Volumetric Fetal Flow Imaging with Magnetic Resonance Imaging

Fetal development relies on a complex circulatory network and accurately assessing the flow distribution is important for understanding pathologies and potential therapies. In this paper, we demonstrate a method for volumetric multidimensional imaging of fetal flow with magnetic resonance imaging (MRI). Fetal application of MRI faces several challenges such as small vascular structures, unpredictable motion, and lack of traditional cardiac gating methods. Here, orthogonal multislice stacks are acquired with accelerated multidimensional radial phase contrast (PC) MRI. Each slice is reconstructed into flow sensitive time-series images (CINEs) with retrospective intraslice motion correction and image-based fetal cardiac gating. CINEs are then combined into a dynamic 3D volume using slice-to-volume reconstruction (SVR) while accounting for interslice spatiotemporal coregistration. Validation of the technique is demonstrated in adult volunteers by comparing mean flows from SVR with 4D radial PCMRI with bias and limits of agreement being -1.1 ml/s and [-12.5 10.2] ml/s. Feasibility is demonstrated in late gestation fetuses by comparing SVR with 2D Cartesian PCMRI with bias and limits of agreement being -0.9 ml/min/kg and [-39.7 37.8] ml/min/kg for mean flows. With SVR, we also demonstrate complex flow pathways (such as parallel flow streams in the proximal inferior vena cava, preferential shunting of blood from the ductus venosus into the left side of the heart, and blood returning from the brain leaving the heart through the main pulmonary artery) for the first time in human fetal circulation. This method allows for comprehensive evaluation of the fetal circulation and enables future studies of fetal physiology.

Volumetric Fetal Flow Imaging with Magnetic Resonance Imaging

Fetal development relies on a complex circulatory network and accurately assessing the flow distribution is important for understanding pathologies and potential therapies. In this paper, we demonstrate a method for volumetric multidimensional imaging of fetal flow with magnetic resonance imaging (MRI). Fetal application of MRI faces several challenges such as small vascular structures, unpredictable motion, and lack of traditional cardiac gating methods. Here, orthogonal multislice stacks are acquired with accelerated multidimensional radial phase contrast (PC) MRI. Each slice is reconstructed into flow sensitive time-series images (CINEs) with retrospective intraslice motion correction and image-based fetal cardiac gating. CINEs are then combined into a dynamic 3D volume using slice-to-volume reconstruction (SVR) while accounting for interslice spatiotemporal coregistration. Validation of the technique is demonstrated in adult volunteers by comparing mean flows from SVR with 4D radial PCMRI with bias and limits of agreement being -1.1 ml/s and [-12.5 10.2] ml/s. Feasibility is demonstrated in late gestation fetuses by comparing SVR with 2D Cartesian PCMRI with bias and limits of agreement being -0.9 ml/min/kg and [-39.7 37.8] ml/min/kg for mean flows. With SVR, we also demonstrate complex flow pathways (such as parallel flow streams in the proximal inferior vena cava, preferential shunting of blood from the ductus venosus into the left side of the heart, and blood returning from the brain leaving the heart through the main pulmonary artery) for the first time in human fetal circulation. This method allows for comprehensive evaluation of the fetal circulation and enables future studies of fetal physiology.

Fetal Blood Flow and Genetic Mutations in Conotruncal Congenital Heart Disease

In congenital heart disease, the presence of structural defects affects blood flow in the heart and circulation. However, because the fetal circulation bypasses the lungs, fetuses with cyanotic heart defects can survive in utero but need prompt intervention to survive after birth. Tetralogy of Fallot and persistent truncus arteriosus are two of the most significant conotruncal heart defects. In both defects, blood access to the lungs is restricted or non-existent, and babies with these critical conditions need intervention right after birth. While there are known genetic mutations that lead to these critical heart defects, early perturbations in blood flow can independently lead to critical heart defects. In this paper, we start by comparing the fetal circulation with the neonatal and adult circulation, and reviewing how altered fetal blood flow can be used as a diagnostic tool to plan interventions. We then look at known factors that lead to tetralogy of Fallot and persistent truncus arteriosus: namely early perturbations in blood flow and mutations within VEGF-related pathways. The interplay between physical and genetic factors means that any one alteration can cause significant disruptions during development and underscore our need to better understand the effects of both blood flow and flow-responsive genes.

Anatomy and spontaneous closure of the ductus arteriosus

The ductus arteriosus and foramen ovale were described by Galen without understanding their functions. His beliefs in soul localization and spiritization within the left ventricle established religious pneumatology which became a theological need in the Middle Ages. Pulmonary transit was recognized by Servetus and Colombo after the Reformation around 1550. This prompted Harvey’s full understanding of the fetal circulation. Botallo did not describe the ductus arteriosus, but in 1564 redescribed the foramen ovale, making his way into the Nomina Anatomica by mistake. Most authors of the 19th and 20th centuries believed ductal patency to be passive, and postnatal closure to be an active process, explained by mechanical theories. After the discovery of prostaglandins by Bergstrom and Vane, Coceani proved that ductal patency is maintained by the relaxant action of prostaglandins.

Nanoparticle-mediated transgene expression of insulin-like growth factor 1 in the guinea pig placenta differentially affects fetal liver gene expression depending on maternal nutrient status

Fetal growth restriction (FGR) occurs in up to 10% of pregnancies and is a leading cause of infant morbidity and mortality. Additionally, FGR has been implicated in contributing to the development of long-term health outcomes including increasing the risk for future cardiovascular and endocrine diseases. Currently, there is limited preventative strategies and no effective treatment options for FGR. To address this need, we are developing a therapeutic targeting the placenta to increase expression of human insulin-like growth factor 1 (hIGF-1) and enhance placental development and function, with the goal of correcting fetal growth trajectories. Methods Initially, an ultrasound-guided, transcutaneous, intra-placental injection of a non-viral, Texas-red conjugated polymer-based nanoparticle containing a plasmid with the green fluorescent protein (GFP) gene under the control of the placenta-specific promotors Plac1 or Cyp19a1 was performed to determine nanoparticle uptake and transgene expression in the guinea pig placenta. Subsequently, using the established maternal nutrient restriction (MNR) guinea pig model of FGR, placentas were treated with an unconjugated nanoparticle containing a plasmid with the hIGF-1 gene under the Cyp19a1 promotor at mid-pregnancy (gestational day (GD) 30-33). Five days after treatment placentas and fetal liver tissue was collected, weighed, and fixed for histology or snap-frozen for qPCR analysis of mRNA expression. Results Histological analysis of Texas-red and GFP fluorescence in placenta and fetal liver tissue confirmed nanoparticle uptake and transgene expression and that nanoparticle was unable to cross the placenta to fetal circulation. In situ hybridization for plasmid-specific mRNA confirmed sustained hIGF-1 expression five days after treatment. MNR resulted in 20-25% decreased fetal weight at mid-pregnancy (P<0.001) that was not changed with nanoparticle treatment (P>0.05). There was no effect of nanoparticle treatment on the volume densities of trophoblasts or fetal capillaries in the placenta (P>0.05 for both). However, treatment did reduce the interhaemal distance between the maternal blood space and fetal circulation in the MNR placentas compared to sham treated MNR placentas (P<0.001). In the fetuses, placental nanoparticle treatment increased circulating glucose by 38-50% (P<0.001) and was associated with differential changes to fetal liver mRNA expression of genes associated with gluconeogenesis. Gene expression changes were dependent on if the fetus was growth restricted or not; nanoparticle treatment: down-regulated gluconeogenesis gene expression in the normal growing fetuses but increased expression in the FGR fetuses. Conclusions The current study shows that treatment of the guinea pig placenta with a polymer-based nanoparticle causes expression of hIGF-1 and ultimately increases fetal glucose concentrations within five days of treatment. Furthermore, the data shows that the placenta and fetal liver respond differently to nanoparticle treatment depending on fetal growth conditions.

Haemodynamic Changes during Preterm Birth Treatment

The well-being of the fetus depends on the efficiency of its circulatory system and the proper maternal-fetal exchange. Hemodynamic changes can occur due to disturbance of fetal and maternal homeostasis, malformations, pregnancy pathology, and medications. Preterm labor directly affects maternal-fetal haemodynamics, both due to uterine contractions and medications used to inhibit it. Research on maternal-fetal haemodynamics in preterm labor is currently focused mainly on the safety of the used tocolytics. In this chapter, we will discuss the basic principles of fetal haemodynamics, ultrasound methods of maternal-fetal circulation assessment, and the influence of preterm labor on maternal-fetal haemodynamics, with particular emphasis on medications used in threatening and progressive preterm labor.

Update on fetal cardiovascular magnetic resonance and utility in congenital heart disease

Background Congenital heart disease (CHD) is the most common birth defect, affecting approximately eight per thousand newborns. Between one and two neonates per thousand have congenital cardiac lesions that require immediate post-natal treatment to stabilize the circulation, and the management of these patients in particular has been greatly enhanced by prenatal detection. The antenatal diagnosis of CHD has been made possible through the development of fetal echocardiography, which provides excellent visualization of cardiac anatomy and physiology and is widely available. However, late gestational fetal echocardiographic imaging can be hampered by suboptimal sonographic windows, particularly in the setting of oligohydramnios or adverse maternal body habitus. Main body Recent advances in fetal cardiovascular magnetic resonance (CMR) technology now provide a feasible alternative that could be helpful when echocardiography is inconclusive or limited. Fetal CMR has also been used to study fetal circulatory physiology in human fetuses with CHD, providing new insights into how these common anatomical abnormalities impact the distribution of blood flow and oxygen across the fetal circulation. In combination with conventional fetal and neonatal magnetic resonance imaging (MRI) techniques, fetal CMR can be used to explore the relationship between abnormal cardiovascular physiology and fetal development. Similarly, fetal CMR has been successfully applied in large animal models of the human fetal circulation, aiding in the evaluation of experimental interventions aimed at improving in utero development. With the advent of accelerated image acquisition techniques, post-processing approaches to correcting motion artifacts and commercial MRI compatible cardiotocography units for acquiring gated fetal cardiac imaging, an increasing number of CMR methods including angiography, ventricular volumetry, and the quantification of vessel blood flow and oxygen content are now possible. Conclusion Fetal CMR has reached an exciting stage whereby it may now be used to enhance the assessment of cardiac morphology and fetal hemodynamics in the setting of prenatal CHD.