Role of quantitative assessment in fetal echocardiography

Fetal echocardiography has evolved considerably over the last two decades. In the past, our focus was to provide a basic (often structural) cardiac diagnosis, and much of our counseling consisted of extrapolation to the fetus from what we understood to be true of postnatal disease. With technological advances and increasing experience, detailed anatomical and functional fetal cardiovascular diagnoses have become the norm1, 2. We have learned that the fetal circulation, with equalization of pressures and redistribution of flow between left and right cardiac chambers and great arteries, results in the absence of many postnatal hemodynamic findings that would in the neonate indicate disease severity. Furthermore, we have come to understand that many fetal cardiovascular abnormalities have the potential to progress to more severe disease in utero, including altered growth of cardiac chambers, great arteries, arches and branch pulmonary arteries2, 3 and the evolution of fetal heart failure3, 4. There have been improvements in the evaluation and serial assessment of fetal heart disease at least in part as a consequence of the generation of normative dimensional and Doppler velocity data used to facilitate diagnosis and track the natural evolution. Our assessment of many conditions relies on indirect measures of severity, most commonly altered dimensions of cardiac and vascular structures. Although comparison of relative left versus right heart dimensions has assisted our evaluation, it is far less specific and thus less useful in making a diagnosis and in defining disease severity. Comparison of fetal cardiovascular measurements to normative data aids in identifying where and the extent to which abnormal growth has occurred, directing the clinician to a diagnosis. An example is that of left versus right heart asymmetry, in which the left heart structures are more diminutive relative to the right ones. Right ventricular and pulmonary artery dilation with normal left heart structure dimensions could suggest increased flow through the right heart as would occur in vein of Galen aneurysm, in which increased superior vena caval return is directed into the right ventricle. Small-for-gestational age left and dilated right heart structures could be observed when there is a redistribution of blood from the left towards the right heart, as observed in left heart obstructive lesions (e.g. aortic coarctation, aortic stenosis), diastolic pathology of the left ventricle, altered pulmonary venous return and foramen ovale restriction. Furthermore, given the risk of progression in fetal heart disease, observations made against normal growth curves have provided critical insight into the role of primary lesions in the evolution of secondary pathology such as critical aortic and pulmonary outflow obstruction and the development of left and right heart hypoplasia3, 5-8. These observations have prompted the development of fetal cardiac intervention to prevent the evolution of more severe secondary pathology, which has the potential to significantly improve the postnatal prognosis of affected fetuses9, 10. Serial evaluation of fetal ventricular and great artery dimensions following intervention provides evidence for the impact of intrauterine intervention, with normalization of growth suggesting success9, 10. Identification of indices that are predictive of prognosis, particularly in cross-sectional studies, has led to a need to quantify across different gestational ages the measurements which change. This has been greatly facilitated by the generation of z-scores, which quantify the degree to which a measurement lies above or below the mean value for a given population. z-scores have also become invaluable for tracking longitudinal changes of growth for individual patients and for comparing changes in growth of cardiac structures for different fetal populations. Although to date most quantitative evaluations in fetal echocardiography have focused on cardiovascular dimensions, Doppler velocities of intracardiac, arch, systemic venous and umbilical artery flows are evaluated most effectively when compared with expected norms for gestational age. For instance, tracking of ventricular stroke volumes and outputs relative to gestational age or fetal biometric indices using normative data facilitates the evaluation of conditions associated with high cardiac output states, including twin pregnancies complicated by twin reversed arterial perfusion or fetal anemia, both before and after fetal intervention11, 12, with serial data assisting in determining the timing and efficacy of intervention. Assessment of fetal cardiac output compared with normal data can provide insight into changes in the fetal circulation in compromised pregnancies, as previously documented for placental insufficiency13 and Ebstein's anomaly of the tricuspid valve, in which evolution of left heart dysfunction and reduced combined cardiac output ejected from the left ventricle may contribute to the high rate of fetal hydrops and spontaneous intrauterine demise14. Critical to the use of any normative fetal data is an understanding as to exactly how a measurement is performed and to what biometric measure it is indexed. Measurement of many dimensions may be difficult to reproduce and thus knowledge of interobserver and intraobserver variability is important in interpreting results. Variations in growth from one population to the next may influence what is considered normal and thus may result in an inaccurate interpretation of the normalcy of a measurement in a different population. Finally, knowledge of how large and normally distributed the control or normal population truly is remains critical to any comparison, as suggested by the differences in the observations of Lee et al.15, in this issue of the Journal, and Schneider et al.16. Cardiovascular scores have been used to estimate the severity of cardiac dysfunction and predict outcome in several conditions associated with poor perinatal outcome. Such scores are particularly useful for fetal populations in which the cardiovascular pathology is relatively uniform and follows a usual course. This is true for twin–twin transfusion syndrome (TTTS), as demonstrated in this issue of the Journal by the work of Stirnemann et al.17, in which they used only a handful of indices, including the myocardial performance or Tei index, to define severity of cardiovascular dysfunction. The myocardial performance index is appropriate in the scoring of TTTS in that the myocardial disease of the recipient twin ultimately involves both systolic and diastolic dysfunction18, 19. This index of global ventricular function, however, does not differentiate between diastolic and systolic pathology and thus, if myocardial performance were the only index used, subtle early abnormalities of diastolic function present in recipient twins prior to significant changes in central venous pressure and ductus venosus flow would be missed. Diastolic pathology has also been shown to be more important than systolic pathology in the context of fetal cardiomyopathies, the earliest features of which include altered ventricular inflow Doppler patterns comparable to that of the recipient twin20. Understanding the individual functional factors that influence the myocardial performance index is critical in defining the true pathophysiology and course of this disease, as we have previously demonstrated in fetal Ebstein anomaly of the tricuspid valve, in which prolonged isovolumic relaxation time (an index of diastolic function) correlates strongly with shorter ejection times with no abnormality of isovolumic contraction21. Insight into disease progression may be further gleaned through the evaluation of many parameters of function and the timing and order of resolution of pathology following intervention, as has been observed in TTTS following laser therapy22. Still, creation of a simplified cardiovascular profile score in the standardization of assessments would potentially facilitate diagnosis and serial assessment before and after intervention and the evaluation of treatment strategies in larger cohorts of affected pregnancies. Caution, however, must be exercised in the use of a uniform scoring system for different disease states, as has been proposed for the cardiovascular score developed for fetal heart failure23, 24 and a recent modification and application of this score to TTTS recipient and donor twins25. Although the cardiovascular score for heart failure correlates with fetal loss among high-risk pregnancies, it has been used for both primary cardiac disease24, in which myocardial dysfunction leads to worse outcome, and for placental insufficiency25, in which fetal hypoxia is the trigger for late and often acute onset (secondary) reduced myocardial function. Doppler indices may reflect different myocardial disease states and even abnormalities of vascular function, umbilical venous return and loading conditions of the fetal heart. Although these scores simplify the evaluation and prognostication of such conditions, details as to the mechanisms of dysfunction (i.e. high ventricular filling versus volume contraction and hypoxia) and the timing of the evolution of dysfunction, important for staging the disease and planning intervention, will be missed. Thus, documentation of the pathogenic mechanisms leading to cardiovascular compromise and then development of separate scoring systems appropriate for the disease state may result in more accurate profiling and a better understanding of the disease for a given pregnancy. To conclude, quantitative assessment of fetal cardiovascular structure and function is now an integral part of fetal echocardiography. This approach facilitates diagnosis and contributes significantly to our understanding of the evolution of structural and functional heart disease, which is critical for improving prenatal and perinatal management and for the development of timely and effective intervention. As we venture forward, however, we must use the tools available to elucidate disease progression, and yet beware the inherent limitations of the standardization of assessments so as not to miss opportunities to establish the true pathogenesis and pathophysiology of fetal cardiovascular disease.

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