Nano-Theranostic Modality for Visualization of the Placenta and Photo-Hyperthermia for Potential Management of Ectopic Pregnancy.

Ectopic pregnancy (EP) is the leading cause of maternity-related death in the first trimester of pregnancy. Approximately 98% of ectopic implantations occur in the fallopian tube, and expedient management is crucial for preventing hemorrhage and maternal death in the event of tubal rupture. Current ultrasound strategies misdiagnose EP in up to 40% of cases, and the failure rate of methotrexate treatment for confirmed EP exceeds 10%. Here the first theranostic strategy for potential management of EP is reported using a near-infrared naphthalocyanine dye encapsulated within polymeric nanoparticles. These nanoparticles preferentially accumulate in the developing murine placenta within 24 h following systemic administration, and enable visualization of implantation sites at various gestational stages via fluorescence and photoacoustic imaging. These nanoparticles do not traverse the placental barrier to the fetus or impact fetal development. However, excitation of nanoparticles localized in specific placentas with focused NIR light generates heat (>43 °C) sufficient for disruption of placental function, resulting in the demise of targeted fetuses with no effect on adjacent fetuses. This novel approach would enable diagnostic confirmation of EP when current imaging strategies are unsuccessful, and elimination of EP could subsequently be achieved using the same nano-agent to generate localized hyperthermia resulting in targeted placental impairment.

Ultrasound parameters of early pregnancy and Doppler indices of blood vessels in the placenta and umbilical cord throughout the pregnancy period in sheep.

BACKGROUND: Ultrasonography is one of the most important techniques that enable the detection and monitoring of pregnancy. One such study using this technique is the assessment of the hemodynamics of fetal and umbilical blood vessels. However, there is little data on blood flow in the placentomes, which is the basic structural unit of the sheep's placenta. Therefore, the aim of this study was to determine the Doppler parameters in the arterial vessels of the caruncles, cotyledons and the umbilical cord as well as measuring venous flow rates during the entire gestation period of the sheep. Additionally, the usefulness of various other ultrasound parameters in the early diagnosis of pregnancy in sheep was analyzed. RESULTS: Most of the Doppler parameters in umbilical, cotyledonary and caruncular arteries were significantly correlated with the day of pregnancy (p < 0.01). In the early stages of pregnancy, the peak systolic velocity (PSV), regardless of the location of the artery, was significantly lower than that in the later stages of pregnancy (p < 0.01). PSV was also found to be significantly higher in the umbilical artery than in the cotyledonary and caruncular arteries (p < 0.01). Until the 50th day of pregnancy, the end diastolic velocity (EDV) was not found in the umbilical and cotyledonary arteries. EDV was significantly higher in the caruncular arteries than in the cotyledonary and umbilical arteries (p < 0.01). The resistance index (RI) and pulsatility index (PI) in the early stages of pregnancy were found to be significantly higher than that in the later stages of pregnancy (p < 0.01). The RI and PI were significantly lower in the caruncular arteries than in the arteries of the cotyledons and umbilical cord (p < 0.01). In the umbilical vein, all Doppler parameters were observed to be significantly higher than those in the placentomal veins (p < 0.01 or p < 0.05). Using transrectal ultrasound, pregnancy was detected between 20 and 28 days after mating. The ovaries were observed to have corpora lutea, the diameter of which was fairly consistent from the 17th to the 56th day of pregnancy. CONCLUSIONS: It has been demonstrated that both the location of the arterial vessel in the placental-umbilical circulation and the gestational age have a significant impact on hemodynamic parameters. The results also provide new insights about the blood flow in caruncular and cotyledonary arteries, which could contribute to a more holistic understanding of hemodynamic changes in the placentas of sheep. Analyzing haemodynamic parameters in the umbilical and placental veins are preliminary studies in sheep, but it could inspire further research in this field. Furthermore, the research conducted confirms the practicality and convenience of transrectal ultrasonography in the early diagnosis of pregnancy in sheep and also indicates that the identification and imaging of the corpus luteum using B-mode ultrasonography can be a very early and simple method of confirming effective mating in sheep.

Multiscale and multimodal imaging of utero-placental anatomy and function in pregnancy.

Placental structures at the nano-, micro-, and macro scale each play important roles in contributing to its function. As such, quantifying the dynamic way in which placental structure evolves during pregnancy is critical to both clinical diagnosis of pregnancy disorders, and mechanistic understanding of their pathophysiology. Imaging the placenta, both exvivo and invivo, can provide a wealth of structural and/or functional information. This review outlines how imaging across modalities and spatial scales can ultimately come together to improve our understanding of normal and pathological pregnancies. We discuss how imaging technologies are evolving to provide new insights into placental physiology across disciplines, and how advanced computational algorithms can be used alongside state-of-the-art imaging to obtain a holistic view of placental structure and its associated functions to improve our understanding of placental function in health and disease.

Effect and mechanism of prophylactic use of tadalafil during pregnancy on l-NAME-induced preeclampsia-like rats.

INTRODUCTION: Preeclampsia (PE) is a serious maternal inflammatory disease with endothelial cell dysfunction, and there is a lack of effective treatment and prevention. Tadalafil is considered to be a promising drug for PE. This study aimed to determine whether and how tadalafil use during early pregnancy alleviates PE induced by N-nitro-l-arginine-methyl-ester (l-NAME), an antagonist of nitric oxide synthase, in rats. METHODS: Twenty-eight Sprague-Dawley (SD) rats were randomly divided into 4 equal groups on gestational day 0 (GD0): a pregnant control group, an l-NAME-treated PE group and two prophylactic low-dose and high-dose tadalafil groups. Blood pressure was measured on GD0, 5, 10, 15 and 20. Proteinuria was assessed on GD0 and 18. Femoral artery ultrasound was performed on GD19. Tissue sampling was performed on GD20. The perinatal outcomes, placenta and kidney tissue morphology, and endothelial and inflammatory markers were examined. RESULTS: Prophylactic administration of low and high doses of tadalafil improved l-NAME induced hypertension, proteinuria, maternal weight loss during pregnancy, fetal growth restriction and flow-mediated dilatation, balanced endothelial-relative factors, and alleviated inflammation activation in placenta and kidney tissue. What's more, in some results, the HT group performed better than the LT group. DISCUSSION: Our results indicate that prophylactic use of tadalafil in l-NAME-induced PE-like rat models alleviates PE symptoms, promotes fetal growth, protects endothelial function and reduces inflammation, suggesting that tadalafil may be a potential drug for the prevention of PE.

Fully automatic 3D reconstruction of the placenta and its peripheral vasculature in intrauterine fetal MRI.

Recent advances in fetal magnetic resonance imaging (MRI) open the door to improved detection and characterization of fetal and placental abnormalities. Since interpreting MRI data can be complex and ambiguous, there is a need for robust computational methods able to quantify placental anatomy (including its vasculature) and function. In this work, we propose a novel fully-automated method to segment the placenta and its peripheral blood vessels from fetal MRI. First, a super-resolution reconstruction of the uterus is generated by combining axial, sagittal and coronal views. The placenta is then segmented using 3D Gabor filters, texture features and Support Vector Machines. A uterus edge-based instance selection is proposed to identify the support vectors defining the placenta boundary. Subsequently, peripheral blood vessels are extracted through a curvature-based corner detector. Our approach is validated on a rich set of 44 control and pathological cases: singleton and (normal / monochorionic) twin pregnancies between 25-37 weeks of gestation. Dice coefficients of 0.82 â€¯±â€¯ 0.02 and 0.81 â€¯±â€¯ 0.08 are achieved for placenta and its vasculature segmentation, respectively. A comparative analysis with state of the art convolutional neural networks (CNN), namely, 3D U-Net, V-Net, DeepMedic, Holistic3D Net, HighRes3D Net and Dense V-Net is also conducted for placenta localization, with our method outperforming all CNN approaches. Results suggest that our methodology can aid the diagnosis and surgical planning of severe fetal disorders.

Fructose during pregnancy provokes fetal oxidative stress: The key role of the placental heme oxygenase-1.

SCOPE: One of the features of metabolic syndrome caused by liquid fructose intake is an impairment of redox status. We have investigated whether maternal fructose ingestion modifies the redox status in pregnant rats and their fetuses. METHODS AND RESULTS: Fructose (10% wt/vol) in the drinking water of rats throughout gestation, leads to maternal hepatic oxidative stress. However, this change was also observed in glucose-fed rats and, in fact, both carbohydrates produced a decrease in antioxidant enzyme activity. Surprisingly, mothers fed carbohydrates displayed low plasma lipid oxidation. In contrast, fetuses from fructose-fed mothers showed elevated levels of plasma lipoperoxides versus fetuses from control or glucose-fed mothers. Interestingly, a clearly augmented oxidative stress was observed in placenta of fructose-fed mothers, accompanied by a lower expression of the transcription factor Nuclear factor-erythroid 2-related factor-2 (Nrf2) and its target gene, heme oxygenase-1 (HO-1), a potent antioxidant molecule. Moreover, histone deacetylase 3 (HDAC3) that has been proposed to upregulate HO-1 expression by stabilizing Nrf2, exhibited a diminished expression in placenta of fructose-supplemented mothers. CONCLUSIONS: Maternal fructose intake provoked an imbalanced redox status in placenta and a clear diminution of HO-1 expression, which could be responsible for the augmented oxidative stress found in their fetuses.

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

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Ultrasound parameters and L/S ratio in prediction of perinatal outcome in term-growth restricted newborns.

AIM: The relation between biophysical profile (BPP), cerebroplacental (C/P) ratio, and lecithin/sphingomyelin (L/S) ratio as a predictor perinatal outcome in term intrauterine growth restricted (IUGR) neonates was evaluated. MATERIALS AND METHODS: A retrospective study of the perinatal outcome of 77 term monofetal pregnancies complicated with IUGR fetuses (< 10 percentile) who were terminated by cesarean section in 2010 was performed at the Institute of Gynecology and Obstetrics, Belgrade. RESULTS: The most frequent early neonatal complication was asphyxia. The authors found a strong correlation between the L/S ratio and birth weight (BW) r = 0.609, as well as between BPP and Apgar score 5 r = 0.583. Significant negative correlation was found between asphyxia and BPP r = -0.398, as well as between asphyxia and C/P ratio r = -0.379. CONCLUSION: In serous IUGR neonates, low values of BPP and L/S ratios predicted asphyxia.

Changes in umbilical venous volume flow after fetoscopic laser occlusion of placental vascular anastomoses in twin-to-twin transfusion syndrome.

OBJECTIVE: To examine effects of fetoscopic laser occlusion of placental vascular anastomoses on umbilical venous volume flow in twin-to-twin transfusion syndrome. STUDY DESIGN: Absolute umbilical venous volume flow, measured preoperatively and 48 hours after fetoscopic laser occlusion was related to Doppler studies, bladder filling in donors, and anastomoses. RESULTS: Among 45 patients, recipients had decreased ductus venosus pulsatility index (ductus venosus-pulsatility index for veins, 1.16 vs 1.01; P < .001) and unchanged umbilical venous volume flow after fetoscopic laser occlusion (74.7 vs 74.5 mL; P = .407). Donors had decreased umbilical artery pulsatility (1.34 vs 1.11; P = .008), increased ductus venous-pulsatility index for veins (0.75 vs 0.91; P < .014), and significantly increased umbilical venous volume flow per kilogram by 52.3% (136.6 vs 208.0 mL/Kg/min; P < .001). Donor bladder filling occurred at higher umbilical venous volume flow per kilogram (142.7 vs 221.4 mL/Kg/min; P < .012). Increase in umbilical venous volume flow per kilogram correlated with the net difference in arteriovenous anastomoses (Pearson r = 0.403, P = .006). CONCLUSION: Fetoscopic laser occlusion in twin-to-twin transfusion syndrome corrects intertwin differences in umbilical venous volume flow by predominant effects in the donor. Reappearance of donor bladder filling correlates with correction of volume flow.

Effects of calcium supplementation on uteroplacental and fetoplacental blood flow in low-calcium-intake mothers: a randomized controlled trial.

OBJECTIVE: We postulated that calcium supplementation of calcium-deficient pregnant women would lower vascular resistance in uteroplacental and fetoplacental circulations. STUDY DESIGN: Pulsatility index (PI) and resistance index (RI) (uterine and umbilical arteries) and presence of bilateral uterine artery diastolic notching were assessed by Doppler ultrasound between 20-36 weeks' gestation in 510 healthy, nulliparous Argentinean women with deficient calcium intake in a randomized, placebo-controlled, double-blinded trial. RESULTS: Average umbilical and uterine artery RI and PI tended to be lower in the supplemented group at each study week. Differences became statistically significant for umbilical artery RI and PI from 32 and 36 weeks, respectively. Estimated probabilities of bilateral uterine artery diastolic notching trended toward lower values in calcium-supplemented women. CONCLUSION: Calcium supplementation of pregnant women with deficient calcium intake may affect uteroplacental and fetoplacental blood flow by preserving the vasodilation of normal gestation.

L-Arginine treatment for severe vascular fetal intrauterine growth restriction: a randomized double-bind controlled trial.

BACKGROUND & AIMS: Infants born with severe IUGR are exposed to higher neonatal mortality and morbidity rates, as compared with appropriate-for-gestational-age. They are exposed to a higher risk of developing chronic disease such as hypertension, coronary artery disease, obesity, and type 2 diabetes in adulthood. L-Arginine is a precursor of nitric oxide (NO) and may play a role in placental vascular mediation or local vasodilatation. OBJECTIVE: The current study was designed to determine whether oral supplementation of gravid patients suffering from severe intrauterine growth restriction (IUGR) with L-arginine, would enhance birth weight and/or decrease neonatal morbidity. PATIENTS AND METHODS: Forty-four patients with a singleton pregnancy who had been referred for IUGR detected by ultrasonic examination were included. Vascular IUGR was defined by fetal abdominal circumference less than or equal to the 3rd percentile, associated with abnormal uterine Doppler. After double-blind randomization, patients received either 14 g/day of L-arginine, or a placebo. RESULTS: The characteristics of the two groups of patients (IUGR with L-arginine vs IUGR with placebo) were similar upon randomization. There was no significant difference between the two groups concerning birth weight (1042+/-476 vs. 1068+/-452 g). At delivery, maternal and neonatal characteristics were similar in the two groups. There was no difference in the Clinical Risk Index for Babies (CRIB) score, the duration of ventilatory assistance, nor the delay between birth and full enteral feeding between the two groups. CONCLUSION: In this study which is, at the best of our knowledge, the first double-bind, multicenter, randomized trial in this condition, L-arginine is not an effective treatment for severe vascular growth restriction.

The short-term effect of nifedipine tocolysis on placental, fetal cerebral and atrioventricular Doppler waveforms.

OBJECTIVE: To evaluate the effect of nifedipine on placental and fetal middle cerebral and atrioventricular Doppler waveforms. METHODS: Doppler waveforms of uterine (UtA), umbilical (UA) and middle cerebral (MCA) arteries and both atrioventricular valves were measured from 21 pregnant women/fetuses prior to and during nifedipine therapy for preterm labor. Maternal and fetal heart rates (FHR), maternal systolic and diastolic blood pressure, the Doppler pulsatility index and systolic/diastolic ratio of the UtA, UA and MCA were measured. The total time velocity integrals (TVI) of tricuspid and mitral valves and their E-wave/A-wave (E/A) TVI ratios were measured. Wilcoxon signed pairs test was used to compare the differences in Doppler parameters before and at 3 h after nifedipine loading up to a maximum dose of 40 mg. RESULTS: Fetal arterial and UtA Doppler parameters were not different before and after nifedipine therapy. Blood flow across the atrioventricular valves and the TVI were equally unaffected by nifedipine. The TVI x FHR product was also unchanged following nifedipine therapy. CONCLUSIONS: In women with otherwise uncomplicated pregnancies, nifedipine loading and tocolysis are generally well tolerated by the mother. Placental and fetal cerebral arterial blood flow, fetal systolic and diastolic cardiac function and downstream distribution of fetal cardiac output are unaffected by nifedipine loading. These results apply to women with unchanged vital parameters. Further studies are necessary to show long-term effects of nifedipine therapy and may help to refine choice of tocolytic agents.

The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term.

Twenty patients with preeclampsia at a gestational age of 26 to 35 weeks were treated with oral nifedipine until delivery. The mean oral daily dose was 45.1 +/- 11 mg/day (range, 40 to 80 mg/day). Fetal aorta, internal carotid artery, umbilical artery, and uteroplacental Doppler flow velocity waveforms were recorded before treatment and then serially. The mean nifedipine concentration at the time of the Doppler studies was 60.3 ng/ml (range, 10 to 90 ng/ml). The use of nifedipine therapy was associated with a significant decrease in both maternal systolic blood pressure (baseline, 154 to 135 mm Hg, p less than 0.001) and diastolic blood pressure (baseline, 100 to 88 mm Hg, p less than 0.001). However, there was no significant difference in the resistance index between baseline and postnifedipine Doppler studies in either the fetal or uteroplacental vessels. The use of oral nifedipine to control blood pressure in preeclampsia does not affect the resistance indices in fetal or uteroplacental vessels as measured by the Doppler technique.

[Placental scintigraphy--a diagnostic method for evaluating indications for hyperbaric oxygenation in pregnant women with high risk of perinatal pathology]. / Stsintigrafiia platsenty--diagnosticheskii metod, pozvoliaiushchii opredeli't pokazaniia k giperbaricheskoi oksigenatsii u beremennykh gruppy vysokogo riska perinata'lnoi patologii.

At most, 40 pregnant females at a high risk for fetal perinatal pathology underwent clinical investigation, ultrasonic scanning of the placenta, recording of the fetal electro- and phonocardiography, the evaluation of the placental levels of lactogen and estradiol and thermoresistant alkaline phosphatase changes of the values considered who were then treated with hyperbaric oxygenation (HBO) under the control of dynamic placental scintigraphy. Based on the placentographic findings, the authors distinguished from the whole of the risk-group the patients whose pattern of uteroplacental blood flow response to the treatment was beneficial and therefore the HBO treatment for fetoplacental insufficiency was advisable.

[The influence of TNS (transcutaneous nerve stimulation) on placental flow (author's transl)]. / DER Einfluss der TNS (transkutane Nervenstimulation) auf die plazentare Durchströmung.

A report about 12. gravid patients with a diminished uteroplacental flow is given. To increase their placental perfusion a transcutaneus lumbo-sacral electric nerve stimulation was performed. In all 12 cases a distinet increase war measured by the method of radioisotope placenta-perfusion. The mean values showed a high significant difference (p less than 0,001). The reasons for this results and the possibilities of this findings for the therapy of funcitonal placental insufficiency are discussed.