Fetal-placental Circulation Research Articles

Hypertrophic Cardiomyopathy Risk Factors in Infants of diabetic mothers

Abstract Background Diabetes mellitus (DM) is a systemic chronic metabolic disorder characterized by increased insulin resistance and/or β- cell defects. Maternal DM significantly affects the fetal heart and fetal–placental circulation in both structure and function. Cardiac defects, myocardial hypertrophy are three times more prevalent in infants of diabetic mothers (IDMs). Objective Assess the frequency of hypertrophic cardiomyopathy (HCM) among infants of diabetic mothers and its relationship to the maternal glycemic control and the birth weight for the gestational age. Patients and Methods This was a cross-sectional study conducted on (50) neonates with gestational age ≥ 35 weeks born to diabetic mothers recruited from the delivery room and Neonatal Observation Unit, Obstetrics and Gynecology Hospital, Ain shams university. Detailed history was taken for the duration of maternal diabetes, glycemic control and any associated complications and the level of hemoglobin A1C (HbA1C) was assessed for all the enrolled mothers. Neonates were subjected to full clinical examination and echocardiographic evaluation in the first week of life. Results Forty % of mothers had gestational diabetes mellitus (GDM), (20%) were pre-gestational diabetes type 1 and 40% were pre-GDM type 2. There were 18 infants (36%) had HCM. HCM was highly statistically significant (p-value < 0.001) more in cases with high maternal HbA1C (8.3 ± 0.9). The frequency of HCM among infants of pre-GDM mothers (15 patients, 50%) was significantly higher (p-value = 0.012) when compared to infants of GDM mothers (3 patients, 15%). But the frequency of HCM was equal in infants of pre-GDM type I mothers and those of pre-GDM type 2 mothers. HCM was more common with large for gestational age (LGA) infants (10 cases 55.6% of infants with HCM were LGA). Conclusion HCM is more frequent among infants of mothers with pre-GDM type 1 than infants of GDM. Poor maternal glycemic control and large for gestational age are associated with higher frequency of HCM among those infants.

Особливості гемодинаміки в системі «мати-плацента-плід» у жінок, які мали ускладнення з групи великих акушерських синдромів, що клінічно проявлялися плацентарною недостатністю

Purpose - to study the features of hemodynamics in the mother-placenta-fetus system during pregnancy in women who had complications from the group of major obstetric syndromes (MOS), clinically manifested by placental insufficiency. Materials and methods. A prospective analysis of ultrasound examination of blood circulation in the mother-placenta-fetus system during pregnancy in 99 pregnant women with complications from the group of MOS - placental insufficiency - was performed. These women constituted the Main group (MG). The Control group (CG) included 50 practically healthy pregnant women with a good reproductive history and an uncomplicated pregnancy. Statistical processing of research results was carried out using standard Microsoft Excel 5.0 and Statistica 6.0 programs. Results. The study revealed an increase in all vascular resistance indices. An increase in the vascular resistance index is associated with an increase in peripheral vascular resistance and a decrease in diastolic blood flow, which, in turn, is due to a decrease in vascularisation of the terminal villi as a morphological and functional manifestation of placental insufficiency after 35 weeks of pregnancy: the resistance index in the umbilical cord artery was 0.71±0.02 in the MG versus 0.48±0.07 in the CG (p>0.05).In the study, the indices of vascular resistance in the fetal aorta increased: the resistance index was 0.74±0.05 in the MG vs. 0.44±0.55 in the CG (p<0.05) and at 22-27 weeks of pregnancy 0.98±0.06 in the MG vs. 0.50±0.40 in the CG (p<0.05). It was found that 69 (69.7%) pregnant women in the MG had hemodynamic disorders: 39 (39.4%) patients had uteroplacental circulation disorders with preserved fetal-placental circulation; 23 (23.2%) pregnant women had fetal-placental circulation disorders with preserved uteroplacental circulation; 7 (7.1%) pregnant women had simultaneous uteroplacental and fetal-placental circulation disorders. Conclusions. Dynamic ultrasound monitoring of the functional state of the fetoplacental complex in women with MOS revealed that from the early stages of gestation, there is a violation of placentogenesis, which is accompanied by functional failure of the fetoplacental complex and leads to early exhaustion of the compensatory capabilities of the fetoplacental system. The study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Local Ethics Committee of the institution mentioned in the paper. Women's informed consent was obtained for the study. No conflict of interests was declared by the author.

Fetal-onset malignant rhabdoid tumor: a case report

BackgroundA fetal-onset cervical mass may cause postnatal airway obstruction, and ex utero intrapartum treatment (EXIT) to secure the airway while maintaining fetal-placental circulation may be life-saving. Malignant rhabdoid tumors (MRT) are highly aggressive tumors, and when they develop in utero, the prognosis is even worse, with almost no reports of survival beyond the neonatal period. Herein, we report a case of a primary cervical MRT and describe our treatment using EXIT for securing the airway, wherein the infant’s life was saved.Case presentationA 40-year-old Japanese woman with no relevant medical or surgical history was diagnosed with a fetal left cervical mass and polyhydramnios during the third trimester. Fetal magnetic resonance imaging indicated the possibility of postnatal airway obstruction, and delivery using EXIT was planned. The infant was delivered by a planned cesarean section at 39 weeks and 5 days gestation, and tracheostomy was performed using EXIT. Postnatal contrast-enhanced computed tomography revealed suspected metastatic lesions in the subcutaneous tissue, lungs, and thymus, in addition to the mass in the left cervical region. MRT was diagnosed by biopsy of a subcutaneous mass in the left thigh, and chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide was initiated. The tumors regressed, and the infant was successfully weaned from artificial ventilation. After discharge from the hospital, she had a recurrent cervical mass and intracranial metastasis, and radiotherapy was initiated.ConclusionsIn our case, fetal diagnosis enabled advance planning of delivery using EXIT, thus saving the infant’s life. The use of chemotherapy for MRT, which has a poor prognosis, allowed tumor regression and enabled the infant to survive beyond the neonatal period.

A Glyphosate-Based Formulation but Not Glyphosate Alone Alters Human Placental Integrity.

Glyphosate (G)-based herbicidal formulations, such as the most commonly used one, Roundup (R), are major pesticides used worldwide on food and feed. Pregnant women may be frequently exposed to R compounds. These are composed of G, which is declared as the active principle, and other products contained in formulations, named formulants, which have been declared as inerts and diluents by the manufacturers. These formulants have, in fact, been demonstrated to be much more toxic than G, in particular to placental and embryonic human cells. In this work, we thus compared the effect of G and a GT+ formulation named R, using placental perfusion ex vivo. R, but not G alone, was demonstrated to alter the placental permeability of a known small model molecule, antipyrine. Similar results were observed for the fetal venous flow rate. The transfer of G alone increases with time, but is significantly decreased in presence of its formulants. The perfusion of R provokes a destruction of fetal vessels, as demonstrated by immunohistochemistry. Formulants obviously alter the fetal-placental circulation and placental integrity according to time of exposure. Therefore, G does not appear to be the main toxic agent of R. Formulants, although undeclared, include polyoxyethanolamines, PAHs, or heavy metals, and may be responsible for this toxicity. These compounds are also present in other pesticides. The progressive blood flow reduction due to the toxic compounds of formulations may diminish the nutrient supply to the fetus, alter the development, and may enhance the poisoning effects. Although these are preliminary results, they could at least partially explain some adverse pregnancy outcomes in mothers exposed to pesticides or other environmental pollutants. The debate on glyphosate alone is proven insufficient for the understanding of the toxicity.

Cardiac changes in infants of diabetic mothers.

Diabetes mellitus (DM) is a systemic chronic metabolic disorder characterized by increased insulin resistance and/or β- cell defects. It affects all ages from the foetal life, neonates, childhood to late adulthood. Gestational diabetes is a critical risk factor for congenital heart diseases (CHDs). Moreover, the risk increases with low maternal education, high body mass index at conception, undiagnosed pre-gestational diabetes, inadequate antenatal care, improper diabetes control, and maternal smoking during pregnancy. Maternal DM significantly affects the foetal heart and foetal–placental circulation in both structure and function. Cardiac defects, myocardial hypertrophy are three times more prevalent in infants of diabetic mothers (IDMs). Antenatal evaluation of the cardiac function and structures can be performed with foetal electrocardiography and echocardiography. Postnatal cardiac evaluation can be performed with natal and postnatal electrocardiography and echocardiography, detection of early atherosclerotic changes by measuring aortic intima-media thickness, and retinal vascular changes by retinal photography. Ameliorating the effects of diabetes during pregnancy on the offspring depends mainly on pregestational and gestational diabetes prevention. However, other measures to reduce the risk, such as using medications, nutritional supplements, or probiotics, still need more research. This review discusses the mechanism of foetal sequels and the risk factors that increase the prevalence of CHDs in gestational DM, the various cardiac outcomes of gestational DM on the foetus and offspring, cardiac evaluation of foetuses and IDMs, and how to alleviate the consequences of gestational DM on the offspring.

Fetal-placental blood flow and neurodevelopment in childhood: population-based neuroimaging study.

ABSTRACTObjectiveAntenatal Doppler measurements of the fetal umbilical and cerebral circulations can predict perinatal complications; however, it is unclear if subtle variations in antenatal Doppler measurements are associated with long‐term neurodevelopmental outcome. In this study, we examined whether antenatal Doppler measurements of the fetal–placental circulation are associated with cognitive and motor abilities and brain morphology in childhood.MethodsTo evaluate differences in long‐term sequelae across the continuum of the umbilical and cerebral artery circulations in the general population, we utilized a population‐based longitudinal cohort study approach. In women from the Generation R study, we measured second‐ and third‐trimester umbilical artery pulsatility index (UA‐PI). Children underwent non‐verbal intelligence testing at 4–8 years of age, and at 8–12 years they underwent finger‐tapping tests to measure fine motor skills, balance beam tests to measure gross motor skills and brain magnetic resonance imaging. We assessed the relationships between prenatal UA‐PI and neurodevelopmental outcome using linear regression. We adjusted for child age and sex, maternal age, education, parity and smoking status.ResultsThe study sample included 2803 pregnancies. Higher third‐trimester UA‐PI was associated with poorer fine motor performance (0.41 (95% CI, 0.11–0.70) fewer taps on the finger‐tapping test per 1 SD higher UA‐PI) and gross motor performance (0.64 (95% CI, 0.20–1.08) fewer steps on the balance beam test per 1 SD higher UA‐PI). One SD higher third‐trimester UA‐PI was also associated with 0.65 (95% CI, 0.04–1.25) points lower intelligence quotient; however, unlike the associations with motor abilities, this finding did not persist after correction for multiple testing. Higher second‐trimester UA‐PI was associated with smaller brain volume (6.1 (95% CI, 1.0–11.3) cm3 reduction per 1 SD higher UA‐PI), but the association did not persist after correction for multiple testing.ConclusionHigher placental vascular resistance may have mild adverse effects on neurodevelopmental outcome at school age. While these effects are subtle at population level, we encourage future research into the role of early circulation in brain development. This information could be used to develop targeted interventions. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Maternal and fetal vascular lesions of malperfusion in the placentas associated with fetal and neonatal death: results of a prospective observational study

Fetal death is one of the major adverse pregnancy outcomes and is common in low- and middle-income countries. Placental lesions may play an important role in the etiology of fetal and neonatal deaths. Previous research relating placental lesions to fetal death causation was hindered by a lack of agreement on a placental classification scheme. The Amsterdam consensus statement that was published in 2016 focused its attention on malperfusions in the maternal and fetal placental circulations. This study aimed to investigate the relationships of placental maternal and fetal vascular malperfusions in fetal and neonatal deaths, focusing on the most important maternal clinical conditions in the pathway to fetal and neonatal deaths, such as maternal hypertension, antepartum hemorrhage, and decreased fetal growth. This was a prospective, observational cohort study conducted at 2 Asian sites. The data collected included clinical history, gross and histologic evaluations of the placenta, and several other investigations and were used to determine the cause of death. The placenta was evaluated at both sites using the Amsterdam consensus framework. We estimated the risk of placental maternal and fetal vascular malperfusions in fetal and neonatal deaths. Between July 2018 and January 2020 in India and Pakistan, 1633 women with placentas available for the study provided consent. Of these women, 814 had fetal deaths, 618 had preterm live births and subsequent neonatal deaths, and 201 had term live births. The prevalence of maternal vascular malperfusion was higher in the placentas associated with fetal deaths (58.4%) and preterm neonatal deaths (31.1%) than in the placentas associated with term live births (15.4%). Adjusting for site, maternal vascular malperfusion had a relative risk of 3.88 (95% confidence interval, 2.70-5.59) in fetal deaths vs term live births and a relative risk of 2.07 (95% confidence interval, 1.41-3.02) in preterm neonatal deaths vs term live births. Infarcts and distal villous hypoplasia were the most common histologic components of maternal vascular malperfusion. Compared with maternal vascular malperfusion (58.4%), fetal vascular malperfusion was less common in the placentas associated with fetal deaths (19.0%). However, there were higher frequencies of fetal vascular malperfusion in the placentas associated with fetal deaths (19.0%) than in placentas associated with neonatal deaths (8.3%) or term live birth (5.0%). Adjusting for site, fetal vascular malperfusion had a relative risk of 4.09 (95% confidence interval, 2.15-7.75) in fetal deaths vs term live births and a relative risk of 1.77 (95% confidence interval, 0.90-3.49) in preterm neonatal deaths vs term live births. Furthermore, there was a higher incidence of maternal vascular malperfusion in cases of maternal hypertension (71.4%), small for gestational age (69.9%), and antepartum hemorrhage (59.1%) than in cases of fetal deaths with none of these conditions (43.3%). There was no significant difference in the occurrence of fetal vascular malperfusion in the 4 clinical categories. Histologic examination of the placenta, especially for malperfusion disorders, is crucial in elucidating pathways to fetal and neonatal deaths in preterm infants. In particular, focusing on placental maternal and fetal vascular malperfusions during pregnancy is a means to identify fetuses at risk of fetal death and is an important strategy to reduce the risk of fetal death early delivery. We hope that the increased risk of fetal and neonatal deaths in these pregnancies can be reduced by the development of an intervention that reduces the likelihood of developing maternal and fetal vascular malperfusion.

Study of Maternal and Fetal Doppler Velocimetry, Histopathology of Placental Bed in Diabetic Pregnancy and Its Correlation to Fetal Outcome

Diabetes mellitus still represents an important medical problem during pregnancy, causing perinatal morbidity and mortality. Despite improved outcome reflected by a steep decline in perinatal mortality over the past few decades, controversy still exists regarding the care of the pregnant woman with both pre-existing and gestational Diabetes Mellitus. Doppler ultrasound is especially valuable during pregnancy because fetal maternal and placental circulations can be studied. The aim of this work was to study the vascular changes in the uteroplacental and fetoplacental circulations, and to correlate these findings with histopathology of the placenta and placental bed, which may occur in association with diabetic pregnancies. The study was carried out on 100 pregnant women of comparable age and parity. They were divided into 2 groups. The control group comprising 20 normal non-diabetic pregnant women and the normotensive diabetic group comprising 80 pregnant diabetic women. All were singleton pregnancies of 34 weeks or more and were delivered by C.S the control and the study cases were subjected to history taking and thorough physical examination. They were also subjected to ultrasonographic examination for fetal biometric parameters and for Doppler examination. Doppler examination included umbilical artery, uterine arteries fetal middle cerebral artery. At the time of C.S the placenta and placental bed biopsy was obtained. After delivery, the Apgar score of the newborn was assessed at 1 and 5 minutes, the body weight was measured, and the fetus was followed up for any complications. Result: There was a positive correlation between the umbilical artery PI and the mean blood glucose levels indicating that poor diabetic control is probably associated with increased umbilical artery PI. However, there was no significant difference between the mean value of the umbilical artery PI in the diabetic and control groups. The uterine arteries Doppler indices showed no significant findings between the diabetic and the control groups. Neither did the uterine arteries Doppler indices show a correlation with the mean blood glucose levels. There was no significant difference between the middle cerebral artery PI in the diabetic and control groups. This observation indicates that there was no redistribution in the fetal circulation in the fetuses of the diabetic group. There was also non correlation between the MCA Doppler indices and the glycemic control. Histopathologic studies of the placental bed showed marked difference between the diabetic group and the control group as regards lack of physiologic changes and arteriosclerotic changes, which emphasizes the effect of diabetes on the placental bed vasculature. Conclusion: Abnormal umbilical artery waveform analysis is one of significant predictors of fetal compromise in diabetic pregnancy, but fetal compromise can occur in association with normal Doppler waveform analysis. In maternal diabetes the classic redistribution seen in fetal hypoxemia due to uteroplacental insufficiency may not occur in diabetic patient even in severely compromised fetuses. In maternal diabetes mellitus, maternal glycemic control has no effect on impedance to flow in the uterine and middle cerebral arteries. No relationship was found between the uterine or umbilical arteries Doppler indices and the placental bed decidual vascular pathology in diabetic pregnancies. There was no correlation between placental findings and the Doppler waveform analysis of the umbilical and the uterine arteries.

Mammalian Placentation: A Tribute to E.C. Amoroso's Contributions to Placenta Development.

Establishment of viviparity in mammals evolved through not only the long-term retainment of the fetus within the maternal uterus but differentiation and expansion of cell layers to form functional membranes to exchange O2/CO2 and nutrients between the placenta and maternal circulations. Development of a fetal placental vascular circulation to interact with the maternal uterus is critical to the survival of all species. However, the fascination with the mammalian placenta is the robust variation in types, form, attachment, invasiveness, structure, cell differentiation, endocrine function, and regulation of the maternal immune system. Despite the obvious role of the placenta to support fetal development, mammals have evolved multiple strategies to give live birth at term. The placenta and the maternal-fetal interface during pregnancy can be quite simple to very complex. Professor E.C. Amoroso contributed greatly to the study of comparative placentation in animals. His paper "Placentation" in Marshall's Physiology of Reproduction published in 1952 remains the standard for comparative placental anatomy today. The present volume on "Mammalian Placentation" brings together current reviews for leading experts to diversity of placentation in a number of mammalian species. Chapters will discuss viviparity, blastocyst formation, and placentation in the cow, pig, horse, mouse, dog, primate, human, elephant, and marsupials.

Maternal Cardiovascular Dysfunction is Associated with Hypoxic Cerebral and Umbilical Doppler Changes.

We investigate the relationship between maternal cardiovascular (CV) function and fetal Doppler changes in healthy pregnancies and those with pre-eclampsia (PE), small for gestational age (SGA) or fetal growth restriction (FGR). This was a three-centre prospective study, where CV assessment was performed using inert gas rebreathing, continuous Doppler or impedance cardiography. Maternal cardiac output (CO) and peripheral vascular resistance (PVR) were analysed in relation to the uterine artery, umbilical artery (UA) and middle cerebral artery (MCA) pulsatility indices (PI, expressed as z-scores by gestational week) using polynomial regression analyses, and in relation to the presence of absent/reversed end diastolic (ARED) flow in the UA. We included 81 healthy controls, 47 women with PE, 65 with SGA/FGR and 40 with PE + SGA/FGR. Maternal CO was inversely related to fetal UA PI and positively related to MCA PI; the opposite was observed for PVR, which was also positively associated with increased uterine artery impedance. CO was lower (z-score 97, p = 0.02) and PVR higher (z-score 2.88, p = 0.02) with UA ARED flow. We report that maternal CV dysfunction is associated with fetal vascular changes, namely raised impedance in the fetal-placental circulation and low impedance in the fetal cerebral vessels. These findings are most evident with critical UA Doppler changes and represent a potential mechanism for therapeutic intervention.

NO placental inflammation.

NO placental inflammation.

\u03949-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta

1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9–tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy.

Early Onset Fetal Growth Restriction: Does Path to Diagnosis Impact Outcomes and Pathology?

Objective:To evaluate demographics and outcomes of maternal-fetal pairs in early onset fetal growth restriction (FGR) requiring delivery prior to 34 weeks’ gestation based on ultrasound indication leading to diagnosis.Study Design:This is a descriptive study of maternal-fetal pairs with early FGR diagnosed prior to 30 weeks’ gestation and delivering between 22w0d and 34w0d under the care of Wake Forest University Perinatology 01/2012–12/2016. Serial ultrasounds to assess fetal growth and umbilical artery flow Doppler velocimetry were evaluated. Pairs were dichotomized into those with maternal comorbidities leading to ultrasound diagnosis, and those with ultrasound indicated only by appreciation of uterine size less than dates on exam. Patient characteristics and outcomes were tracked. Univariate and multivariate analyses were performed as appropriate.Results:56 pregnancies were identified with FGR prior to 30 weeks and subsequent delivery prior to 34 weeks. Common comorbidities present in the group with maternal comorbidities included chronic hypertension (30.5%), hypertensive disorders of pregnancy (36.1%), preexisting diabetes (13.9%), gestational diabetes (5.6%). None of the women in the S<D group developed hypertensive disorders of pregnancy or GDM. Other background characteristics were similar. Pregnancies evaluated for size less than dates were diagnosed on average 3 weeks later in gestation, had higher incidence of reverse end diastolic flow on Doppler evaluation both at diagnosis (80% vs. 22.9%, p=0.01, OR 0.08 (<0.01,0.74) and were more likely to be delivered for an urgent indication. Both groups of babies had similar survival to discharge rates and length of stay in the NICU. A subanalysis evaluating only babies with abnormal Doppler studies showed a shorter diagnosis to delivery interval and continued to show increased risk of urgent delivery due to fetal status in those pregnancies diagnosed based on size<dates.Conclusion:Women measuring size less than dates in the mid-trimester should be evaluated by ultrasound without delays. Early FGR carries a high mortality rate in all cases and in our pilot data, women measuring small were diagnosed later with fetal growth restriction and may represent a severe phenotype with poor fetal-placental circulation. These pregnancies often met criteria for urgent delivery in a short time frame, especially if abnormal umbilical artery Doppler velocimetry was noted.

The NuRD chromatin-remodeling complex enzyme CHD4 prevents hypoxia-induced endothelial Ripk3 transcription and murine embryonic vascular rupture.

Physiological hypoxia can trigger transcriptional events that influence many developmental processes during mammalian embryogenesis. One way that hypoxia affects transcription is by engaging chromatin-remodeling complexes. We now report that chromodomain helicase DNA binding protein 4 (CHD4), an enzyme belonging to the nucleosome remodeling and deacetylase (NuRD) chromatin-remodeling complex, is required for transcriptional repression of the receptor-interacting protein kinase 3 (Ripk3)-a critical executor of the necroptosis cell death program-in hypoxic murine embryonic endothelial cells. Genetic deletion of Chd4 in murine embryonic endothelial cells in vivo results in upregulation of Ripk3 transcripts and protein prior to vascular rupture and lethality at midgestation, and concomitant deletion of Ripk3 partially rescues these phenotypes. In addition, CHD4 binds to and prevents acetylation of the Ripk3 promoter in cultured endothelial cells grown under hypoxic conditions to prevent excessive Ripk3 transcription. These data demonstrate that excessive RIPK3 is detrimental to embryonic vascular integrity and indicate that CHD4 suppresses Ripk3 transcription when the embryonic environment is particularly hypoxic prior to the establishment of fetal-placental circulation at midgestation. Altogether, this research provides new insights into regulators of Ripk3 transcription and encourages future studies into the mechanism by which excessive RIPK3 damages embryonic blood vessels.

The state of the fetus circulation in congenital malformations of the fetus with placental dysfunction

Introduction. Improvement of perinatal care in Ukraine has led to a decrease in early neonatal mortality, but a decrease in antenatal losses has not occurred. In the structure of antenatal fetal death (AFD), congenital malformations (CM) account for about one fifth of reproductive losses and their percentage increases annually. A frequent complication during pregnancy with CM is placental dysfunction (PD), which occurs according to different authors in 19-69%. Primary dysfunction of the placenta with CM has a progressive nature, the consequence of which is AFD in various periods of pregnancy.The aim of the study - to reduce the frequency of antenatal fetal death in women with CM based on the determination of Doppler blood flow indicators in the feto-placental complex (FPC) and their timely delivery. Materials and Methods. The state of the feto-placental complex was monitored in 100 pregnant women with CM of the fetus in the period of 37-40 weeks of pregnancy. Studies were conducted in the uterine arteries (UA), umbilical arteries (UA), mid-cerebral artery (MCA) and fetal aorta (FA) with the definition of indicators of resistance index (RI), systolic-diastolic ratio (SDR) and pulse index (PI) . The control group (CG) consisted of 25 pregnant women, who gave birth to healthy children. The results of the study and their discussion. Examination and dynamic observation of 100 pregnant women with CM of the fetus allowed us to diagnose PD in the overwhelming number of pregnant women (41 pregnant - 41%), who manifested manifestations of fetal distress at 8.0 ± 2.71%, FGR at 29.76 ± 4.46% and FGR in combination with shallow water 3.24 ± 0.91%. For the purpose of a detailed analysis of the possible mechanisms of antenatal tanathogenesis, the patients were divided into two groups - with impaired blood flow in the FPC (OG1 - 41 pregnant) and without them (OG2 - 59 pregnant). It was pregnant OG1 that had manifestations of PD (distress, FGR and combination of FGR with low water). This separation allowed us to see the following picture of blood flow disorders.Analysis of the Doppler indices in UA showed that there is an increase in SDR in both UA, while the RI did not have a significant difference compared with CG and pregnant MG2. However, the correlation analysis did not indicate the presence of a relationship between blood flow disorders in UA and antenatal fetal death, which does not allow considering blood flow disorders in UA as stage of antenatal tanathogenesis.In pregnant MG1, a significantly higher RI index was found in UA compared with CG and MG2. PI did not have a significant difference compared with CG and pregnant women withCDF without PD. An analysis of blood flow in the MCA revealed a significant decrease in PI in pregnant MG1. A significant decrease in peripheral resistance to blood flow in the MCA can be a compensatory response to the deterioration of the fetal-placental blood circulation and is considered as indirect sign of brain congestion (the phenomenon of centralized blood flow). Analysis of the Doppler parameters in the AP testified to an increase in RI compared with the CG. An increase in RI in the aorta of the fetus may indicate a strain on the fetal heart during PD and may be a marker of the formation of congenital cardiomegaly in them.Conclusions. With CM of the fetus in combination with PD, deeper disturbances are observed in the utero-placental and placental-fetal complexes. In-time diagnosis of impaired blood flow allows in-time delivery of women with CM and reducing the risk of AFD.

Insulin Treatment Is Associated With Improved Fetal Placental Vascular Circulation in Obese and Non-obese Women With Gestational Diabetes Mellitus.

Objective: The present study was designed to investigate the impact of carbohydrate restriction and insulin treatment on placental maternal and fetal vascular circulation in obese and non-obese women with gestational diabetes mellitus (GDM).Design and methods: One Hundred Ninety-One women with GDM who gave birth and underwent a placental histopathological examination at Wolfson Medical Center, Israel, were included in the study: 122 women who were treated with carbohydrate/calorie restriction diet (Group 1) and 69 women who were treated with diet plus insulin (Group 2). Additionally, each group was divided into two subgroups according to pre-pregnancy BMI: non-obese and obese.Results: Maternal vascular malperfusion lesions did not differ significantly between groups. Vascular lesions related to fetal malperfusion were significantly lower in GDM women treated by insulin and diet compared to women with diet alone (p = 0.027). Among fetal malperfusion lesions, villous changes consistent with fetal thrombo-occlusive disease (FTOD) were significantly lower in women treated with diet plus insulin and lowest in GDM women with pre-pregnancy BMI < 30 kg/m2 (p = 0.009). In the logistic regression analysis, insulin treatment was significantly associated with a decreased rate of villous changes consistent with FTOD (OR 0.97, 95% CI 0.12–0.80, p = 0.03). Prevalence of gestational hypertension was higher in obese women of both treatment groups (p = 0.024).Conclusion: Combination of obesity and GDM increased rate of FTOD and prevalence of gestational hypertension. Carbohydrate restriction diet plus insulin treatment was associated with improved fetal placental vascular circulation, especially in GDM women with pre-pregnancy BMI < 30 kg/m2.

PECULIARITIES OF THE FUNCTIONAL STATE OF THE MOTHER-PLACENTA–FETUS SYSTEM IN PREGNANT WOMEN WITH PLACENTAL DYSFUNCTION

Among the causes that lead to antenatal affliction of the fetus, namely its hypoxia, hypotrophy, ante- and intranatal distress, is placental dysfunction (PD). Perinatal mortality in PDs is 10.3‰ in newborn infants, 49 ‰ – in preterm infants. Perinatal morbidity with PD reaches 70‰, and mortality rate – 20%. Objective. To investigate the functional state of the fetoplacental complex (FPС) in pregnant women with PD. Material and methods. The functional status of the FPC in 104 patients with PD (main group) and in 136 women with uncomplicated pregnancy and delivery (control group) using ultrasound placentalography, Dopplerometry was examined. Research results. The ultrasound characteristics of the placental dysfunction were the following: discrepancy between the degree of maturity of the placenta of the gestation period, true thickening of the placenta, its hypoplasia, reduction of echogenicity of the placenta, oligohydramnios. Dopplerometric signs of disorder of the utero-placental blood flow were high peripheral vascular resistance, both in dominant and in subdominant UA, asymmetry of blood flow in UA. Hemodynamics of fetal-placental circulation against the ground of PD was characterized by a decrease in the final diastolic blood flow velocity, which was manifested by an increase resistance in the peripheral vascular of the fetal part of the placenta, decrease in placental coefficient. The peculiarity of fetal blood flow in pregnant women with PD was the decrease in the mean value of vascular resistance indices in the middle cerebral artery of the fetus and a significant decrease in the cerebral-umbilical index. Conclusions. In pregnant women with placental dysfunction hemodynamic changes in the utero-placental complex are associated with decrease in the intensity of placental-fetal blood flow and in 16.3% of cases by centralization of the fetal circulation. Timely Dopplerometry is important both in the diagnosis of the compensatory capabilities of the FPK, and during determination of reasonable suggested obstetrical tactics.

Co-localization of microsomal prostaglandin E synthase-1 with cyclooxygenase-1 in layer II of murine placental syncytiotrophoblasts

The placenta is an organ that secretes prostaglandin (PG) E2 into the fetal-placental circulation to regulate both vascular tone and remodeling of the fetal ductus arteriosus. Placental PGE2 synthesis might be mediated by microsomal PGE synthase-1 (mPGES-1), in addition to cyclooxygenase (COX) isoforms. Thus, the purpose of this study is to clarify the temporal and spatial expression patterns of mPGES-1, together with COX-1 and COX-2, in murine placenta. We found that mPGES-1 and COX-1 protein levels continuously increased in the placental labyrinth from gestational day (GD) 13.5 to GD19.5, becoming higher than in the decidua or the junctional zone by GD17.5. The PGE2 level at GD17.5 was also highest in the labyrinth. Immunofluorescence stainings for mPGES-1 and COX-1 in the labyrinth at GD17.5 overlapped and were located on the fetal side of the signals for connexin 26, which forms gap junctions between maternal-facing (SynT-I) and fetal-facing (SynT-II) syncytiotrophoblast layers, and on the maternal side of the signals for glucose transporter 1 on the basal plasma membrane of SynT-II. On the other hand, the signals for COX-2 did not overlap with those for mPGES-1. These results indicate that COX-1 and mPGES-1 are co-localized in murine placental SynT-II, facing the fetal-placental circulation. Therefore, SynT-II could contribute to placental synthesis of PGE2 for release into the fetal-placental circulation.

Особливості морфофункціонального стану плаценти у жінок з кесаревим розтином в анамнезі

The article presents the results of clinico-morphological and functional studies of the placenta status in women with caesarean section (CS) in anamnesis undertaken to determine the possible relationship of morphogenesis of the placenta with features of functional capability of the operated uterus. The aim of the study was to determine peculiarities of morpho-functional condition of placenta in women with a CS in anamnesis, with different variants of functional capability of the scar. Material and methods. Examined 30 women with a CS in anamnesis, including 15 with scheduled repeat CS, and 15 with attempted vaginal delivery. Special research methods: morphometric, histological and immunohistochemical. The research object - the placenta. Results. It is established that morpho-functional state of the placenta in the presence of the operated uterus is characterized by the inclusion of adaptive processes aimed at improving fetal-placental blood circulation. In case of operated uterus, “compromised” the lower segment, in the presence of a proper or pathological changed scar ? in the placenta do not exist involutive-dystrophic and sclerotic processes, takes place the activation of collagen formation, which is a compensatory mechanism. In the presence of insolvent the lower segment of the uterus in the placenta takes place the morphological equivalent of the intensity of compensatory reactions, which has the value of the factor aggravating perinatal prognosis, in turn, limits the chances of success of attempts at vaginal delivery. Conclusions. Morphogenesis of the placenta on the background of operated uterus characterized by the development of adaptive responses, the list of which depends on a morpho-functional characteristics of the lower segment, while the degree of manifestation of adaptive-compensatory mechanisms is determined by the fact of able or unable scar. Key words: cesarean section, placenta, vaginal labor.

High glucose reduces resveratrol‐dependent disruption of CX3CL1/CX3CR1 signaling in human placental circulation

Upregulated activity of chemokine CX3CL1 (fractalkine) and abnormal expression of its sole receptor (CX3CR1) have been reported in many pro‐inflammatory conditions, including diabetes. Resveratrol (3,5,4′‐trihydroxy‐trans‐stilbene) possesses anti‐inflammatory and antioxidant properties related to its interference with NF‐κB (nuclear factor kappa‐beta) signaling pathway, which regulates the expression of various genes involved in inflammation, including CX3CL1. In this study, we examined influence of resveratrol on CX3CL1 production in extra corporeally perfused human term placental lobules under hyperglycemic (glucose 25 mmol/l; group I; N = 24) and normal (glucose 5 mmol/l; group II; N = 24) conditions. During the 150 min of perfusion, including the initial 30‐min adaptive phase, basal (immediately before administration of LPS) and LPS‐evoked (10 ng/ml) CX3CL1 secretion into the fetal side placental circulation was examined quantitatively in perfusion fluid samples using ELISA. After 60 min of perfusion, resveratrol (10~100μM) was added into the perfusion fluid. There were no significant differences between the studied groups in respect of the mean concentration of CX3CL1 (both basal and LPS‐evoked) in the samples collected before administration of resveratrol. Higher doses (50~100μM) of resveratrol produced significant (p &lt; 0.05) reductions in CX3CL1 level in the perfusion fluid in both groups. However, significantly stronger (p &lt; 0.02) reduction was observed in group II, compared to group I (2.37‐ vs. 1.64‐fold decrease, respectively). In conclusion, optimal anti‐inflammatory effects of resveratrol pertained to CX3CL1/CX3CR1 signaling in placental circulation should be expected under euglycemic conditions.Support or Funding InformationSupported by WUM grant: 2M2‐N‐15