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FIG 6.4 (A) Diagram of the fetal circulation illustrating the unique position of the aortic isthmus, between the aortic and pulmonary arches (B) During systole, the left and right ventricular (LV, RV) stroke volumes have opposite effects on the direction of flow through the isthmus (C) During diastole, the two downstream vascular impedances are the only determinants of the direction of the isthmic flow (From Fouron JC The unrecognized physiological and clinical significance of the fetal aortic isthmus Ultrasound Obstet Gynecol 2003;22[5]:441–447.) Maturational Changes in the Early Fetal Heart In vivo Studies Diagnostic imaging of the fetal heart is possible from 12 gestational weeks, even in multiple pregnancies.32,33 Modern ultrasound transducers with limits of resolution of approximately 50 µm in the axial plane at 6 MHz and less than 100 µm in the lateral plane permit diagnostic views at normal obstetric scanning depths As a result, morphologic and physiologic data have become easier to record and more reliable Improved resolution should increase the robustness of calculated measures such as indexed combined cardiac output that relies on measurements of biometric variables and valve diameters z-Scores have been derived to take account of the effects of fetal gestation and growth on the size of vessels, valves, and chambers.34,35 z-Scores are particularly useful for quantitative comparison when cardiac structures are hypoplastic, and values are available online or via a smartphone app.36–38 New indexes reflecting the developmental abnormality of cardiac shape in various disease states have been developed including the sphericity index of the heart (most often abnormalities of fetal growth), and a 24-segment approach to its assessment has been proposed using specialized offline software (Fig 6.5).39,40 FIG 6.5 Computation of the sphericity index (SI) (A) Most common previously published methods to compute the fetal SI in which the enddiastolic basal-apical length (green arrows) is divided by the basal transverse length (blue arrows), or the mid-transverse end-diastolic length (red arrows) is divided by the mid basal-apical length (green arrows) (B) Technique used in which the mid end-diastolic length is divided by each of the 24 transverse segments LA, Left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle (From DeVore GR, Klas B, Satou G, Sklansky M The 24-segment sphericity index: a new technique to evaluate fetal cardiac diastolic shape Ultrasound Obstet Gynecol 2018;51:650–658.) More advanced ultrasound techniques, using three-dimensional (3D) and fourdimensional (4D) technology with shortened acquisition times less than 3 seconds and magnetic resonance imaging (MRI), permit physiologic assessment of ventricular volumes noninvasively but only where imaging is optimal.41,42 Lack of resolution of both modalities and expense of MRI have prevented their introduction into routine clinical practice However, a new automated program, combining color or bidirectional power Doppler ultrasound with fetal intelligent navigation echocardiography shows promise in processing 3D volume sets to generate standard views.43,44 Postmortem Studies The first systematic study of cardiac growth in the human fetus was made using a large series of normal hearts obtained at postmortem This established the relationship between total body weight, total heart weight, and the change of heart weight with gestational age.45 However, impressive, near histologic detail has been made possible by newer technologies There is a clinical imperative to develop techniques to achieve a “noninvasive postmortem,” and these have been investigated, both for whole body autopsy and to examine single-organ specimens obtained following pregnancy loss or termination These techniques include high-resolution episcopic microscopy (HREM), micro-computed tomography, and high-field MRI High-Resolution Episcopic Microscopy HREM is an ex vivo technique Used more frequently to examine small animal hearts, it has been applied in the first and early second trimester human fetal heart when the small size and fragility of structures make other techniques difficult.46 The heart specimens are processed, embedded in plastic resin (JB4, Polyscience), and serially sectioned to produce more than 1000 sections from each heart HREM automatically captures an image of high resolution (minimum 1 µm) from each section and compiles the serial images in perfect alignment to