EFFECTS OF ARYL HYDROCARBON RECEPTOR LIGAND TCDD ON HUMAN TROPHOBLAST CELL DEVELOPMENT.

BACKGROUND: The primary interface between mother and fetus, the placenta, serves two critical functions: extraction of nutrients from the maternal compartment and facilitation of nutrient delivery to the developing fetus. This delivery system also serves as a barrier to environmental exposures. The aryl hydrocarbon receptor (AHR) is an important component of the barrier. AHR signaling is activated by environmental pollutants and toxicants that can potentially affect cellular and molecular processes, including those controlling trophoblast cell development and function. OBJECTIVES: In this study, we investigated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an effective AHR ligand, exposure on human trophoblast cells. METHODS: Human trophoblast stem (TS) cells were used as in vitro model system for investigating the downstream consequences of AHR activation. The actions TCDD were investigated in human TS cells maintained in the stem state or in differentiating TS cells. RESULTS: TCDD exposure stimulated the expression of CYP1A1 and CYP1B1 in human TS cells. TCDD was effective in stimulating CYP1A1 and CYP1B1 expression and altering gene expression profiles in human TS cells maintained in the stem cell state or induced to differentiate into extravillous trophoblast cells (EVT) or syncytiotrophoblast (ST). These actions were dependent upon the presence of AHR. TCDD exposure did not adversely affect maintenance of the TS cell stem state or the ability of TS cells to differentiate into EVT cells or ST. However, TCDD exposure did promote the biosynthesis of 2 methoxy estradiol (2ME), a biologically active catechol estrogen, with the potential to modify the maternal-fetal interface. DISCUSSION: Human trophoblast cell responses to TCDD were dependent upon AHR signaling and possessed the potential to shape development and function of the human placentation site.

Effect of a High Linoleic Acid Diet on Pregnant Women and Their Offspring.

Nutritional intake during pregnancy can affect gestational length, fetal development, and impact postnatal growth and health in offspring. Perturbations in maternal nutrition with either an excess or deficiency in nutrients during pregnancy may have harmful effects on the offspring's development and increase the risk of developing chronic diseases later in life. In pregnancy, nutrients transfer from the mother to the fetus via the placenta. Essential fatty acids, linoleic acid (LA) and alpha linoleic acid (ALA), can only be obtained in the diet. In Western countries, the ratio of LA and ALA in the diet has increased dramatically in recent decades. Some animal and human studies have found a correlation between maternal intake of LA and birth weight; however, the association varies. In contrast, some human studies have demonstrated inconclusive findings regarding the correlation between cord blood levels of LA and birth outcomes. In addition, high dietary LA intake in animal studies in pregnancy increased the production of inflammatory markers such as prostaglandins, leukotrienes, cytokines, and tumour necrosis factor-alpha. This review aims to highlight the effect of high dietary LA intake during pregnancy on birth outcomes, obesity, maternal inflammatory markers, and the transfer of fatty acids across the placenta.

Adverse neurodevelopment in children associated with prenatal exposure to fine particulate matter (PM2.5) - Possible roles of polycyclic aromatic hydrocarbons (PAHs) and mechanisms involved.

Prenatal exposure to ambient fine particles (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse birth outcomes including neurodevelopmental effects with cognitive and/or behavioral implications in early childhood. As a background we first briefly summarize human studies on PM2.5 and PAHs associated with adverse birth outcomes and modified neurodevelopment. Next, we add more specific information from animal studies and in vitro studies and elucidate possible biological mechanisms. More specifically we focus on the potential role of PAHs attached to PM2.5 and explore whether effects of these compounds may arise from disturbance of placental function or more directly by interfering with neurodevelopmental processes in the fetal brain. Possible molecular initiating events (MIEs) include interactions with cellular receptors such as the aryl hydrocarbon receptor (AhR), beta-adrenergic receptors (ßAR) and transient receptor potential (TRP)-channels resulting in altered gene expression. MIE linked to the binding of PAHs to cytochrome P450 (CYP) enzymes and formation of reactive electrophilic metabolites are likely less important. The experimental animal and in vitro studies support the epidemiological findings and suggest steps involved in mechanistic pathways explaining the associations. An overall evaluation of the doses/concentrations used in experimental studies combined with the mechanistic understanding further supports the hypothesis that prenatal PAHs exposure may cause adverse outcomes (AOs) linked to human neurodevelopment. Several MIEs will likely occur simultaneously in various cells/tissues involving several key events (KEs) which relative importance will depend on dose, time, tissue, genetics, other environmental factors, and neurodevelopmental endpoint in study.

Placental Origins of Preeclampsia: Insights from Multi-Omic Studies.

Preeclampsia (PE) is a major cause of maternal and neonatal morbidity and mortality worldwide, with the placenta playing a central role in disease pathophysiology. This review synthesizes recent advancements in understanding the molecular mechanisms underlying PE, focusing on placental genes, proteins, and genetic variants identified through multi-omic approaches. Transcriptomic studies in bulk placental tissue have identified many dysregulated genes in the PE placenta, including the PE signature gene, Fms-like tyrosine kinase 1 (FLT1). Emerging single-cell level transcriptomic data have revealed key cell types and molecular signatures implicated in placental dysfunction and PE. However, the considerable variability among studies underscores the need for standardized methodologies and larger sample sizes to enhance the reproducibility of results. Proteomic profiling of PE placentas has identified numerous PE-associated proteins, offering insights into potential biomarkers and pathways implicated in PE pathogenesis. Despite significant progress, challenges such as inconsistencies in study findings and lack of validation persist. Recent fetal genome-wide association studies have identified multiple genetic loci associated with PE, with ongoing efforts to elucidate their impact on placental gene expression and function. Future directions include the integration of multi-omic data, validation of findings in diverse PE populations and clinical subtypes, and the development of analytical approaches and experimental models to study the complex interplay of placental and maternal factors in PE etiology. These insights hold promise for improving risk prediction, diagnosis, and management of PE, ultimately reducing its burden on maternal and neonatal health.

Integrating Transcriptomics, Proteomics, and Metabolomics to Investigate the Mechanism of Fetal Placental Overgrowth in Somatic Cell Nuclear Transfer Cattle.

A major factor limiting the development of somatic cell nuclear transfer (SCNT) technology is the low success rate of pregnancy, mainly due to placental abnormalities disrupting the maternal-fetal balance during pregnancy. Although there has been some progress in research on the abnormal enlargement of cloned bovine placenta, there are still few reports on the direct regulatory mechanisms of enlarged cloned bovine placenta tissue. In this study, we conducted sequencing and analysis of transcriptomics, proteomics, and metabolomics of placental tissues from SCNT cattle (n = 3) and control (CON) cattle (n = 3). The omics analysis results indicate abnormalities in biological functions such as protein digestion and absorption, glycolysis/gluconeogenesis, the regulation of lipid breakdown, as well as glycerolipid metabolism, and arginine and proline metabolism in the placenta of SCNT cattle. Integrating these analyses highlights critical metabolic pathways affecting SCNT cattle placenta, including choline metabolism and unsaturated fatty acid biosynthesis. These findings suggest that aberrant expressions of genes, proteins, and metabolites in SCNT placentas affect key pathways in protein digestion, growth hormone function, and energy metabolism. Our results suggest that abnormal protein synthesis, growth hormone function, and energy metabolism in SCNT bovine placental tissues contribute to placental hypertrophy. These findings offer valuable insights for further investigation into the mechanisms underlying SCNT bovine placental abnormalities.

Comparison of Molecular Potential for Iron Transfer across the Placenta in Domestic Pigs with Varied Litter Sizes and Wild Boars.

Neonatal iron deficiency anemia is prevalent among domestic pigs but does not occur in the offspring of wild boar. The main causes of this disorder in piglets of modern pig breeds are paucity of hepatic iron stores, high birth weight, and rapid growth. Replenishment of fetal iron stores is a direct result of iron transfer efficiency across the placenta. In this study, we attempted to investigate the molecular potential of iron transfer across the placenta as a possible cause of differences between wild boar and Polish Large White (PLW) offspring. Furthermore, by analyzing placentas from PLW gilts that had litters of different sizes, we aimed to elucidate the impact of the number of fetuses on placental ability to transport iron. Using RNA sequencing, we examined the expression of iron-related genes in the placentas from wild boar and PLW gilts. We did not reveal significant differences in the expression of major iron transporters among all analyzed placentas. However, in wild boar placentas, we found higher expression of copper-dependent ferroxidases such as ceruloplasmin, zyklopen, and hephaestin, which facilitate iron export to the fetal circulation. We also determined a close co-localization of ceruloplasmin and zyklopen with ferroportin, the only iron exporter.

Hydroxychloroquine as an Adjunct Therapy for Diabetes in Pregnancy.

This review discusses the pathophysiology of diabetes in pregnancy in relation to the placental function. We review the potential use of hydroxychloroquine in improving pregnancy outcomes affected by diabetes. The review focuses on the mechanism of action of hydroxychloroquine and its potential effects on diabetes. There are several pathways in which hydroxychloroquine mediates its effects: through the inflammasome complex, inflammatory cytokines, oxidative stress, modulatory effects, and antihyperglycemic effects. As a safe drug to be used in pregnancy, it is worth exploring the possible use hydroxychloroquine as an adjunct treatment to the current therapy of diabetes in pregnancy.

Nutraceuticals in Pregnancy: A Special Focus on Probiotics.

The placenta is crucial to fetal development and performs vital functions such as nutrient exchange, waste removal and hormone regulation. Abnormal placental development can lead to conditions such as fetal growth restriction, pre-eclampsia and stillbirth, affecting both immediate and long-term fetal health. Placental development is a highly complex process involving interactions between maternal and fetal components, imprinted genes, signaling pathways, mitochondria, fetal sexomes and environmental factors such as diet, supplementation and exercise. Probiotics have been shown to make a significant contribution to prenatal health, placental health and fetal development, with associations with reduced risk of preterm birth and pre-eclampsia, as well as improvements in maternal health through effects on gut microbiota, lipid metabolism, vaginal infections, gestational diabetes, allergic diseases and inflammation. This review summarizes key studies on the influence of dietary supplementation on placental development, with a focus on the role of probiotics in prenatal health and fetal development.

The Underlying Molecular Mechanisms of the Placenta Accreta Spectrum: A Narrative Review.

Placenta accreta spectrum (PAS) disorders are characterized by abnormal trophoblastic invasion into the myometrium, leading to significant maternal health risks. PAS includes placenta accreta (invasion < 50% of the myometrium), increta (invasion > 50%), and percreta (invasion through the entire myometrium). The condition is most associated with previous cesarean deliveries and increases in chance with the number of prior cesarians. The increasing global cesarean rates heighten the importance of early PAS diagnosis and management. This review explores genetic expression and key regulatory processes, such as apoptosis, cell proliferation, invasion, and inflammation, focusing on signaling pathways, genetic expression, biomarkers, and non-coding RNAs involved in trophoblastic invasion. It compiles the recent scientific literature (2014-2024) from the Scopus, PubMed, Google Scholar, and Web of Science databases. Identifying new biomarkers like AFP, sFlt-1, ß-hCG, PlGF, and PAPP-A aids in early detection and management. Understanding genetic expression and non-coding RNAs is crucial for unraveling PAS complexities. In addition, aberrant signaling pathways like Notch, PI3K/Akt, STAT3, and TGF-ß offer potential therapeutic targets to modulate trophoblastic invasion. This review underscores the need for interdisciplinary care, early diagnosis, and ongoing research into PAS biomarkers and molecular mechanisms to improve prognosis and quality of life for affected women.

Placental Sonomorphologic Appearance and Fetomaternal Outcome in Fontan Circulation.

Objectives: Pregnancies in women with Fontan circulation are on the rise, and they are known to imply high maternal and fetal complication rates. The altered hemodynamic profile of univentricular circulation affects placental development and function. This study describes placental sonomorphologic appearance and Doppler examinations and correlates these to histopathologic findings and pregnancy outcomes in women with Fontan circulation. Methods: A single-center retrospective analysis of pregnancies in women with Fontan circulation was conducted between 2018 and 2023. Maternal characteristics and obstetric and neonatal outcomes were recorded. Serial ultrasound examinations including placental sonomorphologic appearance and Doppler studies were assessed. Macroscopic and histopathologic findings of the placentas were reviewed. Results: Six live births from six women with Fontan physiology were available for analysis. Prematurity occurred in 83% (5/6 cases) and fetal growth restriction and bleeding events in 66% (4/6 cases) each. All but one placenta showed similar sonomorphologic abnormalities starting during the late second trimester, such as thickened globular shape, inhomogeneous echotexture, and hypoechoic lakes, resulting in a jelly-like appearance. Uteroplacental blood flow indices were within normal range in all women. The corresponding histopathologic findings were non-specific and consisted of intervillous and subchorionic fibrin deposition, villous atrophy, hypoplasia, or fibrosis. Conclusions: Obstetric and perinatal complication rates in pregnancies of women with Fontan circulation are high. Thus, predictors are urgently needed. Our results suggest that serial ultrasound examinations with increased awareness of the placental appearance and its development, linked to the Doppler sonographic results of the uteroplacental and fetomaternal circulation, may be suitable for the early identification of cases prone to complications.

Alteration in folate carrier expression via histone deacetylase inhibition in BeWo human placental choriocarcinoma cells.

Folates are essential nutrients for fetal development during pregnancy. Valproic acid (VPA), an inhibitor of histone deacetylases (HDACs), alters the expression of folate carriers in placental cells; however, the underlying mechanisms remain unclear. Here, we aimed to determine the profiles of folate carriers (folate receptor alpha [FOLR1], solute carrier [SLC]-19A1, and SLC46A1) after inhibition of HDACs, especially class I and IIa HDACs, using different inhibitors and gene knockdown tests. Quantitative polymerase chain reaction revealed that BeWo cells (a trophoblast model) expressed HDACs and folate carriers, similar to human placental villi. FOLR1 expression was upregulated by VPA, apicidin, and trichostatin A, but downregulated by MS-275 after 24 h treatment. VPA and apicidin upregulated the expression of SLC46A1. These inhibitors downregulated SLC19A1 expression. TMP269 (a class IIa inhibitor) did not affect folate carrier levels. HDAC1/2 knockdown upregulated FOLR1 and SLC46A1 levels, whereas HDAC1/3 knockdown downregulated FOLR1 levels. Our findings suggest that the pharmacological inhibition of class I HDACs alters the expression of folate carriers in BeWo cells. By contrast, HDAC inhibitors exert different regulatory effects on folate carriers. Moreover, HDAC1/2 inhibition may be a potential mechanism involved in altering FOLR1 and SLC46A1 levels.

Copaifera spp. oleoresins control Trypanosoma cruzi infection in human trophoblast cells (BeWo) and placental explants.

Congenital Chagas disease (CCD) is a worldwide neglected problem with significant treatment limitations. This study aimed to evaluate the potential of Copaifera spp. oleoresins (ORs) against Trypanosoma cruzi infection in trophoblast cells (BeWo lineage) and human chorionic villous explants (HCVE). The cytotoxicity of ORs was investigated using LDH and MTT assays. T. cruzi (Y strain) proliferation, invasion and reversibility were assessed in OR-treated BeWo cells, and proliferation was evaluated in OR-treated HCVE. The ultrastructure of T. cruzi trypomastigotes and amastigotes treated with ORs were analyzed by scanning and transmission electronic microscopy. ROS production in infected and treated BeWo cells and cytokines in BeWo and HCVE were measured. The ORs irreversibly decreased T. cruzi invasion, proliferation and release in BeWo cells by up to 70 %, 82 % and 80 %, respectively, and reduced parasite load in HCVE by up to 80 %. Significant structural changes in treated parasites were observed. ORs showed antioxidant capacity in BeWo cells, reducing ROS production induced by T. cruzi infection. Also, T. cruzi infection modulated the cytokine profile in both BeWo cells and HCVE; however, treatment with ORs upregulated cytokines decreased by T. cruzi infection in BeWo cells, while downregulated cytokines increased by the T. cruzi infection in HCVE. In conclusion, non-cytotoxic concentrations of Copaifera ORs demonstrated promising potential for controlling T. cruzi infection in models of the human maternal-fetal interface.

Ultrasound based radiomics model for assessment of placental function in pregnancies with preeclampsia.

The goal of our research is to elucidate and better assess placental function in rats with preeclampsia through an innovative application of ultrasound-based radiomics. Using a rat model induced with L-NAME, we carefully investigated placental dysfunction via microstructural analysis and immunoprotein level assessment. Employing the Boruta feature selection method on ultrasound images facilitated the identification of crucial features, consequently enabling the development of a robust model for classifying placental dysfunction. Our study included 12 pregnant rats, and thorough placental evaluations were conducted on 160 fetal rats. Distinct alterations in placental microstructure and angiogenic factor expression were evident in rats with preeclampsia. Leveraging high-throughput mining of quantitative image features, we extracted 558 radiomic features, which were subsequently used to construct an impressive evaluation model with an area under the receiver operating curve (AUC) of 0.95. This model also exhibited a remarkable sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 88.7%, 91.5%, 90.2%, 90.4%, and 90.0%, respectively. Our findings highlight the ability of ultrasound-based radiomics to detect abnormal placental features, demonstrating its potential for evaluating both normative and impaired placental function with high precision and reliability.

Reduced bioenergetics and mitochondrial fragmentation in human primary cytotrophoblasts induced by an EGFR-targeting chemical mixture.

Exposures to complex environmental chemical mixtures during pregnancy reach and target the feto-placental unit. This study investigates the influence of environmental chemical mixtures on placental bioenergetics. Recognizing the essential role of the epidermal growth factor receptor (EGFR) in placental development and its role in stimulating glycolysis and mitochondrial respiration in trophoblast cells, we explored the effects of chemicals known to disrupt EGFR signaling on cellular energy production. Human primary cytotrophoblasts (hCTBs) and a first-trimester extravillous trophoblast cell line (HTR-8/SVneo) were exposed to a mixture of EGFR-interfering chemicals, including atrazine, bisphenol S, niclosamide, PCB-126, PCB-153, and trans-nonachlor. An RNA sequencing approach revealed that the mixture altered the transcriptional signature of genes involved in cellular energetics. Next, the impact of the mixture on cellular bioenergetics was evaluated using a combination of mitochondrial and glycolytic stress tests, ATP production, glucose consumption, lactate synthesis, and super-resolution imaging. The chemical mixture did not alter basal oxygen consumption but diminished the maximum respiratory capacity in a dose-dependent manner, indicating a disruption of mitochondrial function. The respiratory capacity and ATP production were increased by EGF, while the Chem-Mix reduced both EGF- and non-EGF-mediated oxygen consumption rate in hCTBs. A similar pattern was observed in the glycolytic medium acidification, with EGF increasing the acidification, and the Chem-Mix blocking EGF-induced glycolytic acidification. Furthermore, direct stochastic optical reconstruction microscopy (dSTORM) imaging demonstrated that the Chem-Mix led to a reduction of the mitochondrial network architecture, with findings supported by a decrease in the abundance of OPA1, a mitochondrial membrane GTPase involved in mitochondrial fusion. In conclusion, we demonstrated that a mixture of EGFR-disrupting chemicals alters mitochondrial remodeling, resulting in disturbed cellular bioenergetics, reducing the capacity of human cytotrophoblast cells to generate energy. Future studies should investigate the mechanism by which mitochondrial dynamics are disrupted and the pathological significance of these findings.

Long-term culture and passaging of term trophoblast for the investigation of syncytiotrophoblast function.

Recent advances in the use of trophoblast stem cells and organoid models have markedly enhanced our understanding of placental development and function. These models offer significant improvements over previous systems due to their extended viability in culture and capacity to replicate various trophoblast functions, such as extravillous trophoblast invasion, syncytialisation and 3D architecture. Initially, the generation of trophoblast organoids was confined to first trimester placental tissue; however, it was recently reported that term placentae can also serve as a source of trophoblast stem cells. Here, we report that both 2D proliferative cytotrophoblasts and 3D trophoblast organoids can be effectively derived from cryopreserved term cytotrophoblasts isolated by the 'Kliman' method of sequential trypsin digestion and Percoll density gradient centrifugation, when cultured in specialised medium. This was confirmed by the expression of characteristic trophoblast markers including cytokeratin-7, E-cadherin, and human chorionic gonadotropin beta (ß-hCG). The proliferative cytotrophoblasts were induced to differentiate to syncytiotrophoblasts, marked by elevated ß-hCG expression, reduced Ki67-positive nuclei, and a fused syncytial phenotype. The protocol described here enables the application of organoid models and in vitro functional studies to stored cytotrophoblast samples for the study of placental function from unique patient cohorts. Moreover, the utilization of term placental sources may alleviate ethical concerns with using cells from pregnancy terminations, thus expanding access for a broader research community.

Maternal physical activity in healthy pregnancy: Effect on fetal oxygen supply.

AIM: We review evidence for effects of physical activity before and during gestation on the course of pregnancy and ask if there are circumstances where physical activity can stress the fetus due to competition for oxygen and energy substrates. RESULTS: We first summarize physiological responses to exercise in nonpregnant people and known physiological adaptations to pregnancy. Comparing the two, we conclude that physical activity prior to and continuing during gestation is beneficial to pregnancy outcome. The effect of starting an exercise regimen during pregnancy is less easy to assess as few studies have been undertaken. Results from animal models suggest that the effects of maternal exercise on the fetus are transient; the fetus can readily compensate for a short-term reduction in oxygen supply. CONCLUSION: In general, we conclude that physical activity before and during pregnancy is beneficial, and exercise started during pregnancy is unlikely to affect fetal development. We caution, however, that there are circumstances where this may not apply. They include the intensive exercise regimens of elite athletes and pregnancies at high altitudes where hypoxia occurs even in the resting state.

MCM Proteins are Upregulated in Placentas of Women with Reduced Insulin Sensitivity.

In the first trimester of pregnancy the human placenta grows rapidly, making it sensitive to changes in the intrauterine environment. To test whether exposure to an environment in utero often associated with obesity modifies placental proteome and function, we performed untargeted proteomics (LC-MS/MS) in placentas from 19 women (gestational age 35-48 days). Maternal clinical traits (body mass index, leptin, glucose, C-peptide and insulin sensitivity) and gestational age were recorded. DNA replication and cell cycle pathways were enriched in the proteome of placentas of women with low maternal insulin sensitivity. Driving these pathways were the minichromosome maintenance (MCM) proteins MCM2-7 (MCM-complex). These proteins are part of the pre-replicative complex and participate in DNA damage repair. Indeed, MCM6 and γH2AX (DNA-damage marker) protein levels correlated in first trimester placental tissue (r=0.514, p<0.01). MCM6 and γH2AX co-localized to nuclei of villous cytotrophoblast cells, the proliferative cell type of the placenta, suggesting increased DNA damage in this cell type. To mimic key features of the intrauterine obesogenic environment, a first trimester trophoblast cell line, i.e., ACH-3P, was exposed to high insulin (10nM) or low oxygen tension (2.5% O2). There was a significant correlation between MCM6 and γH2AX protein levels, but these were independent of insulin or oxygen exposure. These findings show that chronic exposure in utero to reduced maternal insulin sensitivity during early pregnancy induces changes in the early first trimester placental proteome. Pathways related to DNA replication, cell cycle and DNA damage repair appear especially sensitive to such an in utero environment.

Microplastics caused embryonic growth retardation and placental dysfunction in pregnant mice by activating GRP78/IRE1α/JNK axis induced apoptosis and endoplasmic reticulum stress.

Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0-14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy.

Fetoscopic laser photocoagulation: a medically reasonable treatment option in the management of types II and III vasa previa.

Vasa previa is a condition where unprotected fetal vessels cross the cervix within the membranes, posing a considerable risk of fetal death or severe morbidity if the membranes rupture before or during delivery. There has not been a definitive in utero treatment for this condition. Patients are typically closely monitored and hospitalized in the early third trimester and scheduled for cesarean delivery before term. This approach poses considerable physical, social, psychological, and financial challenges for pregnant patients and their families. Furthermore, fetal vessel rupture may lead to severe hypoxic-ischemic injury and consequent neurodevelopmental impairment. Finally, babies delivered early due to vasa previa may face both the short- and long-term consequences of prematurity. Recently, fetoscopic laser photocoagulation using a single-port fetoscope has emerged as a potential therapeutic option for patients with types II and III vasa previa. This innovative approach aims to reduce hospital stays, increases the chance of successful vaginal delivery, and potentially allows pregnancies to reach full term, providing lifelong benefits for the infant. Preliminary clinical studies on human subjects have demonstrated promising results concerning the feasibility, safety, and efficacy of this intervention for a subset of patients with types II and III vasa previa. After reviewing the current state of the art, we argued that offering fetoscopic laser photocoagulation in specialized centers under IRB supervision meets the ethical obligations of beneficence and non-maleficence for both pregnant and fetal patients, as well as the autonomy-based obligations for pregnant patients.

Maternal vascular - placental axis in the third trimester in women with gestational diabetes mellitus, hypertensive disorders and unaffected pregnancies.

OBJECTIVES: The objectives of the study were first, to compare different markers of maternal vascular function in women with gestational diabetes mellitus (GDM), preeclampsia (PE), or gestational hypertension (GH) and women whose pregnancies were unaffected by these complications. Second, to assess the association between maternal vascular function and markers of placental perfusion, maternal vascular - placental axis, in these four groups of women. STUDY DESIGN: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation at King's College Hospital, London, UK. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, Doppler studies of the uterine arteries and ophthalmic arteries, carotid-femoral pulse-wave velocity (PWV) measurements, estimation of augmentation index (AIx) and total peripheral resistance and measurements of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT-1). Linear regression was performed for the outcomes of uterine artery pulsatility index (UtA-PI) multiples of median (MoM), PLGF MoM and sFLT-1 MoM. Ophthalmic artery peak systolic velocity (PSV) ratio, PWV , AIx and total peripheral vascular resistance were assessed as potential predictors. This analysis was carried out in all women and separately in the different groups. RESULTS: The study population of 6502 women included 614 (9.4%) with GDM, 140 (2.1%) who subsequently developed PE and 129 (2.0%) who developed GH. Women with GDM, compared to those with pregnancies unaffected by GDM, PE or GH, had increased PWV. Women with PE or GH, compared to those with unaffected pregnancies, had lower PlGF MoM and higher UtA-PI MoM, sFLT1 MoM, AIx, PWV, total peripheral resistance and ophthalmic artery PSV ratio. In unaffected pregnancies, ophthalmic artery PSV ratio was predictive of UtA-PI MoM, and ophthalmic artery PSV ratio, AIx, total peripheral resistance, and PWV were predictive of PLGF MoM and sFLT-1 MoM. In women with GDM, ophthalmic artery PSV ratio was predictive of UtA-PI MoM and ophthalmic artery PSV ratio, total peripheral resistance, and PWV were predictive of PLGF MoM, and total peripheral resistance was predictive of sFLT-1 MoM. In women with PE, ophthalmic artery PSV ratio was predictive of UtA-PI MoM, PLGF MoM and sFLT-1 MoM. In women unaffected by GDM, PE or GH, ophthalmic artery PSV ratio was predictive of UtA-PI MoM and AIx, total peripheral resistance, PWV and ophthalmic artery PSV ratio were predictive of PLGF MoM and sFLT-1 MoM. CONCLUSIONS: In the third trimester of pregnancy, women with PE, GH, and GDM present with increased arterial stiffness. In addition, those diagnosed with hypertensive complications show increased peripheral vascular resistance. Ophthalmic artery PSV ratio provides predictive information for placental perfusion and function for all pregnant women, whereas vascular indices are more informative for placental function in women with unaffected pregnancy and those with GDM, than in those with PE or GH. These data suggest that vascular assessment in women during pregnancy may not only provide information about maternal vascular health but can be used to offer information about individual risk for development of placental insufficiency. The selection of vascular index will have to be tailored according to maternal profile and pregnancy complication.