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Techniques for assessing cardiac output and fetal cardiac function
Seminars in Fetal & Neonatal Medicine 16 (2011) 13e21
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Techniques for assessing cardiac output and fetal cardiac function Boris Tutschek a, b, *, Klaus G. Schmidt c a
Department of Obstetrics, Bern University Hospital, Effingerstrasse 102, 3010 Bern, Switzerland Medical Faculty, Düsseldorf University, Düsseldorf, Germany c Department of Pediatric Cardiology, Düsseldorf University Hospital, Düsseldorf, Germany b
s u m m a r y Keywords: Cardiac output Intrauterine growth restriction Myocardial performance index Strain analysis Tei index Twinetwin transfusion syndrome
Fetal echocardiography was initially used to diagnose structural heart disease, but recent interest has focused on functional assessment. Effects of extracardiac conditions on the cardiac function such as volume overload (in the recipient in twinetwin transfusion syndrome), a hyperdynamic circulation (arterio-venous malformation), cardiac compression (diaphragmatic hernia, lung tumours) and increased placental resistance (intrauterine growth restriction and placental insufficiency) can be studied by ultrasound and may guide decisions for intervention or delivery. A variety of functional tests can be used, but there is no single clinical standard. For some specific conditions, however, certain tests have shown diagnostic value. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Although fetal echocardiography was initially used for the identification of structural congenital heart disease, attention has more recently moved to its value in functional assessment of the fetal heart and circulation.1,2 Whereas attention initially focused on cardiac function in fetuses with intrinsic cardiac problems such as severe semilunar valvular stenosis or poor myocardial contraction, the potential importance of these techniques in assessing wellbeing of the fetus with other pathologies is gradually being recognized. Extracardiac causes of cardiac dysfunction such as volume overload (the recipient in twinetwin transfusion syndrome, TTTS), a hyperdynamic circulation (arterio-venous malformation), cardiac compression (diaphragmatic hernia, lung tumours) and increased placental resistance (intrauterine growth restriction and placental insufficiency) can be assessed prenatally and may guide decisions for intervention or delivery. A normally functioning heart maintains appropriate cardiac output in a sustained fashion and is able to adapt to changing circulatory demands. Postnatally, the cardiac ventricles work in series and left ventricular (systemic) output (Qs) is normally the same as right ventricular (pulmonary) output (Qp). Cardiac output measurements are related to the left ventricle. In fetal life, however, both ventricles work in parallel (with the exception of the relatively small pulmonary blood flow pumped by the right ventricle) and cardiac output * Corresponding author. Department of Obstetrics, Bern University Hospital, Effingerstrasse 102, 3010 Bern, Switzerland. Tel.: þ41 31 951 1606; fax: þ41 31 632 9806. E-mail address: [email protected] (B. Tutschek). 1744-165X/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2010.09.005
measurements usually consider the combined output of both ventricles. Cardiac output is dependent on fetal heart rate and stroke volume, on preload (circulatory volume), afterload (circulatory resistance) and myocardial contractility. Direct measurement of cardiac output is difficult. Postnatal methods of assessment are based on Fick’s principle and either require measurements of oxygen consumption at venous and arterial sites, or use thermo- or dye dilution methods e invasive methods that are not suitable for fetal assessment. The assessment of myocardial performance is complicated by the small size of the fetal heart, fetal position and movement which can hinder accurate assessment.3 Cardiac function is typically assessed with a variety of techniques (Table 1): direct measurement of cardiac dimensions (M-mode and B-mode ultrasound) or ventricular volumes (4D ultrasound) at different points of the cardiac cycle can be used to estimate cardiac output, as can measurement of blood flow (Doppler ultrasound) through vessels near to the heart, although these methods are often technically challenging.4e6 Indirect indices involve qualitative assessment of blood flow, tissue excursion or time intervals during the cardiac cycle and are often easier to measure. Investigation of arterial and venous Doppler measurements of the peripheral vasculature also provide an indirect means of assessing cardiac function; these tools are described in this issue by A. Baschat. Measurement of time intervals during the cardiac cycle, in particular the relationship of isovolumic relaxation and contraction time to ejection time, have also been used to evaluate the fetal heart with impaired function.7e9 Tissue Doppler echocardiography and related techniques such as strain analysis are other promising tools for the assessment of fetal cardiac function in special situations.10,11 This article reviews established techniques and describes new developments in the assessment of fetal cardiac function.
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Table 1 Sonographic methods for assessing cardiac function
Measurement of cardiac dimensions
Dimension
Method
Functional parameter
Short axis diameters (EDD, ESD)
M-mode, B-mode
Long-axis length, volume (EDV, ESV)
Extrapolated from M-mode (Teichholz) or B-mode (Biplane Simpson’s rule) Directly from 3D/volume ultrasound
Ventricular size Fractional shortening Long-axis function, ventricular volumes, ejection fraction, cardiac output Ventricular volumes (possibly ventricular mass), ejection fraction, cardiac output
Measurement of cardiac output
Vessel area, mean blood flow velocity
B-mode, pulsed-wave Doppler
Cardiac output
Other measures of cardiac function
Ventricular inflow velocities
Pulsed-wave Doppler
Valve insufficiency Isovolumetric relaxation and contraction times, ejection time
Color Doppler, pulsed-wave Doppler Pulsed-wave (or tissue) Doppler
Preload, ventricular relaxation and passive filling Preload Myocardial performance index
Myocardial tissue movement (global or regional)
Tissue Doppler imaging
Assessment of myocardial tissue motion
Strain analysis
Myocardial contraction force (global, possibly regional) Myocardial contraction force (global, possibly regional)
EDD, end-diastolic diameter; ESD, end-systolic diameter; EDV, end-diastolic volume; ESV, end-systolic volume; 3D, three-dimensional.
2. Cardiac dimensions
EDV ¼ (7/(2.4 þ EDD)) * EDD3
In axial section, the four-chamber view of the heart occupies one third of the chest. The cardio-thoracic ratio is calculated by measuring the fetal cardiac and thoracic areas or circumferences and is normally 33% and 50%, respectively.12,13 The key to functional cardiac assessment in the fetus is measurement of cardiac dimensions and their changes during the cardiac cycle that relate to cardiac function and output. Individual chambers, measured using either M-mode or B-mode echocardiography, can be assessed in end-diastole (ED) and endsystole (ES), estimated by the largest and smallest ventricular cavity size as electrocardiographic gating is not available in clinical practice. M-mode echocardiography reports tissue density along a single axis. The short axis view, aligned perpendicular to the interventricular septum and free walls of the ventricles at the tips of the AV valve leaflets in a lateral four-chamber view, allows one-dimensional measurements of the ventricular chambers and myocardial thicknesses in systole and diastole (Fig. 1). Normal data for such measurements in the human fetus throughout the second half of gestation have been published and ventricular diameters used to calculate functional indices such as shortening and ejection fractions.2,14,15 The shortening fraction (SF) is derived from the enddiastolic and end-systolic diameters (EDD and ESD):
This formula has also been used in the human fetus.21 The problem of volume calculations based on M-mode is that inaccuracies in measurement are compounded by a formula that extrapolates ventricular volume. An alternative method of examining ventricular function assesses motion of the atrioventricular (AV) valve annulus during the cardiac cycle (Fig. 2). The M-mode cursor is placed over the AV valve parallel to its excursion in an apical or basal insonation and the maximal displacement of the valve ring between diastole and systole (analyzed visually) is recorded. A study of 159 normal fetuses found a linear increase in valve annulus displacement with gestation for tricuspid and mitral valves of 4e9 and 3e6 mm, respectively, between 15 and 38 weeks of gestation.22 Measurement of individual cardiac structures can be made using B-mode ultrasound (Fig. 3).23e25 The relatively regular ‘truncated ellipsoid’ shape of the left ventricle lends itself to volume calculations, which may simply
SF ¼ (EDD ESD)/EDD This is best applied to the left ventricle with a simpler geometric shape; the right ventricle is better assessed functionally in long axis view.7 M-mode studies are dependent on a correct insonation angle and therefore on fetal position. Angle dependency can be overcome by using an M-mode with an adjustable angle.16 Regardless of the relative values, an increase in diastolic dimensions is often found in decreased cardiac function and should be evaluated further.17 Shortening fraction decreases with fetal cardiac compromise.18,19 Ventricular diameters can also be used to estimate end-diastolic and end-systolic volumes (EDV, ESV) which are in turn used to calculate the ejection fraction (EF): EF ¼ (EDVESV)/EDV In adults the best correlation between angiographic and Mmode echocardiographic left ventricular volume measurements uses the Teichholz formula,20 where
Fig. 1. A lateral four-chamber view of the fetal heart showing the M-mode interrogation line placed perpendicular to the interventricular septum and just apical to the tips of the atrioventricular valves. Measurements of the cardiac ventricular diameters in end-diastole (EDD) and end-systole (ESD) are shown. LV, left ventricle; RV, right ventricle.
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Fig. 2. An apical four-chamber view of a normal fetal heart in systole showing the Mmode interrogation line placed through the ventricular free wall attachment of the tricuspid valve annulus (TVA). The difference of maximal systolic (sys) and diastolic (dia) excursion can be measured. RV and LV, right and left ventricle; RA and LA, right and left atrium.
involve assessment of the circumference and length of the chamber or use the more complex Simpson’s biplane method.26,27 By calculating ventricular volumes in end-diastole and end-systole, cardiac output and ejection fraction can be calculated from 2D imaging, although this method is time-consuming and not suited for daily clinical practice. This approach has been used to show an
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exponential increase in both right and left EDV during the second half of gestation, whereas the EF remains at a constant level in normal fetuses.28 As M-mode and B-mode echocardiography are limited by accuracy of measurement, several groups have investigated the potential of 3D or ‘volume’ ultrasound for the assessment of fetal cardiac chamber size.29e35 Volumes are most commonly generated by spatialetemporal image correlation (STIC) using an automatic two-dimensional sweep across the heart that acquires several hundred frames that are rearranged spatially and temporarily to form a ‘virtual’ high resolution cardiac cycle containing up to 40 volumes for one heart beat.36 The endocardial contour can be detected semi-automatically and is used to quantify chamber volumes in end-diastole and end-systole, enabling the calculation of ejection fraction and cardiac output (Fig. 4).37 STIC volumes have been validated using in-vitro volumes comparable to second and third trimester fetal hearts; STIC it has been found to be suited for diastolic measurements and volumes >2.5 mL, and measurements appear to be reproducible.9 Normal ranges for right and left stroke volumes and cardiac output have been proposed and this technique has been used to demonstrate that chamber volumes in structurally malformed hearts differ markedly from the norm.34,38e40 STIC is dependent on fetal position (ideally supine) and quiescence, allowing acquisition of the entire fetal heart in one volume sequence.40 These views are particularly difficult to obtain at later gestations e with less amniotic fluid, more mineralization of fetal bones and often a dorso-anterior fetal position e which may prohibit its use for functional assessment in the later part of pregnancy. Despite this, a comparison of STIC with 2D and Doppler sonography found that although these methods gave similar results
Fig. 3. Schematic diagrams showing B-mode echocardiographic measurements. (a) Long-axis view of the left ventricle with aortic valve (1) and ascending aorta (2). (b) Aortic arch view with aortic valve (1), ascending and descending aorta (2, 3) and the inferior vena cava (4). (c) Short-axis view with the pulmonary valve (1), main, right and left (2, 3, 4) pulmonary arteries. (d) Oblique short-axis view showing the arterial duct (5). (e) Four-chamber view showing the tricuspid valve (1), right ventricular end-diastolic diameter (2), right ventricular inlet length (3), right ventricular area (dashed line, 4). On the left side are the mitral valve (5), left ventricular end-diastolic diameter (6), left ventricular inlet length (7) and left ventricular area (dotted line, 8). Ao, aorta; Desc Ao, descending aorta; IVC, inferior vena cava; LA, left atrium; LPA, left pulmonary artery; LV, left ventricle; MPA, main pulmonary artery; RA, right atrium; RPA, right pulmonary artery; RV, right ventricle. (Reproduced with permission from Schneider et al.24)
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Fig. 4. Fetal cardiac volumetry using three-dimensional datasets. (a) Use of a spatialetemporal image correlation (STIC) volume with semi-automatic volume tracing and automatic endocardial border detection (with permission from Messing et al.34). (b) Ventricular volume calculation from a non-reconstructed real-time volume acquired with a matrix transducer (with permission from Tutschek and Sahn37). (c) Semi-automatically generated endocardial casts derived from a STIC volume (with permission from Tutschek and Sahn35). Colour-filled areas of the left atrium (LA), right (RV) and left (LV) ventricles and aortic origin (Ao) are visible. The cavity of the right ventricle appears shorter than the left because of its apical trabeculation.
STIC was less operator dependent and required significantly less time for acquisition and offline analysis.40 3. Blood flow and cardiac intervals Stroke volume (and therefore cardiac output) can also be calculated by combining B-mode and pulsed-wave Doppler ultrasound to measure valvular diameter (D) and the velocity of flow (V) across the valve (see also Fig. 5):4,6,41,42 SV ¼ (p * D2/4)* V Both the diameters of the aortic and pulmonary valves and the flow velocities through the outflow tracts increase in a linear fashion with advancing gestation, so the stroke volumes and combined cardiac output increase exponentially from 160 to 1300 mL/min between 16 weeks and term. The right ventricle appears to make a greater contribution to combined cardiac output as the ratio of pulmonary artery to aorta is 1.2.4,6,42e44 This technique is limited by the fact that any inaccuracy in measurement of valvular diameter is compounded by squaring this value. It also assumes that the valve is circular and fails to account for vessel wall compliance. Velocity measurement by pulsed-wave Doppler also becomes unreliable if the angle for insonation is >15e20 , and angle correction is required in this situation. Comparison of the reproducibility of fetal cardiac ventricular volume estimations by M-mode, cross-sectional B-mode and Doppler-derived volume flow measurements finds that M-mode measurements are least
reproducible whereas the other two techniques have comparable intra- and interobserver error.21 Doppler ultrasound can also be used to examine cardiac function indirectly by examining the pattern of flow through the atrioventricular valves. The pattern of passive and active ventricular filling during diastole reflects relaxation properties of the cardiac ventricles. In fetal life, normal ventricular inflow is characterized by a smaller early (E) wave, followed by a larger (A) wave during atrial contraction. With advancing gestation the E/A ratio increases which is considered a sign of normal maturation towards a normally compliant (less stiff) myocardium.45,46 An increased or even reversed fetal E/A ratio is related to ventricular diastolic dysfunction.47 Monophasic atrioventricular inflow patterns are seen at high fetal heart rates and also in fetuses with reduced cardiac function.17,48 In the normal fetal heart, both AV valves are competent. The finding of more than a trace of regurgitation across the tricuspid and mitral valve should prompt further investigation for altered cardiovascular physiology.17 Whereas a trace of TR is typically benign, holosystolic TR is likely to be abnormal and warrants further investigation.49 Functional TR may reverse when the underlying pathology is corrected: for example in fetal anaemia, sustained fetal tachycardia or in the recipient in TTTS. Several groups have suggested scoring systems that combine methods of assessment to give a more global overview of cardiac function and that can be used to define imminent or absolute cardiac failure (Table 2).17,48 These scoring systems aim to standardize the current practice of multimodal assessment which is in part based on subjective parameters such as grading of ‘ventricular dysfunction’.
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Fig. 5. Quantitative assessment of cardiac output (CO) using pulsed-wave Doppler. (a) Pulsed-wave flow profile in the aorta; the sample volume is placed just distal to the aortic valve. The angle of insonation for Doppler assessment is minimized so that the flow velocity time integral (VTI) can be measured directly from the spectral display. (b) The aortic root diameter (red line) is used to calculate aortic valve area (VA). (c) Graph demonstrating the increase in left ventricular output with gestational age (Modified from Allan et al.4). (LV output ¼ VTI VA heart rate.) LV, left ventricle; RV, right ventricle; Ao, aorta; asc. Ao, ascending aorta.
Scores may be superior to single measurements in defining compromised cardio-circulatory function. Some recent studies have examined the potential for measuring time intervals during the cardiac cycle to assess global cardiac function. Systolic dysfunction causes prolongation of the isovolumic contraction time (ICT) and shortening of the ejection time (ET), and diastolic dysfunction prolongs the isovolumic relaxation time (IRT).50 These factors can be used to define the myocardial performance (MPI) or ‘Tei’ index51: MPI ¼ (IRT þ ICT)/ET Initial studies in adults found these parameters were easily and reproducibly measured and were predictive for cardiac failure in a stage-dependent fashion in patients with dilated cardiomyopathy.51 In the fetus these time intervals are best calculated using
a single pulse-wave Doppler recording of ventricular flow by recording a large sample volume that covers both mitral inflow and aortic outflow, demonstrating opening and closure of the valves (Fig. 6).52 The MPI has been applied to several clinical situations in fetal medicine (see below). 4. Clinical applications Fetal cardiac function can be compromised either by placental dysfunction, resulting in intrauterine growth restriction, by maternal illness (e.g. diabetes) or by the presence of some congenital anomalies. A better understanding of fetal cardiovascular status has been shown to improve our understanding and management in several clinical situations including the assessment of intrauterine growth restriction, TTTS and congenital diaphragmatic hernia.
Table 2 Fetal cardiovascular profile score combining direct and indirect functional parameters (Modified from Huhta17)
Cardiomegaly Valve insufficiency Hydrops Venous blood flow Umbilical artery blood flow
Normal (score 2 points)
Abnormal (minus 1 point)
Severely abnormal (minus 2 points)
CTR <0.35 No TR, no MR, biphasic filling No Normal umbilical vein, positive DV a-wave Positive EDF
CTR 0.35e0.50 Holosystolic TR Ascites or pleural effusion or pericardial effusion Normal umbilical vein, reversed DV a-wave No EDF
CTR >0.50 Holosystolic MR or monophasic filling Skin edema Pulsatile umbilical vein Reversed EDF
CTR, cardio-thoracic ratio; DV, ductus venosus; TR, tricuspid regurgitation; MR, mitral regurgitation; EDF, end-diastolic flow. For ‘normal’ fetal cardiac function the five parameters yield a score of 10.
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Fig. 6. The myocardial performance index (MPI or Tei index) in a normal fetus. The (modified) MPI is calculated from time intervals derived from pulsed-wave Doppler of left ventricular inflow (negative velocities, biphasic with E and A waves) and outflow (aortic outflow, positive velocities), incorporating the mitral and aortic valve clicks; T1, isovolumic contraction time; T2, ejection time; T3, isovolumic relaxation.
Crispi et al. used several markers of cardiac function including the MPI, E/A ratio and calculation of cardiac output to compare growth-restricted fetuses with appropriately grown fetuses.53 The MPI and E/A ratio (but not cardiac output) correlated with hemodynamic deterioration and were significantly increased in fetuses that died. Hernandez-Andrade et al. studied cardiovascular function in preterm growth-restricted fetuses. Although perinatal mortality was independently predicted by an abnormal MPI (>95th centile), this had less predictive power than other factors such as gestational age at delivery or abnormal venous Doppler findings (reversal of the A-wave of the ductus venosus).54 A combination of these parameters best predicted perinatal mortality. For example, for a fetus below 28 weeks with positive a-wave and normal MPI, the estimated perinatal mortality (PNM) was 18%, but with DV areversal and abnormal MPI, PNM was 97%. The circulations of monochorionic twins are almost invariably intertwined by placental vascular anastamoses. In the majority of cases volume exchange is balanced, but in 15% an imbalance causes net transfusion from one twin (the ‘donor’) to the other (the ‘recipient’), Twin-to-twin transfusion syndrome or TTTS.55 The twins have unique cardiovascular problems: the recipient
has a persistent increase in cardiac preload, whereas the donor has inadequate placental return of oxygen and nutrients. Treatment by laser ablation of the communicating placenta vasculature provides a further cardiovascular challenge.56 The recipient that previously had to compensate for a chronic increase in preload needs to readjust cardiac function to a lower preload. The donor experiences an abrupt increase in peripheral resistance due to occlusion of the communicating vessels and a relative loss of perfusable placental territory; from a cardiac perspective, this fetus must adapt to an increase in afterload.57 Although transient and permanent cardiovascular anomalies are frequently seen in fetuses with TTTS, the current staging system only includes indirect signs of cardiac dysfunction.58,59 Cardiovascular dysfunction in the recipient twin can be detected using a score that encompasses arterial and venous Doppler alterations, cardiac size, and atrio-ventricular valve regurgitation as well as abnormal inflow patterns.48 Because the preload of the recipient is increased, the right ventricle MPI is also increased; assessing cardiac function using MPI might improve the selection of appropriate candidates for intrauterine therapy and also be of value in monitoring improvement in fetal condition after treatment.60 Maternal diabetes is the most common cause of a fetal hypertrophic cardiomyopathy, characterized by thickening of the interventricular septum and ventricular outflow obstruction in an otherwise structurally normal fetal heart; it occurs in about a quarter of affected pregnancies.47,61,62 In affected fetuses diastolic function, judged for example by the diastolic filling pattern or flow velocity waveforms in the ductus venosus, can be altered even in well-controlled maternal glycemia.62e65 In severe congenital diaphragmatic hernia (CDH), compression of the fetal heart by herniated viscera impairs cardiac function.66 LV volumes as determined by the Teichholz formula in CDH were about one-third smaller compared to normal fetuses.67 Temporal fetal endoscopic tracheal occlusion, in addition to improving lung size, also has an effect on cardiac function: placement of the tracheal occlusion improved the myocardial performance index by shortening the isovolumic contraction time interval.68 Other examples of extracardiac abnormalities affecting cardiac function are sacrococcygeal teratoma or arterio-venous malformations (AVM), characterized by high blood flow through the tumour that can lead to cardiac failure. As the fetus with
Fig. 7. Strain rate (SR) analysis, using speckle tracking, of a normal fetal heart at 32 weeks of gestation. Left panel: the ventricular wall is tracked throughout the cardiac cycle; lengthening and shortening during diastole and systole are calculated for individual segments (colored dots). Right panel: quantitative analysis of regional (colored lines) and global (white dotted line) strain rates; x-axis denotes time (ms), y-axis indicates strain rate (1/s). The major peaks indicate (from left to right): two diastolic SR peaks above the x-axis (SRE, SRA) indicating lengthening during early and late diastolic tissue motion, followed by a negative SR peak (SRS) during systole.
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a sacrococcygeal teratoma deteriorates, the inferior vena cava and the cardiac ventricles dilate due to increased venous return from the tumour, even though these fetuses typically maintain a normal shortening fraction.69 Similarly a dilated superior vena cava and cardiomegaly develop in deteriorating fetuses with a large cerebral AVM such as an aneurysm of the vein of Galen.69 In both these conditions neonatal outcomes are poorer in fetuses that develop hydrops prior to delivery and recognition of more subtle signs of cardiac failure may prompt antenatal intervention or delivery.70 Fetal tachyarrhythmias may also impair cardiac function, but may be difficult to assess functionally, because indices such as the MPI are difficult to measure at high heart rates. For this condition, scoring systems as described above may be better suited.17
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Practice points Quantification of cardiac function in the human fetus is technically difficult. Cardiac volume measurements enable calculation of cardiac output and ejection fraction. 3D fetal echocardiography is promising, but still lacks standardization. At present, assessment of peripheral and central blood flow remain the most useful clinical tools.
Research directions 5. Other new technologies Whereas traditional Doppler studies of blood flow are based on high velocityelow intensity signals, tissue Doppler records low velocityehigh intensity signals; it can be used to assess the force of cardiac contraction and relaxation in the fetus.71e73 Both pulsedwave and colour Doppler can record motion of cardiac structures. Sampling with pulsed-wave Doppler over the AV valve annulus uses the same insonation as that used for M-mode recording of this structure. A theoretical advantage is that tissue Doppler data might be more closely related to mechanical force than blood flow Doppler. Unfortunately quantification is limited by the angle dependency and poor lateral resolution of Doppler imaging. Strain analysis is a concept adopted from adult cardiology. Strain describes tissue ‘deformation’: lengthening in diastole and shortening in systole. By definition, strain can only be calculated by comparison of fixed points in the myocardium that are tracked throughout the cardiac cycle. Strain is defined as the relative change in the distance between two points in systole and diastole. Strain rate is the time taken to reach a specific level of tissue deformation. Both tissue Doppler imaging and strain analysis are used postnatally to assess and quantify regional and global cardiac wall motion. Fetal strain analysis can be performed using tissue Doppler imaging, but angle dependency, sensitivity to extracardiac movement and high fetal heart rate hamper this approach.72,74e76 Strain analysis requires high spatial and temporal resolution which is inherently difficult to achieve in fetal studies due to the small cardiac size and the high heart rate. Speckle tracking is a novel imaging modality that can be used to assess cardiac function; it is not based on the Doppler principle, but tracks individual reflectors in the myocardium over time. It is therefore less angle dependent. Fig. 7 shows an example of fetal strain rate analysis by speckle tracking. Early studies suggest that functional indices are in a similar range to the adult, although they vary with gestational age.3,77e79 6. Conclusions Clinical assessment of fetal ‘well-being’ currently relies on a multimodal approach examining fetal growth, behavioural state, amount of amniotic fluid, peripheral Doppler studies and fetal heart rate tracing. Fetal cardiac function may be affected by a number of environmental or congenital anomalies. Research efforts have recently recognized the potential value of monitoring cardiac function for clinical management. Unfortunately, there is no single simple test to measure fetal cardiac function. Further studies will show which approach to functional cardiac assessment in the fetus has true value in terms of improved neonatal outcome.
Newer methods of assessment such as measurement of cardiac intervals and tissue deformation require further validation. Potential markers for defined pathologies need to be clarified. The effect of the intrauterine environment on fetal cardiac development needs to be explored.
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Cardiac dimensions determined by cross-sectional echocardiography in the normal human fetus from 18 weeks to term. Am J Cardiol 1992;70:1459e67. 24. Schneider C, McCrindle BW, Carvalho JS, Hornberger LK, McCarthy KP, Daubeney PE. Development of Z-scores for fetal cardiac dimensions from echocardiography. Ultrasound Obstet Gynecol 2005;26:599e605. 25. Lee W, Riggs T, Amula V, et al. Fetal echocardiography: z-score reference ranges for a large patient population. Ultrasound Obstet Gynecol 2010;35:28e34. 26. Schiller NB, Acquatella H, Ports TA, et al. Left ventricular volume from paired biplane two-dimensional echocardiography. Circulation 1979;60:547e55. 27. Silverman NH, Ports TA, Snider AR, Schiller NB, Carlsson E, Heilbron DC. Determination of left ventricular volume in children: echocardiographic and angiographic comparisons. Circulation 1980;62:548e57. 28. Schmidt KG, Silverman NH, Hoffman JI. Determination of ventricular volumes in human fetal hearts by two-dimensional echocardiography. Am J Cardiol 1995;76:1313e6. 29. Deng J, Gardener JE, Rodeck CH, Lees WR. Fetal echocardiography in three and four dimensions. Ultrasound Med Biol 1996;22:979e86. 30. Meyer-Wittkopf M, Cole A, Cooper SG, Schmidt S, Sholler GF. Three-dimensional quantitative echocardiographic assessment of ventricular volume in healthy human fetuses and in fetuses with congenital heart disease. J Ultrasound Med 2001;20:317e27. 31. Bhat AH, Corbett V, Carpenter N, et al. Fetal ventricular mass determination on three-dimensional echocardiography: studies in normal fetuses and validation experiments. Circulation 2004;110:1054e60. 32. Bhat AH, Corbett VN, Liu R, et al. Validation of volume and mass assessments for human fetal heart imaging by 4-dimensional spatiotemporal image correlation echocardiography: in vitro balloon model experiments. J Ultrasound Med 2004;23:1151e9. 33. Esh-Broder E, Ushakov FB, Imbar T, Yagel S. Application of free-hand threedimensional echocardiography in the evaluation of fetal cardiac ejection fraction: a preliminary study. Ultrasound Obstet Gynecol 2004;23:546e51. 34. Messing B, Cohen SM, Valsky DV, et al. Fetal cardiac ventricle volumetry in the second half of gestation assessed by 4D ultrasound using STIC combined with inversion mode. Ultrasound Obstet Gynecol 2007;30:142e51. 35. Tutschek B, Sahn DJ. Semi-automatic segmentation of fetal cardiac cavities: progress towards an automated fetal echocardiogram. Ultrasound Obstet Gynecol 2008;32:176e80. 36. DeVore GR, Falkensammer P, Sklansky MS, Platt LD. Spatio-temporal image correlation (STIC): new technology for evaluation of the fetal heart. Ultrasound Obstet Gynecol 2003;22:380e7. 37. Tutschek B, Sahn DJ. Three-dimensional echocardiography for studies of the fetal heart: present status and future perspectives. Cardiol Clin 2007;25:341e55. 38. Molina FS, Faro C, Sotiriadis A, Dagklis T, Nicolaides KH. Heart stroke volume and cardiac output by four-dimensional ultrasound in normal fetuses. Ultrasound Obstet Gynecol 2008;32:181e7. 39. Uittenbogaard LB, Haak MC, Peters RJ, van Couwelaar GM, Van Vugt JM. Validation of volume measurements for fetal echocardiography using fourdimensional ultrasound imaging and spatiotemporal image correlation. Ultrasound Obstet Gynecol 2010;35:324e31. 40. Rizzo G, Capponi A, Cavicchioni O, Vendola M, Arduini D. Fetal cardiac stroke volume determination by four-dimensional ultrasound with spatio-temporal image correlation compared with two-dimensional and Doppler ultrasonography. Prenat Diagn 2007;27:1147e50. 41. Kenny JF, Plappert T, Doubilet P, et al. Changes in intracardiac blood flow velocities and right and left ventricular stroke volumes with gestational age in the normal human fetus: a prospective Doppler echocardiographic study. Circulation 1986;74:1208e16. 42. Mielke G, Benda N. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001;103:1662e8. 43. De Smedt MC, Visser GH, Meijboom EJ. Fetal cardiac output estimated by Doppler echocardiography during mid- and late gestation. Am J Cardiol 1987;60:338e42. 44. Kenny J, Plappert T, Doubilet P, Salzman D, Sutton MG. Effects of heart rate on ventricular size, stroke volume, and output in the normal human fetus: a prospective Doppler echocardiographic study. Circulation 1987;76:52e8. 45. Tulzer G, Khowsathit P, Gudmundsson S, et al. Diastolic function of the fetal heart during second and third trimester: a prospective longitudinal Dopplerechocardiographic study. Eur J Pediatr 1994;153:151e4.
46. van Splunder IP, Wladimiroff JW. Cardiac functional changes in the human fetus in the late first and early second trimesters. Ultrasound Obstet Gynecol 1996;7:411e5. 47. Baschat AA, Gembruch U. Development of fetal cardiac and extracardiac Doppler flows in early gestation. In: Yagel S, Solverman N, Gembruch U, editors. Fetal cardiology. London: Informa Healthcare; 2009. p. 152e71. 48. Rychik J, Tian Z, Bebbington M, et al. The twinetwin transfusion syndrome: spectrum of cardiovascular abnormality and development of a cardiovascular score to assess severity of disease. Am J Obstet Gynecol 2007;197:392. e391e8. 49. Respondek ML, Kammermeier M, Ludomirsky A, Weil SR, Huhta JC. The prevalence and clinical significance of fetal tricuspid valve regurgitation with normal heart anatomy. Am J Obstet Gynecol 1994;171:1265e70. 50. Mori Y, Rice MJ, McDonald RW, et al. Evaluation of systolic and diastolic ventricular performance of the right ventricle in fetuses with ductal constriction using the Doppler Tei index. Am J Cardiol 2001;88:1173e8. 51. Tei C, Ling LH, Hodge DO, et al. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function e a study in normals and dilated cardiomyopathy. J Cardiol 1995;26:357e66. 52. Hernandez-Andrade E, Lopez-Tenorio J, Figueroa-Diesel H, et al. A modified myocardial performance (Tei) index based on the use of valve clicks improves reproducibility of fetal left cardiac function assessment. Ultrasound Obstet Gynecol 2005;26:227e32. 53. Crispi F, Hernandez-Andrade E, Pelsers MM, et al. Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses. Am J Obstet Gynecol 2008;199:254. e251e8. 54. Hernandez-Andrade E, Crispi F, Benavides-Serralde JA, Nicolaides KH, Gratacos E. Contribution of the myocardial performance index and aortic isthmus blood flow index to predicting mortality in preterm growth-restricted fetuses. Ultrasound Obstet Gynecol 2009;34:430e6. 55. Habli M, Lim FY, Crombleholme T. Twin-to-twin transfusion syndrome: a comprehensive update. Clin Perinatol 2009;36:391e416. x. 56. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136e44. 57. Van Hare GF, Hawkins JA, Schmidt KG, Rudolph AM. The effects of increasing mean arterial pressure on left ventricular output in newborn lambs. Circ Res 1990;67:78e83. 58. Barrea C, Alkazaleh F, Ryan G, et al. Prenatal cardiovascular manifestations in the twin-to-twin transfusion syndrome recipients and the impact of therapeutic amnioreduction. Am J Obstet Gynecol 2005;192:892e902. 59. Herberg U, Gross W, Bartmann P, Banek CS, Hecher K, Breuer J. Long term cardiac follow up of severe twin to twin transfusion syndrome after intrauterine laser coagulation. Heart 2006;92:95e100. 60. Van Mieghem T, Klaritsch P, Done E, et al. Assessment of fetal cardiac function before and after therapy for twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2009;200:400. e401e7. 61. Corrigan N, Brazil DP, McAuliffe F. Fetal cardiac effects of maternal hyperglycemia during pregnancy. Birth Defects Res A Clin Molec Teratol 2009;85:523e30. 62. Stuart A, Amer-Wahlin I, Gudmundsson S, Marsal K, Thuring A, Kallen K. Ductus venosus blood flow velocity waveform in diabetic pregnancies. Ultrasound Obstet Gynecol 2010;36:344e9. 63. Rizzo G, Arduini D, Romanini C. Accelerated cardiac growth and abnormal cardiac flow in fetuses of type I diabetic mothers. Obstet Gynecol 1992;80:369e76. 64. Zielinsky P, Marcantonio S, Nicoloso LH, et al. Ductus venosus flow and myocardial hypertrophy in fetuses of diabetic mothers. Arq Bras Cardiol 2004;83:51e6. 45e50. 65. Zielinsky P, Nicoloso LH, Firpo C, et al. Alternative parameters for echocardiographic assessment of fetal diastolic function. Braz J Med Biol Res 2004;37:31e6. 66. Jani JC, Nicolaides KH, Gratacos E, et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol 2009;34:304e10. 67. Van Mieghem T, Gucciardo L, Done E, et al. Left ventricular cardiac function in fetuses with congenital diaphragmatic hernia and the effect of fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol 2009;34:424e9. 68. Schmidt KG, Silverman NH, Harison MR, Callen PW. High-output cardiac failure in fetuses with large sacrococcygeal teratoma: diagnosis by echocardiography and Doppler ultrasound. J Pediatr 1989;114:1023e8. 69. Sepulveda W, Platt CC, Fisk NM. Prenatal diagnosis of cerebral arteriovenous malformation using color Doppler ultrasonography: case report and review of the literature. Ultrasound Obstet Gynecol 1995;6:282e6. 70. Langer JC, Harrison MR, Schmidt KG, et al. Fetal hydrops and death from sacrococcygeal teratoma: rationale for fetal surgery. Am J Obstet Gynecol 1989;160:1145e50. 71. Harada K, Tsuda A, Orino T, Tanaka T, Takada G. Tissue Doppler imaging in the normal fetus. Int J Cardiol 1999;71:227e34. 72. Paladini D, Lamberti A, Teodoro A, Arienzo M, Tartaglione A, Martinelli P. Tissue Doppler imaging of the fetal heart. Ultrasound Obstet Gynecol 2000;16:530e5. 73. Tutschek B, Zimmermann T, Buck T, Bender HG. Fetal tissue Doppler echocardiography: detection rates of cardiac structures and quantitative assessment of the fetal heart. Ultrasound Obstet Gynecol 2003;21:26e32.
B. Tutschek, K.G. Schmidt / Seminars in Fetal & Neonatal Medicine 16 (2011) 13e21 74. Larsen LU, Petersen OB, Norrild K, Sorensen K, Uldbjerg N, Sloth E. Strain rate derived from color Doppler myocardial imaging for assessment of fetal cardiac function. Ultrasound Obstet Gynecol 2006;27:210e3. 75. Di Salvo G, Russo MG, Paladini D, et al. Two-dimensional strain to assess regional left and right ventricular longitudinal function in 100 normal foetuses. Eur J Echocardiogr 2008;9:754e6. 76. Larsen LU, Sloth E, Petersen OB, Pedersen TF, Sorensen K, Uldbjerg N. Systolic myocardial velocity alterations in the growth-restricted fetus with cerebroplacental redistribution. Ultrasound Obstet Gynecol 2009;34:62e7.
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77. Ta-Shma A, Perles Z, Gavri S, et al. Analysis of segmental and global function of the fetal heart using novel automatic functional imaging. J Am Soc Echocardiogr 2008;21:146e50. 78. Younoszai AK, Saudek DE, Emery SP, Thomas JD. Evaluation of myocardial mechanics in the fetus by velocity vector imaging. J Am Soc Echocardiogr 2008;21:470e4. 79. Barker PC, Houle H, Li JS, Miller S, Herlong JR, Camitta MG. Global longitudinal cardiac strain and strain rate for assessment of fetal cardiac function: novel experience with velocity vector imaging. Echocardiography 2009;26:28e36.
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Techniques for assessing cardiac output and fetal cardiac function Boris Tutschek a, b, *, Klaus G. Schmidt c a
Department of Obstetrics, Bern University Hospital, Effingerstrasse 102, 3010 Bern, Switzerland Medical Faculty, Düsseldorf University, Düsseldorf, Germany c Department of Pediatric Cardiology, Düsseldorf University Hospital, Düsseldorf, Germany b
s u m m a r y Keywords: Cardiac output Intrauterine growth restriction Myocardial performance index Strain analysis Tei index Twinetwin transfusion syndrome
Fetal echocardiography was initially used to diagnose structural heart disease, but recent interest has focused on functional assessment. Effects of extracardiac conditions on the cardiac function such as volume overload (in the recipient in twinetwin transfusion syndrome), a hyperdynamic circulation (arterio-venous malformation), cardiac compression (diaphragmatic hernia, lung tumours) and increased placental resistance (intrauterine growth restriction and placental insufficiency) can be studied by ultrasound and may guide decisions for intervention or delivery. A variety of functional tests can be used, but there is no single clinical standard. For some specific conditions, however, certain tests have shown diagnostic value. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Although fetal echocardiography was initially used for the identification of structural congenital heart disease, attention has more recently moved to its value in functional assessment of the fetal heart and circulation.1,2 Whereas attention initially focused on cardiac function in fetuses with intrinsic cardiac problems such as severe semilunar valvular stenosis or poor myocardial contraction, the potential importance of these techniques in assessing wellbeing of the fetus with other pathologies is gradually being recognized. Extracardiac causes of cardiac dysfunction such as volume overload (the recipient in twinetwin transfusion syndrome, TTTS), a hyperdynamic circulation (arterio-venous malformation), cardiac compression (diaphragmatic hernia, lung tumours) and increased placental resistance (intrauterine growth restriction and placental insufficiency) can be assessed prenatally and may guide decisions for intervention or delivery. A normally functioning heart maintains appropriate cardiac output in a sustained fashion and is able to adapt to changing circulatory demands. Postnatally, the cardiac ventricles work in series and left ventricular (systemic) output (Qs) is normally the same as right ventricular (pulmonary) output (Qp). Cardiac output measurements are related to the left ventricle. In fetal life, however, both ventricles work in parallel (with the exception of the relatively small pulmonary blood flow pumped by the right ventricle) and cardiac output * Corresponding author. Department of Obstetrics, Bern University Hospital, Effingerstrasse 102, 3010 Bern, Switzerland. Tel.: þ41 31 951 1606; fax: þ41 31 632 9806. E-mail address: [email protected] (B. Tutschek). 1744-165X/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2010.09.005
measurements usually consider the combined output of both ventricles. Cardiac output is dependent on fetal heart rate and stroke volume, on preload (circulatory volume), afterload (circulatory resistance) and myocardial contractility. Direct measurement of cardiac output is difficult. Postnatal methods of assessment are based on Fick’s principle and either require measurements of oxygen consumption at venous and arterial sites, or use thermo- or dye dilution methods e invasive methods that are not suitable for fetal assessment. The assessment of myocardial performance is complicated by the small size of the fetal heart, fetal position and movement which can hinder accurate assessment.3 Cardiac function is typically assessed with a variety of techniques (Table 1): direct measurement of cardiac dimensions (M-mode and B-mode ultrasound) or ventricular volumes (4D ultrasound) at different points of the cardiac cycle can be used to estimate cardiac output, as can measurement of blood flow (Doppler ultrasound) through vessels near to the heart, although these methods are often technically challenging.4e6 Indirect indices involve qualitative assessment of blood flow, tissue excursion or time intervals during the cardiac cycle and are often easier to measure. Investigation of arterial and venous Doppler measurements of the peripheral vasculature also provide an indirect means of assessing cardiac function; these tools are described in this issue by A. Baschat. Measurement of time intervals during the cardiac cycle, in particular the relationship of isovolumic relaxation and contraction time to ejection time, have also been used to evaluate the fetal heart with impaired function.7e9 Tissue Doppler echocardiography and related techniques such as strain analysis are other promising tools for the assessment of fetal cardiac function in special situations.10,11 This article reviews established techniques and describes new developments in the assessment of fetal cardiac function.
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Table 1 Sonographic methods for assessing cardiac function
Measurement of cardiac dimensions
Dimension
Method
Functional parameter
Short axis diameters (EDD, ESD)
M-mode, B-mode
Long-axis length, volume (EDV, ESV)
Extrapolated from M-mode (Teichholz) or B-mode (Biplane Simpson’s rule) Directly from 3D/volume ultrasound
Ventricular size Fractional shortening Long-axis function, ventricular volumes, ejection fraction, cardiac output Ventricular volumes (possibly ventricular mass), ejection fraction, cardiac output
Measurement of cardiac output
Vessel area, mean blood flow velocity
B-mode, pulsed-wave Doppler
Cardiac output
Other measures of cardiac function
Ventricular inflow velocities
Pulsed-wave Doppler
Valve insufficiency Isovolumetric relaxation and contraction times, ejection time
Color Doppler, pulsed-wave Doppler Pulsed-wave (or tissue) Doppler
Preload, ventricular relaxation and passive filling Preload Myocardial performance index
Myocardial tissue movement (global or regional)
Tissue Doppler imaging
Assessment of myocardial tissue motion
Strain analysis
Myocardial contraction force (global, possibly regional) Myocardial contraction force (global, possibly regional)
EDD, end-diastolic diameter; ESD, end-systolic diameter; EDV, end-diastolic volume; ESV, end-systolic volume; 3D, three-dimensional.
2. Cardiac dimensions
EDV ¼ (7/(2.4 þ EDD)) * EDD3
In axial section, the four-chamber view of the heart occupies one third of the chest. The cardio-thoracic ratio is calculated by measuring the fetal cardiac and thoracic areas or circumferences and is normally 33% and 50%, respectively.12,13 The key to functional cardiac assessment in the fetus is measurement of cardiac dimensions and their changes during the cardiac cycle that relate to cardiac function and output. Individual chambers, measured using either M-mode or B-mode echocardiography, can be assessed in end-diastole (ED) and endsystole (ES), estimated by the largest and smallest ventricular cavity size as electrocardiographic gating is not available in clinical practice. M-mode echocardiography reports tissue density along a single axis. The short axis view, aligned perpendicular to the interventricular septum and free walls of the ventricles at the tips of the AV valve leaflets in a lateral four-chamber view, allows one-dimensional measurements of the ventricular chambers and myocardial thicknesses in systole and diastole (Fig. 1). Normal data for such measurements in the human fetus throughout the second half of gestation have been published and ventricular diameters used to calculate functional indices such as shortening and ejection fractions.2,14,15 The shortening fraction (SF) is derived from the enddiastolic and end-systolic diameters (EDD and ESD):
This formula has also been used in the human fetus.21 The problem of volume calculations based on M-mode is that inaccuracies in measurement are compounded by a formula that extrapolates ventricular volume. An alternative method of examining ventricular function assesses motion of the atrioventricular (AV) valve annulus during the cardiac cycle (Fig. 2). The M-mode cursor is placed over the AV valve parallel to its excursion in an apical or basal insonation and the maximal displacement of the valve ring between diastole and systole (analyzed visually) is recorded. A study of 159 normal fetuses found a linear increase in valve annulus displacement with gestation for tricuspid and mitral valves of 4e9 and 3e6 mm, respectively, between 15 and 38 weeks of gestation.22 Measurement of individual cardiac structures can be made using B-mode ultrasound (Fig. 3).23e25 The relatively regular ‘truncated ellipsoid’ shape of the left ventricle lends itself to volume calculations, which may simply
SF ¼ (EDD ESD)/EDD This is best applied to the left ventricle with a simpler geometric shape; the right ventricle is better assessed functionally in long axis view.7 M-mode studies are dependent on a correct insonation angle and therefore on fetal position. Angle dependency can be overcome by using an M-mode with an adjustable angle.16 Regardless of the relative values, an increase in diastolic dimensions is often found in decreased cardiac function and should be evaluated further.17 Shortening fraction decreases with fetal cardiac compromise.18,19 Ventricular diameters can also be used to estimate end-diastolic and end-systolic volumes (EDV, ESV) which are in turn used to calculate the ejection fraction (EF): EF ¼ (EDVESV)/EDV In adults the best correlation between angiographic and Mmode echocardiographic left ventricular volume measurements uses the Teichholz formula,20 where
Fig. 1. A lateral four-chamber view of the fetal heart showing the M-mode interrogation line placed perpendicular to the interventricular septum and just apical to the tips of the atrioventricular valves. Measurements of the cardiac ventricular diameters in end-diastole (EDD) and end-systole (ESD) are shown. LV, left ventricle; RV, right ventricle.
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Fig. 2. An apical four-chamber view of a normal fetal heart in systole showing the Mmode interrogation line placed through the ventricular free wall attachment of the tricuspid valve annulus (TVA). The difference of maximal systolic (sys) and diastolic (dia) excursion can be measured. RV and LV, right and left ventricle; RA and LA, right and left atrium.
involve assessment of the circumference and length of the chamber or use the more complex Simpson’s biplane method.26,27 By calculating ventricular volumes in end-diastole and end-systole, cardiac output and ejection fraction can be calculated from 2D imaging, although this method is time-consuming and not suited for daily clinical practice. This approach has been used to show an
15
exponential increase in both right and left EDV during the second half of gestation, whereas the EF remains at a constant level in normal fetuses.28 As M-mode and B-mode echocardiography are limited by accuracy of measurement, several groups have investigated the potential of 3D or ‘volume’ ultrasound for the assessment of fetal cardiac chamber size.29e35 Volumes are most commonly generated by spatialetemporal image correlation (STIC) using an automatic two-dimensional sweep across the heart that acquires several hundred frames that are rearranged spatially and temporarily to form a ‘virtual’ high resolution cardiac cycle containing up to 40 volumes for one heart beat.36 The endocardial contour can be detected semi-automatically and is used to quantify chamber volumes in end-diastole and end-systole, enabling the calculation of ejection fraction and cardiac output (Fig. 4).37 STIC volumes have been validated using in-vitro volumes comparable to second and third trimester fetal hearts; STIC it has been found to be suited for diastolic measurements and volumes >2.5 mL, and measurements appear to be reproducible.9 Normal ranges for right and left stroke volumes and cardiac output have been proposed and this technique has been used to demonstrate that chamber volumes in structurally malformed hearts differ markedly from the norm.34,38e40 STIC is dependent on fetal position (ideally supine) and quiescence, allowing acquisition of the entire fetal heart in one volume sequence.40 These views are particularly difficult to obtain at later gestations e with less amniotic fluid, more mineralization of fetal bones and often a dorso-anterior fetal position e which may prohibit its use for functional assessment in the later part of pregnancy. Despite this, a comparison of STIC with 2D and Doppler sonography found that although these methods gave similar results
Fig. 3. Schematic diagrams showing B-mode echocardiographic measurements. (a) Long-axis view of the left ventricle with aortic valve (1) and ascending aorta (2). (b) Aortic arch view with aortic valve (1), ascending and descending aorta (2, 3) and the inferior vena cava (4). (c) Short-axis view with the pulmonary valve (1), main, right and left (2, 3, 4) pulmonary arteries. (d) Oblique short-axis view showing the arterial duct (5). (e) Four-chamber view showing the tricuspid valve (1), right ventricular end-diastolic diameter (2), right ventricular inlet length (3), right ventricular area (dashed line, 4). On the left side are the mitral valve (5), left ventricular end-diastolic diameter (6), left ventricular inlet length (7) and left ventricular area (dotted line, 8). Ao, aorta; Desc Ao, descending aorta; IVC, inferior vena cava; LA, left atrium; LPA, left pulmonary artery; LV, left ventricle; MPA, main pulmonary artery; RA, right atrium; RPA, right pulmonary artery; RV, right ventricle. (Reproduced with permission from Schneider et al.24)
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Fig. 4. Fetal cardiac volumetry using three-dimensional datasets. (a) Use of a spatialetemporal image correlation (STIC) volume with semi-automatic volume tracing and automatic endocardial border detection (with permission from Messing et al.34). (b) Ventricular volume calculation from a non-reconstructed real-time volume acquired with a matrix transducer (with permission from Tutschek and Sahn37). (c) Semi-automatically generated endocardial casts derived from a STIC volume (with permission from Tutschek and Sahn35). Colour-filled areas of the left atrium (LA), right (RV) and left (LV) ventricles and aortic origin (Ao) are visible. The cavity of the right ventricle appears shorter than the left because of its apical trabeculation.
STIC was less operator dependent and required significantly less time for acquisition and offline analysis.40 3. Blood flow and cardiac intervals Stroke volume (and therefore cardiac output) can also be calculated by combining B-mode and pulsed-wave Doppler ultrasound to measure valvular diameter (D) and the velocity of flow (V) across the valve (see also Fig. 5):4,6,41,42 SV ¼ (p * D2/4)* V Both the diameters of the aortic and pulmonary valves and the flow velocities through the outflow tracts increase in a linear fashion with advancing gestation, so the stroke volumes and combined cardiac output increase exponentially from 160 to 1300 mL/min between 16 weeks and term. The right ventricle appears to make a greater contribution to combined cardiac output as the ratio of pulmonary artery to aorta is 1.2.4,6,42e44 This technique is limited by the fact that any inaccuracy in measurement of valvular diameter is compounded by squaring this value. It also assumes that the valve is circular and fails to account for vessel wall compliance. Velocity measurement by pulsed-wave Doppler also becomes unreliable if the angle for insonation is >15e20 , and angle correction is required in this situation. Comparison of the reproducibility of fetal cardiac ventricular volume estimations by M-mode, cross-sectional B-mode and Doppler-derived volume flow measurements finds that M-mode measurements are least
reproducible whereas the other two techniques have comparable intra- and interobserver error.21 Doppler ultrasound can also be used to examine cardiac function indirectly by examining the pattern of flow through the atrioventricular valves. The pattern of passive and active ventricular filling during diastole reflects relaxation properties of the cardiac ventricles. In fetal life, normal ventricular inflow is characterized by a smaller early (E) wave, followed by a larger (A) wave during atrial contraction. With advancing gestation the E/A ratio increases which is considered a sign of normal maturation towards a normally compliant (less stiff) myocardium.45,46 An increased or even reversed fetal E/A ratio is related to ventricular diastolic dysfunction.47 Monophasic atrioventricular inflow patterns are seen at high fetal heart rates and also in fetuses with reduced cardiac function.17,48 In the normal fetal heart, both AV valves are competent. The finding of more than a trace of regurgitation across the tricuspid and mitral valve should prompt further investigation for altered cardiovascular physiology.17 Whereas a trace of TR is typically benign, holosystolic TR is likely to be abnormal and warrants further investigation.49 Functional TR may reverse when the underlying pathology is corrected: for example in fetal anaemia, sustained fetal tachycardia or in the recipient in TTTS. Several groups have suggested scoring systems that combine methods of assessment to give a more global overview of cardiac function and that can be used to define imminent or absolute cardiac failure (Table 2).17,48 These scoring systems aim to standardize the current practice of multimodal assessment which is in part based on subjective parameters such as grading of ‘ventricular dysfunction’.
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17
Fig. 5. Quantitative assessment of cardiac output (CO) using pulsed-wave Doppler. (a) Pulsed-wave flow profile in the aorta; the sample volume is placed just distal to the aortic valve. The angle of insonation for Doppler assessment is minimized so that the flow velocity time integral (VTI) can be measured directly from the spectral display. (b) The aortic root diameter (red line) is used to calculate aortic valve area (VA). (c) Graph demonstrating the increase in left ventricular output with gestational age (Modified from Allan et al.4). (LV output ¼ VTI VA heart rate.) LV, left ventricle; RV, right ventricle; Ao, aorta; asc. Ao, ascending aorta.
Scores may be superior to single measurements in defining compromised cardio-circulatory function. Some recent studies have examined the potential for measuring time intervals during the cardiac cycle to assess global cardiac function. Systolic dysfunction causes prolongation of the isovolumic contraction time (ICT) and shortening of the ejection time (ET), and diastolic dysfunction prolongs the isovolumic relaxation time (IRT).50 These factors can be used to define the myocardial performance (MPI) or ‘Tei’ index51: MPI ¼ (IRT þ ICT)/ET Initial studies in adults found these parameters were easily and reproducibly measured and were predictive for cardiac failure in a stage-dependent fashion in patients with dilated cardiomyopathy.51 In the fetus these time intervals are best calculated using
a single pulse-wave Doppler recording of ventricular flow by recording a large sample volume that covers both mitral inflow and aortic outflow, demonstrating opening and closure of the valves (Fig. 6).52 The MPI has been applied to several clinical situations in fetal medicine (see below). 4. Clinical applications Fetal cardiac function can be compromised either by placental dysfunction, resulting in intrauterine growth restriction, by maternal illness (e.g. diabetes) or by the presence of some congenital anomalies. A better understanding of fetal cardiovascular status has been shown to improve our understanding and management in several clinical situations including the assessment of intrauterine growth restriction, TTTS and congenital diaphragmatic hernia.
Table 2 Fetal cardiovascular profile score combining direct and indirect functional parameters (Modified from Huhta17)
Cardiomegaly Valve insufficiency Hydrops Venous blood flow Umbilical artery blood flow
Normal (score 2 points)
Abnormal (minus 1 point)
Severely abnormal (minus 2 points)
CTR <0.35 No TR, no MR, biphasic filling No Normal umbilical vein, positive DV a-wave Positive EDF
CTR 0.35e0.50 Holosystolic TR Ascites or pleural effusion or pericardial effusion Normal umbilical vein, reversed DV a-wave No EDF
CTR >0.50 Holosystolic MR or monophasic filling Skin edema Pulsatile umbilical vein Reversed EDF
CTR, cardio-thoracic ratio; DV, ductus venosus; TR, tricuspid regurgitation; MR, mitral regurgitation; EDF, end-diastolic flow. For ‘normal’ fetal cardiac function the five parameters yield a score of 10.
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Fig. 6. The myocardial performance index (MPI or Tei index) in a normal fetus. The (modified) MPI is calculated from time intervals derived from pulsed-wave Doppler of left ventricular inflow (negative velocities, biphasic with E and A waves) and outflow (aortic outflow, positive velocities), incorporating the mitral and aortic valve clicks; T1, isovolumic contraction time; T2, ejection time; T3, isovolumic relaxation.
Crispi et al. used several markers of cardiac function including the MPI, E/A ratio and calculation of cardiac output to compare growth-restricted fetuses with appropriately grown fetuses.53 The MPI and E/A ratio (but not cardiac output) correlated with hemodynamic deterioration and were significantly increased in fetuses that died. Hernandez-Andrade et al. studied cardiovascular function in preterm growth-restricted fetuses. Although perinatal mortality was independently predicted by an abnormal MPI (>95th centile), this had less predictive power than other factors such as gestational age at delivery or abnormal venous Doppler findings (reversal of the A-wave of the ductus venosus).54 A combination of these parameters best predicted perinatal mortality. For example, for a fetus below 28 weeks with positive a-wave and normal MPI, the estimated perinatal mortality (PNM) was 18%, but with DV areversal and abnormal MPI, PNM was 97%. The circulations of monochorionic twins are almost invariably intertwined by placental vascular anastamoses. In the majority of cases volume exchange is balanced, but in 15% an imbalance causes net transfusion from one twin (the ‘donor’) to the other (the ‘recipient’), Twin-to-twin transfusion syndrome or TTTS.55 The twins have unique cardiovascular problems: the recipient
has a persistent increase in cardiac preload, whereas the donor has inadequate placental return of oxygen and nutrients. Treatment by laser ablation of the communicating placenta vasculature provides a further cardiovascular challenge.56 The recipient that previously had to compensate for a chronic increase in preload needs to readjust cardiac function to a lower preload. The donor experiences an abrupt increase in peripheral resistance due to occlusion of the communicating vessels and a relative loss of perfusable placental territory; from a cardiac perspective, this fetus must adapt to an increase in afterload.57 Although transient and permanent cardiovascular anomalies are frequently seen in fetuses with TTTS, the current staging system only includes indirect signs of cardiac dysfunction.58,59 Cardiovascular dysfunction in the recipient twin can be detected using a score that encompasses arterial and venous Doppler alterations, cardiac size, and atrio-ventricular valve regurgitation as well as abnormal inflow patterns.48 Because the preload of the recipient is increased, the right ventricle MPI is also increased; assessing cardiac function using MPI might improve the selection of appropriate candidates for intrauterine therapy and also be of value in monitoring improvement in fetal condition after treatment.60 Maternal diabetes is the most common cause of a fetal hypertrophic cardiomyopathy, characterized by thickening of the interventricular septum and ventricular outflow obstruction in an otherwise structurally normal fetal heart; it occurs in about a quarter of affected pregnancies.47,61,62 In affected fetuses diastolic function, judged for example by the diastolic filling pattern or flow velocity waveforms in the ductus venosus, can be altered even in well-controlled maternal glycemia.62e65 In severe congenital diaphragmatic hernia (CDH), compression of the fetal heart by herniated viscera impairs cardiac function.66 LV volumes as determined by the Teichholz formula in CDH were about one-third smaller compared to normal fetuses.67 Temporal fetal endoscopic tracheal occlusion, in addition to improving lung size, also has an effect on cardiac function: placement of the tracheal occlusion improved the myocardial performance index by shortening the isovolumic contraction time interval.68 Other examples of extracardiac abnormalities affecting cardiac function are sacrococcygeal teratoma or arterio-venous malformations (AVM), characterized by high blood flow through the tumour that can lead to cardiac failure. As the fetus with
Fig. 7. Strain rate (SR) analysis, using speckle tracking, of a normal fetal heart at 32 weeks of gestation. Left panel: the ventricular wall is tracked throughout the cardiac cycle; lengthening and shortening during diastole and systole are calculated for individual segments (colored dots). Right panel: quantitative analysis of regional (colored lines) and global (white dotted line) strain rates; x-axis denotes time (ms), y-axis indicates strain rate (1/s). The major peaks indicate (from left to right): two diastolic SR peaks above the x-axis (SRE, SRA) indicating lengthening during early and late diastolic tissue motion, followed by a negative SR peak (SRS) during systole.
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a sacrococcygeal teratoma deteriorates, the inferior vena cava and the cardiac ventricles dilate due to increased venous return from the tumour, even though these fetuses typically maintain a normal shortening fraction.69 Similarly a dilated superior vena cava and cardiomegaly develop in deteriorating fetuses with a large cerebral AVM such as an aneurysm of the vein of Galen.69 In both these conditions neonatal outcomes are poorer in fetuses that develop hydrops prior to delivery and recognition of more subtle signs of cardiac failure may prompt antenatal intervention or delivery.70 Fetal tachyarrhythmias may also impair cardiac function, but may be difficult to assess functionally, because indices such as the MPI are difficult to measure at high heart rates. For this condition, scoring systems as described above may be better suited.17
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Practice points Quantification of cardiac function in the human fetus is technically difficult. Cardiac volume measurements enable calculation of cardiac output and ejection fraction. 3D fetal echocardiography is promising, but still lacks standardization. At present, assessment of peripheral and central blood flow remain the most useful clinical tools.
Research directions 5. Other new technologies Whereas traditional Doppler studies of blood flow are based on high velocityelow intensity signals, tissue Doppler records low velocityehigh intensity signals; it can be used to assess the force of cardiac contraction and relaxation in the fetus.71e73 Both pulsedwave and colour Doppler can record motion of cardiac structures. Sampling with pulsed-wave Doppler over the AV valve annulus uses the same insonation as that used for M-mode recording of this structure. A theoretical advantage is that tissue Doppler data might be more closely related to mechanical force than blood flow Doppler. Unfortunately quantification is limited by the angle dependency and poor lateral resolution of Doppler imaging. Strain analysis is a concept adopted from adult cardiology. Strain describes tissue ‘deformation’: lengthening in diastole and shortening in systole. By definition, strain can only be calculated by comparison of fixed points in the myocardium that are tracked throughout the cardiac cycle. Strain is defined as the relative change in the distance between two points in systole and diastole. Strain rate is the time taken to reach a specific level of tissue deformation. Both tissue Doppler imaging and strain analysis are used postnatally to assess and quantify regional and global cardiac wall motion. Fetal strain analysis can be performed using tissue Doppler imaging, but angle dependency, sensitivity to extracardiac movement and high fetal heart rate hamper this approach.72,74e76 Strain analysis requires high spatial and temporal resolution which is inherently difficult to achieve in fetal studies due to the small cardiac size and the high heart rate. Speckle tracking is a novel imaging modality that can be used to assess cardiac function; it is not based on the Doppler principle, but tracks individual reflectors in the myocardium over time. It is therefore less angle dependent. Fig. 7 shows an example of fetal strain rate analysis by speckle tracking. Early studies suggest that functional indices are in a similar range to the adult, although they vary with gestational age.3,77e79 6. Conclusions Clinical assessment of fetal ‘well-being’ currently relies on a multimodal approach examining fetal growth, behavioural state, amount of amniotic fluid, peripheral Doppler studies and fetal heart rate tracing. Fetal cardiac function may be affected by a number of environmental or congenital anomalies. Research efforts have recently recognized the potential value of monitoring cardiac function for clinical management. Unfortunately, there is no single simple test to measure fetal cardiac function. Further studies will show which approach to functional cardiac assessment in the fetus has true value in terms of improved neonatal outcome.
Newer methods of assessment such as measurement of cardiac intervals and tissue deformation require further validation. Potential markers for defined pathologies need to be clarified. The effect of the intrauterine environment on fetal cardiac development needs to be explored.
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