Placental Resistance Research Articles

The trophoblast surface becomes refractory to adhesion by congenitally transmitted Toxoplasma gondii and Listeria monocytogenes during cytotrophoblast to syncytiotrophoblast development.

The placenta is a critical barrier against viral, bacterial, and eukaryotic pathogens. For most teratogenic pathogens, the precise molecular mechanisms of placental resistance are still being unraveled. Given the importance of understanding these mechanisms and challenges in replicating trophoblast-pathogen interactions using in vitro models, we tested an existing stem-cell-derived model of trophoblast development for its relevance to infection with Toxoplasma gondii. We grew human trophoblast stem cells (TSCT) under conditions leading to either syncytiotrophoblast (TSSYN) or cytotrophoblast (TSCYT) and infected them with T. gondii. We evaluated T. gondii proliferation and invasion, cell ultrastructure, as well as for transcriptome changes after infection. TSSYNs cells showed similar ultrastructure compared to primary cells and villous explants when analyzed by transmission electron microscopy and scanning electron microscopy (SEM), a resistance to T. gondii adhesion could be visualized on the SEM level. Furthermore, TSSYNs were highly refractory to parasite adhesion and replication, while TSCYTs were not. RNA-seq data on mock-treated and infected cells identified differences between cell types as well as how they responded to T. gondii infection. We also evaluated if TSSC-derived SYNs and CYTs had distinct resistance profiles to another vertically transmitted facultative intracellular pathogen, Listeria monocytogenes. We demonstrate that TSSYNs are highly resistant to L. monocytogenes, while TSCYTs are not. Like T. gondii, TSSYN resistance to L. monocytogenes was at the level of bacterial adhesion. Altogether, our data indicate that stem-cell-derived trophoblasts recapitulate resistance profiles of primary cells to T. gondii and highlight the critical importance of the placental surface in cell-autonomous resistance to teratogens.IMPORTANCECongenital toxoplasmosis can cause a devastating consequence to the fetus. To reach the fetus's tissues, Toxoplasma gondii must cross the placenta barrier. However, how this parasite crosses the placenta and the precise molecular mechanisms of placental resistance to this parasite are still unknown. In this study, we aimed to characterize a new cellular model of human trophoblast stem cells to determine their resistance, susceptibility, and response to T. gondii. Syncytiotrophoblast derived from trophoblast stem cells recapitulate the resistance profile similarly to placenta cells. We also showed that these cells are highly resistant to Listeria monocytogenes, at the level of bacterial adhesion. Our results suggest that resisting pathogen adhesion/attachment may be a generalized mechanism of syncytiotrophoblast resistance, and trophoblast stem cells represent a promising model to investigate cell-intrinsic mechanisms of resistance to pathogen adhesion and replication.

Exosomes-mediated transmission of standard bovine viral diarrhea strain OregonC24Va in bovine trophoblast cells

Bovine viral diarrhoea virus (BVDV) can infect cows on days 30–110 of gestation and crossing the placental barrier, resulting in persistently infected (PI) and causing significant economic losses to dairy farming. Bovine placental trophoblast cells (BTCs) are the major cells in the early chorionic tissue of the placenta and play important roles in placental resistance to viral transmission. In this study, we have confirmed that BTCs is among a groups of cell types those could be infected by BVDV in vivo, and BVDV infection stimulates the autophagic responses in BTCs and promotes the release of exosomes. Meanwhile, the exosomes derived from BTCs can be used by BVDV to spread between placental trophoblast cells, and this mode of transmission cannot be blocked by antibodies against the BVDV E2 protein, whereas the replication and spread of BVDV in BTCs can be blocked by inhibiting autophagy and exosomogenesis. Our study provides a theoretical and practical basis for scientific prediction and intervention of reproductive disorders caused by BVDV infection in cows of different gestation periods from a novel perspective.

Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation, with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth, but current evidence on dosing, candidacy and outcomes is limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. This single-center, open-label, pilot phase-1 safety and feasibility clinical trial included 25 pregnant individuals with a diagnosis of fetal SVP. Participants self-administered continuous MSO using medical-grade oxygen concentrators for up to 24 h per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation using echocardiography and late-gestation cardiovascular magnetic resonance imaging. Early outcomes were assessed, including perinatal growth and preoperative brain injury, and neurodevelopmental outcomes were assessed at 18 months using the Bayley Scales of Infant and Toddler Development 3rd edition, and compared with those of a contemporary fetal SVP cohort (n = 217) that received the normal standard of care (SOC). Among the 25 participants, the median maternal age at conception was 35 years, and fetal SVP diagnoses included 16 with right ventricle dominant, eight with left ventricle dominant and one with indeterminate ventricular morphology. Participants started the trial at approximately 29 + 2 weeks' gestation and self-administered MSO for a median of 16.1 h per day for 63 days, accumulating a median of 1029 h of oxygen intake from enrolment until delivery. The only treatment-associated adverse events were nasal complications that were resolved typically by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio or head-circumference-to-abdominal-circumference ratio Z-scores over gestation compared with SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over the study period compared with SOC (P = 0.02), this was probably due to initial baseline differences in placental resistance. At late-gestation cardiovascular magnetic resonance imaging, MSO was not associated with an increase in fetal cerebral oxygen delivery. Similarly, no differences were observed in neonatal outcomes, including preoperative brain weight Z-score and brain injury, mortality by 18 months of age and neurodevelopmental outcomes at 18 months of age. This pilot phase-1 clinical trial indicates that low-dose MSO therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with an increase in fetal cerebral oxygen delivery or improvements in early neurological or neurodevelopmental outcomes. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain

Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue exvivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.

Fetal Doppler in monochorionic pregnancies complicated by twin-to-twin transfusion syndrome and selective in utero growth restriction

BackgroundMonochorionic (MC) twin pregnancies may be complicated by placental pathologies that impact fetal cardiac function, such as twin-twin transfusion syndrome (TTTS) and selective intrauterine growth-restriction (sIUGR). In the TTTS, the unbalanced blood flow through placental anastomoses lead a recipient volume overload, hypertension and hypertrophic cardiomyopathy and the donor twin experiences hypovolemia and hypertension due to increased placental resistance and poor renal perfusion. When MC pregnancies were complicated by sIUGR, the increase of placental resistances lead to complex fetal compensatory mechanisms with redistribution of cardiac output to vital organs. Increased placental vascular resistances, hypoxia and hemodynamic compensation mechanisms lead to higher pre and/or afterload for both ventricles, right cardiac failure and eventually left cardiac failure observed just before fetal death. ObjectivesThe purpose of this study was to describe the anomalies of umbilical, ductal and aortic isthmic Doppler as well as left and right myocardial performance index (MPI) across various clinical phenotypes of MC twin pregnancies, uncomplicated or complicated by TTTS or sIUGR, in order to help differentiating these conditions and to improve the understanding of TTTS and sIUGR pathophysiology. Study designAortic isthmic systolic index (ISI), umbilical artery pulsatility index (UAPI), ductus venosus pulsatility index (DVPI), and MPI were studied in uncomplicated MC twins (control group) and cases of sIUGR or TTTS. ResultsThe measurements were obtained in 113 pregnancies (24 uncomplicated, 22 sIUGR, 51 TTTS). In comparison with controls, the sIUGR smaller twin sets had lower ISI and higher UAPI, and the larger twin had higher ISI. The TTTS donor and recipient had lower ISI, higher UAPI and DVPI. Compared to the co-twin, the ISI values were lower in the sIUGR smaller twin and the TTTS donor had lower ISI and MPI. Comparing TTTS and sIUGR, the recipient had higher DVPI and MPI than the sIUGR larger twin. ConclusionsThe Doppler anomalies observed in the smaller twin reflected increased placental blood flow resistance, presumably due to abnormal feto-fetal transfusion in TTTS and to unequal placental sharing in sIUGR. Early hemodynamic changes suggestive of cardiac overload in the recipient twin may help to differentiate TTTS and sIUGR.

Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis.

Multiple parallels exist between placentation and cancer dissemination at molecular, cellular, and anatomical levels, presenting placentation as a unique model to mechanistically understand the onset of cancer metastasis. In humans, interaction of placenta and the endometrium results eventually in deep invasion of placental extravillous trophoblasts (EVTs) into the maternal stroma, a process similar to stromal trespass by disseminating carcinoma cells. In anticipation of implantation, endometrial fibroblasts (ESFs) undergo a process called decidualization during the secretory phase of the menstrual cycle. Decidualization, among other substantial changes associated with ESF differentiation, also involves a component of fibroblast activation, and myofibroblast transformation. Here, using traction force microscopy, we show that increased cellular contractility in decidualized ESFs is reversed after interaction with EVTs. We also report here the large changes in energetic state of ESFs upon decidualization, showing increased oxidative phosphorylation, mitochondrial competency and ATP generation, as well as enhanced aerobic glycolysis, presenting mechanical contractility and energetic state as new functional hallmarks for decidualization. These energetic changes accompanying the marked increase in contractile force generation in decidualization were reduced in the presence of EVTs. We also show that increase in decidual contractility and mechanical resistance to invasion is achieved by SRF-MRTF transcriptional activation, achieved via increased phosphorylation of fibroblast-specific myosin light chain 9 (MYL9). EVT induced paracrine secretion of Heparin Binding Epidermal Growth Factor (HBEGF), a potent MAPK activator, which shifts the balance of SRF association away from MRTF based transcription, reducing decidual ESF contractility and mechanical resistance to placental invasion. Our results identify a new axis of intercellular communication in the placental bed modulating stromal force generation and resistance to invasion with concurrent downregulation of cellular energetics. These findings have important implications for implantation related disorders, as well as stromal control of cancer dissemination.

A Metabolomic Profiling of Intra-Uterine Growth Restriction in Placenta and Cord Blood Points to an Impairment of Lipid and Energetic Metabolism.

(1) Background: Intrauterine growth restriction (IUGR) involves metabolic changes that may be responsible for an increased risk of metabolic and cardiovascular diseases in adulthood. Several metabolomic profiles have been reported in maternal blood and urine, amniotic fluid, cord blood and newborn urine, but the placenta has been poorly studied so far. (2) Methods: To decipher the origin of this metabolic reprogramming, we conducted a targeted metabolomics study replicated in two cohorts of placenta and one cohort of cord blood by measuring 188 metabolites by mass spectrometry. (3) Results: OPLS-DA multivariate analyses enabled clear discriminations between IUGR and controls, with good predictive capabilities and low overfitting in the two placental cohorts and in cord blood. A signature of 25 discriminating metabolites shared by both placental cohorts was identified. This signature points to sharp impairment of lipid and mitochondrial metabolism with an increased reliance on the creatine-phosphocreatine system by IUGR placentas. Increased placental insulin resistance and significant alteration of fatty acids oxidation, together with relatively higher phospholipase activity in IUGR placentas, were also highlighted. (4) Conclusions: Our results show a deep lipid and energetic remodeling in IUGR placentas that may have a lasting effect on the fetal metabolism.

Clinical significance of umbilical artery intermittent vs persistent absent end-diastolic velocity in growth-restricted fetuses

Umbilical artery absent end-diastolic velocity indicates increased placental resistance and is associated with increased risk of perinatal demise and neonatal morbidity in fetal growth restriction. However, the clinical implications of intermittent vs persistent absent end-diastolic velocity are unclear. We compared umbilical artery Doppler velocimetry changes during pregnancy and neonatal outcomes between pregnancies with fetal growth restriction and intermittent absent end-diastolic velocity and those with persistent absent end-diastolic velocity. In this retrospective study of singletons with fetal growth restriction and absent end-diastolic velocity, umbilical artery Doppler abnormalities were classified as follows: intermittent absent end-diastolic velocity (<50% of cardiac cycles with absent end-diastolic velocity) and persistent absent end-diastolic velocity (≥50% of cardiac cycles with absent end-diastolic velocity). The primary outcome was umbilical artery Doppler progression to reversed end-diastolic velocity. Secondary outcomes included sustained umbilical artery Doppler improvement, latency to delivery, gestational age at delivery, neonatal morbidity composite, rates of neonatal intensive care unit admission, and length of neonatal intensive care unit stay. Outcomes were compared between intermittent absent end-diastolic velocity and persistent absent end-diastolic velocity. Multivariate logistic regression was used to adjust for confounders. A receiver operating characteristic curve was generated to assess the sensitivity and specificity of the percentage of waveforms with absent end-diastolic velocity in predicting the neonatal composite. The Youden index was used to calculate the optimal absent end-diastolic velocity percentage cut-point for predicting the neonatal composite. Of the 77 patients included, 38 had intermittent absent end-diastolic velocity and 39 had persistent absent end-diastolic velocity. Maternal characteristics, including age, parity, and preexisting conditions did not differ significantly between the 2 groups. Progression to reversed end-diastolic velocity was less common in intermittent absent end-diastolic velocity than in persistent absent end-diastolic velocity (7.9% vs 25.6%; odds ratio, 0.25; 95% confidence interval, 0.06-0.99). Sustained umbilical artery Doppler improvement was more common in intermittent absent end-diastolic velocity than in persistent absent end-diastolic velocity (50.0% vs 10.3%; odds ratio, 8.75; 95% confidence interval, 2.60-29.5). Pregnancies with intermittent absent end-diastolic velocity had longer latency to delivery than those with persistent absent end-diastolic velocity (11 vs 3 days; P<.01), and later gestational age at delivery (33.9 vs 28.7 weeks; P<.01). Composite neonatal morbidity was less common in the intermittent absent end-diastolic velocity group (55.3% vs 92.3%; P<.01). Neonatal death occurred in 7.9% of intermittent absent end-diastolic velocity cases and 33.3% of persistent absent end-diastolic velocity cases (P<.01). The differences in neonatal outcomes were no longer significant when controlling for gestational age at delivery. The percentage of cardiac cycles with absent end-diastolic velocity was a modest predictor of neonatal morbidity, with an area under the receiver operating characteristic curve of 0.71 (95% confidence interval, 0.58-0.84). The optimal percentage cut-point for fetal cardiac cycles with absent end-diastolic velocity observed at the sentinel ultrasound for predicting neonatal morbidity was calculated to be 47.7%, with a sensitivity of 65% and specificity of 85%. Compared with persistent absent end-diastolic velocity, diagnosis of intermittent absent end-diastolic velocity in the setting of fetal growth restriction is associated with lower rates of progression to reversed end-diastolic velocity, higher likelihood of umbilical artery Doppler improvement, longer latency to delivery, and higher gestational age at delivery, leading to lower rates of neonatal morbidity and death. Our data support using an absent end-diastolic velocity percentage cut-point in 50% of cardiac cycles to differentiate intermittent absent end-diastolic velocity from persistent absent end-diastolic velocity. This differentiation in growth-restricted fetuses with absent end-diastolic velocity may allow further risk stratification.

Using the Isolated Rat Placenta to Assess Fetoplacental Hemodynamics.

Placental health is critical to fetal growth and maternal health during gestation. However, investigating placental flow in an ex-vivo isolated system where inflow is independently controlled has yet to be developed in the rat. Here, we describe a novel technique, isolated perfused placenta technique that allows for analysis of placental pressure outflow pressure, placental flow in rats at gestational day 20. Using this method, we successfully perfused placentas from dams and were able to observe increases in outflow pressure and flow as the inflow pressure to the placenta was increased in a step wise fashion. This method will help to advance the functional analysis of placental flow and therefore placental resistance and efficiency.

Significance of intermittent absent end-diastolic flow in the umbilical artery in predicting neonatal morbidity

Umbilical artery Doppler (UAD) velocimetry is utilized to assess fetal status in fetal growth restriction (FGR). Absent end-diastolic flow (AEDF) is indicative of increased placental resistance and is associated with poor fetal/neonatal outcomes. However, there is a dearth of data regarding the significance of intermittent AEDF (iAEDF) compared to persistent AEDF (pAEDF). This study compared the fetal and neonatal outcomes in FGR with iAEDF and pAEDF.

Near-Term Cerebroplacental Doppler, Heart Morphology, and Neonatal Biometry in Hypoplastic Left Heart Syndrome.

To analyze near-term cerebroplacental Doppler, heart morphology, and neonatal biometry in isolated hypoplastic left heart syndrome (HLHS) relative to healthy controls. This retrospective study included 55 fetuses with HLHS (29 with mitral valve stenosis [MS]/aortic valve atresia [AA], 14 with MS/aortic valve stenosis, and 12 with mitral valve atresia [MA]/[AA]) diagnosed prenatally between 2010 and 2019 at 2 referral centers and 101 healthy controls. Ultrasound assessment included umbilical artery (UA), middle cerebral artery (MCA) pulsatility index (PI), and cerebroplacental ratio (CPR), with neonatal weight, length, head circumference (HC), Apgar score, and UA pH measured at birth. In total, 32.7% of HLHS fetuses had abnormal MCA-PI and UA-PI, and 38.2% had CPRs below the fifth percentile before birth. All tested Doppler parameters differed from those of the healthy controls (P ≤ .01). Birth weight and length were comparable between HLHS and control fetuses, whereas birth HCs were smaller in the HLHS group than in the control group (P=.018). In both groups, increased UA-PI correlated with lower birth weight, but only HLHS fetuses with UA-PI > the 95th percentile had a lower median HC at birth than those with normal UA-PI (P=.045). The median UA-PI percentile was higher in fetuses with MA than in fetuses with MS (P=.015). The ascending aortic diameter correlated with birth weight (P=.036) and birth length (P=.039). Abnormal cerebroplacental hemodynamics are evident in a high percentage of near-term fetuses with HLHS, and increased placental resistance may contribute to birth weight and HC. Moreover, heart morphology may impact placental circulation and neonatal biometry.

Preterm Birth Associates With Increased Placental Expression of MDR Transporters Irrespective of Prepregnancy BMI.

Preterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition; however, few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected proinflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype. To determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and proinflammatory cytokine levels are altered by PTB and maternal BMI. A cross-sectional study was conducted to assess the effect of PTB (with/without chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin (IL)-6 and -8 expression in 60 preterm and 36 term pregnancies. ABCB1 expression was increased in preterm compared to term placentae (P = .04). P-gp (P = .008) and BCRP (P = .01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, P = .007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (P = .0005) and PTC associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes. PTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.

Doppler Ultrasound of the Fetal Descending Aorta: An Objective Tool to Assess Placental Blood Flow Resistance in Pregnancies With Discordant Umbilical Arteries.

To determine the relationship between blood flow in the fetal descending aorta and discordant umbilical arteries (UAs). Pulsed wave Doppler of both UAs and the descending aorta was performed at 4-weekly intervals between 14 and 40 weeks of gestation in 209 pregnant women. In datasets with discordant UAs, a linear mixed effects model was used to determine the categorical relationship between the UA pulsatility index (PI) (high, low and average) and the descending aorta PI. Of the 209 cases, 81 had a discordance of greater than 25% in UA PI during one of their visits. There were no differences in birth outcomes between the groups with concordant and discordant UA PIs. In the cases with discordant UA PIs, the descending aorta PI was most strongly associated with both the average UA PI (P= .008), and with the UA with the lower PI (P= .008). The relationship between blood flow in the descending aorta and UAs is consistent with the law for combining resistances in parallel. Measurements of the descending aorta PI, particularly in a scenario with discordant UAs, may inform the stability of the feto-placental circulation where discordant UA PIs are found.

Mild Fetal Tricuspid Regurgitation in the First Trimester as a Predictor of Perinatal Outcomes.

sBackground and Objectives: This study aimed to investigate whether mild fetal tricuspid regurgitation (TR) at 11+ 0 to 13+ 6 weeks of gestation affects perinatal outcomes. Since fetal right ventricular load is associated with placental resistance, we hypothesized that fetal mild TR would be associated with perinatal outcomes as a consequence of abnormal placentation. Materials and Methods: We retrospectively evaluated 435 women with first-trimester scan data. Blood flow across the tricuspid valve was examined in singleton pregnancies between 11+ 0 and 13+ 6 weeks of gestation. Women were categorized according to the presence or absence of fetal mild TR, and the maternal and pregnancy characteristics and perinatal outcomes were compared. Multiple linear and logistic regression analyses were conducted to identify independent predictors of perinatal outcome. Results: In the group with mild TR, there were more cases of borderline amniotic fluid index, including oligohydramnios (p = 0.031), and gestational age- and sex-specific birth weights were lower (p = 0.012). There were no significant differences in other perinatal outcomes, including preeclampsia, gestational hypertension and small for gestational age. Gestational diabetes (adjusted odds ratio (OR) 0.514, 95% confidence interval (CI) 0.312–0.947) and fetal mild TR (adjusted OR 1.602, 95% CI 1.080–2.384) were identified as factors associated with below borderline amniotic fluid index before birth. The factors that affected gestational age and sex-specific birth weight were also gestational diabetes (adjusted beta coefficient 9.673, p = 0.008) and the presence of fetal mild TR (adjusted beta coefficient −6.593, p = 0.007). Conclusions: Mild fetal TR observed in the first trimester is negatively associated with fetal growth and the amniotic fluid index at term but not with other adverse pregnancy or perinatal outcomes due to abnormal placentation.

Kynurenine Relaxes Arteries of Normotensive Women and Those With Preeclampsia.

[Figure: see text].

Fetal cardiac function at 35-37 weeks' gestation in pregnancies that subsequently develop pre-eclampsia.

To compare fetal cardiac morphology and function between pregnancies that subsequently developed pre-eclampsia (PE) and those that remained normotensive. This was a prospective observational study in 1574 pregnancies at 35-37 weeks' gestation, including 76 that subsequently developed PE. We carried out comprehensive assessment of fetal cardiac morphology and function including novel imaging modalities, such as speckle-tracking echocardiography, and measured uterine artery pulsatility index, mean arterial pressure (MAP), serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and cerebroplacental ratio (CPR). The findings in the group that subsequently developed PE were compared to those in pregnancies that remained normotensive. In fetuses of mothers who subsequently developed PE, compared to those from normotensive pregnancies, there was a more globular right ventricle, as shown by reduced right ventricular sphericity index, reduced right ventricular systolic contractility, as shown by reduced global longitudinal strain, and reduced left ventricular diastolic function, as shown by increased E/A ratio. On multivariable regression analysis, these indices demonstrated an association with PE, independent of maternal characteristics and fetal size. In pregnancies that subsequently developed PE, compared to those that remained normotensive, MAP, sFlt-1 and the incidence of low birth weight were higher, whereas serum PlGF, CPR and the interval between assessment and delivery were lower. These findings demonstrate that, in pregnancies that develop PE, there is evidence of impaired placentation, reflected in low PlGF and reduced birth weight, placental ischemia, evidenced by increased sFlt-1 which becomes apparent in the interval of 2-4 weeks preceding the clinical onset of PE, and consequent fetal hypoxia-induced redistribution in the fetal circulation, reflected in the low CPR. Although the etiology of the observed fetal cardiac changes in pregnancies that subsequently develop PE remains unclear, it is possible that the reduction in right-heart systolic function is the consequence of high afterload due to increased placental resistance, whilst the early left ventricular diastolic changes could be due to fetal hypoxia-induced redistribution in the fetal circulation. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Acardiac twin pregnancies part V: Why does an acardiac twin with renal tissue produce polyhydramnios?

BackgroundAcardiac twinning is a complication of monochorionic twin pregnancies. From literature reports, 30 of 41 relatively large acardiac twins with renal tissue produced polyhydramnios within their amniotic compartment. We aim to investigate the underlying mechanisms that cause excess amniotic fluid using an established model of fetal fluid dynamics.MethodsWe assumed that acardiac onset is before 13 weeks, acardiacs with renal tissue have normal kidney function and produce urine flow from 11 weeks on, and acardiac urine production requires a pressure of half the pump twin's mean arterial pressure. We apply a resistance network with the pump twin's arterio‐venous pressure as source, pump umbilical arteries, placenta, placental arterio‐arterial (AA) anastomoses and acardiac resistances. Acardiac amniotic fluid dynamics excluded acardiac lung fluid secretion, swallowing and the relatively small intramembranous flow.ResultsIn small acardiacs with sufficient urine production, polyhydramnios will occur due to the lack of amniotic fluid resorption. Urine production is dependent upon having sufficient mean arterial pressure, which requires nearly a two‐fold larger resistance within the acardiac as compared to the placental AA resistance. Subphysiologic arterial pressure may result in renal dysgenesis.ConclusionOur findings suggest the potential for prediction of which clinical acardiac cases may or may not develop polyhydramnios based upon noninvasive assessments of renal tissue, blood flow and urine production. This information would be of great value in determining early obstetric interventions as opposed to conservative management. These findings may also contribute to an improved knowledge of the fascinating pathophysiology that surrounds acardiac twinning.

The effect of 75-g oral glucose tolerance test on maternal and foetal Doppler parameters in healthy pregnancies: a cross-sectional observational study

Hyperglycaemia can alter placental resistance to blood flow and hyperglycaemia has adverse perinatal outcomes. Oral glucose tolerance testing (OGTT) increases the maternal plasma glucose levels temporarily and mimics metabolic hyperglycaemia. The blood flow of the uterine artery (UtA), umbilical artery (UA), middle cerebral artery (MCA) were assessed before, 1 and 2 h following the OGTT by using Doppler ultrasonography. Z-score of cerebroplacental ratio (CPR), pulsatility index (PI) for three vessels were evaluated separately. All measurements of the MCA, UA, UtA Doppler parameters were not statistically different for fasting, and 1 and 2 h following the 75 g OGTT in the 53 pregnant women with a singleton gestation in the low-risk group. This study results show that acute hyperglycaemia induced by OGTT has no effect on maternal and foetal Doppler parameters in healthy pregnancies. IMPACT STATEMENT What is already known on this subject? Foetal glucose is affected by maternal blood glucose concentrations and placental blood flow. Acute hyperglycaemia may have an effect on maternal, and foetal Doppler parameters among healthy pregnancies What do the results of this study add? Our findings indicate that blood flow velocity metric measurements in the UA, MCA and UtA were not affected by the OGTT in healthy pregnant women. What are the implications of these findings for clinical practice and/or further research? Acute hyperglycaemia induced by OGTT does not have any effect on fetomaternal circulation, especially foetal brain blood flow. Other foetal vessels including ductus venosus, renal artery, etc. may be affected by maternal blood glucose levels during the OGTT or in diabetic patients. Future prospective studies consisting of diabetic patients are warranted to verify the exact effect of glucose levels on foetal and maternal circulation.

The role of Smad4 in the regulation of insulin resistance, inflammation and cell proliferation in HTR8-Svneo cells.

Gestational diabetes mellitus (GDM) is a metabolic disorder whose major pathophysiological basis is demonstrated as placental insulin resistance (IR), while Smad4 always functions in the signal transduction of transforming growth factor beta (TGF-β) pathway. Our study aims to figure out the role of Smad4 in an insulin resistance (IR) cellular model using placental trophoblast cell line. Importantly, HTR8-Svneo cells, in the status of IR, indicated a significant increase in the expression of Smad4. Subsequently, the HTR8-Svneo cell line with up-regulated or depleted Smad4 was respectively achieved by the effective over-expressed plasmid or siRNA of Smad4. We found out that the deficiency of Smad4 could promote the insulin sensitivity and restrict the inflammatory response in IR group of cells with significant augment in glucose uptake, up-regulation of insulin signalling-related molecules and attenuation in inflammatory biomarker expressions. On the contrary, the over-expression of Smad4 showed a reversal effect on these alterations in IR group of cells. Besides, the positive effect of Smad4 on cell viability was also observed in our study. SIGNIFICANCE OF THE STUDY: Gestational diabetes mellitus (GDM) is a metabolic disorder whose major pathophysiological basis is demonstrated as insulin resistance (IR). Importantly, our findings indicate that the deficiency of Smad4 significantly improves the insulin sensitivity and relieves the inflammation in the cellular model of IR. Besides, the positive effect of Smad4 on cell viability was also observed in our study. Our present findings provide novel insights for the investigation on molecular details about the GDM pathogenesis.

Role of potassium channels in female reproductive system.

Potassium channels are widely expressed in most types of cells in living organisms and regulate the functions of a variety of organs, including kidneys, neurons, cardiovascular organs, and pancreas among others. However, the functional roles of potassium channels in the reproductive system is less understood. This mini-review provides information about the localization and functions of potassium channels in the female reproductive system. Five types of potassium channels, which include inward-rectifying (Kir), voltage-gated (Kv), calcium-activated (KCa), 2-pore domain (K2P), and rapidly-gating sodium-activated (Slo) potassium channels are expressed in the hypothalamus, ovaries, and uterus. Their functions include the regulation of hormone release and feedback by Kir6.1 and Kir6.2, which are expressed in the luteal granulosa cells and gonadotropin-releasing hormone neurons respectively, and regulate the functioning of the hypothalamus–pituitary–ovarian axis and the production of progesterone. Both channels are regulated by subtypes of the sulfonylurea receptor (SUR), Kir6.1/SUR2B and Kir6.2/SUR1. Kv and Slo2.1 affect the transition from uterine quiescence in late pregnancy to the state of strong myometrial contractions in labor. Intermediate- and small-conductance KCa modulate the vasodilatation of the placental chorionic plate resistance arteries via the secretion of nitric oxide and endothelium-derived hyperpolarizing factors. Treatment with specific channel activators and inhibitors provides information relevant for clinical use that could help alter the functions of the female reproductive system.