Placental Vessels Research Articles

Selenium attenuates the cadmium-induced placenta glucocorticoid barrier damage by up-regulating the expression of specificity protein 1.

Cadmium (Cd) is an environmental pollutant and pregnant women are especially susceptible to the effects of exposure to Cd. Our previous study found Cd can be accumulated in the placenta and causes fetal growth restriction (FGR) through damage the placental glucocorticoid barrier. Selenium (Se), as an essential micronutrient, can allivate Cd-induced toxicity. In this study, we aim to explore the protective mechanism of Se against Cd-induced the placental glucocorticoid barrier damage and FGR. Pregnant Sprague Dawley (SD) rats were exposed to CdCl2 (1 mg/kg/day) and Na2 SeO3 (0.1-0.2-0.3 mg/kg/day) by gavage from gestational day (GD) 0 to GD 19. The results showed that reduced fetal weight, increased corticosterone concentrations in the maternal and fetal serum, and impaired placental labyrinth layer blood vessel development, appeared in pregnant rats after Cd exposure and improved after treated with Se. In cell experiments, we confirmed that Se reduces Cd-induced apoptosis. Moreover, Se can abolish Cd-induced 11β-HSD2 and specificity protein 1 (Sp1) decreasing in vivo and vitro. In human JEG-3 cells, the knockdown of Sp1 expression by small interfering RNA can suppressed the protective effect of Se on Cd-induced 11β-HSD2 decreasing. In general, our results demonstrated that Se is resistant to Cd-induced FGR through upregulating the placenta barrier via activation of the transcription factor Sp1.

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism†.

Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether this metabolic dysfunction is associated with changes in placental vascular development and is fueled by endoplasmic reticulum (ER) stress-mediated changes in fetal hepatic development. We also determined whether paternal obesity indirectly affects the in utero environment by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow or high fat diet (60%kcal fat) for 8–10 weeks were time-mated with female mice to generate pregnancies and offspring. Glucose tolerance was evaluated in dams at mid-gestation (embryonic day (E) 14.5) and late gestation (E18.5). Hypoxia, angiogenesis, endocrine function, macronutrient transport, and ER stress markers were evaluated in E14.5 and E18.5 placentae and/or fetal livers. Maternal glucose tolerance was assessed at E14.5 and E18.5. Metabolic parameters were assessed in offspring at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance but induced placental hypoxia and altered placental angiogenic markers, with the most pronounced effects in female placentae. Paternal obesity increased ER stress-related protein levels (ATF6 and PERK) in the fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Offspring of obese fathers were glucose intolerant and had impaired whole-body energy metabolism, with more pronounced effects in female offspring. Metabolic deficits in offspring due to paternal obesity may be mediated by sex-specific changes in placental vessel structure and integrity that contribute to placental hypoxia and may lead to poor fetal oxygenation and impairments in fetal metabolic signaling pathways in the liver.

Preeclampsia associated changes in volume density of fetoplacental vessels in Chinese women and mouse model of preeclampsia

Preeclampsia (PE) is associated with abnormal placental vascular structure. However, the volume density of fetoplacental vessels in PE remains unclear. Additionally, manually annotated CT angiography, which is widely used to analyze placental vessels, has issues regarding inaccuracy. Thus, computer-aided CT angiography for analyzing the volume density of fetoplacental vessels would facilitate the understanding of PE pathogenesis. We performed computer-aided CT angiography to compare differences in placentas among 17 women with PE and 34 normotensive women. The contrast ratio in CT angiography was significantly enhanced using a three-dimensional (3-D) Hessian matrix algorithm. The PE-like mouse model was established by administration of 125mg/kg/day NG-nitro-l-arginine methyl ester (l-NAME) for 10 days. The presence of endothelial marker CD31 was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The expression of angiogenic factors (PlGF, VEGFA, and sFlt1) in placentas was detected using qRT-PCR and western blotting. The volume density in fetoplacental vessels and CD31 expression were significantly reduced in women with PE and l-NAME-induced mice. Additionally, the downregulation of angiogenic factors (PlGF/VEGFA) and upregulation of an anti-angiogenic factor (sFlt1) were determined in a mouse model. Contrast-enhanced CT angiography with the aid of a 3-D Hessian matrix algorithm was performed. PE significantly affects the formation of vascular vessels, resulting in a lower volume density of fetoplacental vessels in humans and mice. This may be explained by the abnormal release of angiogenic factors during PE.

Distal villous lesions are clinically more relevant than proximal large muscular vessel lesions of placental fetal vascular malperfusion.

Fetal vascular malperfusion (FVM) can be diagnosed on placental examination based on histology of distal placental villi and large muscular placental vessels. While histology of both those placental compartments can be low grade or high grade, it is not known if these are clinically equivalent. This retrospective study aimed to compare the impact of placental distal villous and large vessel FVM lesions on clinical and placental phenotypes. Clinical and placental phenotypes of 479 consecutive ≥20 weeks of gestation at delivery cases of placental FVM were analyzed among 3 groups: Group 1: 86 cases with distal FVM (clusters of sclerotic distal villi and/or those with stromal vascular karyorrhexis and/or mineralization, and/or endothelial fragmentation by CD34 immunostain) without large vessel lesions; Group 2: 186 cases with large vessel lesions (fetal vascular ectasia, vascular thrombi, stem vessel obliteration, intramural fibrin deposition) without distal villous lesions; and Group 3: 207 cases showing both distal villous lesions and large fetal vessel lesions. Statistically significant differences (Bonferroni correction) were observed in: average gestational age at delivery 31, 35, 34 weeks, fetal growth restriction 24, 9, 25%, average placental weight 318, 413, 366 g, postuterine pattern of chronic hypoxic placental injury 12, 2, 6%, luminal vascular abnormalities in stem vessels 16, 3, 11%, and high grade FVM 33, 16, 39%, among Groups 1-3, respectively. Because of longer time needed for its development, distal FVM portends poorer prognosis for the fetus than large vessel FVM.

HUBUNGAN PARITAS DAN RIWAYAT HIPERTENSI DENGAN KEJADIAN PREEKLAMSI BERAT (PEB) DI RUANGAN VK RUMAH SAKIT MEDIKA STANNIA KABUPATEN BANGKA

Preeclampsia were still a threatening problem in pregnancy, especially in developing countries. In Indonesia, preeclampsia were a high cause of maternal mortality in addition to bleeding and infection. Preeclampsia could cause problems for both the fetus and the mother. The conditions of preeclampsia and eclampsia would adversely affect the health of the fetus due to decreased uteroplacental perfusion, hypovolemia, vasospasm, and damage to endothelial cells of the placental vessels. The exact cause of preeclampsia were not known. There are various risk factors, including parity factors and a history of hypertension. This type of research was a descriptive study with a case control design and using univariate and bivariate data analysis techniques with chi-square test where the population were inpartu mothers in the VK Room of Medika Stannia Hospital, Bangka Regency. Sampling using accidental sampling technique with a significant level of 95% (p 0.05). The results of this study indicate that there was a relationship between parity (p value 0.009) and history of hypertension (p value 0.023) to the incidence of severe preeclampsia. Based on the results of the study, it is hoped that the hospital will be able to control the risk of severe preeclampsia in the mother during pregnancy, especially mothers with primigravida parity and have a history of hypertension.

A Review of Roles of Uterine Artery Doppler in Pregnancy Complications

The invasion of trophoblasts into the uterine decidua and decidual vessels is critical for the formation of placenta. The defects of placentation are related to the etiologies of preeclampsia (PE), fetal growth restriction (FGR), and small-for-gestational age (SGA) neonates. It is possible to predict significant vascular events during pregnancy through uterine artery Doppler (UAD). From the implantation stage to the end of pregnancy, detecting changes in uterine and placental blood vessels can provide a favorable diagnostic instrument for pregnancy complications. This review aims to collect literature about the roles of UAD in pregnancy complications. We consider all relevant articles in English from January 1, 1983 to October 30, 2021. Predicting pregnancy complications in advance allows practitioners to carry out timely interventions to avoid or lessen the harm to mothers and neonates. Administering low-dose aspirin daily before 16 weeks of pregnancy can significantly reduce the incidence of pregnancy complications. From early pregnancy to late pregnancy, UAD can combine with other maternal factors, biochemical indicators, and fetal measurement data to identify high-risk population. The identification of high-risk groups can also lessen maternal mortality. Besides, through moderate risk stratification, stringent monitoring for high-risk pregnant women can be implemented, decreasing the incidence of adversities.

Vaginal Exposure to Candida albicans During Early Gestation Results in Adverse Pregnancy Outcomes via Inhibiting Placental Development.

Vulvovaginal candidiasis (VVC) is considered the second most common cause of vaginitis after bacterial vaginosis and the most common lower genital tract infection during pregnancy. Candida albicans (C. albicans), an opportunistic pathogen, is the major species causing VVC. Recently, increasing researches have shown that lower reproductive tract infection during pregnancy can lead to various adverse pregnancy outcomes. However, the underlying mechanisms are not fully understood. Hence, we successfully established a mouse model of vaginal C. albicans infection and characterized the adverse pregnancy outcomes. C. albicans infection strikingly increased abortion rate and decreased litter size. Further analysis of placental development demonstrated that placental structure was abnormal, including that the area of spongiotrophoblast (Spo) and labyrinth (Lab) was reduced, and the formation of placental vessel was decreased in Lab zone. Accordingly, the expression of marker genes during placental development was downregulated. Collectively, the above findings revealed that vaginal C. albicans infection during pregnancy can inhibit placental development and ultimately lead to adverse pregnancy outcomes. This study enhances our comprehension of the effect of VVC on pregnancy, and placental dysplasia as a feasible orientation to explore VVC during pregnancy.

Роль тромбоцитов в формировании иммунологической толерантности при привычном выкидыше

Objective of the Review: Аnalysis of literature and summarizing of data on the participation of platelets in the formation of immunological tolerance during the physiological pregnancy and recurrent miscarriage. Key points. Platelet-derived soluble factors determine their involvement in the endocrine regulation of the placenta, initiate and maintain trophoblast invasion. Platelets are able to influence the balance of M1 and M2 macrophages, inhibit the cytotoxic potential of NK cells and the antigen-presenting ability of dendritic cells. The interaction of platelets with regulatory T cells initiates the recruitment of lymphocyte cells to the site of inflammation and their activation. It has been shown that the differentiation of immune cells and changes in their functional activity, aimed at creating conditions favorable for prolonging pregnancy, are largely determined by both platelet-derived soluble factors and the formation of platelet-leukocyte complexes. Conclusion. Platelets and products of their activation play an important role in creating the conditions necessary for the onset of pregnancy and its prolongation to full term. The functional state of platelets determines the success of placentation both directly (through the control of hemodynamic parameters in the placental vessels, increased invasiveness of the extracellular trophoblast, the effect on the endocrine background) and indirectly by modulating the functions of decidual immune cells, which determines their contribution in the implementation of idiopathic pregnancy loss. Keywords: platelets, platelet-leukocyte interaction, immunoregulation, recurrent abortion, pregnancy loss.

Semi-Supervised Placental Vessel Segmentation from Fetoscopy Videos

Semi-Supervised Placental Vessel Segmentation from Fetoscopy Videos

Preeclampsia and pathology of placentation

Etiology of pre-eclampsiaremainsunclear. However, it is recognized that genetic factors of both mothers and fathers sides can determine the development of this awesome complication of pregnancy. The interplay of genetic factors with external influences determines the risk level of pre-eclampsia. Today it is reasonable to assert that pre-eclampsia is a complication of pregnancy associated with the disturbances of the process of trophoblast invasion and changes in haemodynamics in spiral arteries. The process of trophoblast invasion proved to be coordinated by combined interaction of cytokines, factors of adhesion and different growth factors.Functional abnormalities of endothelium of placental and pre-placental vessels may be a result but not a cause of development ofpre-eclampsia, pathophysiology of which is studied still insufficiently. However, the disturbance оf NO, endothelein release and thrombocytes homeostasis as well are certain to be the main manifestations of this pregnancy complication. A fter revealing all the mechanisms of process of trophoblast invasion disturbances an actual possibility of early prevention and treatment of pre-eclampsia may be elaborated.

Integrated 2D Doppler indices of uteroplacental and fetal blood flow in diagnosis of intrauterine hypoxia

Relevance . Intrauterine hypoxia associated with placental disorders is a significant factor of ante-, intra- and postnatal fetal and newborn death. Despite clinical examination of pregnant women using ultrasound and cardiotocography, cases of intrauterine hypoxia often remain undetected prenatally. Clinical manifestation of placental disorders and intrauterine hypoxia are associated with pathological changes of blood flow resistance in the uterine, placental and fetal vessels. A combined Doppler assessment of blood flow in the uterine, placental and fetal vessels could improve detection of intrauterine hypoxia. The aim of the study was to assess the prognostic significance of integrated 2D Doppler indices of uteroplacental and fetal blood flow for the detection of fetal hypoxia in the 3rd trimester and to predict unfavorable perinatal outcomes. Materials and Methods. The outcomes of pregnancy of 48 women with fetal hypoxia delivered at 29 - 40 gestational weeks (study group), and 21 women who gave birth to healthy full-term infants (control group) were retrospectively analyzed. On the eve of delivery all women had 2D Doppler assessment of the uterine arteries, umbilical arteries, and fetal middle cerebral artery with an assessment of the cerebro-placental ratio, umbilical-cerebral ratio and cerebro-placental-uterine ratio. Results and Discussion . Analysis of the obtained values of cerebro-placental-uterine ratio, cerebro-placental ratio and umbilical-cerebral ratio showed the benefit from use of integrated 2D Doppler indices in the diagnosis of fetal hypoxia at 29 - 40 gestations weeks and in predicting complications in newborns. The high sensitivity of the cerebro-placental-uterine ratio (90.5%) makes it possible to effectively use this index for the diagnosis of intrauterine hypoxia. Conclusion. Pathological cerebro-placental-uterine ratio 2.44 is a clinically significant 2D Doppler criterion that predicts a high risk of asphyxia, respiratory distress syndrome, hypotrophy, and perinatal hypoxic-ischemic encephalopathy. Lower values of the cerebro-placental ratio and umbilical-cerebral ratio sensitivity (77.1% and 81.3%, respectively) limit their use for the diagnosis of fetal hypoxia as compared with cerebro-placental-uterine ratio.

An Unusual Monochorionic Pregnancy.

An Unusual Monochorionic Pregnancy.

Globally Optimal Fetoscopic Mosaicking Based on Pose Graph Optimisation With Affine Constraints

Fetoscopic laser ablation surgery could be guided using a high-quality panorama of the operating site, representing a map of the placental vasculature. This can be achieved during the initial inspection phase of the procedure using image mosaicking techniques. Due to the lack of camera calibration in the operating room, it has been mostly modelled as an affine registration problem. While previous work mostly focuses on image feature extraction for visual odometry, the challenges related to large-scale reconstruction (re-localisation, loop closure, drift correction) remain largely unaddressed in this context. This letter proposes using pose graph optimisation to produce globally optimal image mosaics of placental vessels. Our approach follows the SLAM framework with a front-end for visual odometry and a back-end for long-term refinement. Our front-end uses a recent state-of-the-art odometry approach based on vessel segmentation, which is then managed by a key-frame structure and the bag-of-words (BoW) scheme to retrieve loop closures. The back-end, which is our key contribution, models odometry and loop closure constraints as a pose graph with affine warpings between states. This problem in the special Euclidean space cannot be solved by existing pose graph algorithms and available libraries such as G2O. We model states on affine Lie group with local linearisation in its Lie algebra. The cost function is established using Mahalanobis distance with the vectorisation of the Lie algebra. Finally, an iterative optimisation algorithm is adopted to minimise the cost function. The proposed pose graph optimisation is first validated on simulation data with a synthetic trajectory that has different levels of noise and different numbers of loop closures. Then the whole system is validated using real fetoscopic data that has three sequences with different numbers of frames and loop closures. Experimental results validate the advantage of the proposed method compared with baselines.

Improving Neurosurgery Resident Microdissection Through Placental Simulation

ABSTRACT Prior work has shown that the human placenta is an available and realistic model for microdissection simulation. We sought to find a measurable improvement in the technical skills of neurosurgical residents with deliberate practice of microdissection tasks using a placental model. Postgraduate year (PGY) 1 to 3 neurosurgery residents were consented. A 1-min video of each participant's baseline skills skeletonizing placental vessels was recorded. Participants underwent 10 practice sessions with intermittent informal feedback for 30-60 min over 18 mo. Another 1-min video was recorded following the 10th dissection. The videos were blinded and assessed by 3 board eligible or certified microsurgical neurosurgeons using a modified Objective Structured Assessment of Aneurysm Clipping Skills. Performance was compared via t-testing among four domains: instrument handling, time flow and forward planning, quality of dissection, and respect for tissue. Microdissection, instrument handling, and quality of dissection were significantly improved after deliberate practice with the placental simulator (P < .05). Improvement was seen in time flow and forward planning and respect for tissue; however, this failed to be significant. Subjectively, residents expressed enjoyment performing the exercise. They also expressed a desire for demonstrations or videos to watch before practice sessions. The placental simulation model provides microsurgical skill development with minimal deliberate practice sessions. Practice exercises are favorably regarded and interest in continuing them is strong by residents. Residents expressed a desire to make the dissection more deliberate with demonstration, breakdown of steps, and mimicry, which could improve the effectiveness and enjoyment of the skills session.

The Protective Benefit of Heme Oxygenase-1 Gene-Modified Human Placenta-Derived Mesenchymal Stem Cells in a N-Nitro-L-Arginine Methyl Ester-Induced Preeclampsia-Like Rat Model: Possible Implications for Placental Angiogenesis.

We previously reported that cytoprotective Heme oxygenase-1, HO-1 (HMOX1) gene-modified human placenta-derived mesenchymal stem cell (HO-1-PMSC) improved placental vascularization in vitro. In the current study, we explored the protective benefit of HO-1-PMSC transplantation in a preeclampsia (PE)-like rat model. A model of PE was successfully constructed by intraperitoneal injection of N-nitro-L-arginine methyl ester (L-NAME). Blood pressure and urinary protein levels were measured. Doppler ultrasound was examined to understand uteroplacental perfusion. ELISA was used to examine the serum levels of VEGF, PlGF, sFlt-1, and sEng. The placentas and fetuses were weighed to verify the improvement in pregnancy outcome. Immunohistochemical and H&E staining was used to detect microvessel density (MVD) in placental tissues and kidney pathology, respectively. The distribution of GFP-labeled PMSC in the placenta were observed under fluorescence microscopy. Blood pressure and proteinuria were reduced and kidney damage was improved. PE rat models treated with PMSC and HO-1-PMSC exhibited an increase in the quality of fetuses and placentas, MVD, VEGF, and PlGF expression, but substantially decreased expression of sFlt-1 and sEng. Doppler ultrasound showed that the placental perfusion was improved. Green fluorescent tracing experiments verified that the cells were successfully transplanted into the placenta and distributed in the blood vessels, indicating that the cells might participate in the process of angiogenesis. These results indicate that therapy with HO-1-PMSC could improve placental vascular dysplasia, increase placental perfusion, control PE symptoms, and promote pregnancy outcome by regulating the balance of angiogenic and antiangiogenic factors or directly participating in the repair of placental vessels in a PE-like rat model.

Placental Vascular Abnormalities in Association With Prenatal and Long-Term Health Characteristics Among HIV-Exposed Uninfected Adolescents and Young Adults.

HIV-exposed uninfected (HEU) individuals are predisposed to adverse health outcomes, which in part may stem from the influence of an altered intrauterine milieu on fetal programming. The placenta serves as a readout for the effects of the maternal environment on the developing fetus and may itself contribute to the pathogenesis of disease. US academic health system. We leveraged a previously established registry-based cohort of HEU adolescents and young adults to identify 26 subjects for whom placental histopathology was available. We further obtained placental tissue from 29 HIV-unexposed pregnancies for comparison. We examined differences in placental histopathology between the groups and related villous vascularity in the HEU group to prenatal maternal characteristics and long-term health outcomes. Placentas from HEU pregnancies demonstrated a higher blood vessel count per villus as compared with controls (5.9 ± 1.0 vs. 5.4 ± 0.8; P = 0.05), which was independent of maternal prenatal age, race, body mass index, smoking status, hemoglobin, and gestational age. Furthermore, within the HEU group, lower CD4+ T-cell count during pregnancy was associated with greater placental vascularity (r = -0.44; P = 0.03). No significant relationships were observed between placental blood vessel count per villus and body mass index z-score or reactive airway disease among HEU individuals later in life. Placentas from HEU pregnancies demonstrated increased villous vascularity compared with HIV-unexposed controls in proportion to the severity of maternal immune dysfunction. Further studies are needed to examine intrauterine exposure to hypoxia as a potential mechanism of fetal programming in HIV.

Abstract P136: First Steps In Uncovering Mechanisms In Late Onset Preeclampsia

Preeclampsia is a leading cause of maternal morbidity and mortality worldwide, complicating 2-8% of pregnancies. The etiology of PE is poorly understood, the role of placental extracellular matrix (pECM) in PE is understudied. Extravillous trophoblasts (HTR8/svneo) and pECM are crucial in placental blood vessel formation, including spiral arteries. The objective is to identify changes in signaling mechanisms in late onset PE and how HTR8/svneo respond. Additionally, we explored a novel therapeutic to restore HTR8/svneo phenotype by phototherapy using a 670nm LED light. Western blot analysis shows eNOS, phospho-eNOS and Hsp90 expressions are unchanged in late onset PE placental samples despite previous reports in early onset of PE. The association of Hsp90 to eNOS and eNOS to phospho-eNOS is reduced in the PE sample. Soluble Flt, a diagnostic marker for PE, levels are increased in media from HTR8/svneo trophoblasts cultured on PE pECM. Endothelial function is significantly reduced in an isolated vessel as determined by acetylcholine stimulation. 670nm light reverses this impairment. Migration of HTR8/SVneo on PE pECM is reduced (control 86.29±18.58, PE 30.16±15.49) but proliferation of HTR8/SVneo on PE pECM is unaffected in patients (control: 59.125±6262.9, PE:67.125±7706.5). Proliferation and migration are improved by 670nm light (proliferation control 101.375±2075.4; PE 106.875±4870.7, migration control 125±11.97, PE 144.84±16.01). An increase of apoptotic HTR8/SVneo cultured on PE pECM is observed compared to healthy pECM in patients control 2.4±0.24, PE 3±0.4 samples. 670nm light treatment decreases the number of apoptotic cells, control 1.2 ±0.58, PE 1.4±0.5. Conclusion: In late onset preeclampsia, endothelial function is decreased, sFlt release is increased, the eNOS/Hsp90/p-eNOS axis is slightly reduced pointing to O 2 - synthesis. Migration is decreased likely due to impaired trophoblast invasion, but proliferation is unaffected. 670nm light treatment can reverse some of the effects of the preeclamptic microenvironment. Extracellular matrix is altered in late onset PE leading to an abnormal HTR8/SVneo phenotype. 670nm light restores the phenotype of HTR8/SVneo on PE pECM suggesting 670nm light as a therapeutic treatment.

A new approach to assessment of reproductive losses of the first trimester of pregnancy

Background . At present, the role of cytomegalovirus infection in the disruption of acental formation and associated pathological conditions of the fetus is bvious, which are based on oxidative and inflammatory reactions that cause disruption of igration and invasion of trophoblasts, angiogenic modulation of placental and uterine vessels. Objective: To analyze the quantitative indicators of hypoxia-inducible factor 1α, α-tocopherol and docosahexaenoic acid in the peripheral blood in comparison with morphological changes in the placenta and uterine mucosa in seropositive women with spontaneous abortion associated with reactivation of ytomegaloviral infection. Methods: Studies were carried out at 7-9 weeks of gestation. 67 observations were analyzed, including 35 seropositive women in the first trimester with spontaneous abortion associated with reactivation of cytomegaloviral infection and 32 healthy seronerative women with voluntary termination of pregnancy. Stabilized blood from vein, epithelium of the inner surface of the cheek, cervical canal, urine, villous chorion, and uterine mucosa were used as the test material. Enzyme immunoassay was used to detect serological markers of cytomegaloviral infection (CMV-IgG/IgM antibodies, CMV-IgG avidity), hypoxia-induced factor 1α, α-tocopherol – by fluorometric method, PCR (polymerase chain reaction) in real time – DNA CMV, the method of gas-liquid chromatography – docosahexaenoic acid, histological methods – the general plan of the structure of the chorionic villus and the mucous membrane of the uterus. Results: In seropositive women with spontaneous abortion associated with reactivation of cytomegaloviral infection, the average of hypoxia-induced factor 1α was 1.54 times higher, α-tocopherol and docosahexaenoic acid were 1.71 times lower and 1.40 times lower (p < 0.001, respectively) than in the group of eronegative women. Strong inverse correlations were revealed. Morphologically, there were signs of delayed formation of villi, decidualization of the endometrial stroma and the formation of uteroplacental vessels. Conclusion. In seropositive women with spontaneous abortion associated with reactivation of cytomegaloviral infection, a strong association of high HIF-1α values with decrease in α-tocopherol and docosahexaenoic acid in the peripheral blood was revealed, which can be considered as an unfavorable factor in the disruption of placenta formation.

Nox2 impairs VEGF-A-induced angiogenesis in placenta via mitochondrial ROS-STAT3 pathway

Aberrant placental angiogenesis is associated with fetal intrauterine growth restriction (IUGR), but the mechanism underlying abnormal placental angiogenesis remains largely unknown. Here, lower vessel density and higher expression of NADPH oxidases 2 (Nox2) were observed in the placentae for low birth weight (LBW) fetuses versus normal birth weight (NBW) fetuses, with a negative correlation between Nox2 and placental vessel density. Moreover, it was revealed for the first time that Nox2 deficiency facilitates angiogenesis in vitro and in vivo, and vascular endothelial growth factor-A (VEGF-A) has an essential role in Nox2-controlled inhibition of angiogenesis in porcine vascular endothelial cells (PVECs). Mechanistically, Nox2 inhibited phospho-signal transducer and activator of transcription 3 (p-STAT3) in the nucleus by inducing the production of mitochondrial reactive oxygen species (ROS). Dual-luciferase assay confirmed that knockdown of Nox2 reduces the expression of VEGF-A in an STAT3 dependent manner. Our results indicate that Nox2 is a potential target for therapy by increasing VEGF-A expression to promote angiogenesis and serves as a prognostic indicator for fetus with IUGR.

Transplacental transfer of congenital B‐cell acute lymphoblastic leukemia to the maternal vasculature

To the Editor: Monozygotic twin infants with KMT2A-rearranged (KMT2Ar) acute lymphoblastic leukemia (ALL) demonstrate near-uniform disease concordance due to prenatal transfer of pre-leukemic cells via placental vascular anastomoses.1-4 However, despite several historical reports recognizing the presence of fetal nucleated cells in the maternal circulation during pregnancy,5 fetal–maternal dissemination of leukemic clones has not been reported. We present a neonate with congenital KMT2Ar-ALL with documentation of metastasis to the maternal decidual placental vessels without clinical consequence. A newborn infant born at 37 4/7 weeks gestation was found to have leukocytosis (white blood cells 72.1 × 103/μl) with 62% blasts characterized by convoluted nuclear contour, prominent nucleoli, and scant deep-blue cytoplasm. Flow cytometry revealed expression of HLA-DR, CD15, CD19, CD22, CD34, cytoplasmic TdT, and cCD79a, consistent with B-cell ALL. G-banding karyotyping analysis revealed t(4;11)(q21;q23) with a dominant clone (five metaphase cells) containing a (4;11)(q21;q23) translocation and a subclone (one cell) containing an additional copy of der(4). Placental microscopy demonstrated clusters of blasts in both chorionic surface (fetal) vessels and decidual (maternal) vessels (Figure 1). Fluorescence in situ hybridization (FISH) analysis showed these clusters to be positive for the KMT2A rearrangement in both fetal and maternal vessels. These findings indicate that malignant fetal cells had infiltrated the maternal placental vasculature. Unlike in older children and adolescents, the prognosis of ALL in the neonatal age group is dismal.6 Despite intensive therapy, our patient experienced a highly complicated clinical course with eventual decompensation from Enterococcus faecalis bacteremia and infectious rotavirus leading to death on day 47 of life. Notably, throughout the patient's nearly 7-week clinical course, his mother did not demonstrate any clinically apparent findings to suggest sequelae of transplacental leukemia cell transfer. The discovery of leukemia cells of shared clonal lineage between monozygotic twins with ALL supports the so-called “intraplacental metastasis hypothesis”1 and confirms the capacity for pre-leukemic cells to spread from one twin to the other.7 These pre-leukemic cells are thought to transfuse via monochorionic placental vascular anastomoses rather than across the placental membrane barrier itself. Although placental involvement of congenital neuroblastoma has been reported,8 numerous reports of pregnant patients with hematologic malignancies demonstrate a noteworthy absence of clinically apparent transplacental “metastases” to exposed neonates.9-12 For example, in a report of prenatally diagnosed maternal ALL with leukemia cells detected in the cord blood, these cells were efficiently cleared and did not result in leukemic engraftment in the neonate.13 In this report, numerous lymphoblasts characterized by the KMT2A rearrangement were observed in the decidual (maternal) placental blood vessels, suggesting substantial cross-placental infiltration or local proliferation following infiltration. Our findings suggest the capacity for pre-leukemic cells to circumvent the placental membrane barrier as an additional means of transplacental penetration. The absence of a clinical impact on maternal health suggests that infiltrated malignant fetal cells undergo extraplacental maternal immune clearance and do not result in clinical consequence to the exposed mother. The authors declare that there is no conflict of interest.