Placental Circulation Research Articles

Bowel Circulation in Normally Grown and Growth-Restricted Fetuses

The purpose of this study was to characterize bowel blood flow and its relationship with cerebral and placental circulations in normally grown and growth-restricted fetuses. In a cross-sectional prospective study of singleton normally grown fetuses, Doppler blood flow pulsatility indices were measured in the superior mesenteric artery, middle cerebral artery, and umbilical artery from 19 to 38 weeks' gestation. The same Doppler parameters were examined in intrauterine growth-restricted (IUGR) fetuses and analyzed as two groups: (1) without a brain-sparing effect, defined as an umbilical artery/middle cerebral artery ratio of less than 1; and (2) with a brain-sparing effect, defined as an umbilical artery/middle cerebral artery ratio of greater than 1. A total of 262 appropriate-for-gestational-age fetuses were analyzed for superior mesenteric artery Doppler pulsatility index values; 196 were simultaneously examined for umbilical artery and middle cerebral artery pulsatility index values. Forty-three IUGR fetuses were similarly analyzed. In appropriate-for-gestational-age fetuses, both the bowel and brain circulations showed a globally higher pulsatility index as pregnancy advanced, resulting in an almost constant middle cerebral artery/superior mesenteric artery ratio (r(2) = 0.079). The IUGR fetuses had a lower superior mesenteric artery pulsatility index compared to the appropriate-for-gestational-age fetuses, which was more pronounced in those with brain sparing (group 2) than in group 1 (Z = -0.97 and -0.53, respectively; P < .0001). The middle cerebral artery/superior mesenteric artery ratio was higher with respect to the appropriate-for-gestational-age fetuses in group 1, whereas the ratio in group 2 was lower (Z = 0.16 and -0.60). We have shown the existence of a superior mesenteric artery sparing effect in IUGR fetuses. This reaction seems to correlate positively with the severity of the growth restriction.

Thromboxane and isoprostane share the same prostanoid receptors to increase human placental tone

As the placenta is devoid of autonomic innervation, umbilical-placental vascular tone should be under the control of tissue and humoral factors. Among the numerous stimuli capable of challenging the placental circulation, we propose that prostanoids could be responsible for the regulation of placental vascular tone. Consequently, we measured vasomotor responses to the thromboxane A2 (TXA2) mimetic U-46619 and the isoprostane 8-iso-prostaglandin E2 (8-isoPGE2) in the human placental vasculature. Placental tissues were collected from normotensive women after elective caesarean delivery. Cotyledons were set up in a perfusion system, whereas chorionic arteries were prepared as rings and installed in glass-jacketed tissue baths. The effects of U-46619 and 8-isoPGE2 were measured in the absence and presence of blockers of TXA2 receptors (TP), SQ29,548 and ICI192,605, and of PGE2 receptors (EP), AH6809. The influence of nitric oxide (NO) was assessed with NG-nitro-L-arginine methyl ester (L-NAME). U-46619 and 8-isoPGE2 markedly increased perfusion pressure in cotyledons and tension in chorionic arteries. Dose-response curves to both prostanoids were competitively shifted to the right by all antagonists, but to different extents. L-NAME had no significant impact on the dose-response curves to U-46619. The effects of U-46619 and 8-isoPGE2 were found to be mediated by both TP and EP. The presence of these receptors and the actions exerted by their agonists support our postulate that prostanoids play an important regulatory role in placental vascular tone and resistance. NO, however, does not seem to be involved.

Psychological distress after recent detection of fetal malformation: short-term effect on second-trimester uteroplacental and fetoplacental circulation

We examined the short-term effect of severe maternal psychological distress on the placental circulation in second trimester in a prospective observational study. In 86 pregnant women with a newly detected fetal malformation, and 98 women with normal ultrasound findings, distress was assessed using the Impact of Event Scale and the General Health Questionnaire-28. Uterine and umbilical artery pulsatility indices, notching and heart rates were measured by Doppler ultrasound. Psychological distress was high in the anomaly group, but circulatory outcome measures did not differ between groups. Multiple regression analyses did not show an increase in circulatory resistance measures even at high distress levels.

The effect of a derivative of indole morphine administered during the induction of labor on the activity of antioxidant enzymes in the brains of fetal rabbits

We studied the effects of a derivative of indole morphine (Trisan) during induction of labor on the activity of enzymes of antioxidant defense in the brains of fetuses that developed under normal (intact) and disturbed (experimental) placental blood circulation. We show that Trisan has antihypoxic and moderate antioxidant characteristics and decreased intranatal oxidative stress in the CNS of intact and experimental fetuses.

Positive end-expiratory pressure and surfactant decrease lung injury during initiation of ventilation in fetal sheep

The initiation of ventilation in preterm, surfactant-deficient sheep without positive end-expiratory pressure (PEEP) causes airway injury and lung inflammation. We hypothesized that PEEP and surfactant treatment would decrease the lung injury from initiation of ventilation with high tidal volumes. Fetal sheep at 128-day gestational age were randomized to ventilation with: 1) no PEEP, no surfactant; 2) 8-cmH(2)O PEEP, no surfactant; 3) no PEEP + surfactant; 4) 8-cmH(2)O PEEP + surfactant; or 5) control (2-cmH(2)O continuous positive airway pressure) (n = 6-7/group). After maternal anesthesia and hysterotomy, the head and chest were exteriorized, and the fetus was intubated. While maintaining placental circulation, the fetus was ventilated for 15 min with a tidal volume escalating to 15 ml/kg using heated, humidified, 100% nitrogen. The fetus then was returned to the uterus, and tissue was collected after 30 min for evaluation of early markers of lung injury. Lambs receiving both surfactant and PEEP had increased dynamic compliance, increased static lung volumes, and decreased total protein and heat shock proteins 70 and 60 in bronchoalveolar lavage fluid compared with other groups. Ventilation, independent of PEEP or surfactant, increased mRNA expression of acute phase response genes and proinflammatory cytokine mRNA in the lung tissue compared with controls. PEEP decreased mRNA for cytokines (2-fold) compared with groups receiving no PEEP. Surfactant administration further decreased some cytokine mRNAs and changed the distribution of early growth response protein-1 expression. The use of PEEP during initiation of ventilation at birth decreased early mediators of lung injury. Surfactant administration changed the distribution of injury and had a moderate additive protective effect.

Insignificant response of the fetal placental circulation to arterial hypotension in sheep

Infusion of the angiotensin-converting enzyme inhibitor enalaprilat into fetal sheep caused a profound arterial hypotension within days. Five fetal lambs were infused with enalaprilat for 8 days starting at day 128 of gestation. Total accumulated dose was 0.30 ± 0.11 mg/kg. Arterial pressure decreased from 43.6 to 25.6 mmHg; venous pressure did not change. Biventricular output was not statistically significantly changed; placental blood flow decreased almost in proportion to the decrease in pressure but the increase in somatic flow was not statistically significant. There were no significant changes in pressure 30 min after the initial 50-μg loading dose of enalaprilat. However, the arterial pressure responses to test doses of ANG I were largely abolished. After 1 day, however, there was a significant decrease in somatic vascular resistance, which became stronger with time, but almost no decrease in the placental resistance. We conclude that the fetal somatic circulation exhibits a slow but strong decrease in resistance but that the response to hypotension is weak or absent in the fetal placenta, possibly because it is already fully relaxed.

Imaging and assessment of placental function

The placenta is the vital support organ for the developing fetus. This article reviews current ultrasound (US) methods of assessing placental function. The ability of ultrasound to detect placental pathology is discussed. Doppler technology to investigate the fetal, placental, and maternal circulations in both high-risk and uncomplicated pregnancies is discussed and the current literature on the value of three-dimensional power Doppler studies to assess placental volume and vascularization is also evaluated. The article highlights the need for further research into three-dimensional ultrasound and alternative methods of placental evaluation if progress is to be made in optimizing placental function assessment.

Remifentanil for fetal immobilization and analgesia during the ex utero intrapartum treatment procedure under combined spinal–epidural anaesthesia

Remifentanil undergoes extensive placental transfer and has been used to provide fetal immobilization and anaesthesia for in utero fetal endoscopic interventions. We report three cases of the ex utero intrapartum treatment performed under neuraxial anaesthesia where the maternal administration of remifentanil was used to provide fetal immobilization and analgesia. Fetal pathology included goiter and arthrogryposis, with one case requiring a tracheostomy. The longest time on placental circulation was 21 min. No clinically significant maternal sedation or respiratory depression was observed. In all cases, remifentanil provided adequate fetal immobilization and obviated the need to administer other analgesics or neuromuscular blocking agents. Remifentanil is a useful adjunct for ex utero fetal procedures.

Absent end diastolic flow: progression and perinatal outcome at a tertiary referral centre

IntroductionAbsent end diastolic flow (AEDF) results from obliteration of around 60% of placental circulation and represents a major pathological sign in fetal management.MethodsRetrospective cohort study of maternity database. Maternal demographics,...

Effects of intermittent high glucose on BeWo choriocarcinoma cells in culture

The aim of this study was to investigate the cellular effects of intermittent high glucose on the human BeWo placental choriocarcinoma cell line, used as a model of the effects of glucose fluctuation in diabetic pregnancies. BeWo cells were subjected to three different glucose conditions for 48 h: 7 mmol/L (control), 42 mmol/L (high glucose), or 7 and 42 mmol/L glucose (intermittent, alternated every 6 h). Cell viability was assessed using cell counts, a cell proliferation assay, and a cell viability assay. Apoptosis was also studied using a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and by immunocytochemistry of fractin, the N-terminal fragment of actin, which can distinguish apoptotic from necrotic cells. Furthermore, the expression of the well-known survival factors of trophoblast cells, heparin-binding epidermal growth factor-like growth factor and leptin, was evaluated by real-time polymerase chain reaction and Western blot analyses. Intermittent high-glucose conditions significantly decreased cell viability and enhanced apoptosis compared with control or continuous high-glucose conditions. Furthermore, the expression of heparin-binding epidermal growth factor-like growth factor, but not that of leptin, was significantly increased under intermittent high-glucose conditions compared to its expression under either control or continuous high-glucose conditions. These data indicate that intermittent high glucose is more deleterious to BeWo cells than continuous high-glucose conditions. Although further in vitro and in vivo study is necessary, excess fluctuation of glucose levels in the placental circulation might be involved in the impairment of placental development leading to the placental dysfunction.

Survival and Size Are Differentially Regulated by Placental and Fetal PKBalpha/AKT1 in Mice1

The importance of placental circulation is exemplified by the correlation of placental size and blood flow with fetal weight and survival during normal and compromised human pregnancies in such conditions as preeclampsia and intrauterine growth restriction (IUGR). Using noninvasive magnetic resonance imaging, we evaluated the role of PKBalpha/AKT1, a major mediator of angiogenesis, on placental vascular function. PKBalpha/AKT1 deficiency reduced maternal blood volume fraction without affecting the integrity of the fetomaternal blood barrier. In addition to angiogenesis, PKBalpha/AKT1 regulates additional processes related to survival and growth. In accordance with reports in adult mice, we demonstrated a role for PKBalpha/AKT1 in regulating chondrocyte organization in fetal long bones. Using tetraploid complementation experiments with PKBalpha/AKT1-expressing placentas, we found that although placental PKBalpha/AKT1 restored fetal survival, fetal PKBalpha/AKT1 regulated fetal size, because tetraploid complementation did not prevent intrauterine growth retardation. Histological examination of rescued fetuses showed reduced liver blood vessel and renal glomeruli capillary density in PKBalpha/Akt1 null fetuses, both of which were restored by tetraploid complementation. However, bone development was still impaired in tetraploid-rescued PKBalpha/Akt1 null fetuses. Although PKBalpha/AKT1-expressing placentas restored chondrocyte cell number in the hypertrophic layer of humeri, fetal PKBalpha/AKT1 was found to be necessary for chondrocyte columnar organization. Remarkably, a dose-dependent phenotype was exhibited for PKBalpha/AKT1 when examining PKBalpha/Akt1 heterozygous fetuses as well as those complemented by tetraploid placentas. The differential role of PKBalpha/AKT1 on mouse fetal survival and growth may shed light on its roles in human IUGR.

Newborn Respiratory Disorders

Newborn Respiratory Disorders

M9.5 Association of single nucleotide polymorphism in the vascular endothelial growth factor gene with small for gestational age birth

Introduction: Impaired placental angiogenesis is implicated in the pathophysiology of small for gestational age (SGA) infants. Placental expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor which regulates placental angiogenesis, is reduced in SGA pregnancies. We evaluated the association of two functional single nucleotide polymorphisms in the VEGF gene (VEGF+2578C/A and VEGF+936C/T) in SGA pregnancies. Methods: 3196 nulliparous pregnant women, their partners and babies were recruited in Adelaide and Auckland to a prospective multicenter cohort study (SCOPE Study). Amongst 2597 Caucasian women, 269 (10.4%) delivered a SGA infant defined as <10th customised centile (adjusted for gestational age at delivery, infant sex, maternal ethnicity, weight, height and parity). Uncomplicated Caucasian pregnancies served as controls (n=1463). Uterine and umbilical artery Doppler velocimetry was performed at 20 weeks gestation. DNA was extracted from peripheral blood from couples and cord blood from babies. Genotyping was performed using the Sequenom MassARRAY system. Genotype frequency of SGA was compared with controls using dominant and recessive genotype models by logistic regression analysis. ANCOVA was used to compare genotypes with birthweight and placental weight (adjusted for gestational age) in the Caucasian cohort. Results: Neonatal VEGF+936 CT+TT genotypes [dominant model] were increased in SGA (OR: 1.63, 95%CI: 1.1-2.3). Neonatal VEGF+936 CT+TT genotypes were associated with lower birthweight (p=0.005), customised birthweight centile (p=0.03) and placental weight (p=0.04) than CC. Maternal VEGF+936 CT+TT genotypes were associated with increased umbilical artery resistance index (OR: 1.5, 95%CI: 1.1-2.1) and the presence of bilateral uterine artery waveform notching (OR: 1.4, 95%CI: 1.0-1.8) compared to CC. Neonatal VEGF+936 CT+TT genotypes were associated with increased uterine artery resistance index (p=0.004). All associations remained significant after adjusting for confounding factors. Conclusion: The low VEGF producing VEGF+936 CT and TT genotypes associate with increased resistance in the placental circulation. These genotypes confer an increased risk for SGA and may be implicated in impaired placental function.

P1 A new book recommended

In this book “New Concept of Hypertension in Pregnancy”, a brand new classification and pathophysiologic concept with clinical staging of hypertension in pregnancy has been raised. The book provides a theoretical and clinical explanation as well as a solution for this puzzlingly intricate problem. It reveals the solution from a new angle. Things that used to be difficult to understand or solve before are becoming easier to understand. 1. New Concept: Hypertension in pregnancy is caused by primary pathologic change of the placenta. It is a process of damage from clinical compensation to decompensation caused by chronic stress reactions and stress injuries. It is primarily caused by a developmental disorder of placental trophoblastic terminal villi (during the maturing process of the placenta), which in turn causes a decrease in the number of trophoblastic terminal villi arterioles. This decrease of the number of the trophoblastic terminal villi arterioles can cause fetal-placental circulation ischemia*. On the other hand, environmental factors (such as fatigue, tension, heavy work load, grief, fury etc.) also contribute to the damage process. 2. A New Classification: Endogenous (early-onset, placenta-derived) Mixed (both endogenous and exogenous) Exogenous (late-onset, non-placenta-derived, high pressure from the environment) 3. New pathophysiology and clinical staging of hypertension in pregnancy: Latent stage: Noradrenergic neurotransmitters raised in response to ischemia of the fetal–placental circulation and/ or in response to environmental factors. Clinical compensatory stage: Small arteries spasm and vascular endothelial cells are damaged. Clinical decompensation stage: Tissue injury and ischemic necrosis. Failure period: Systemic organ failure *The volume of the feto-placental circulation can be measured by the velocity of umbilical artery blood flow using Doppler Ultrasound. However if the absolute volume of blood flow to the placenta is decreased, ischemia can result, even though the systolic/ diastolic ratio might be normal. In this study, absolute volumes of fetoplacental blood flow are made by Doppler ultrasound as a means of predicting ischemia in low fetoplacental flow volumes.

Vascular Biology of the Placenta

Abstract The placenta is an organ that connects the developing fetus to the uterine wall, thereby allowing nutrient uptake, waste elimination, and gas exchange via the mother’s blood supply. Proper vascular development in the placenta is fundamental to ensuring a healthy fetus and successful pregnancy. This book provides an up-to-date summary and synthesis of knowledge regarding placental vascular biology and discusses the relevance of this vascular bed to the functions of the human placenta. Table of Contents: Introduction / Placental Blood Circulation / Structure of the Placenta / Cell Types of the Placenta / Oxygen Tension and Placental Vascular Development / Vasculogenesis and Angiogenesis of Human Placenta / Angiogenic Factors / Vasoactivators and Placental Vasoactivity / Lymphatic Phenotypic Characteristics of the Human Placenta / Placental Tissue and Cord Blood Stem Cells / Summary / Acknowledgment / References

Detection of enlarged yolk sac on early ultrasound is associated with adverse pregnancy outcomes

Pregnancies with mean yolk sac diameter>or=5 mm on early ultrasound require monitoring and counseling about a threefold increased risk for first-trimester loss independent of maternal risk factors such as age, body mass index, polycystic ovary syndrome, smoking, and diabetes. In addition, our study shows for the first time that enlarged yolk sac diameter may be associated with an increased risk of preterm delivery.

Growth factor concentrations and their placental mRNA expression are modulated in gestational diabetes mellitus: possible interactions with macrosomia

BackgroundGestational diabetes mellitus (GDM) is a form of diabetes that occurs during pregnancy. GDM is a well known risk factor for foetal overgrowth, termed macrosomia which is influenced by maternal hypergycemia and endocrine status through placental circulation. The study was undertaken to investigate the implication of growth factors and their receptors in GDM and macrosomia, and to discuss the role of the materno-foeto-placental axis in the in-utero regulation of foetal growth.Methods30 women with GDM and their 30 macrosomic babies (4.75 ± 0.15 kg), and 30 healthy age-matched pregnant women and their 30 newborns (3.50 ± 0.10 kg) were recruited in the present study. Serum concentrations of GH and growth factors, i.e., IGF-I, IGF-BP3, FGF-2, EGF and PDGF-B were determined by ELISA. The expression of mRNA encoding for GH, IGF-I, IGF-BP3, FGF-2, PDGF-B and EGF, and their receptors, i.e., GHR, IGF-IR, FGF-2R, EGFR and PDGFR-β were quantified by using RT-qPCR.ResultsThe serum concentrations of IGF-I, IGF-BP3, EGF, FGF-2 and PDGF-B were higher in GDM women and their macrosomic babies as compared to their respective controls. The placental mRNA expression of the growth factors was either upregulated (FGF-2 or PDGF-B) or remained unaltered (IGF-I and EGF) in the placenta of GDM women. The mRNA expression of three growth factor receptors, i.e., IGF-IR, EGFR and PDGFR-β, was upregulated in the placenta of GDM women. Interestingly, serum concentrations of GH were downregulated in the GDM women and their macrosomic offspring. Besides, the expression of mRNAs encoding for GHR was higher, but that encoding for GH was lower, in the placenta of GDM women than control women.ConclusionsOur results demonstrate that growth factors might be implicated in GDM and, in part, in the pathology of macrosomia via materno-foeto-placental axis.

The Effects of All-Trans Retinoic Acid on Leukocytes in Rat's Embryo

This study was planned to determine the effects of All-Trans Retinoic Acid (ATRA) on the progenitors of White Blood Cells (WBC) and survey their outcomes in rat's embryo during both late-yolk sac and fetal liver stages of hematopoiesis. Single oral dose (100 mg kg(-1)) of ATRA was administered to rat on Gestation Day (GD) 10 and fetuses were observed on GD 18. The fetus's blood (from experimental group and control each, n = 24) were obtained directly from heart, as placental and mother circulation was continued and subsequently processed for Giemsa staining and followed by WBC counting and measuring. Statistical analysis was made by student t-test. A p-value <0.05 was considered significant. In the experimental embryos on GD 18, the mean number of WBC (29.2%), neutrophil, lymphocyte and monocyte were increased. There was a significant difference in WBC (p<0.0001) and neutrophil (p<0.001) between the groups in this regard. The mean diameter of neutrophil, lymphocyte and monocyte were compared in two groups. The results showed no significant change on experimental and control groups. We concluded that ATRA may have positive effects on proliferation, differentiation and maturation of neutrophil without having any significant effects on the diameter of cells throughout normal granulocyte differentiation in embryo during both late-yolk sac and fetal liver stages of hematopoiesis.

Association between antenatal distress and uterine artery pulsatility index

Although studies have found associations between maternal distress/anxiety and alterations in blood flow, data across different trimesters are inconsistent. We, therefore, sought to determine the association between measures of distress and uterine blood flow in all three trimesters. Healthy women with low-risk singleton pregnancies were recruited from antenatal clinics. Women were assessed at 13-14 weeks (T1), 21-22 weeks (T2), and 32-33 weeks (T3) of gestation with measures of distress and anxiety (the K10, Perceived Stress Scale, and the State Subscale of the Spielberger State-Trait Anxiety Inventory [STAI]) and with uterine Doppler flow velocity studies. The Trait Subscale of the STAI was done either at T1 or T2. Thirty women were seen at T1, 79 women were seen at T2, and 59 women were seen at T3. No significant correlations were found between measures of distress and anxiety and umbilical artery pulsatility index (PI) or middle cerebral artery PI at any time-point. Small positive correlations between trait anxiety and uterine artery PI were found, but these were not significant after adjustment for alcohol and nicotine use (any use as well as problem drinking/nicotine dependence). At T3 but not T1 or T2, women scoring above 20 on the K10 (a standardized cutoff for the presence of axis I psychiatric disorders) had higher uterine artery PI than those scoring below 20.This was significant after adjusting for alcohol and nicotine use, as well as when nicotine dependence was considered. This work highlights the complexities of the relationship between increased measures of distress and anxiety and changes in the placental circulation. Further work in this area is needed to explore the underlying mechanisms which account for this relationship and to delineate fully the extent to which the relationship is determined by the presence of psychiatric and substance use disorders.

Review: Reactive oxygen and nitrogen species and functional adaptation of the placenta

The placenta regulates fetal growth and development via transport of nutrients and gases, and synthesis and secretion of steroid and peptide hormones. These functions are determined by vascular development and blood flow and by growth and differentiation of the trophoblast, which contains receptors, transporters and enzymes. The placenta generates reactive oxygen species which may contribute to the oxidative stress seen even in normal pregnancy but this is increased in pregnancies complicated by preeclampsia, IUGR and pregestational diabetes where oxidative and nitrative stress have been clearly documented. Nitrative stress is the covalent modification of proteins and DNA by peroxynitrite formed by the interaction of superoxide and nitric oxide. We have demonstrated nitrative stress by localizing nitrotyrosine residues in these placentas and found increased expression of NADPH oxidase (NOX) enzyme isoforms 1 and 5 as a potential source of superoxide generation. The presence of nitrative stress was associated with diminished vascular reactivity of the fetal placental circulation, a situation that could be reproduced by treatment with peroxynitrite in vitro. We find many nitrated proteins in the placenta, including p38 MAP kinase which has a role in development of the villous vasculature. Nitration of p38 MAPK was increased in the preeclamptic placenta and associated with loss of catalytic activity. We hypothesize that nitration of proteins in the placenta including receptors, transporters, enzymes and structural proteins can alter protein and placental function and this influences fetal growth and development. Increasing nitrative stress but a decrease in oxidative stress, measured as protein carbonylation, is found in the placenta with increasing BMI. Formation of peroxynitrite may then consume superoxide, decreasing nitrative stress. As protein carbonylation is a covalent modification at Lys, Arg, Pro and Thr residues the switch from carbonylation to nitration at tyrosine residues may alter protein function and hence placental function.