Fetal Brain Blood Research Articles

A cancer-unique glycan: de-N-acetyl polysialic acid (dPSA) linked to cell surface nucleolin depends on re-expression of the fetal polysialyltransferase ST8SIA2 gene

BackgroundPolysialic acid (polySia) modifies six cell surface proteins in humans mainly during fetal development and some blood cells in adults. Two genes in humans, ST8SIA2 and ST8SIA4, code for polysialyltransferases that synthesize polySia. ST8SIA2 is highly expressed during fetal development and in cancer but not in adult normal human cells. ST8SIA4 is expressed in fetal and adult brain, spleen, thymus, and peripheral blood leukocytes and in cancer. We identified a derivative of polySia containing de-N-acetyl neuraminic acid residues (dPSA), which is expressed on the cell surface of human cancer cell lines and tumors but not normal cells.MethodsdPSA-modified proteins in several human cancer cell lines and normal blood cells were identified using co-immunoprecipitation with anti-dPSA antibodies, mass spectroscopy and Western blot. RNAi and CRISPR were used to knockdown and knockout, respectively, the polysialyltransferase genes in human melanoma SK-MEL-28 and neuroblastoma CHP-134 cell lines, respectively, to determine the effect on production of cell surface dPSA measured by flow cytometry and fluorescence microscopy.ResultsWe found that dPSA is linked to or associated with nucleolin, a nuclear protein reported to be on the cell surface of cancer but not normal cells. Knocking down expression of ST8SIA2 with RNAi or knocking out each gene individually and in combination using CRISPR showed that cell surface dPSA depended on expression of ST8SIA2.ConclusionsThe presence of dPSA specifically in a broad range of human cancers but not human adult normal cells offers novel possibilities for diagnosis, prevention and treatment targeting the dPSA antigen that appears to be cancer-specific, consistent across not only human cancers but also species, and may be an unrecognized mechanism of immune shielding.

Fetal Head Compression.

EDITOR’S NOTE The Legal Briefs in the July 2019 issue of NeoReviews focuses on the topic of fetal head compression. Several readers wanted to learn more about our current knowledge about this topic. Thus, we asked Dr Weiss, a neonatologist with a particular interest in neonatal brain injury, to summarize the evidence behind our current understanding of fetal head compression during labor and how this compression affects the fetal brain. During labor, external forces are exerted on the fetal head by uterine contractions and maternal pushing. The exact effect of the external forces on the intracranial pressure, fetal brain, and cerebral blood flow are not known. The reason for this lack of information is the difficulty studying the effect of external forces in human neonates with our current technology. However, several studies have been published that give us insight into the effect of these forces on the fetal head and brain during labor. These studies will be briefly reviewed. Please note that more extensive reviews are also available on the subject. (1) Several studies have examined the pressure applied to the fetal head during labor and maternal pushing using pressure sensors placed alongside the fetal head. Most studies have indicated that the peak pressure between the fetal head and the pelvis may be as high as 120 to 300 mm Hg during normal labor. (1)(2)(3) …

The Effect of Maternal Mathematical Activities on the Fetal Brain

Background: In recent years, there has been growing interest in the effect of maternal exposure to physiological, environmental, and also psychological factors during gestation on child development. Several independent studies link maternal stress during pregnancy to emotional and behavioral problems in the child. Objectives: This study aimed to observe the effect of maternal cognitive activity on fetal brain blood flow to determine whether systematic maternal mathematical activity during pregnancy might influence child brain development. Method: Thirty-five women in the 28th to 40th week of pregnancy engaged in mathematical activities. Fetal middle cerebral artery (MCA), pulsatility index (PI) and peak systolic velocity (PSV) were monitored before, during, and after the activity. Results: Brain activity and blood flow were shown to be intimately linked. We observed a significant decrease in fetal brain MCA resistance, as evidenced by decreased MCA PI, towards the end of the mathematical activity. This may result in increased blood flow in the arteries supplying most brain regions and, possibly, increased brain activity. Conclusions: A correlation between the mother’s engagement in mathematical activities and fetal brain blood flow may lead to enhancement of the fetus’s brain function and a cognitive advantage for the child.

Variations from morning to afternoon of middle cerebral and umbilical artery blood flow, and fetal heart rate variability, and fetal characteristics in the normally developing fetus.

To determine if there are changes in maternal uterine blood flow, fetal brain blood flow, fetal heart rate variability, and umbilical blood flow between morning (AM) and afternoon (PM) in healthy, uncomplicated pregnancies. In this prospective study, 68 uncomplicated singleton pregnancies (mean 35 + 0.7 weeks gestation) underwent a standard observational protocol at both 08:00 (AM) and 13:30 (PM) of the same day. This protocol included Doppler measurements of uterine, umbilical, and fetal middle cerebral artery (MCA) volume flow parameters (flow, HR, peak systolic velocity [PSV], PI, and RI) followed by computerized cardiotocography. Standard descriptive statistics, χ2 and t tests were used where appropriate. P < .05 was considered significant. A significant increase in MCA flow and MCA PSV was observed in the PM compared to the AM. This was accompanied by a fall in MCA resistance. Higher umbilical artery resistance indices were also observed in the PM compared to AM. In contrast, fetal heart rate characteristics, maternal uterine artery Doppler flow and resistance indices did not vary significantly between the AM and PM. In normal pregnancies, variations in fetal cerebral and umbilical blood flow parameters were observed between AM and PM independent of other fetal movements or baseline fetal heart rate. In contrast, uterine flow parameters remained stable across the day. These findings may have implications for the use of serial Doppler parameters used to guide clinical management in high-risk pregnancies.

Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder

Integration of emerging epigenetic information with autism spectrum disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. Here we use the genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists). Additionally, we use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; P < 0.001) and peripheral blood meQTLs (OR = 1.58; P < 0.001). The CpG targets of ASD meQTLs across cord, blood, and brain tissues are enriched for immune-related pathways, consistent with other expression and DNAm results in ASD, and reveal pathways not implicated by genetic findings. This joint analysis of genotype and DNAm demonstrates the potential of both brain and blood-based DNAm for insights into ASD and psychiatric phenotypes more broadly.

Three-dimensional ultrasonographic depiction of fetal brain blood vessels.

The objective of this study is to evaluate the fetal cerebral vasculature by three-dimensional (3D) ultrasonography and Doppler technologies in normal fetuses and to describe a systematic method for analysis of volume data sets. 3D volumes of the fetal brain were acquired prospectively in 25 patients between 12.3 and 36.3 weeks' gestation. Volumes were acquired with high-definition Doppler flow. The feasibility of identifying the fetal cerebral blood vessels and venous sinuses was analyzed. A step-by-step systematic approach to identify the cerebral vasculature from ultrasonographic volume data sets was developed. The volumes were rotated into a standard anatomic orientation in the multiplanar display, and then, by systematic navigation, the vessels were demonstrated. Arteries of the circle of Willis, basilar artery, pericallosal artery, and internal carotid arteries were demonstrated in more than half of the fetuses. Tiny vessels such as those that supply the cerebellum and those that branch from the pericallosal artery were demonstrated in less than 50% of the volumes. The essential fetal cerebral vessels can be visualized by 3D volume analysis. Systematic analysis enables identification of the fetal brain arteries, veins, and sinuses and provides knowledge about anatomical variations and the diversity of human anatomy. © 2016 John Wiley & Sons, Ltd.

Reduced fetal cerebral oxygen consumption is associated with smaller brain size in fetuses with congenital heart disease.

Fetal hypoxia has been implicated in the abnormal brain development seen in newborns with congenital heart disease (CHD). New magnetic resonance imaging technology now offers the potential to investigate the relationship between fetal hemodynamics and brain dysmaturation. We measured fetal brain size, oxygen saturation, and blood flow in the major vessels of the fetal circulation in 30 late-gestation fetuses with CHD and 30 normal controls using phase-contrast magnetic resonance imaging and T2 mapping. Fetal hemodynamic parameters were calculated from a combination of magnetic resonance imaging flow and oximetry data and fetal hemoglobin concentrations estimated from population averages. In fetuses with CHD, reductions in umbilical vein oxygen content (P<0.001) and failure of the normal streaming of oxygenated blood from the placenta to the ascending aorta were associated with a mean reduction in ascending aortic saturation of 10% (P<0.001), whereas cerebral blood flow and cerebral oxygen extraction were no different from those in controls. This accounted for the mean 15% reduction in cerebral oxygen delivery (P=0.08) and 32% reduction cerebral Vo2 in CHD fetuses (P<0.001), which were associated with a 13% reduction in fetal brain volume (P<0.001). Fetal brain size correlated with ascending aortic oxygen saturation and cerebral Vo2 (r=0.37, P=0.004). This study supports a direct link between reduced cerebral oxygenation and impaired brain growth in fetuses with CHD and raises the possibility that in utero brain development could be improved with maternal oxygen therapy.

Effects of L-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol.

Not much is known about effects of gestational alcohol exposure on maternal and fetal cardiovascular adaptations. This study determined whether maternal binge alcohol exposure and L-glutamine supplementation could affect maternal-fetal hemodynamics and fetal regional brain blood flow during the brain growth spurt period. Pregnant sheep were randomly assigned to one of four groups: saline control, alcohol (1.75-2.5g/kg body weight), glutamine (100mg/kg body weight) or alcohol+glutamine. A chronic weekend binge drinking paradigm between gestational days (GD) 99 and 115 was utilized. Fetuses were surgically instrumented on GD 117±1 and studied on GD 120±1. Binge alcohol exposure caused maternal acidemia, hypercapnea, and hypoxemia. Fetuses were acidemic and hypercapnic, but not hypoxemic. Alcohol exposure increased fetal mean arterial pressure, whereas fetal heart rate was unaltered. Alcohol exposure resulted in ~40% reduction in maternal uterine artery blood flow. Labeled microsphere analyses showed that alcohol induced >2-fold increases in fetal whole brain blood flow. The elevation in fetal brain blood flow was region-specific, particularly affecting the developing cerebellum, brain stem, and olfactory bulb. Maternal L-glutamine supplementation attenuated alcohol-induced maternal hypercapnea, fetal acidemia and increases in fetal brain blood flow. L-Glutamine supplementation did not affect uterine blood flow. Collectively, alcohol exposure alters maternal and fetal acid-base balance, decreases uterine blood flow, and alters fetal regional brain blood flow. Importantly, L-glutamine supplementation mitigates alcohol-induced acid-base imbalances and alterations in fetal regional brain blood flow. Further studies are warranted to elucidate mechanisms responsible for alcohol-induced programming of maternal uterine artery and fetal circulation adaptations in pregnancy.

Quantitative analysis of normal fetal brain volume and flow by three-dimensional power Doppler ultrasound

BackgroundAssessment of the fetal brain volume and blood flow is important in the evaluation of fetal growth. We used three-dimensional (3D) ultrasound and power Doppler to assess the fetal brain volume and the blood flow index during normal gestation. The relationships of these parameters were further analyzed. MethodsWe assessed the total volume and the blood flow index of the fetal brain in normal pregnancies using 3D ultrasound (Voluson 730). The bilateral parietal diameter (BPD) plane was measured by a 3D transabdominal probe to scan the fetal brain under the power Doppler mode. Then, we quantitatively assessed the total volume of the fetal brain, mean grey area (MG), vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) by applying Kretz VOCAL software. ResultsThe study included 126 fetuses, ranging from 15 to 38 weeks of gestation. The total volume of the fetal brain was highly positively correlated with the gestational age (GA) (correlation coefficient [r] = 0.976, p < 0.0001). The MG, VI, and VFI were negatively correlated with the GA (correlation coefficient [r] = −0.520, p < 0.0001; [r] = −0.421, p < 0.001; [r] = −0.319, p < 0.0001). The FI was positively correlated with the GA (correlation coefficient [r] = 0.483, p < 0.0001). Conclusion3D ultrasound can be used to assess the fetal brain volume and blood flow development quantitatively. Our study indicates that the fetal brain vascularization and blood flow correlates significantly with the advancement of GA. This information may serve as a reference point for further studies of the fetal brain volume and blood flow in abnormal conditions.

Single-ventricle anatomy predicts delayed microstructural brain development

BackgroundTerm newborns with congenital heart disease (CHD) show delayed brain development as early as the third trimester, especially in single ventricle physiology (SVP). Mechanisms causing delayed brain development in CHD are uncertain, but may include impaired fetal brain blood flow. Our objective was to determine if cardiac anatomy associated with obstruction to antegrade flow in the ascending aorta is predictive of delayed brain development measured by diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI).MethodsEchocardiograms (ECHO) from 36 term newborns with SVP were reviewed for presence of aortic atresia and the diameter of the ascending aorta. Quantitative MR imaging parameters measuring brain microstructural (fractional anisotropy (FA), average diffusivity (Dav)) or metabolic development (N-acetylaspartate (NAA), Lactate/choline (Lac/cho)) were recorded.ResultsIncreasing NAA/cho and white matter FA, and decreasing Dav and lactate/cho characterize normal brain development. Consistent with the hypothesis that delayed brain development is related to impaired brain perfusion, smaller ascending aortic diameter and aortic atresia were associated with higher Dav and lower white matter FA. ECHO variables were not associated with brain metabolic measures.ConclusionsThese observations support the hypothesis that obstruction to fetal cerebral blood flow impairs brain microstructural development.

OP03.09: Three‐dimensional ultrasonographic depiction of fetal brain blood vessels

OP03.09: Three‐dimensional ultrasonographic depiction of fetal brain blood vessels

Normal reference ranges of fetal regional cerebral blood perfusion as measured by fractional moving blood volume

To establish normal reference intervals of fetal regional brain blood perfusion using power Doppler ultrasound as measured by fractional moving blood volume (FMBV). A cohort of consecutive singleton normally grown fetuses was selected including at least 12 fetuses for each completed week of gestation between 24 and 41 weeks. Cerebral blood perfusion was estimated using conventional power Doppler ultrasound in the following brain regions: frontal area, basal ganglia and posterior brain. Five consecutive good-quality images were recorded in each area and the region of interest was delineated offline. The FMBV was quantified as the average of all images and expressed as a percentage. Normal reference ranges were constructed by means of the LMS (lambda-mu-sigma) method. A total of 230 fetuses were included. The median gestational age at evaluation and at delivery was 33.1 (range, 24.0-41.0) and 39.7 (range, 34.9-42.3) weeks, respectively. From 24 to 41 weeks' gestation, the mean FMBV increased from 13.21 to 14.97% in the frontal area, 11.17 to 14.86% in the basal ganglia and 4.83 to 6.70% in the posterior brain. Normal data of fetal cerebral blood perfusion in the frontal area, basal ganglia and posterior brain are provided, which could be of clinical use in the assessment of fetal brain circulation.

Análise da reprodutibilidade do Doppler de amplitude tridimensional na avaliação da circulação do cérebro fetal

OBJETIVO: Avaliar a reprodutibilidade intra e interobservador do Doppler de amplitude tridimensional (3D power Doppler) na avaliação do fluxo sanguíneo cerebral do território da artéria cerebral média. MATERIAIS E MÉTODOS: Foi realizado estudo transversal com 20 gestantes normais entre 26 e 34 semanas. O território da artéria cerebral média mais próximo ao transdutor foi selecionado e o volume foi calculado utilizando-se o método Virtual Organ Computer-aided AnaLysis. Posteriormente, obtiveram-se os índices do 3D power Doppler: índice de vascularização (VI), índice de fluxo (FI) e índice de vascularização-fluxo (VFI). Utilizaram-se, para os cálculos, o coeficiente de correlação intraclasse (CCI) e gráficos de Bland-Altman. RESULTADOS: Foi observada boa concordância intra e interobservador, com CCI &gt; 0,90 para todos os índices do 3D power Doppler: VI [CCI = 0,992 (IC 95%: 0,981-0,997)], FI [CCI = 0,999 (IC 95%: 0,998-0,999)], VFI [CCI = 0,995 (IC 95%: 0,987-0,998)]. Reprodutibilidade interobservador: VI [CCI = 0,988 (IC 95%: 0,970-0,995)], FI [CCI = 0,999 (IC 95%: 0,997-1,000)], VFI [CCI = 0,994 (IC 95%: 0,994-0,998)]. CONCLUSÃO: O 3D power Doppler mostrou-se um método prático, fácil e com boa reprodutibilidade intra e interobservador, com o IF evidenciando a melhor concordância intra e interobservador

P10.06: Three‐dimensional power Doppler ultrasound for the assessment of the fetal brain vascularization and blood flow in normal pregnancy

P10.06: Three‐dimensional power Doppler ultrasound for the assessment of the fetal brain vascularization and blood flow in normal pregnancy

P25.09: Reproducibility of three‐dimensional power Doppler for the assessment of the fetal brain blood flow in the anterior cerebral artery territory

P25.09: Reproducibility of three‐dimensional power Doppler for the assessment of the fetal brain blood flow in the anterior cerebral artery territory

Fetal brain during a binge drinking episode: a dynamic susceptibility contrast MRI fetal brain perfusion study

We assessed the effects of a single episode of maternal alcohol intoxication on fetal brain blood perfusion in three pregnant dams (baboons) at the 24th week of pregnancy using dynamic susceptibility contrast magnetic resonance imaging. After the oral administration of alcohol, there was a four-fold increase in the peak contrast concentrations in the fetal brain. In addition, we observed a two- to three-fold increase in the contrast uptake and washout rates in the fetal brain. The underlying mechanisms of these changes are unknown, but we hypothesized that these could include the alcohol-mediated changes in placental permeability and fetal cerebral blood flow. Our findings indicate that alcohol intoxication produces profound changes, which may detrimentally influence neurodevelopmental processes in the brain.

P10.05: Quantitative 3D power Doppler ultrasound in the assessment of normal fetal brain blood flow: a reproducibility study of this method

Primary renal agenesis is not a diagnostical challenge as oligohydramnios is almost always present at the time of the anomaly scan. In contrast secondary (or progressive) renal agenesis (e.g. in multicystic dysplastic kidney) is frequently missed as kidneys are present but smaller in size and they tend to vanish with advancing gestational age. We present a case of a 24-year-old woman, gravida 1 para 0, referred to our center at 24+3 weeks’ gestation for suspicion of IUGR and oligohydramnios. Ultrasound showed a small multicystic left kidney. The right kidney could not be visualized. In view of the challenging scan conditions and the fact that normal kidneys were documented on previous exams a fetal MRI was requested. This case stresses the possibility of MCDK and other forms of cystic renal dysplasia in fetuses with oligohydramnios – even if a normal urinary tract was visualized on earlier exams. From our experience MRI as an alternative to amnioninfusion was decisive in confirming the diagnosis.

Cerebral venous blood flow in growth restricted fetuses with an abnormal blood flow in the umbilical artery before 32 weeks of gestation

Objective To evaluate the brain venous circulation in fetuses with severe intrauterine growth restriction (IUGR) before 32 weeks of gestation. Study design Fifty fetuses with severe IUGR diagnosed between 27 and 32 weeks of gestation and 50 appropriate-for-gestational age (AGA) fetuses matched by gestational age were evaluated. IUGR fetuses were classified according to their hemodynamic deterioration pattern in relation to the Doppler examination of the umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV). The fetal venous brain blood flow was evaluated in the vein of Galen (VG), superior sagittal (SS), straight and transverse venous sinuses. Results Only the transverse sinus (TS) showed a significant reduction in the pulsatility index (PI) values in IUGR fetuses. All other veins showed similar PI values between IUGR and AGA fetuses. All cerebral veins of IUGR fetuses showed significantly increased maximum and mean velocities. All these findings did not change in relation to the hemodynamic IUGR deterioration. In nearly all normal and all IUGR fetuses, a pulsatile blood flow pattern was observed in the straight and transverse sinuses, whereas an increased pulsatile pattern in the VG and in the SS was noted in IUGR fetuses. Conclusion Brain venous blood flow in IUGR fetuses shows an increment in the maximum and mean velocities of all veins and a reduction in the PI in the transverse sinus.

OP09.13: 3D analysis of fetal brain blood flow during normal pregnancy, effect of contractions and comparison with fetuses with hemodynamic redistribution

OP09.13: 3D analysis of fetal brain blood flow during normal pregnancy, effect of contractions and comparison with fetuses with hemodynamic redistribution

Magnesium sulfate exposure increases fetal blood flow redistribution to the brain during acute non-acidemic hypoxemia in goats

Background It is still controversial that intrapartum exposure to magnesium may or may not reduce brain damage in premature infants in human and animal models. Aims We investigated the effect of hypoxemia alone under magnesium exposure on fetal cardiovascular changes in chronically catheterized goat fetuses. Study design We performed a 3-day experimental protocol with control (10% glucose) on day 1, recovery on day 2, and magnesium on day 3. Magnesium sulfate was directly infused to fetuses in a bolus dose of 270 mg/kg followed by 80 mg/kg/h. Hypoxemia was induced by maternal inhalation of nitrogen gas on day 1 and on day 3. Cerebral blood flow was measured by colored microsphere techniques. Repeated measure ANOVA and Bonferroni's/Dunn's test were used for comparison. Subjects Six Japanese Saanen goats at 0.85 gestation. Outcome measures Fetal heart rate, blood pressure, and cerebral blood flow. Results Ionized magnesium concentrations were significantly increased. Fetal PO 2 decreased significantly from 30 mmHg to 14 mmHg without acidemia. Magnesium exposure significantly attenuated hypoxemia-induced bradycardia but did not affect blood pressure. Hypoxemia significantly increased fetal brain blood flow from the pre-hypoxic levels on day 1. Magnesium exposure further increased hypoxemia-induced brain blood flow on day 3, but statistical significance was limited to the cerebral cortex. Conclusion In near-term, initially healthy goat fetuses, brain blood flow during acute hypoxemia was significantly increased with magnesium sulfate exposure.