Placental Blood Flow Research Articles

OC22.05: Comparison of placental blood flow in the third trimester of normal and diabetic pregnancy using a novel stereological 3D power Doppler technique

OC22.05: Comparison of placental blood flow in the third trimester of normal and diabetic pregnancy using a novel stereological 3D power Doppler technique

OP16.01: Comparison of placental blood flow in the second trimester between normal and diabetic pregnancy using 3D power Doppler standardised to a local vessel

Objectives: In maternal diabetes the placenta is large with abnormal vascular development and increased villous volume. A prospective, longitudinal observational study of 3D power Doppler vascular indices was performed to investigate differences in-vivo in placental vascularity between women with and without diabetes. Methods: 28 normal women and 20 with pre-gestational diabetes, were recruited. Each subject had 3 scans between 12 and 20 weeks gestation using a Voluson 730 Expert scanner. The VOCAL tool within 4D View (GE Medical Systems) was used to outline the placenta in the A plane using the 9◦ rotation step. To compensate for depth attenuation the 3D vascular indices were standardised against the FI at the centre of a nearby vessel. Results: Subjects were matched for age, BMI and parity. Mean FI.fmbv was 52.07 (±6.0), 50.48 (±5.1) and 53.83 (±4.6) at 12, 16 and 20 weeks respectively. ANOVA demonstrated a significant difference across gestation for the FI.fmbv [F(1.86, 83.82) = 6.37; P = 0.003] and between groups (P = 0.001). There was no difference across gestation or between groups (VI.fmbv, P = 0.29; VFI.fmbv P = 0.48) for the other two standardised 3D vascular indices. The FI.fmbv was significantly higher in subjects with microalbuminuria but not related to retinopathy, hypertension, diabetes type or duration. Conclusions: Standardised placental FI (FI.fmbv) is increased in women with diabetes between 12 and 20 weeks gestation. Structural changes in the large and apparently vascular placenta are therefore accompanied by altered function, with increased signal intensity but not markers of vessel numbers demonstrable in-vivo.

P12.13: Assessment of placental blood flow between 22 and 34 weeks by 3D‐US power Doppler vascular indices

P12.13: Assessment of placental blood flow between 22 and 34 weeks by 3D‐US power Doppler vascular indices

The role of blood flow distribution in the regulation of cerebral oxygen availability in fetal growth restriction

Fetal growth restriction (FGR) elicits hemodynamic compensatory mechanisms in the fetal circulation. These mechanisms are complex and their effect on the cerebral oxygen availability is not fully understood. To quantify the contribution of each compensatory mechanism to the fetal cerebral oxygen availability, a mathematical model of the fetal circulation was developed. The model was based on cardiac-output distribution in the fetal circulation. The compensatory mechanisms of FGR were simulated and their effects on cerebral oxygen availability were analyzed. The mathematical analysis included the effects of cerebral vasodilation, placental resistance to blood flow, degree of blood shunting by the ductus venosus and the effect of maternal-originated placental insufficiency. The model indicated a unimodal dependency between placental blood flow and cerebral oxygen availability. Optimal cerebral oxygen availability was achieved when the placental blood flow was mildly reduced compared to the normal flow. This optimal ratio was found to increase as the hypoxic state of FGR worsens. The model indicated that cerebral oxygen availability is increasingly dependent on the cardiac output distribution as the fetus gains weight.

Role of Complement Component C1q in the Onset of Preeclampsia in Mice

Preeclampsia (PE) is a life-threatening, pregnancy-induced disease and a leading cause of maternal and fetal morbidity and mortality. Despite considerable research, the causes of PE remain unclear, and there is no effective treatment. Studies in animal models that resemble this complex pregnancy-related disorder may help to identify possible therapies for PE. Complement component C1q has an important role in trophoblast migration, spiral arteries remodeling, and normal placentation. Here we show that pregnant C1q-deficient (C1q(-/-)) mice recapitulate the key features of human PE: hypertension, albuminuria, endotheliosis, decreased placental vascular endothelial growth factor (VEGF) and elevated levels of soluble VEGF receptor 1 (sFlt-1) that correlate with increased fetal death. In addition, decreased blood flow and increased oxidative stress are observed in placentas from C1q(-/-) mice. Treatment of C1q(-/-) mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of PE. Serum-soluble receptors for VEGF-1 levels were reduced and placental VEGF levels were significantly increased in C1q(-/-) mice treated with pravastatin compared with untreated C1q(-/-) mice (VEGF: 1067±171 versus 419±194 pg/mL; P<0.01). Pravastatin treatment reduced hypertension (change in mean arterial pressure: 1±1 versus 18±3 mm Hg in C1q(-/-) untreated mice), and albuminuria (of creatinine) was reduced from 820±175 to 117±45 μg/mg (both P<0.01). Renal damage and endothelial dysfunction were significantly attenuated with pravastatin. This model that highlights the causative role of impaired trophoblast invasion in the pathogenesis of PE allowed us to identify pravastatin as a good therapeutic option to prevent PE.

The effect of resveratrol on blood pressure in a rat model of preeclampsia

Objective: To examine the hypothesis that resveratrol administration could result in blood pressure and blood flow decrease in a rat preeclampsia model. Materials and Methods: Desoxycorticosterone acetate (DOCA) was used to produce hypertension. The Wistar albino rats were divided randomly into three groups: control (n = 12), DOCA injected (n = 11), and DOCA injected and resveratrol treated (n = 13). Rats were sacrificed on gestational day 16–20. The systolic blood pressure was measured by the tail-cuff method. Urine protein was expressed as protein/creatinine. Laser Doppler measurements of the blood flow were made in one placenta, the left kidney and both parietal lobes of brain. Placentas were examined by light microscopy. Results: DOCA injected group exhibited significant differences in blood pressure and protein/creatinine. Mean blood pressure in DOCA-treated rats was 130.1 ± 12.9 mmHg at baseline and 148.4 ± 20.1 mmHg at the time of euthanization (p = 0.044). Resveratrol did not significantly affect blood pressure, placental and renal blood flows. There were also no significant differences in placental pathology parameters among the three groups. Conclusion: The present study demonstrated that resveratrol did not decrease blood pressure, and did not result in a significant response in blood flows and placental pathology parameters.

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.

Effects of dietary l-arginine or N-carbamylglutamate supplementation during late gestation of sows on the miR-15b/16, miR-221/222, VEGFA and eNOS expression in umbilical vein

Placental vascular formation and blood flow are crucial for fetal survival, growth and development, and arginine regulates vascular development and function. This study determined the effects of dietary arginine or N-carbamylglutamate (NCG) supplementation during late gestation of sows on the microRNAs, vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) expression in umbilical vein. Twenty-seven landrace × large white sows at day (d) 90 of gestation were assigned randomly to three groups and fed the following diets: a control diet and the control diet supplemented with 1.0% l-arginine or 0.10% NCG. Umbilical vein of fetuses with body weight around 2.0 kg (oversized), 1.5 kg (normal) and 0.6 kg (intrauterine growth restriction, IUGR) were obtained immediately after farrowing for miR-15b, miR-16, miR-221, miR-222, VEGFA and eNOS real-time PCR analysis. Compared with the control diets, dietary Arg or NCG supplementation enhanced the reproductive performance of sows, significantly increased (P < 0.05) plasma arginine and decreased plasma VEGF and eNOS (P < 0.05). The miR-15b expression in the umbilical vein was higher (P < 0.05) in the NCG-supplemented group than in the control group. There was a trend in that the miR-222 expression in the umbilical vein of the oversized fetuses was higher (0.05 < P < 0.1) than in the normal and IUGR fetuses. The expression of eNOS in both Arg-supplemented and NCG-supplemented group were lower (P < 0.05) than in the control group. The expression of VEGFA was higher (P < 0.05) in the NCG-supplemented group than in the Arg-supplemented and the control group. Meanwhile, the expression of VEGFA of the oversized fetuses was higher (P < 0.05) than the normal and IUGR fetuses. In conclusion, this study demonstrated that dietary Arg or NCG supplementation may affect microRNAs (miR-15b, miR-222) targeting VEGFA and eNOS gene expressions in umbilical vein, so as to regulate the function and volume of the umbilical vein, provide more nutrients and oxygen from the maternal to the fetus tissue for fetal development and survival, and enhance the reproductive performance of sows.

MRI for the assessment of placental blood flow in diabetic pregnancies

IntroductionOptimal placental blood flow is essential for adequate materno-fetal nutrient exchange and a successful gestation. In maternal diabetes the placenta is often large with abnormal vascular development. To date, it...

Regulation of ankyrin repeat and suppressor of cytokine signalling box protein 4 expression in the immortalized murine endothelial cell lines MS1 and SVR: a role for tumour necrosis factor alpha and oxygen

During vascular development, endothelial cells are exposed to a variety of rapidly changing factors, including fluctuating oxygen levels. We have previously shown that ankyrin repeat and suppressor of cytokine signalling box protein 4 (ASB4) is the most highly differentially expressed gene in the vascular lineage during early differentiation and is expressed in the embryonic vasculature at a time when oxygen tension is rising because of the onset of placental blood flow. To further our understanding of the regulation of ASB4 expression in endothelial cells, we tested the effect of various stressors for their ability to alter ASB4 expression in the immortalized murine endothelial cell lines MS1 and SVR. ASB4 expression is decreased during hypoxic insult and shear stress, whereas it is increased in response to tumour necrosis factor alpha (TNF-α). Further investigation indicated that nuclear factor kappa B (NF-κB) is the responsible transcription factor involved in the TNF-α-induced upregulation of ASB4, placing ASB4 downstream of NF-κB in the TNF-α signalling cascade and identifying it as a potential regulator for TNF-α's numerous functions associated with inflammation, angiogenesis and apoptosis.

Quantitative effects of tobacco smoking exposure on the maternal-fetal circulation

BackgroundDespite the existence of various published studies regarding the effects of tobacco smoking on pregnancy, and especially in regards to placental blood flow and vascular resistance, some points still require clarification. In addition, the amount of damage due to tobacco smoking exposure that occurs has not been quantified by objective means. In this study, we looked for a possible association between flow resistance indices of several arteries and the levels of urinary cotinine and the concentration of carbon monoxide in the exhaled air (COex) of both smoking and non-smoking pregnant women. We also looked for a relationship between those findings and fetal growth and birth weight.MethodsIn a prospective design, thirty pregnant smokers and thirty-four pregnant non-smokers were studied. The volunteers signed consent forms, completed a self-applied questionnaire and were subjected to Doppler velocimetry. Tobacco smoking exposure was quantified by subject provided information and confirmed by the measurement of urinary cotinine levels and by the concentration of carbon monoxide in the exhaled air (COex). The weight of newborns was evaluated immediately after birth.ResultsComparing smoking to non-smoking pregnant women, a significant increase in the resistance index was observed in the uterine arteries (P = 0.001) and umbilical artery (P = 0.001), and a decrease in the middle cerebral artery (P = 0.450). These findings were associated with progressively higher concentrations of COex and urinary cotinine. A decrease in the birth weight was also detected (P < 0.001) in association with a progressive increase in the tobacco exposure of the pregnant woman.ConclusionsIn pregnant women who smoke, higher arterial resistance indices and lower birth weights were observed, and these findings were associated with increasing levels of tobacco smoking exposure. The values were significantly different when compared to those found in non-smoking pregnant women. This study contributes to the findings that smoking damage during pregnancy is dose-dependent, as demonstrated by the objective methods for measuring tobacco smoking exposure.

Placental oxidative DNA damage and its repair in preeclamptic women with fetal growth restriction

Preeclampsia is frequently accompanied by fetal growth restriction (FGR). Preeclampsia increases oxygen free radical production, and the resulting oxidative stress impairs placental blood flow. To determine whether placental oxidative stress is associated with FGR in preeclamptic women, we evaluated placental oxidative DNA damage and its repair in 13 preeclamptic women with FGR, 10 preeclamptic women without FGR, and 11 healthy pregnant women without complications. We measured maternal and umbilical serum derivatives of reactive oxygen metabolites (d-ROMs), as a marker of oxygen free radicals, and pulsatility index (PI) of uterine and umbilical arteries, and performed an immunohistochemical analysis to measure the proportion of nuclei in the placental trophoblast that stained positive for 8-hydroxy-2′-deoxyguanosin (8-OHdG), an indicator of oxidative DNA damage, and redox factor-1 (ref-1), indicative of the repair function towards oxidative DNA damage. D-ROMs were increased in the maternal blood of both preeclamptic groups (with FGR, 687.3 ± 50.4 CARR U, p < 0.01; without FGR, 750.4 ± 87.2 CARR U, p < 0.001) compared with controls (504.7 ± 25.0 CARR U). In contrast, d-ROM levels in the umbilical artery were elevated in preeclamptic women with FGR (134.9 ± 13.3 CARR U, p < 0.01), but not in preeclamptic women without FGR (44.0 ± 7.3 CARR U) compared with controls (38.2 ± 5.0 CARR U). Mean PI for uterine arteries was significantly increased in both preeclamptic groups, and the PI in preeclamptic women with FGR was significantly greater than that in women without FGR (0.94 ± 0.07 vs. 1.31 ± 0.07, p < 0.001). The PI for umbilical arteries was significantly increased in preeclamptic women with FGR (0.90 ± 0.05vs. 1.19 ± 0.07, p < 0.001), but not in preeclamptic women without FGR. The proportion of nuclei positive for 8-OHdG was higher in both groups of preeclamptic women than in the control group, but was higher in preeclamptic women with FGR (0.21 ± 0.05 vs. 0.87 ± 0.01, p < 0.001). The proportion of nuclei positive for ref-1 was higher in preeclamptic women without FGR (0.54 ± 0.06, p < 0.001) than in the control group, whereas the proportion did not differ significantly between normal and preeclamptic women with FGR. Our findings indicate that increased oxidative stress and disrupted compensatory reaction against placental oxidative DNA damage may be associated with FGR in preeclamptic women.

Maternal smoking during pregnancy, fetal arterial resistance adaptations and cardiovascular function in childhood

To unravel the mechanisms underlying the previously demonstrated associations between low birthweight and cardiovascular disease in adulthood, we examined whether maternal smoking during pregnancy leads to fetal arterial resistance adaptations, and subsequently to fetal growth retardation and changes in postnatal blood pressure and cardiac development. Prospective cohort study from early fetal life onwards. Academic hospital. Analyses were based on 1120 children aged 2 years. Maternal smoking during pregnancy [non-smoking, first trimester smoking, continued smoking (< 5 and ≥ 5 cigarettes/day)] was assessed by questionnaire. Third trimester placental and fetal arterial resistance indices and fetal growth were assessed by ultrasound and Doppler measurements. Postnatal blood pressure and cardiac structures (aortic root diameter, left atrial diameter, left ventricular mass) were measured at 2 years of age. First trimester smoking was not associated with third trimester placental and fetal blood flow adaptations. Continued smoking of ≥ 5 cigarettes/day was associated with an increased resistance in uterine, umbilical and middle cerebral arteries, and with a decreased flow and diameter of the ascending aorta. Among mothers who continued to smoke, the third trimester estimated fetal weights and birthweights were most affected in children with the highest umbilical artery resistance. Fetal arterial resistance indices were also associated with aortic root diameter and left atrial diameter. Fetal arterial resistance adaptations may be involved in the pathways leading from maternal smoking during pregnancy to low birthweight and cardiovascular developmental changes in childhood in the offspring.

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.

The effects of azathioprine on birth outcomes in women with inflammatory bowel disease (IBD)

Aim To investigate the effects of azathioprine/6-mercaptopurine (AZA/6-MP) on birth outcomes in women with inflammatory bowel disease (IBD). Methods Details of pregnant women with IBD were obtained through an ObstetriX Database in 3 major teaching hospitals in Sydney from 1996 to 2006. Medical records were reviewed. Birth outcomes of interest were single live births, low birth weight (LBW) at term (< 2500 g), preterm births (< 37 weeks gestation), neonatal adverse outcomes, and congenital anomaly. Placental blood flow during third trimester of pregnancy was measured using arterial Doppler ultrasonography, where available. Results All women had IBD diagnosed before pregnancy. 19 births were exposed to AZA/6-MP. 74 births that were never exposed to AZA/6-MP were selected as controls. Preterm birth was seen in 26.3% of the exposed group as compared to 13.5% of controls (p < 0.001). However, in univariate analysis, preterm birth was not associated with AZA/6-MP (OR=2.28; CI: 0.67–7.73). There was 1 neonatal adverse outcome in the exposed group as compared to 4 in controls (5.3% vs 5.4%, p = 0.97). One congenital anomaly was seen in each group (p = 0.27). No LBW at term was seen in either group. Placental blood flow in 4 women exposed to AZA/6-MP was normal. Conclusion The use of AZA/6-MP during pregnancy in IBD women was not associated with an increased risk of preterm birth, LBW at term, neonatal adverse outcomes and congenital anomalies.

Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion

Abnormal maternal inflammation during pregnancy is associated with spontaneous pregnancy loss and intrauterine fetal growth restriction. However, the mechanisms responsible for these pregnancy outcomes are not well understood. In this study, we used a rat model to demonstrate that pregnancy loss resulting from aberrant maternal inflammation is closely linked to deficient placental perfusion. Administration of LPS to pregnant Wistar rats on gestational day 14.5, to induce maternal inflammation, caused fetal loss in a dose-dependent manner 3-4 h later, and surviving fetuses were significantly growth restricted. Pregnancy loss was associated with coagulopathy, structural abnormalities in the uteroplacental vasculature, decreased placental blood flow, and placental and fetal hypoxia within 3 h of LPS administration. This impairment in uteroplacental hemodynamics in LPS-treated rats was linked to increased uterine artery resistance and reduced spiral arteriole flow velocity. Pregnancy loss induced by LPS was prevented by maternal administration of the immunoregulatory cytokine IL-10 or by blocking TNF-α activity after treatment with etanercept (Enbrel). These results indicate that alterations in placental perfusion are responsible for fetal morbidities associated with aberrant maternal inflammation and support a rationale for investigating a potential use of immunomodulatory agents in the prevention of spontaneous pregnancy loss.

Interruption of Placental Blood Flow during Labor: Potential Systemic and Cerebral Organ Consequences

Interruption of placental blood during labor, also termed "asphyxia," affects approximately 3 of every 1000 term infants. The systemic and cerebral consequences of asphyxia are in part related to circulatory adaptive responses, which in turn are modulated by the severity and duration of the insult. Long-term neurological outcome has been well categorized, whereas the systemic consequences remain unclear.

Placental volume and vascularization flow indices by 3D power Doppler US using VOCAL technique and correlation with IGF-1, free beta-hCG, PAPP-A, and uterine artery Doppler at 11–14 weeks of pregnancy

The purpose of this study was to investigate correlations between first trimester placental volume (PV) and blood flow indexes (FIs), bilateral uterine artery pulsatility indexes, notching, and biochemical parameters: pregnancy-associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (f-β-hCG), and insulin-like growth factor-1 (IGF-1) to predict the high-risk pregnancies in the first trimester. We prospectively examined 310 patients at 11-14 weeks of pregnancy using transabdominal 3D gray scale and power Doppler ultrasound for assessing PV, vascularization index, FI, and vascularization FI (VFI). The acquired volumes were analyzed using VOCAL™ imaging software. The results were correlated with biochemical parameters. We found significant correlations between PV and biochemical parameters, and between placental blood flow studies and other parameters. Finally, PV/crown-rump length so called the placental quotient is also related to both PAPP-A and VFI. Placental volumetry, uterine artery Doppler studies, blood flow calculations and biochemical parameters, such as f-β-hCG, PAPP-A, and IGF-1 could be important in the early and rapid diagnosis of high-risk pregnancies. Thus, they may be useful in first trimester prediction of fetal growth restriction presenting with alterations in PV and vascularity.

Alteration of mitochondrial function in adult rat offspring of malnourished dams

Under-nutrition as well as over-nutrition during pregnancy has been associated with the development of adult diseases such as diabetes and obesity. Both epigenetic modifications and programming of the mitochondrial function have been recently proposed to explain how altered intrauterine metabolic environment may produce such a phenotype. This review aims to report data reported in several animal models of fetal malnutrition due to maternal low protein or low calorie diet, high fat diet as well as reduction in placental blood flow. We focus our overview on the β cell. We highlight that, notwithstanding early nutritional events, mitochondrial dysfunctions resulting from different alteration by diet or gender are programmed. This may explain the higher propensity to develop obesity and diabetes in later life.

195: Vitamin C supplementation normalizes the decreased placental blood flow in a non-human primate model of prenatal nicotine exposure

195: Vitamin C supplementation normalizes the decreased placental blood flow in a non-human primate model of prenatal nicotine exposure