressure was 151 +/‐ 5 mmHg in PE (n=18) and 137+/‐4 in PE+17‐OHPC (n=13). Our results suggest that 17‐OHPC reduced inflammation, markers of endothelial dysfunction, lowered blood pressure and prolonged time do delivery in PE women.

The relationship between pregnancies complicated with fetal growth restriction and umbilical cord blood endocan concentrations

Abstract Objectives The main etiological factor in intrauterine growth restriction (IUGR) is the impairment of the fetoplacental unit. Due to the placental endothelial disintegrity and vascular permeability disruptions, endocan has been an interesting molecule to search for associations with IUGR. The aim of this study was to investigate the umbilical cord blood endocan concentrations in IUGR pregnancies. Methods This cross-sectional case-control study was conducted on 50 IUGR-complicated (patients) and 50 control pregnancies. The demographics and clinical findings were recruited from records. The umbilical cord blood was studied for endocan concentrations. Results The patient group compared to controls had significantly more previous IUGR history, lower maternal weight gain, an earlier gestational week at delivery, and more cesarean sections (p&lt;0.001). The umbilical cord endocan concentrations were significantly higher in patients than in controls (p&lt;0.001). Oligohydramnios (n=38) was significantly higher in the patients and had a significant relationship with high endocan concentrations (p&lt;0.001). Moderate and mild positive correlations were found among endocan concentration and biparietal diameter/head circumference and femur length values, respectively, while a moderate negative correlation was observed in abdominal circumference values (p&lt;0.001). Conclusions A significant increase in the umbilical cord blood endocan concentrations was found in IUGR pregnancies.

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit.

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.

Maternal Fatty Acid Metabolism in Pregnancy and Its Consequences in the Feto-Placental Development.

During pregnancy, maternal plasma fatty acids are critically required for cell growth and development, cell signaling, and the development of critical structural and functional aspects of the feto-placental unit. In addition, the fatty acids modulate the early stages of placental development by regulating angiogenesis in the first-trimester human placenta. Preferential transport of maternal plasma long-chain polyunsaturated fatty acids during the third trimester is critical for optimal fetal brain development. Maternal status such as obesity, diabetes, and dietary intakes may affect the functional changes in lipid metabolic processes in maternal-fetal lipid transport and metabolism. Fatty acids traverse the placental membranes via several plasma membrane fatty acid transport/binding proteins (FAT, FATP, p-FABPpm, and FFARs) and cytoplasmic fatty acid-binding proteins (FABPs). This review discusses the maternal metabolism of fatty acids and their effects on early placentation, placental fatty acid transport and metabolism, and their roles in feto-placental growth and development. The review also highlights how maternal fat metabolism modulates lipid processing, including transportation, esterification, and oxidation of fatty acids.

Gestational periodontitis impact on the fetus and neonate

Maternal oral pathologies during pregnancy represent a controversial subject. The incidence of periodontal disease is approximatively 40% among pregnant women. Periodontal disease has been associated with several unfortunate outcomes; among them, the most important are cardiovascular disorders, respiratory infections, diabetes and Alzheimer's disease. Regarding mechanisms, bacteria enter the blood stream and cross the placenta or the inflammatory mediators can affect the fetoplacental unit or generate an increased inflammatory response with subsequent consequences on the fetus. The most disputed subjects concerning periodontal disease in pregnancy are related to the effects on the pregnancy outcome and the offspring, respectively the associations between maternal periodontal disease and small for gestational age, preeclampsia, arteriosclerosis, gestational diabetes and perinatal mortality. In order to improve neonatal outcome and ensure maternal oral health, we should assure that the necessary dental treatment is provided during the entire pregnancy, preferably between 14 and 20 gestational weeks. Moreover, women should be encouraged to received dental treatment preconceptionally.

Oral Anaerobic Microflora and Pregnancy Complication

Bacterial vaginosis and periodontal diseases share very similar pathogenesis. Each of these diseases occurs when healthy microbiome changes to predominately anaerobic bacterial flora. Bacterial vaginosis is proven factor for adverse pregnancy outcomes. In recent years it has been hypothesized that infection from distant sites of the fetoplacental unit may also elicit an inflammatory response in utero. Aim: The study is designed to determine whether the presence of specific oral anaerobic bacteria in subgingival sulcus of mother increase the risk of adverse obstetric outcomes. Material and Methods: Case-control study. Control group: 50 patients who gave birth to neonate whit normal birth weight at term. Group cases: I group - 40 pregnant women who were hospitalized with signs of preterm labor. II - 20 pregnant women, who have an ultrasound diagnosis of fetal growth retardation. Sub-gingival microbiological paper-point swab was taken in all patients. Results: The total number of isolated oral anaerobic bacteria was statistically significantly higher in the cases group compared to control group p &lt;0.01. In our study, pregnant women who tested positive for Porphyrmonas gingivalis for 6.65 times were more likely to have preterm labor compare with pregnant women with negative oral swabs (95.0% CI: 1.38-32.11 / p &lt;0.05), and for 2,79 times more likely to have fetus with intrauterine growth restriction (95.0% CI: 1.10-7.91 / p &lt;0.05 Conclusions: The study confirmed the hypothesis of a statistically significant association between oral anaerobic infection and adverse pregnancy outcomes. In the future, more studies are needed to investigate the role of the microbial load, maternal immune response, pathophysiological pathway that leads to negative pregnancy outcome.&#x0D;

Importance of Windows of Exposure to Maternal High-Fat Diet and Feto-Placental Effects: Discrimination Between Pre-conception and Gestational Periods in a Rabbit Model.

Context and Aim: Lipid overnutrition in female rabbits, from prepuberty, leads to impaired metabolism (dyslipidemia and increased adiposity) and follicular atresia, and, when continued during gestation, affects offspring phenotype with intrauterine growth retardation (IUGR) and leads to placental and lipid metabolism abnormalities. Growth retardation is already observed in embryo stage, indicating a possible implication of periconceptional exposure. The objective of this study was to discriminate the effects of preconception and gestational exposures on feto-placental development.Materials and Methods: Rabbit 1-day zygotes were collected from female donors under control (CD) or high-fat-high-cholesterol (HD) diet and surgically transferred to the left and right uterus, respectively, of each H (n = 6) or C (n = 7) synchronized recipients. Close to term, four combinations, CC (n = 10), CH (n = 13), HC (n = 13), and HH (n = 6), of feto-placental units were collected, for biometry analyses. Fatty acid (FA) profiles were determined in placental labyrinth, decidua, fetal plasma, and fetal liver by gas chromatography and explored further by principal component analysis (PCA). Candidate gene expression was also analyzed by RT-qPCR in the placenta and fetal liver. Data were analyzed by Kruskal–Wallis followed by Dunn’s pairwise comparison test. Combinations of different data sets were combined and explored by multifactorial analysis (MFA).Results: Compared to controls, HH fetuses were hypotrophic with reduced placental efficiency and altered organogenesis, CH presented heavier placenta but less efficient, whereas HC presented a normal biometry. However, the MFA resulted in a good separation of the four groups, discriminating the effects of each period of exposure. HD during gestation led to reduced gene expression (nutrient transport and metabolism) and big changes in FA profiles in both tissues with increased membrane linoleic acid, lipid storage, and polyunsaturated-to-saturated FA ratios. Pre-conception exposure had a major effect on fetal biometry and organogenesis in HH, with specific changes in FA profiles (increased MUFAs and decreased LCPUFAs).Conclusion: Embryo origin left traces in end-gestation feto-placental unit; however, maternal diet during gestation played a major role, either negative (HD) or positive (control). Thus, an H embryo developed favorably when transferred to a C recipient (HC) with normal biometry at term, despite disturbed and altered FA profiles.

Comparison of Perinatal and Maternal Outcomes in Borderline Versus Normal Amniotic Fluid Index in a Tertiary Care Center in Odisha: An Observational Prospective Study.

BackgroundAmniotic fluid is a protective fluid in the amniotic sac of a gravid uterus that serves many crucial functions by becoming part of an indicator of a functioning fetoplacental unit during the intrauterine life of a fetus. The most commonly used method for measuring amniotic fluid is the amniotic fluid index (AFI). In this study, we aimed to investigate the perinatal and maternal outcomes in borderline AFI versus normal AFI.MethodologyThis observational prospective study included 200 pregnant women who were admitted to Pradyumna Bal Memorial Hospital, Bhubaneswar from September 2019 to February 2021. Women with singleton pregnancy in their third trimester were enrolled in this study after applying inclusion and exclusion criteria. Of the included women, 100 were cases with borderline AFI, and 100 were control with normal AFI. Fetal and maternal outcomes were compared between the two groups. Data analysis was done using SPSS version 23 (IBM Corp., Armonk, NY, USA).ResultsMaternal outcomes such as preterm delivery, meconium-stained liquor, and lower segment cesarean section in women with borderline AFI were significantly higher (p ≤ 0.001). The borderline AFI group had a higher rate of perinatal complications such as Apgar score of <7 (p = 0.001), respiratory distress syndrome (p = 0.001), neonatal intensive care unit admission (p <0.001), intrauterine growth restriction (p < 0.001), and low birth weight (p < 0.001).ConclusionsThe borderline AFI group was associated with adverse perinatal and maternal outcomes which were significantly higher in this group compared to the control group. Therefore, patients with borderline AFI should be monitored carefully during the antepartum and intrapartum period.

Transcriptomic Drivers of Differentiation, Maturation, and Polyploidy in Human Extravillous Trophoblast.

During pregnancy, conceptus-derived extravillous trophoblast (EVT) invades the endomyometrium, anchors the placenta to the maternal uterus, and remodels the spiral arteries in order to establish maternal blood supply to the fetoplacental unit. Recent reports have described early gestation EVT as polyploid and senescent. Here, we extend these reports by performing comprehensive profiling of both the genomic organization and transcriptome of first trimester and term EVT. We define pathways and gene regulatory networks involved in both initial differentiation and maturation of this important trophoblast lineage at the maternal–fetal interface. Our results suggest that like first trimester EVT, term EVT undergoes senescence and endoreduplication, is primarily tetraploid, and lacks high rates of copy number variations. Additionally, we have highlighted senescence and polyploidy-related genes, pathways, networks, and transcription factors that appeared to be important in normal EVT differentiation and maturation and validated a key role for the unfolded protein response in this context.

Abstract P227: Gq Signaling In The Placental Syncytiotrophoblast Layer During Preeclampsia

Hormones implicated in preeclampsia (PE) such as angiotensin, endothelin, and vasopressin signal via receptors coupled to the Gq cascade, and Regulator of G protein Signaling-2 (RGS2) buffers this signaling. We have published that RGS2 expression is decreased in human PE placenta, and reducing RGS2 in placenta causes development of key features of PE in mice. New in situ hybridization data indicate that in both humans and mice, RGS2 is abundant among many cell types in the placenta, including the syncytiotrophoblast (STB) layer. In addition, RGS2 expression in the human STB layer is reduced during PE. As this layer is strongly implicated in PE, these data lead us to hypothesize a critical Gq-buffering role for RGS2 in STB cells to prevent PE. To explore the effect of excess Gq signaling within the STB layer, we utilized a Cre-Lox approach to cause expression of the Gq-coupled hM3Dq DREADD throughout the fetoplacental unit (dam: hM3Dq+, sire: Actb-Cre+) or only within the STB layer (dam: hM3Dq+, sire: Gcm1-Cre+), and then activated the hM3Dq receptor via clozapine N-oxide (CNO, 0.5 to 2 mg/kg) injection in mid-gestation (GD12.5-14.5) before tissue collection at GD14.5. Gαq activation throughout the fetoplacental unit (Actb-Cre model) severely restricted fetoplacental growth compared to saline-injected controls (n=2 vs 3; placenta: 0.027±0.006 vs 0.115±0.021 g; p&lt;0.05, and fetus: 0.048±0.007 vs 0.268±0.010 g; p&lt;0.05). Similarly, placentas expressing hM3Dq only in STB cells (Gcm1-Cre model) had reduced placental (n=3 0.116±0.022 vs 0.201±0.036 g; p=0.05) and possibly fetal (n=3 0.1112±0.036 vs 0.247±0.028 g; p=0.06) masses after CNO. Vascularization (assessed by CD31 immunostain) was disproportionately reduced in the labyrinth layer of the Actb-Cre model after CNO (n=2 vs 3; 20.189±3.382 vs 35.762±1.976 % area; p&lt;0.05), despite no relative change in layer (ie, decidua/junctional zone/labyrinth) thicknesses. Preliminary results indicate similar findings in the Gcm1-Cre model (n=1 17 vs 25 % area). These data highlight the pathological consequence of excess Gq signaling in the STB layer. Ongoing studies are aimed at characterizing maternal phenotypes in these models and the consequence of STB-specific deletion of RGS2 upon sensitivity to Gq stimulators.

Effect of Selected Antidepressants on Placental Homeostasis of Serotonin: Maternal and Fetal Perspectives.

Depression is a prevalent condition affecting up to 20% of pregnant women. Hence, more than 10% are prescribed antidepressant drugs, mainly serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs). We hypothesize that antidepressants disturb serotonin homeostasis in the fetoplacental unit by inhibiting serotonin transporter (SERT) and organic cation transporter 3 (OCT3) in the maternal- and fetal-facing placental membranes, respectively. Paroxetine, citalopram, fluoxetine, fluvoxamine, sertraline, and venlafaxine were tested in situ (rat term placenta perfusion) and ex vivo (uptake studies in membrane vesicles isolated from healthy human term placenta). All tested antidepressants significantly inhibited SERT- and OCT3-mediated serotonin uptake in a dose-dependent manner. Calculated half-maximal inhibitory concentrations (IC50) were in the range of therapeutic plasma concentrations. Using in vitro and in situ models, we further showed that the placental efflux transporters did not compromise mother-to-fetus transport of antidepressants. Collectively, we suggest that antidepressants have the potential to affect serotonin levels in the placenta or fetus when administered at therapeutic doses. Interestingly, the effect of antidepressants on serotonin homeostasis in rat placenta was sex dependent. As accurate fetal programming requires optimal serotonin levels in the fetoplacental unit throughout gestation, inhibition of SERT-/OCT3-mediated serotonin uptake may help explain the poor outcomes of antidepressant use in pregnancy.