Placental Blood Flow Research Articles

Guidelines for the Doppler Assessment of the Umbilical and Middle Cerebral Arteries in Obstetrics

ABSTRACT The use of Doppler ultrasound is an important tool in the obstetrical assessment of an at-risk fetus. Principles of the Doppler effect can be used to monitor placental and fetal blood flow in pregnancies complicated by fetal growth restriction or in the surveillance for fetal anemia from maternal alloimmunization. Indications and techniques for umbilical artery and middle cerebral artery Doppler assessment are reviewed. How to cite this article Broady A, Zalud I. Guidelines for the Doppler Assessment of the Umbilical and Middle Cerebral Arteries in Obstetrics. Donald School J Ultrasound Obstet Gynecol 2016;10(4):418-421.

OP20.01: Nulliparous and multiparous women differ in placental vascular development

Nulliparas differ from multiparas by giving birth to smaller babies and being at higher risk of developing pre-eclampsia. We tested the hypothesis that nulliparas and multiparas differ in their first-trimester development of placental vascularisation and volume. We measured placental flow index (FI), vascularisation index (VI) and placental volume (PV) by 3D power Doppler and VOCAL at 2 week intervals between 8 and 12 weeks pregnancy in 34 apparently healthy nulliparous and 16 multiparous, with normal pregnancy outcome. FI increased between 8 and 10 weeks in both nulliparous (p = 0.006) and multiparous women (p = 0.009) see figure 1. Between 10 and 12 weeks, the FI continued to increase significantly in nulliparas (p = 0.017) together with VI (p = 0.002), but not in multiparas. At 12 weeks, FI was indistinguishable between both groups. FI and VI varied markedly at all measurement points. The altered placental blood flow was not accompanied by a difference in placental volume growth. The placental vascularisation of multiparous women differs from nulliparous women. Multiparous women have an earlier development of first-trimester placental flow, without difference in the concomitant growth in placental volume. Supporting information can be found in the online version of this abstract Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The rat placental renin-angiotensin system - a gestational gene expression study.

BackgroundThe placenta is an essential organ that provides nutrients and oxygen to the developing fetus and removes toxic waste products from the fetal circulation. Maintaining placental blood osmotic pressure and blood flow is crucial for viable offspring. The renin-angiotensin system (RAS) in the placenta is a key player in the regulation of maternal-fetal blood flow during pregnancy. Therefore, the aim of this study was to determine if RAS genes are differentially expressed in mid to late gestation in rat placenta.MethodsWhole placental tissue samples from pregnant Sprague Dawley rats at embryonic (E) days 14.25, 15.25, 17.25 and 20 (n = 6 for each gestational age) were used for genome-wide gene expression by microarray. RAS genes with expression differences of >2 fold were further analyzed. Quantitative Real-Time PCR (qPCR) was performed on independent samples to confirm and validate microarray data. Immunohistochemisty and Western blotting were performed on a differentially expressed novel RAS pathway gene (ANPEP).ResultsSix out of 17 genes of the RAS pathway were differentially expressed at different gestational ages. Gene expression of four genes (Angiotensin converting enzyme (Ace), angiotensin converting enzyme 2 (Ace2), membrane metalloendopeptidase (Mme) and angiotensin II receptor 1A (Agtr1a)) were significantly upregulated at E20 whereas two others (Thimet oligopeptidase 1 (Thop1) and Alanyl aminopeptidase (Anpep)) were downregulated at E20 prior to the onset of labour. These changes were confirmed by qPCR. Western blots revealed no overall differences in ANPEP protein expression in the placentae. Immunohistochemical studies, however, indicated that the localization of ANPEP differed at E17.25 and E20 as ANPEP localization in the giant trophoblast cell of the junctional zone was no longer detectable at E20.ConclusionsThe current study investigated the expression of members of the RAS pathway in rat placentae and observed significantly altered expression of 6 RAS genes at 4 gestational ages. These findings present the need for further comprehensive investigation of RAS genes in normal and complicated pregnancies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0088-y) contains supplementary material, which is available to authorized users.

2,3,7,8-Tetrachlorodibenzo-p-dioxin differentially suppresses angiogenic responses in human placental vein and artery endothelial cells.

Placental angiogenesis is dramatically increased during pregnancy in association with the elevated placental blood flows to support the rapidly growing fetus. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxicant and a ligand of aryl hydrocarbon receptor (AhR). Herein, we investigated the effects of TCDD on proliferation, migration, and viability of fetoplacental endothelial cells in response to a complete growth medium which contained serum and growth supplement using human umbilical cord vein (HUVECs) and artery (HUAECs) cells as models. We found that TCDD dose- and time-dependently inhibited (p < 0.05) proliferation of HUVECs and HUAECs. Treatment with TCDD at 10 nM for 6 days inhibited (p < 0.05) migration (by ∼ 30%) of HUAECs, but not HUVECs. TCDD at 10nM also decreased (p < 0.05) viability of HUVECs and HUAECs. Interestingly, specific AhR siRNA blocked (p < 0.05) the TCDD-inhibited cellular responses in HUAECs, but not HUVECs. Nonetheless, TCDD at 10nM neither affected the cell cycle progression, nor did it induce cell apoptosis in HUVECs and HUAECs. In addition, TCDD at 10 nM also did not alter activation of ERK1/2 and AKT1 in HUVECs and HUAECs. Collectively, TCDD suppresses proliferation and/or migration (two key steps of angiogenesis) of HUVECs and HUAECs independent and dependent of AhR, respectively. These data suggest that TCDD inhibited growth of HUVECs and HUAECs via decreasing cell viability. Thus, TCDD may inhibit fetoplacental angiogenesis, leading to negative pregnancy outcomes.

Placental laterality and uterine blood flow at 20–40 weeks’ gestation in low-risk pregnancies

We sought to examine flow velocity waveforms of the uterine arteries with respect to placental location at 20–40 weeks’ gestation. Blood flow (BF) volume, pulsatility index (PI), resistance index (RI), end-diastolic velocity, mean velocity, peak systolic velocity and systolic/diastolic ratio (S/D) were obtained by colour Doppler ultrasonography from bilateral uterine arteries in 288 low-risk singleton pregnancies. In cases with lateral placentation the mean PI and RI values at 36–40 weeks’ gestation and the mean S/D value at 38–40 weeks were significantly higher in the contralateral than in the ipsilateral uterine arteries. Both BF volume and RI correlated inversely with gestational age in these groups (r = − 0.20 and p = 0.01; r = − 0.17 and p = 0.03, respectively). The contralateral and central uterine arteries were comparable for all Doppler indices. In conclusion, lateral placentation may affect uterine artery blood flow throughout gestation and some Doppler indices near term. Clinical significance of these findings needs to be elucidated.

PreImplantation Factor (PIF*) endogenously prevents preeclampsia: Promotes trophoblast invasion and reduces oxidative stress

Preeclampsia is a unique pregnancy disorder whose patho-physiology is initiated early in gestation, while clinical manifestations typically occur in mid-to-late pregnancy. Thus, prevention should optimally be initiated in early gestation. The intimate interaction between PIF, secreted early by viable embryos, and its host-mother provides insight into putative mechanisms of preeclampsia prevention.PIF is instrumental at the two critical events underlying preeclampsia. At first, shallow implantation leads to impaired placentation, oxidative stress, protein misfolding, and endothelial dysfunction. Later in gestation, hyper-oxygenation due to overflow of maternally derived oxygenated blood compromises the placenta. The first is likely involved in early preeclampsia occurrence due to reduced effectiveness of trophoblast/uterus interaction. The latter is observed with later-onset preeclampsia, caused by a breakdown in placental blood flow regulation. We reported that 1. PIF promotes implantation, endometrium receptivity, trophoblast invasion and increases pro-tolerance trophoblastic HLA-G expression and, 2. PIF protects against oxidative stress and protein misfolding, interacting with specific targets in embryo, 3. PIF regulates systemic immunity to reduce oxidative stress. Using PIF as an early preventative preeclampsia intervention could ameliorate or even prevent the disease, whose current main solution is early delivery.

Expecting questions about exercise and pregnancy?

The appropriateness of various forms of exercise during pregnancy is controversial. Numerous physiologic and anatomic adaptations to pregnancy affect a woman's ability to exercise and her body's response to exercise. Placental blood flow, the potential for hyperthermia and trauma, changes in coordination and balance, body position during exercise, increased nutritional requirements, and the potential for back and pelvic pain must all be considered in light of each woman's particular exercise program. Clinical guidelines for recommending exercise or participation in competitive sports during pregnancy are provided.

Pregnancy in advanced chronic kidney disease and end-stage renal disease.

This article reviews the available literature about the incidence, outcomes, and the management of pregnancy in women with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) who require renal replacement therapy. Pregnancy in women with advanced CKD and ESRD can result in serious adverse maternal and fetal outcomes, but improved outcomes have been noted in recent years, likely secondary to intensified dialysis regimens. More intensive dialysis allows for the gentle removal of water, solutes, and uremic toxins, which theoretically results in near-normal maternal renal physiology, an improvement in placental blood flow, and therefore a better environment for fetal growth and development. As management remains complex, a close joint collaboration between the high-risk obstetrical team and nephrology is essential. Pregnancy on dialysis is becoming a viable option for women with advanced CKD and ESRD who do not have immediate access to transplantation.

Functional MRI of the placenta – From rodents to humans

The placenta performs a wide range of physiological functions; insufficiencies in these functions may result in a variety of severe prenatal and postnatal syndromes with long-term negative impacts on human adult health. Recent advances in magnetic resonance imaging (MRI) studies of placental function, in both animal models and humans, have contributed significantly to our understanding of placental structure, blood flow, oxygenation status, and metabolic profile, and have provided important insights into pregnancy complications.

Updates in Preeclampsia

Hypertensive disorders of pregnancy, specifically preeclampsia, cause significant morbidity and mortality in both the mother and fetus. Changes in the diagnostic criteria have attempted to improve the ability to identify and initiate treatment. Recently, it has been discovered that a placenta-derived anti-angiogenic environment directly contributes to the pathological cause of preeclampsia. The early identification of these anti-angiogenic markers may enhance diagnosis of the disease in the future. Patients with preeclampsia need to be treated with caution in regard to airway and coagulation; however, neuraxial anesthesia, when appropriate, is preferred. During labor, the increase in placental blood flow secondary to epidural analgesia can improve fetal perfusion. Spinal and epidural anesthesia are safe for cesarean delivery in mothers with preeclampsia, and may be preferred over general anesthesia. Preeclampsia is a complex disorder that impacts day to day decisions of anesthesia care provider.

Features of placental blood flow in pregnant women with noncarrying

Features of placental blood flow in pregnant women with noncarrying

Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates

We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in nonhuman primates, and maternal vitamin C supplementation attenuates these deleterious effects. However, the effect of nicotine on placental perfusion and development is not fully understood. This study utilizes noninvasive imaging techniques and histological analysis in a nonhuman primate model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development but is ameliorated by vitamin C. Time-mated macaques (n = 27) were divided into 4 treatment groups: control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), and nicotine plus vitamin C (n = 9). Nicotine animals received 2 mg/kg per day of nicotine bitartrate (approximately 0.7 mg/kg per day free nicotine levels in pregnant human smokers) from days 26 to 160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100, or 250 mg/kg per day with or without nicotine. All underwent placental dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at 135-140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. Animals were delivered by cesarean delivery at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology. Placental volume blood flow was significantly reduced in nicotine-only animals compared with controls and nicotine plus vitamin C groups (P = .03). Maternal placental blood flow was not different between experimental groups by DCE-MRI, ranging from 0.75 to 1.94 mL/mL per minute (P = .93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (P < .05) and increased syncytiotrophoblast sprouting (P < .001) in nicotine-only animals, which was mitigated by vitamin C. Prenatal nicotine exposure significantly decreased fetal blood supply via reduced placental volume blood flow, which corresponded with placental histological findings previously associated with cigarette smoking. Vitamin C supplementation mitigated the harmful effects of prenatal nicotine exposure on placental hemodynamics and development, suggesting that its use may limit some of the adverse effects associated with smoking during pregnancy.

Placental Adaptations in Growth Restriction

The placenta is the primary interface between the fetus and mother and plays an important role in maintaining fetal development and growth by facilitating the transfer of substrates and participating in modulating the maternal immune response to prevent immunological rejection of the conceptus. The major substrates required for fetal growth include oxygen, glucose, amino acids and fatty acids, and their transport processes depend on morphological characteristics of the placenta, such as placental size, morphology, blood flow and vascularity. Other factors including insulin-like growth factors, apoptosis, autophagy and glucocorticoid exposure also affect placental growth and substrate transport capacity. Intrauterine growth restriction (IUGR) is often a consequence of insufficiency, and is associated with a high incidence of perinatal morbidity and mortality, as well as increased risk of cardiovascular and metabolic diseases in later life. Several different experimental methods have been used to induce placental insufficiency and IUGR in animal models and a range of factors that regulate placental growth and substrate transport capacity have been demonstrated. While no model system completely recapitulates human IUGR, these animal models allow us to carefully dissect cellular and molecular mechanisms to improve our understanding and facilitate development of therapeutic interventions.

Impaired fetoplacental angiogenesis in growth-restricted fetuses with abnormal umbilical artery doppler velocimetry is mediated by aryl hydrocarbon receptor nuclear translocator (ARNT).

Fetal growth restriction with abnormal umbilical artery Doppler velocimetry (FGRadv), reflective of elevated fetoplacental vascular resistance, is associated with increased risks of fetal morbidity and mortality even in comparison to those of growth-restricted fetuses with normal placental blood flow. One major cause of this abnormally elevated fetoplacental vascular resistance is the aberrantly formed, thin, elongated villous vessels that are seen in FGRadv placentas. The purpose of this study was to determine the role of fetoplacental endothelial cells (ECs) in angiogenesis in normal pregnancies and in those complicated by FGRadv. Human placental specimens were obtained from FGRadv and gestational age-matched, appropriately grown control pregnancies for EC isolation/culture and for immunohistochemical studies. Additional mechanistic studies were performed on ECs isolated from subjects with term, uncomplicated pregnancies. We evaluated tube formation and differential angiogenic gene expression in FGRadv and control ECs, and we used ECs from uncomplicated pregnancies to further elucidate the molecular mechanisms by which angiogenesis is impaired in FGRadv pregnancies. Tube formation assays showed that FGRadv ECs demonstrate fewer branch points and total length compared with those from gestational age-matched controls, and this defect was not rescued by exposure to hypoxia. FGRadv ECs also demonstrated lower aryl hydrocarbon receptor nuclear translocator (ARNT) expression. ARNT knockdown resulted in suppression of key angiogenic genes including vascular endothelial growth factor A expression and led to deficient tube formation. ARNT expression in the placental vasculature mediates key angiogenic expression and fetoplacental EC angiogenesis, and low ARNT expression in FGRadv ECs appears to be a key factor in deficient angiogenesis. This, in turn, results in malformed thin villous vessels that structurally contribute to the abnormally elevated fetoplacental vascular resistance that is associated with high morbidity and mortality in fetal growth restriction.

Galectins in angiogenesis: consequences for gestation

Members of the galectin family have been shown to exert several roles in the context of reproduction. They contribute to placentation, maternal immune regulation and facilitate angiogenesis encompassing decidualisation and placenta formation during pregnancy. In the context of neo-vascularisation, galectins have been shown to augment signalling pathways that lead to endothelial cell activation, cell proliferation, migration and tube formation in vitro in addition to angiogenesis in vivo. Angiogenesis during gestation ensures not only proper foetal growth and development, but also maternal health. Consequently, restriction of placental blood flow has major consequences for both foetus and mother, leading to pregnancy diseases. In this review we summarise both the established and the emerging roles of galectin in angiogenesis and discuss the possible implications during healthy and pathological gestation.

Three-dimensional Power Doppler Ultrasound Study of the Placenta

ABSTRACT Advanced ultrasound technology has been a valuable tool in the assessment of placental anatomy and physiology. Conventional two-dimensional (2D) sonography reveals placental morphological characteristics, 2D color Doppler can assess blood flow in the placenta, 2D power Doppler can evaluate placental vascular trees, and three-dimensional (3D) ultrasound gives more detailed information on the surface anatomy. Recent advances, such as 3D power Doppler with virtual organ computer aided-analysis (VOCAL) and histogram analysis can measure the placental volume, and assess uteroplacental and fetoplacental perfusions. In particular, ‘placental vascular sonobiopsy’ can specifically evaluate the second- and thirdtrimester placental blood flow and vascularity by obtaining several spherical samples from the placenta that will represent the entire placenta. This article presents normal placental development and pathological findings of the placenta using 3D power Doppler ultrasound, and discusses 3D power Doppler assessments of placental perfusion in high-risk pregnancies, such as fetal growth restriction, pregnancy-induced hypertension and preeclampsia, and, from this basis, re-establishes the importance of 3D power Doppler ultrasound as a screening, diagnostic, and surveillance tool in normal and abnormal pregnancies. How to cite this article Tanaka H, Cajusay-Velasco S, Noguchi J, Hata T. Three-dimensional Power Doppler Ultrasound Study of the Placenta. Donald School J Ultrasound Obstet Gynecol 2014;8(4):400-409.

Changes in vitelline and utero-placental hemodynamics: implications for cardiovascular development.

Analyses of cardiovascular development have shown an important interplay between heart function, blood flow, and morphogenesis of heart structure during the formation of a four-chambered heart. It is known that changes in vitelline and placental blood flow seemingly contribute substantially to early cardiac hemodynamics. This suggests that in order to understand mammalian cardiac structure-hemodynamic functional relationships, blood flow from the extra-embryonic circulation needs to be taken into account and its possible impact on cardiogenesis defined. Previously published Doppler ultrasound analyses and data of utero-placental blood flow from human studies and those using the mouse model are compared to changes observed with environmental exposures that lead to cardiovascular anomalies. Use of current concepts and models related to mechanotransduction of blood flow and fluid forces may help in the future to better define the characteristics of normal and abnormal utero-placental blood flow and the changes in the biophysical parameters that may contribute to congenital heart defects. Evidence from multiple studies is discussed to provide a framework for future modeling of the impact of experimental changes in blood flow on the mouse heart during normal and abnormal cardiogenesis.

Abstract 090: Increased Uterine Artery Resistance Index Results In Placental Hypoxia And Tnf-α In The Dahl Salt Sensitive Rat During Pregnancy

In normal pregnancy, uterine artery resistance index (UARI) decreases as pregnancy progresses to accommodate the increased blood supply to the growing fetus. In preeclampsia, increased UARI impedes the utero-placental blood flow. Recent studies in our lab indicate that the Dahl salt sensitive (S) rat spontaneously develops a preeclamptic phenotype, characterized by increased blood pressure and proteinuria as pregnancy progresses and a decrease in litter and pup size. Here, we tested the hypothesis that the phenotype in the Dahl S rat is due to decreased placental blood flow, causing the placenta to become hypoxic, resulting in increased production of TNF-α. Female Dahl S and Sprague Dawley rats were mated with males of their same strain, and pregnancy was confirmed by presence of sperm (D1). UARI was measured during mid and late pregnancy (D14 and 18, respectively) via Doppler ultrasound in anesthetized animals (n= 4-12). Rats were sacrificed on D20, and placentas were harvested for further analysis. TNF-α and HIF-1α were measured in homogenized placentas via commercially available ELISA (n= 5) and Western Blot analysis (n= 9-11), respectively. UARI decreased in the Sprague Dawley rat between D14-18, but increased in the Dahl S rat (Table). HIF-1α was significantly increased in the Dahl S placenta vs Sprague Dawley (Table), and TNF-α also showed a tendency to increase in the Dahl S placenta (p=0.08). These data suggest that the relative decrease in blood flow to the placenta during pregnancy in the Dahl S rat causes a hypoxic environment, leading to the release of vasoactive factors that contribute to the development of the preeclamptic phenotype observed in this strain.

Diving and pregnancy: what do we really know?

Exercise during pregnancy has been advocated by many professional organizations to promote fetal heath and maternal well-being. Those same professional organizations do not recommend diving during pregnancy because of the potential adverse outcomes that have been observed in the animal model. In nonpregnant women, diving becomes problematic at depth as the ambient pressure increases and more gases become dissolved in the bloodstream. This can result in oxygen toxicity and nitrogen narcosis. Too rapid an ascent from depth can cause nitrogen emboli that can lodge in joints and tissue, resulting in decompression sickness, known as "the bends." The best animal model to study the effects of diving on pregnancy is the sheep model. Bubbling has been observed in both ewes and their fetuses, with bubbles more common in the ewes. Repeated decompressions done improperly can lead to fetal death. Information on pregnancy outcomes in humans is more limited, with inconsistent data on diving and birth defects, spontaneous abortions, and stillbirth. Even in the face of overall increased resistance in the maternal or fetal placental circulations, the total placental blood flow is usually maintained, preventing adverse outcomes. It appears that the safest choice during pregnancy is to avoid diving; however, if the woman dove when she did not know she was pregnant, there is usually a normal outcome. If a women insists on diving during pregnancy, she should go to a depth of only 60 ft, and duration of her dive should be half that recommended by Navy dive table times.

Intrauterine nutrition: long-term consequences for vascular health.

There is a growing body of evidence that improper intrauterine nutrition may negatively influence vascular health in later life. Maternal malnutrition may result in intrauterine growth retardation and, in turn, metabolic disorders such as insulin resistance, diabetes, hypertension, and dyslipidemia, and also enhanced risk of atherosclerosis and cardiovascular death in the offspring. Energy and/or protein restriction is the most critical determinant for fetal programming. However, it has also been proposed that intrauterine n-3 fatty acid deficiency may be linked to later higher blood pressure levels and reduced insulin sensitivity. Moreover, it has been shown that inadequate supply of micronutrients such as folate, vitamin B12, vitamin A, iron, magnesium, zinc, and calcium may contribute to impaired vascular health in the progeny. In addition, hypertensive disorders of pregnancy that are linked to impaired placental blood flow and suboptimal fetal nutrition may also contribute to intrauterine growth retardation and aggravated cardiovascular risk in the offspring. On the other hand, maternal overnutrition, which often contributes to obesity and/or diabetes, may result in macrosomia and enhanced cardiometabolic risk in the offspring. Progeny of obese and/or diabetic mothers are relatively more prone to develop obesity, insulin resistance, diabetes, and hypertension. It was demonstrated that they may have permanently enhanced appetites. Their atheromatous lesions are usually more pronounced. It seems that, particularly, a maternal high-fat/junk food diet may be detrimental for vascular health in the offspring. Fetal exposure to excessive levels of saturated fatty and/or n-6 fatty acids, sucrose, fructose and salt, as well as a maternal high glycemic index diet, may also contribute to later enhanced cardiometabolic risk.