Placental Blood Flow Research Articles

The heme oxygenases: important regulators of pregnancy and preeclampsia.

The heme oxygenase system has long been believed to act largely as a housekeeping unit, converting prooxidant free heme from heme protein degradation into the benign bilirubin for conjugation and safe excretion. In recent decades, however, heme oxygenases have emerged as important regulators of cardiovascular function, largely through the production of their biologically active metabolites: carbon monoxide, bilirubin, and elemental iron. Even more recently, a number of separate lines of evidence have demonstrated an important role for the heme oxygenases in the establishment and maintenance of pregnancy. Early preclinical and clinical studies have associated defects in the heme oxygenase with the obstetrical complication preeclampsia, as well as failure to establish adequate placental blood flow, an underlying mechanism of the disorder. Several recent preclinical studies have suggested, however, that the heme oxygenase system could serve as a valuable therapeutic tool for the management of preeclampsia, which currently has few pharmacological options. This review will summarize the role of heme oxygenases in pregnancy and highlight their potential in advancing the management of patients with preeclampsia.

PFM.15 Is there a role for Placental Volume, Vasculature and Calcification in monitoring Post-term Pregnancies?

ObjectivesThis study aims to assess if three dimensional power Doppler (3DPD) ultrasound of the placenta, evaluating placental volume, vascularisation, and blood flow in post-term pregnancies differs from normal. It also...

167 TRPV4; a Potential New Target to Increase Placental Blood Flow in Fetal Growth Restricted Pregnancies?

IntroductionFetal growth restriction (FGR) is a pregnancy complication that predisposes to an increased risk of neonatal morbidity and mortality. A low birth weight is also associated with increased risk of...

Factors affecting drug absorption and distribution

The pharmacokinetic properties of a drug comprise the relationship between its absorption, distribution and inactivation. The passage of drugs across cell membranes is a key part of most pharmacokinetic processes. The most important means by which a drug crosses cell membranes is passive diffusion, the rate of which is determined by molecular size, the concentration gradient, lipid solubility, degree of ionization of the drug and protein binding. Pharmacokinetic processes can be summarized and the time course of drug action can be predicted using mathematical compartment models. In a single-compartment model, a drug is evenly distributed throughout the plasma and tissues and eliminated in an exponential manner. However, multicompartment models make allowance for the uptake of drugs from the plasma by different tissues and for different flow rates to these tissues. Drug distribution across the placenta is a special case and considered separately. The placental membrane is a lipid barrier that is less selective than the blood–brain barrier, allowing the passage of lipid-soluble drugs more easily than water-soluble drugs. The distribution and rate of equilibration across the placenta are determined by placental blood flow and the free drug concentration gradient.

Maternal Plasma and Amniotic Fluid Cytokines in Monochorionic, Diamniotic Twin Pregnancies Complicated by Twin-to-Twin Transfusion Syndrome

Introduction: Cytokine imbalance has been implicated in placental-related pathologies, i.e. recurrent miscarriage and pre-eclampsia. Such conditions are more prevalent in multiple pregnancies. Twin-to-twin transfusion syndrome (TTTS) is associated with asymmetric placental blood flow and intra-cardiac pressures. We hypothesised that cytokine expression may be aberrant in this condition and that fetoscopic laser ablation (FLA) may cause local cytokine release. Material and Methods: A prospective cohort of monochorionic, diamniotic twins with TTTS (n = 23) was studied. Circulating T helper cell type 1 (TH1)/TH2 maternal cytokines and cytokine-related and angiogenic factors were measured in plasma and amniotic fluid before and after FLA by human FASTQuant or ELISA. Basal comparisons were made with uncomplicated monochorionic and dichorionic (DC) twins. Results: Median maternal plasma platelet-derived growth factor-BB was highest in uncomplicated DC twins (p = 0.049), whereas tissue inhibitor of metalloproteinases (TIMP)-1 was highest in TTTS twins (p = 0.003). In TTTS amniotic fluid, interleukin (IL)-6, IL-1β, tumour necrosis factor-α, IL-10, IL-4, IL-8, interferon-γ, TIMP-1 and intercellular adhesion molecule-1 were significantly higher than maternal plasma concentrations. There were no significant differences in plasma or amniotic fluid cytokines after FLA, with the exception of amniotic fluid keratinocyte growth factor, which was significantly reduced. Discussion: TTTS is associated with minimal changes in cytokine levels when compared to uncomplicated twins, although the majority of cytokine levels were higher in amniotic fluid than maternal blood. It does not appear that FLA evokes a significant change in cytokines.

A cohort study of Plasmodium falciparum malaria in pregnancy and associations with uteroplacental blood flow and fetal anthropometrics in Kenya

ObjectiveTo use ultrasound to explore the impact of malaria in pregnancy on fetal growth and newborn outcomes among a cohort of women enrolled in an intermittent presumptive treatment in pregnancy (IPTp) with sulfadoxine/pyrimethamine (SP) program in coastal Kenya. MethodsEnrolled women were tested for malaria at first prenatal care visit, and physical and ultrasound examinations were performed. In total, 477 women who had term, live births had malaria tested at delivery and their birth outcomes assessed, and were included in the study. ResultsPeripheral malaria was detected via polymerase chain reaction among 10.9% (n=87) at first prenatal care visit and 8.8% (n=36) at delivery. Insecticide-treated bed nets (ITNs) were used by 73.6% (n=583) and were associated with decreased malaria risk. There was a trend for impaired fetal growth and placental blood flow in malaria-infected women in the second trimester, but not later in pregnancy. Among women with low body mass index (BMI), malaria was associated with reduced birth weight (P=0.04); anthropometric measures were similar otherwise. ConclusionWith IPTp-SP and ITNs, malaria in pregnancy was associated with transient differences in utero, and reduced birth weight was restricted to those with low BMI.

Changes in fetal Doppler indices as a marker of failure to reach growth potential at term

To evaluate whether changes in the middle cerebral artery (MCA), umbilical artery (UA) and cerebroplacental ratio (CPR) Doppler indices at term might be used to identify those appropriate-for-gestational-age (AGA) fetuses that are failing to reach their growth potential (FRGP). This was a retrospective cohort study of data obtained in a single tertiary referral center over a 10-year period from 2002 to 2012. The UA pulsatility index (PI), MCA-PI and CPR were recorded between 37+0 and 41+6 weeks within 14 days before delivery. The Doppler parameters were converted into multiples of the median (MoM), adjusting for gestational age, and their correlation with birth-weight (BW) centiles was evaluated by means of regression analysis. Doppler indices were also grouped according to BW quartiles and compared using Kruskal-Wallis and Dunn's post-hoc tests. The study included 11576 term fetuses, with 8645 (74.7%) classified as AGA. Within the AGA group, fetuses with lower BW had significantly higher UA-PI, lower MCA-PI and lower CPR MoM values. Large-for-gestational-age (LGA) fetuses were considered as the group least likely to be growth-restricted. The CPR MoM < 5(th) centile (0.6765 MoM) in these fetuses was used as a threshold for diagnosing FRGP. Using this definition, in the AGA pregnancies the percentage of fetuses with FRGP was 1% in the 75-90(th) BW centile group, 1.7% in the 50-75(th) centile group, 2.9% in the 25-50(th) centile group and 6.7% in the 10-25(th) centile group. AGA pregnancies may present with fetal cerebral and placental blood flow redistribution indicative of fetal hypoxemia. Fetal Doppler assessment may be of value in detecting AGA pregnancies that are subject to placental insufficiency, fetal hypoxemia and FRGP. Future studies are needed to evaluate the appropriate threshold for the diagnosis of FRGP and the diagnostic performance of this new approach for the management of growth disorders.

Maternal Psychological Distress and Placental Circulation in Pregnancies after a Previous Offspring with Congenital Malformation

IntroductionAntenatal maternal psychological distress may be associated with reduced placental circulation, which could lead to lower birthweight. Studies investigating this in humans show mixed results, which may be partially due to type, strength and timing of distress. In addition, the arterial vascular resistance measures often used as outcome measures do not detect smaller changes in placental volume blood flow. We aimed to investigate the effect of a specific stressor, with increased levels of stress early in pregnancy, on the fetoplacental volume blood flow in third trimester.MethodsThis was a prospective observational study of 74 pregnant women with a congenital malformation in a previous fetus or child. Psychological distress was assessed twice, around 16 and 30 weeks' gestation. Psychometric measures were the General Health Questionnaire-28 (subscales anxiety and depression), Edinburgh Postnatal Depression Scale, and Impact of Event Scale-22 (subscales intrusion, avoidance, and arousal). Placental circulation was examined at 30 weeks, using Doppler ultrasonography, primarily as fetoplacental volume blood flow in the umbilical vein, normalized for abdominal circumference; secondarily as vascular resistance measures, obtained from the umbilical and the uterine arteries.ResultsMaternal distress in second but not third trimester was associated with increased normalized fetoplacental blood flow (P-values 0.006 and 0.013 for score > mean for depression and intrusion, respectively). Post-hoc explorations suggested that a reduced birthweight/placental weight ratio may mediate this association. Psychological distress did not affect vascular resistance measures in the umbilical and uterine arteries, regardless of adjustment for confounders.ConclusionsIn pregnant women with a previous fetus or child with a congenital malformation, higher distress levels in second trimester were associated with third trimester fetoplacental blood flow that was higher than expected for the size of the fetus. The results do not support placental blood flow reduction as a pathway between maternal distress and reduced birthweight.

3D Power Doppler ultrasound and computerised placental assessment in normal pregnancy

BackgroundIn recent years there have been significant developments in the use of 3D Power Doppler (3DPD) imaging and quantitative 3DPD histogram analysis to estimate both placental volume and intra-placental vasculature. This study aims to determine if placental volume, vascularisation and blood flow are correlated with gestational age in normal pregnancy. It also examines whether or not a new software method for analysis of percentage calcification (the ‘placentometer’) correlates well with gestation. Material and methodThis was a prospective cohort study of 250 women with normal pregnancies (12 + 6 to 39 + 5 weeks gestation). 3DPD ultrasound was used to evaluate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Placental volume (calculated at 35–40 weeks gestation), was correlated with birth weight. Following each scan the percentage of calcification was also calculated using the placentometer. ResultsPlacental volume correlated significantly with gestational age: 66.676 + 0.623 × GA (P < 0.001). No significant change with gestation was noted in VI, FI and VFI (VI: P = 0.199, FI: P = 0.299, VFI: P = 0.557). Software analysis of the percentage of calcification, demonstrated the expected increase in calcification as gestation increased: −4.605 + 0.032 × GA (P < 0.001). From 35 to 40 weeks gestation volume was related to birth weight (P < 0.01). ConclusionThis study shows that in normal low-risk pregnancy placental volume increases with gestational age, whereas vascularisation and blood flow are independent of gestation. Placental volume in late pregnancy is related to birth weight. Software analysis of the percentage of calcification demonstrates an increase with advancing gestation.

Estimation of the Functional Condition of a Fetus of Pregnancy in Chronic Pyelonephritis

Aim of this study was to investigate the condition of the fetus and feto placental system in chronic pyelonephritis by identifying features in the fetoplacental blood flow and middle cerebral artery system. We examined 68 pregnant women with chronic pyelonephritis and 50 healthy pregnant women as a control group. The study conducted a qualitative assessment of fetus and placental blood flow and blood flow in the middle cerebral artery of the fetus. The data on the condition of feto-placental blood flow and blood flow in the middle cerebral artery in the examined pregnant and control group show a higher incidence of elevated systolic and diastolic performance ratio in the umbilical artery in patients with chronic pyelonephritis than somatically healthy women. Studies have shown that the most accurate and informative indicator of violations feto-placental circulation is an increase in the umbilical artery whose value (2,9 and above) reflects the high degree of suffering of the fetus on a background of chronic pyelonephritis. Diagnostically significant is the indicator of the middle cerebral artery blood flow, which reflects the mechanism of enhancement of cerebral circulation in chronic hypoxia due to violation of feto-placental circulation in patients with renal disease.

Sildenafil Citrate Increases Fetal Weight in a Mouse Model of Fetal Growth Restriction with a Normal Vascular Phenotype

Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5th centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5th centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. 14C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR.

Fetal Pharmacotherapy 1: Prenatal Glucocorticoids

The fetus is a dependent patient, relying on the transfer of oxygen, nutrients, hormones, and medications from the maternal circulation through the placenta. Therefore, before initiating fetal pharmacological treatment, several factors that may affect drug transfer need to be considered, including the size of the molecule, its physico-chemical properties, plasma protein binding, pathological processes in the mother or fetus, placental blood flow, placental drug binding, and placental metabolism.1

P02.09: Prediction value of 3D CPA combined with color Doppler ultrasound for hypertensive disorder complicating pregnancy

To investigate the predictive value of placental volume, 3D-CPA of placenta and placental bed blood flow for HDCP. The routine prenatal ultrasound was performed by 3D color Doppler ultrasound in 1679 singletons with 11 to 28 weeks. Each fetus were examined with GE Voluson E8 ultrasound. Color Doppler was scanned for uterine artery, umbilical artery and placental bed artery. The placental volume was calculated by VOCAL. 3D-CPA was used to test VI, FI, VFI of the placenta. All cases were followed to the delivery. HDCP was defined as blood pressure higher than 140/90 mmHg. Sensitivity and specificity was calculated by chi-square test to investigate the predictive value of ultrasound indexes for HDCP by SPSS 13.0. The sensitivity was 0.3226, 0.4839, 0.5161 and the specificity was 0.9206, 0.9298, and 0.9298 respectively when VI < 10th%, FI < 10th%, VTI < 10th%. The sensitivity was 0.1052 and the specificity was 0.9112 of volume < 10th%. The sensitivity was 0.0702 and the specificity was 0.9655 when placental bed artery RI>2SD. The sensitivity and specificity was 0.0526 and 0.9982 in a series connection of placental bed artery RI>2SD and the left uterine artery RI>2SD for prediction of HDPC, While the sensitivity and specificity was 0.1176 and 0.9390 in a parallel connection of these two indexes. 3D-CPA and color Doppler ultrasound could be used for prediction of HDCP as a non-invasive method.

P08.11: Predictive value of placental volume and related artery parameter forecasting fetal growth restriction from 11 to 28 gestational weeks

To construct nomograms of placental volume and to study the correlation of FGR with placental volume, uterine artery and placental bed blood flow dynamic index. Placental volume was prospectively measured by real time 3-D color Doppler ultrasonography in 1007 normal pregnancies from 11 to 28 gestational weeks from the obstetric clinic and ward of the first affiliated hospital, Xi'an Jiaotong University. Inclusion criteria was healthy women, singleton pregnancies with normal fetal morphologic characteristics on ultrasonography and confirmed GA by first-trimester ultrasonography. Placenta volume was measured and calculated by real time 3-D color Doppler ultrasonography. 1. There was predictive value of placental volumes forecasting FGR. The sensitivity was 0.4493. The specificity was 0.9371. 2. There was predictive value of double uterine artery dynamic index and RI of placental bed artery forecasting FGR. 3. There was predictive value of placental volumes combined with RI of placental bed artery forecasting FGR. The sensitivity of serial test was 0.0145. The specificity of serial test was 0.9989. The sensitivity of parallel test was 0.5362. The specificity of parallel test was 0.9030. There was predictive value of placental volumes, double uterine artery dynamic index and RI of placental bed artery forecasting FGR.

Placental virtual biopsy: 3D-US hemodynamics of normal pregnancy versus gestational diabetes

Objectives: We used three-dimensional ultrasound with trans-abdominal Power-Doppler (3D-US PD) to determine placental vascular evolution in normal pregnancies (NP) and in insulin-dependent Gestational Diabetes Pregnancies (GDP). Study design: We obtained 473 measurements from 43 NP at 20 weeks -40 weeks gestation and 122 measurements from 70 insulin-dependent GDP at 22 weeks -40 weeks. Standardization was achieved recording three successive placental vascular tree volumes, measuring the spherical volume between the chorionic and basal plates always under or near funicular insertion. Parameters analysed were: mean intensity of blood flow (Flow Index, FI); percentage of volume occupied by vessels (Vascularisation Index, VI); and intensity of blood flow in the volume occupied by vessels (Vascularisation-flow index, VFI). Results: In NP, FI increased throughout early pregnancy and decreased before delivery and correlated with fetal parameters. In contrast, in GDP, FI was high from the onset, better correlated with placental parameters, and had a diagnostic cutoff value of 45, which was only found in 7% of NP at the end of the pregnancy. VI was variable and had a low diagnostic value, being related to placental parameters; VI values were significantly lower in NP ( 17.4 ± 7.4%) than in GDP (21 ± 12%) with a diagnostic cutoff point at 31%. In NP, FI-peak was at 32 weeks, two weeks after the VI-peak, while VFI showed no significant differences. Conclusions: The results showed that placental blood flow (FI) was related to fetal circulation, while the percentage of vessels per volume (VI) was related to maternal circulation. 3D-US PD indicated a diagnosis of GDP for FI > 45 and VI > 30%. We also discuss the values of change in VI that predict changes in fetal FI.

Recapitulation of characteristics of human placental vascular insufficiency in a novel mouse model

ObjectiveWe tested the effects of selective reduction of placental blood flow by mesenteric uterine artery branch ligation (MUAL) resulting in fetal growth restriction (FGR). MethodsTimed mated C57BL/6J Day(D) 18 dams were divided into two groups: MUAL (n = 18); and control-sham (n = 18). Pups were delivered on D20, cross-fostered to surrogate CD-1 mothers for 4 weeks, and followed for 8 weeks. Outcome data included birth and placental weight, postnatal growth, placental volume determined by stereology, quantification of placental insulin-like growth factors-1(IGF-1) and IGF-2 and IGF binding proteins(IGFBP 2 and 6) by ELISA and gene expression by qPCR and GeneChip microarray analysis. ResultsCompared with control, MUAL had an 11% reduction in mean birth weight (1.06 ± 0.13 g vs. 0.94 ± 0.13 g, p < 0.001) but no difference in placental weight. At 4 weeks of age, mean body weights of MUAL pups were significantly lower than sham. By 8 weeks, males but not females MUAL mice achieved equivalent mean body weight to control. Placental labyrinth depth, volume, and placental gene expression of IGF-1 and 2 were significantly reduced by MUAL. In contrast, placental protein level of IGFBP-2 and 6 were significantly elevated in the MUAL. Genomic expression analysis demonstrated that MUAL pups significantly up-regulated genes that were associated with apoptosis and growth pathways. ConclusionThis novel mouse animal model of FGR using selective ligation recapitulates multiple characteristics of placental vascular insufficiency (PI) in humans. This is the first non-genetic mouse model of PI which offers its application in transgenic mice to better study the underlying mechanisms in PI. CondensationA new mouse model of placental vascular insufficiency by selective ligation of mesenteric uterine artery branch recapitulates multiple findings observed in human placental vascular insufficiency.

Re: Severe left heart obstruction with retrograde arch flow influences fetal cerebral and placental blood flow. Y. Yamamoto, N. S. Khoo, P. A. Brooks, W. Savard, A. Hirose and L. K. Hornberger. Ultrasound Obstet Gynecol 2013; 42: 294–299

Linked Comment: Ultrasound Obstet Gynecol 2013:42:294–299

Severe left heart obstruction with retrograde arch flow influences fetal cerebral and placental blood flow

Decreased middle cerebral artery (MCA) pulsatility index (PI) is a marker of fetal brain-sparing in placental insufficiency and it is also found in fetuses with severe congenital heart disease. This study sought to explore the impact of anatomical subtypes in fetal heart disease on MCA-PI and head growth. We retrospectively reviewed fetal echocardiograms of pregnancies complicated by fetal hypoplastic left heart syndrome (HLHS; n = 42) with and without anatomic coarctation (n = 28 and n = 10, respectively), isolated severe aortic coarctation (n = 21), D-transposition of the great arteries (TGA; n = 11) and pulmonary outflow tract obstruction without forward flow across the pulmonary valve (POTO; n = 15), comparing observations with gestational age-matched controls (n = 89). No fetus had major extracardiac pathology or aneuploidy. MCA and umbilical artery (UA) PI, the cerebral placental ratio (CPR = MCA-PI/ UA-PI) and neonatal head circumference were obtained and expressed as Z-scores. Lower MCA-PI, higher UA-PI and lower CPR were observed in fetal HLHS and isolated coarctation with reversed arch flow (n = 6) (P < 0.001) but not TGA, POTO or isolated coarctation with antegrade arch flow (n = 15) compared with controls. No difference was found between HLHS with anatomical coarctation and those without; however, MCA-PI correlated positively with neonatal head circumference in HLHS with reversed distal arch flow (r = 0.33, P < 0.05). Severe left heart obstruction with reversed aortic arch flow is associated with altered fetal cerebral blood flow, and in these conditions, MCA-PI positively correlates with head growth. Anatomical arch obstruction itself may not be a contributing factor to altered MCA flow in fetal HLHS.

Maternal Stress and Placental Vascular Function and Remodeling

This review discusses the importance of placental vascular development, as reflected by placental angiogenesis and placental blood flow, to placental function in normal pregnancies. We then summarize our current understanding of how maternal stress, including inadequate maternal nutrition as well as the application of assisted reproductive technologies (ART), leads to compromised placental angiogenesis and function and the subsequent effects on fetal and neonatal growth and development. Finally, we discuss several promising therapeutic approaches to 'rescue' placental vascular development and function in compromised pregnancies, leading to improved pregnancy and postnatal outcomes.

Decrease of uteroplacental blood flow after feticide during second-trimester pregnancy termination with complete placenta previa: Quantitative analysis using contrast-enhanced ultrasound imaging

Contrast enhanced ultrasound (CEUS) was used to quantify the dynamic changes in uteroplacental blood flow before and after the interruption of fetal villus circulation resulting from feticide during a second trimester pregnancy termination in a patient with complete placenta previa. Quantitative analysis was performed on time–intensity curves acquired 24 h before and 48 h and 120 h after feticide and demonstrated the persistence of utero-placental blood flow with a progressive and two-step reduction in intervillous space and uteroplacental blood flow. Our results suggest that placental blood flow reduction after interruption of fetal circulation is a progressive and delayed mechanism.