Latest advances in fetal echocardiography

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Ultrasound Rev Obstet Gynecol 2004;??:000–000

Latest advances in fetal echocardiography CARMINA COMAS Centro Gutenberg, Ma ´laga, Spain

Keywords: Fetal echocardiography, cardiac anomalies, prenatal diagnosis, ultrasound

Abstract Cardiac anomalies are the most commonly overlooked defects in prenatal ultrasound assessment. The issue of missed prenatal diagnosis is disturbing, particularly when it occurs against a background of tremendous skill and technologic support. New policies to minimize mistakes in this critical aspect need to reach a consensus. Recent new strategies should be put in place in a multidisciplinary manner if they are to have a significant clinical impact. Particularly relevant are the strategies to improve prenatal diagnosis of congenital heart defects, to advance gestational age at diagnosis, to identify new prenatal markers of heart defects and to incorporate new tools in the field of fetal echocardiography. As a result of these advances, the prenatal detection and diagnosis of coronary heart disease has developed an increasing impact on the perinatal outcome of pregnancies complicated by fetal heart disease. We review some of the recent developments in this multidisciplinary area.

INTRODUCTION Prenatal detection of fetal congenital heart defects (CHDs) remains the most problematic issue of prenatal diagnosis3. Major CHDs are the most common severe congenital malformations, with an incidence of about 5 in 1000 live births, whenever complete ascertainment is done and minor lesions are excluded1,2. Congenital heart anomalies have a significant effect on the affected child’s life with up to 25–35% mortality rate during pregnancy and the postnatal period. It is during the first year of life that 60% of this mortality occurs. Moreover, major CHDs are responsible for nearly 50% of all neonatal and infant deaths due to congenital anomalies, and the percentage is likely to be significantly higher if spontaneous abortions are considered. Although CHDs used to appear in isolation, they are now frequently associated with other defects: chromosomal anomalies and genetic syndromes. Their incidence is six times greater than that of chromosomal abnormalities and four times greater than that of neural tube defects1–3. Nonetheless, structural cardiac defects are among the most frequently missed abnormalities by prenatal ultrasound4. Although the at-risk population-based approach has been crucial in decreasing disease, prenatal diagnosis of CHD remains largely a scenario of too much effort for too few diagnoses. Clinicians need to

re-examine the reasons for this shortfall and redefine new strategies to improve the efficacy of our efforts. It must be remembered that 90% of CHDs occur in low-risk mothers. The way forward to increase detection of CHD is to improve the effectiveness of screening programs so that a higher number of cases from low-risk populations is referred for a specialized scan. The positive aspect of screening for cardiac defects compared with other anomalies (e.g. Down syndrome, neural tube defects) is that it does not automatically result in termination of pregnancy. It is one of the anomalies where optimizing management of the neonate in the perinatal period might improve outcome. Improved morbidity/mortality has been clearly shown as a result of prenatal diagnosis. The outcome is improved of all forms of CHD that are dependent on the patency of the ductus arteriosus in the immediate postnatal period, the transposition of the great arteries being the single most important lesion to diagnose prenatally5,6. The purpose of this review was to describe several of the most relevant advances in the field of fetal cardiology. The major advancements in fetal echocardiography can be divided into four categories:

# 2004 Parthenon Publishing. A member of the Taylor & Francis Group DOI: 10.1080/14722240500045190

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Fetal echocardiography

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Methods used in fetal cardiology Indications and methodology Routes for examination of the fetal heart Prenatal therapy

Methods used in fetal cardiology The birth of fetal echocardiography occurred in the late 1970s, when fetal heart movements were first visualized by primitive A-scan ultrasound or by M-mode techniques. Since then, different technologies and modalities have been incorporated in order to improve the diagnostic accuracy and possibilities in this field. We review the diagnostic tools that are available and the potential roles of fetal echocardiography in the field of fetal medicine7. Real-time ultrasound is still the gold standard for the structural evaluation of the fetal heart. In the most sophisticated ultrasound machines there is an ideal setting for fetal heart evaluation that is based on a high image resolution, a high frame rate and good penetration. Two main features have facilitated the prenatal assessment of the fetal heart: the use of transducers with a high frequency (5–7 MHz transducers), and the incorporation of the cine-loop and zoom functions. Tissue harmonic imaging (THI) has recently been introduced to enhance diagnostic performance in individuals with a limited acoustic window, mainly due to obesity or abdominal scarring8. Their different behavior from the fundamental frequency ultrasound, the energy of which decreases linearly with depth, is the reason why the use of THI has been shown to improve image quality in some circumstances, particularly in obese individuals (Figure 1). Time motion (M-mode) was a revolutionary tool in fetal cardiology when simultaneous real-time

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visualization became available. First used for cardiac biometry, it was soon relegated to a second line, since such measurements became easier using the cine-loop techniques for selective imaging of diastole and systole. Two main fields of interest are still in the domain of M-mode: the assessment and classification of fetal arrhythmias (where this mode can document atrioventricular conduction by putting the cursor simultaneously in an atrial and ventricular structure) and assessment of myocardial contractility (calculating indices such as shortening fraction, ejection fraction, etc.). The acquisition of flow velocity waveforms from different fetal cardiac structures and vessels by using pulsed or continuous wave Doppler ultrasound enables a non-invasive quantification of perfusion; evaluation of peak velocities in different sites of the circulatory system, measurement of contractility indices, stroke volume, and the recent incorporation of the assessment of coronary and venous system are some examples. The pathological conditions investigated are no longer confined to fetal heart defects but have expanded to include other fetal conditions involving the cardiovascular system. Investigation of intracardiac flow in severe intrauterine growth restriction, diabetes or fetal anemia represent some examples of the huge potential of this technical modality. In addition to gray-scale examination of the fetal heart, color Doppler is now considered to be a second-line investigation for cardiac evaluation. This method allows rapid orientation within the fetal heart and completes the evaluation supplied by gray-scale information. Once abnormal flow is suspected, quantification by deriving Doppler flow velocity waveforms becomes mandatory. Color Doppler is an essential tool for the

Figure 1. Comparison between conventional B-mode imaging and tissue harmonic imaging (THI) in fetal echocardiography. (a) The left panel is obtained with conventional frequency ultrasound (6 MHz). (b) The right panel is obtained with THI (5 MHz)). Note that, in this case with suboptimal visualization of cardiac structures, THI can obtain a clearer image with better resolution.

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fetal cardiologist, but is not considered standard of care for a routine obstetric scan. Power Doppler ultrasound is a technique introduced in the early 1990s using the information from the amplitude of the Doppler signal rather than the frequency shift and direction, opening the possibility of displaying flow independently of its velocity and direction. Since this technique is significantly more sensitive than conventional color Doppler, it has been applied in regions with low flow and small vessels. This technique can be used in fetal cardiology, facilitating the detection of some CHDs (such as small ventricular septal defects) and enabling spatial orientation of the great vessels (Figure 2). On the other hand, we are not informed about the blood direction or turbulences. However, these characteristics make it suitable for three-dimensional power Doppler evaluation of the cardiovascular system. In tissue Doppler echocardiography (TDE), colorcoding is used to visualize wall movements rather than blood flow. Tissue Doppler echocardiography has only recently been applied to the fetus, with promising preliminary results9,10. Color and power Doppler mapping could be applied on a regular high-resolution ultrasound machine by sampling the relatively high reflected acoustic energy from cardiac walls. Fetal TDE is a new technique that can provide additional insights into fetal cardiac function that are not available with the conventional approach. Although fetal three-dimensional (3D) imaging currently faces important image resolution concerns, the technique has the potential markedly to improve both the prenatal detection and diagnosis of CHD. Already demonstrated to improve the diagnosis of CHD in infants, children and adults, 3D imaging of the fetal heart offers important potential advantages over conventional two-dimensional (2D) imaging5.

By acquiring volumetric data within a few seconds from a single window, 3D imaging may reduce scanning time and operator dependence. For screening the low-risk pregnancy, 3D imaging may facilitate visualization of the four-chamber view and outflow tracts, particularly when 2D imaging fails because of time constraint, limited window, or sonographer inexperience11,12. Volume data sets can be transmitted electronically to experts for further evaluation13. For teaching purposes, the volumetric data sets can be sent to a remote virtual scanning station14. Finally, quantitative measurements using 3D imaging promise to be more accurate and reproducible than those derived from 2D imaging. Sophisticated volume processing algorithms that allow quantitative measurements of volume and function may offer additional insights into cardiac function and development15,16. Recently, spatio-temporal image correlation (STIC) has been introduced as a new 3D technique allowing the automatic acquisition of a volume of data from the fetal heart, being displayed as a cine-loop of a single cardiac cycle17–19. This technique allows dynamic multiplanar slicing and surface rendering of the heart anatomy (Figure 3). STIC in combination with color or power Doppler ultrasound is a promising new tool for multiplanar and 3D/four-dimensional (4D) rendering of the fetal heart, making possible the assessment of hemodynamic changes throughout the cardiac cycle20. Telemedicine represents an emerging but potentially critical advance in prenatal screening for CHD21,22. Telemedicine, like 3D ultrasound, may enable fetuses to be scanned at remotes sites, with their respective studies reviewed instantaneoulsy or whithin minutes at more centrally located, highly specialized centers, avoiding the need to transport the pregnant patient.

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Figure 2. Power Doppler ultrasound scan of a four-chamber view (a) and an aortic arch (b) at 18 weeks’ gestation.


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Figure 3. Three-dimensional multiplanar slicing of the four-chamber view, with spatiotemporal image correlation (STIC) technology (a,b,c). The reference dot can be positioned at any position, simultaneously displaying the three orthogonal planes. (d) The rendered three-dimensional image.

Increasingly sophisticated computer processing systems and improvements in imaging technology have enabled the development of new technology, such as automated 3D ultrasound imaging systems or telemedicine, which promise to revolutionize prenatal diagnosis of congenital heart defects.

genetics in the pathogenesis of CHD, demonstrating recurrence risks higher than expected in hypothetics multifactorial patterns. (1) Prenatal detection and diagnosis of congenital structural heart defects (2) Fetal cardiac function assessment (3) Fetal echocardiography and genetics

Indications and methodology Until recently, fetal heart assessment has been mainly focused on the detection of fetal heart anomalies, either by examining high-risk groups or by applying the four-chamber view as a screening tool. Cardiac defects are indeed still the main field of interest in fetal cardiology, but fetal echocardiography is more than merely the examination of fetal cardiac structures to exclude malformations. Doppler ultrasound has enabled non-invasive studies to be carried out of the fetal circulation under physiological and pathological conditions. These studies have demonstrated cardiovascular changes occurring in the human fetus in different clinical conditions7. The knowledge from these data may prove useful in improving the diagnosis, monitoring and treatment of compromised fetuses. On the other hand, recent epidemiological studies have suggested an important role of

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Prenatal detection and diagnosis of congenital structural heart defects. For screening techniques: Most major CHD can be diagnosed prenatally by detailed transabdominal second-trimester echocardiography at 20–22 weeks’ gestation1,323–25. The identification of pregnancies at high risk for CHD needing referral to specialist centers is of paramount importance in order to reduce the rate of overlooked defects25,26. However, the main problem in prenatal diagnosis of CHD is that the majority of cases occur in pregnancies with no identifiable risk factors. Therefore, there is wide agreement that cardiac ultrasound screening should be introduced as an integral part of the routine scan at 20–22 weeks. In the 1990s, the American Institute of Ultrasound in Medicine and the American College of Radiology incorporated the four-chamber view into their

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formal guidelines for fetal ultrasound screening. Although early investigators found the fourchamber view to have a high sensitivity for the prenatal detection of CHD, subsequent studies have found the four-chamber view to be far less sensitive. Even in the best hands, this view may fail to detect a significant percentage of major ductal-dependent CHDs. Many investigators have demonstrated an incremental value of adding outflow tracts to the routine fetal ultrasound screening27,28. When applied to the low-risk population, scrutiny of the four-chamber view allows the detection of only 40% of the anomalies, while additional visualization of the outflow tracts and the great arteries increase the rate to 60–70%3,23,24. The systematic incorporation of the four – chamber view and outflow tracts into the routine fetal ultrasound screening represents an important advance in fetal cardiac imaging. Incorporation of the four-chamber view and outflow tracts into routine fetal ultrasound evaluation improves prenatal detection of congenital heart diseases.

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Doppler findings can substantially increase the likelihood of prenatal diagnosis and decrease the incidence of false-positives. Spectral power Doppler can also add important information to normal and abnormal color flow patterns. Recently, a sequential segmental approach for the complete evaluation of fetal heart disease as a screening technique has been described, using five or six short-axis views from the fetal upper abdomen to the mediastinum29,30. The transverse view of the fetal upper abdomen is obtained to determine the arrangement of the abdominal organs, which, in most cases, provides important clues to the determination of the atrial arrangement. The four-chamber view is obtained to evaluate the atrioventricular junctions. The views of the left and right ventricular outflow tracts are obtained to evaluate the ventriculoarterial junctions. The three-vessel view and the aortic arch view are obtained for the evaluation of the arrangement and size of the great arteries, which provides additional clues to the diagnosis of the abnormalities involving the ventriculoarterial junctions and the great arteries

The standard fetal cardiac examination protocol. The basic fetal cardiac screening examination entails an analysis of the four-chamber view, obtained from an axial plane across the fetal thorax. If technically feasible, optional views of the outflow tracts can be obtained as part of an extended cardiac screening examination. The systematic incorporation of the four–chamber view and outflow tracts into the routine fetal ultrasound screening represents an important advance in fetal cardiac imaging. Summarizing the data from screening studies, a detection rate of less than 10% can be expected if the heart is not explicitly examined, a rate of 10–40% detection if the four-chamber view is visualized and a rate of 40–80% if the visualization of the great vessels is added3,23,24. In a high-risk pregnancy, in addition to information provided by the basic screening examination, a detailed analysis of cardiac structure and function may further characterize visceroatrial situs, systemic and pulmonary venous connections, the foramen ovale mechanism, atrioventricular connections, ventriculoarterial connections, relationships between the great vessels and sagittal views of the aortic and ductal arches. Additional sonographic techniques can be used for this purpose, such as Doppler ultrasonography or the M-mode modality. Color Doppler is an essential tool for the fetal cardiologist, but is not considered the standard of care for a routine obstetric scan. Color

Fetal echocardiography. A basic cardiac examination including the fourchamber view and the outflow tract views is recommended to all pregnant women. A targeted echocardiogram including an exhaustive evaluation of heart structures is recommended in high-risk pregnancies. There are suggestions to improve the detection rate of congenital heart defects. Inadequate examination is likely to be the most common cause of heart defects being overlooked in the four-chamber view. Chaoui has suggested some hints to improve visualization of the heart31. Examination of the fetal heart should be carried out at every secondtrimester screening examination. This should ideally be at 20–22 weeks’ gestation, using a 5MHz transducer. Optimal analysis of the heart may be achieved by magnification of the image, using the zoom function, so that the heart fills a third to a half of the screen, and by the use of the cine-loop to assess different phases of the cardiac cycle (Figure 4). Established ultrasound screening programs also increase detection rates4. They have to focus on equivocal prenatal signs of heart abnormality, so-called borderline findings, which should prompt referral to a specialist. These include echogenic foci in the ventricles, small pericardial effusions, mild discrepancy in ventricular size, tricuspid regurgitation or deviation of the cardiac axis (Figure 5). Since heart anomalies developing in


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Figure 4. Zoom function. Apical four-chamber view at a non-optimal magnification (a) and after application of zoom function and magnification of the image (b). Lateral four-chamber view at a non-optimal magnification (c) and after application of zoom function and magnification of the image (d).

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Figure 5. Borderline findings in fetal echocardiography are prenatal signs of heart abnormality, of controversial clinical implications, which should prompt referral to a specialist: (a) early mild ventricular asymetry, (b) tricuspid regurgitation, (c) small pericardial effusion, (d) deviation of cardiac axis and (e) echogenic foci (in both ventricles).

utero can be missed at the second-trimester scan, the fetal heart should be examined if third-

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trimester scanning is performed. The use of color Doppler during cardiac scanning will also


improve detection rates, increasing the speed and the accuracy of the fetal cardiac scan, although it is controversial to use this modality for screening purposes. There are sufficient studies and clinical experience to conclude that screening for fetal cardiac defects at the second-trimester ultrasound examination gives excellent results if performed properly. There are some indications of improved visualization of the fetal heart.

INDICATIONS FOR TARGETED FETAL ECHOCARDIOGRAPHY A fetal echocardiogram should be performed if recognized risk factors raise the likelihood of congenital heart disease beyond what would be expected for a low-risk screening population. As a consensus, common indications for fetal echocardiography by an expert in fetal cardiology are as follows: . .

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increased nuchal translucency ( 4 95th or 99th centile); abnormal ductus venosus blood flow, regardless of the measurement of the nuchal translucency; fetuses affected by other structural malformations (hygroma, hydrops, omphalocele, situs inversus, arrythmia); fetal arrhythmias; suspected cardiac anomalies at ultrasound screening; maternal illness with increasing risk of CHD, such as pregestational diabetes, autoimmune disease, metabolic disorders; high-risk family, with a previously affected child, a first-degree relative affected by a congenital heart disease or a genetic disease in which CHD is common; women at high risk of chromosomal abnormality declining invasive test for karyotyping; pregnancies affected by a chromosomal abnormality; or cardiac teratogen exposure (alcohol, lithium, valproic acid, vitamin A).

Currently, in terms of cost-effectiveness, targeted fetal echocardiography is justified in fetuses at high risk of having cardiac anomalies. Clinicians should be familiar with the main reasons why patients might be referred for this comprehensive evaluation.

TIMING OF FETAL ECHOCARDIOGRAPHY Timing of a first or subsequent fetal echocardiogram needs to be a balance between the

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feasibility of seeing an abnormality and the accuracy of such a finding. The current consensus is a single preliminary examination at 20 weeks of gestation in the low-risk population (by an obstetric scanner) or preliminary examination around 14 weeks followed by another examination at 20 weeks in a high-risk population (by a fetal cardiology expert)12,32. A basic cardiac examination is recommended to all pregnant women at 20–22 weeks’ gestation. A targeted echocardiogram is recommended at any time when a risk factor is detected, preferably at an early stage of pregnacy (14 weeks’ gestation), followed by a later second-trimester examination.

IDENTIFICATION OF NEW MARKERS OF CONGENITAL HEART DEFECTS Nuchal translucency (NT) measurement at 10– 14 weeks’ gestation is a widely accepted method to screen for chromosomal abnormalities. Recent studies have suggested the potential role of increased NT thickness33–39 or an abnormal ductus venosus (DV) flow pattern40–42 at early pregnancy as a screening tool for CHD, in addition to its role in screening for chromosomal defects (Figure 6). The risk of CHD after the finding of an increased NT in chromosomally normal fetuses seems to vary between 4 and 9%43,44. Hyett et al. reported that about 55% of major CHDs were associated with a fetal NT thickness above the 95th centile at 10–14 weeks of gestation33. However, others have failed to demonstrate such a strong association, emphasizing that the routine assessment of the four chambers and great vessels at mid-second trimester remains as the most important screening tool for the detection of major CHD45,46. Theoretically, both types of screening used in combination should improve the overall sensitivity of the prenatal diagnosis of major cardiac defects. The physiopathogenic mechanism of this relationship is not easy to explain37,42,47–51. Pathological examinations of fetuses with increased NT thickness at 10–14 weeks have demonstrated a high prevalence of cardiac defects and abnormalities of the great arteries and of subtle defects, such as widening of the aortic valve and ascending aorta, narrowing of the aortic isthmus and persistence of the left superior vena cava. Another proposed mechanism to explain the increased NT is an early cardiac function impairment suggested by an abnormal DV flow pattern. However, Matias et al.40 reported that most of the chromosomally normal fetuses with increased NT but normal DV flow did not have a CHD. This finding


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Figure 6. Recent studies have suggested the potential role of an increased NT thickness or an abnormal ductus venosus (DV) flow pattern at early pregnancy as a screening tool for congenital heart defects, in addition to its role in screening for chromosomal defects. (a) Normal nuchal translucency (NT) measurement and (b) abnormal increased NT thickness. (c) Normal DV flow pattern and (d) abnormal increased resistence in the DV, with a reversed end-diastolic flow during atrial contraction.

might contradict a cardiac involvement in the pathogenesis of the increased NT in most of the fetuses, and suggest that only fetuses with abnormal DV blood flow are those at high risk of CHD. On the other hand, in cases with CHD and both enlarged NT and abnormal DV, because the type of cardiac defects cannot always explain the hemodynamic changes found in these fetuses, some other mechanisms seem to be envolved42. Based on ultrasonographic and post-mortem morphological studies, the findings in increased NT fetuses can be classified into three categories51. First, an association between increased NT and cardiac anomalies, combined with an abnormal ductus venosus flow pattern, has been described in some cases, leading to the theory that cardiac failure causes NT enlargement. Second, various types of abnormality have been found in the extracellular matrix of the nuchal skin of fetuses with increased NT. Third, abnormal lymphatic development has been demonstrated in fetuses with increased NT. Many hypotheses on NT enlargement are based on associations and speculations. Therefore, within this context, it is not clear whether all these cardiovascular anomalies are the cause of the increased nuchal translucency or both events are the result of another pathophysiological mechanism. Recent studies have suggested the potential role of an increased NT thickness or an abnormal

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DV flow pattern at early pregnancy as a screening tool for CHD, in addition to its role in screening for chromosomal defects.

FETAL CARDIAC FUNCTION ASSESSMENT Fetal echocardiography is more than the examination of the fetal cardiac structures to exclude malformations. It can be widely applied to assess the state of the fetal heart in a variety of clinical conditions. The advent of all this new technology has allowed the non-invasive examination of fetal cardiovascular pathophysiology, thus enabling hemodynamic studies to be carried out of the fetus, under both normal and abnormal conditions. Potential applications would be the investigation of growth-restricted fetuses, fetuses of diabetic mothers, or fetuses with heart failure. Methodologically, fetal cardiac function can be assessed by different modalities. Systolic indices such as M-mode and 2D-based ejection fraction are commonly used, but may be misleading because of systematic overestimation of volumes by these modalities. Tissue Doppler echocardiography has only recently been applied to the fetus, with promising preliminary results9,10. Tissue Doppler echocardiography-based measurements of contraction or relaxation velocities, systolic and diastolic function, and intramyocardial velocities have been shown to


be feasible and can be used as quantitative tools. Doppler-based myocardial performance indices may be obtainable but are not yet well established52. Three-dimensional and four-dimensional methods are relatively free of geometric assumptions and are promising modalities for cardiac function evaluation. Some gating techniques have been described, but are clinically impractical. Spatiotemporal image correlation is a new, fully integrated automatic volume acquisition technology that realigns Bmode images according to their spatial and temporal domain, effectively allowing a cineloop of 3D fetal cardiac motion. This cine-loop can then be manipulated just like a 3D data set. Preliminary experiences show its feasibility in normal and abnormal structured hearts17–20.

Fetal echocardiography in the growthrestricted fetus Fetuses with intrauterine growth restriction (IUGR) secondary to uteroplacental insufficiency are characterized by selective changes of peripheral vascular resistence that influence cardiac hemodynamics53. Secondary to the brain-sparing effect, selective modifications occur in cardiac afterload with a decreased left ventricular afterload due to cerebral vasodilatation and an increased right ventricular afterload as a result of the systemic vasocontriction. As a consequence, IUGR fetuses show impaired ventricular filling properties with a lower E/A ratio at the level of the atrioventricular valves, lower peak velocity in the aorta and pulmonary arteries, increased aortic and decreased pulmonary time to peak velocity and a relative increase of left cardiac output associated with decreased right cardiac output. These hemodynamic cardiac changes are compatible with a preferential shift of cardiac output in favor of the left ventricle, leading to improved perfusion of the brain. Longitudinal studies of progressively deteriorating IUGR fetuses have allowed the elucidation of the natural history of these hemodynamic modifications, suggesting a progressive decline in cardiac function, reflected by progressive modifications in the fetal venous system (increased reverse flow during atrial systole). Recently, some new vessels have been explored in order to improve the knowledge of the natural history of this condition, such as the aortic isthmus or coronary arteries. Some authors have investigated the effects of impairment to placental flow on flow patterns through the aortic isthmus, a vascular segment which is the link between the parallel vascular systems perfused by the left and right ventricles during

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fetal life. The aortic isthmus has a dynamic role in connecting these two parallel circulatory systems, and it has been suggested as a site for early detection of blood flow redistribution54,. Other authors have recently suggested that demonstration of coronary blood flow in severe IUGR cases may indicate maximal coronary vasodilatation in response to a progressive ischemia and lack of nutrients, in order to maintain myocardial oxygenation. This phenomenon, called the ‘heart-sparing effect’, represents a preterminal compensatory event preceding intrauterine fetal death55. Other conditions such as anemia, ductus arteriosus restriction or bradycardia may be associated with evidence of enhanced coronary blood flow, suggesting that short-term autoregulation and long-term alterations in myocardial flow reserve are present in the human fetus56 At present, examination of the coronary sinus blood flow has limited clinical utility, while increases of the coronary sinus diameter or attenuation of coronary sinus dynamics may provide useful markers of abnormalities of central venous drainage56.

Fetal echocardiography in diabetes mellitus Diabetes mellitus is considered to be an indication for targeted fetal echocardiography, mainly to rule out cardiac malformations. The other very interesting but underestimated group is still that of gestational diabetes. Infants of diabetic mothers have long been recognized to be at risk of developing hypertrophic cardiomyopathy, which may be present prenatally and develop progressively with fetal growth. M-mode studies have also shown an increased thickness of ventricular walls that is particularly evident at the level of the interventricular septum. The increased cardiac size does not only reflect the larger size of fetuses of diabetic mothers (macrosomia), but also represents a selective organomegaly, being particularly evident during the late second trimester. Because no differences were present in metabolic control, it has been speculated that this may reflect a different degree of sensitivity of the fetal myocardium to factors accelerating growth.

Fetal echocardiography during maternal pharmacological treatment The effect of drugs on the fetal circulation and on the fetal heart has been widely demonstrated. The influence of betamimetics, magnesium, corticosteroids, digoxin, thyrotropin releasing hormone and others have been investigated, but most studies have concentrated on the


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influence of indomethacin on the ductus arteriosus. Characteristic cardiac Doppler findings under this condition are increased peak systolic and diastolic velocities and decreased pulsatility indices at the level of the ductus, and the onset of tricuspid regurgitation (Figure 7). Whereas the effect of indomethacin on prenatal ductal constriction is well known, exposure to other maternal pharmacological treatments may have equally deleterious effects on the fetal circulation. These include widely prescribed nonsteroidal anti-inflammatory drugs (diclofenac)57. Fetal echocardiography has subsequently become an established method of surveillance to confirm safety and fetal well-being during maternal exposure to these drugs.

tion. Doppler echocardiography has made it possible to elucidate the hemodynamic response of the human fetus to anemia and its rapid correction. Under this condition, the changes in fetal cardiac function are mainly related to the low blood viscosity leading to a hyperdynamic situation characterized by a high left and right cardiac output (with a normal ratio between them), a high peak velocity at outflow tract level, an increase in the E/A ratio at both atrioventricular valves and an increase of peak velocities in the ductus venosus. Fetal infections can be suspected because of indirect signs detected by ultrasound, such as myocarditis or pericardial effusion.

Fetal echocardiography in fetal diseases

Fetal echocardiography in prolonged pregnancies

Fetal diseases interfering with the cardiovascular system are numerous and can be intrinsic (malformations or inborn diseases) or extrinsic due to maternal influence (infections, metabolic disease, maternal antibodies). The evaluation of the fetal heart could help in the assessment of the fetal condition and jeopardy. Fetuses with volume overload are at high risk for cardiac failure and development of hydrops (peripheral arteriovenous fistulae, vein of Galen aneurysm). A combination of volume overload and myocardial dysfunction can be found in fetal anemia either in rhesus disease or in parvovirus infec-

In post-term fetuses, cardiac function deteriorates in cases that develop a non-reassuring intrapartum fetal heart rate (FHR), and the changes in left cardiac function correlate with changes in the amniotic fluid index58. Doppler studies indicate that both left and right fetal cardiac function are impaired in prolonged pregnancies before the appearance of an abnormal intrapartum FHR. These results suggest that a better understanding of the events leading to oligohydramnios and an abnormal FHR pattern may improve fetal surveillance in prolonged pregnancies.

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Figure 7. The influence of indomethacin on the fetal cardiac circulation has been widely documented. (a,b) Normal waveform in the ductus arteriosus during the second trimester of pregnancy, with normal peak systolic (upper panel) and diastolic flow velocities (low panel). (c,d) Characteristic cardiac Doppler findings under indomethacin treatment at 32 weeks’ gestation are tricuspid regurgitation in the four-chamber view (upper panel) and increased peak systolic and diastolic velocities and decreased pulsatility indices at the level of the ductus arteriosus in a tranverse view of the thorax at the level of the high mediastinum (lower panel).

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Fetal echocardiography and the lung Proximal and peripheral fetal pulmonary arteries and veins have been recently visualized thanks to the introduction of color Doppler. Recently, pulmonary Doppler has been experimentally performed in fetuses at high risk for lung hypoplasia, under hypoxia and hyperoxygenation as well as in heart defects. In the future, this new field of investigation may have great potential, especially because lung diseases are the leading cause of death in the neonatal period.

Fetal echocardiography in discordant twins Twin pregnancies have a high rate of perinatal complications which are particularly evident in pairs with discordant growth. Discordant growth in twin pregnancies can be mainly caused by placental insufficiency or twin-totwin transfusion syndrome. Under the first condition, the small twin shows progressive changes of Doppler indices similar to those described in singleton growth-retarded fetuses secondary to placental insufficiency. Under the second condition, the discordance of growth is related to the classic pathophysiological background of this syndrome: a shift of blood volume from the donor twin to the recipient twin. The changes are present at cardiac and venous levels and are consistent with a condition of anemia (increased peak velocity at outflow tracts, decreased percentage reverse flow in the inferior vena cava) in the donor twin and a massive blood transfusion (decreased peak velocity at outflow tracts, increased percentage reverse flow in the inferior vena cava, umbilical vein pulsations, cardiomegaly and congestive heart failure) in the recipient twin59.

FETAL ECHOCARDIOGRAPHY AND GENETICS Heart defects in newborns are associated in 12% of cases with aneuploidies, as opposed to double this number in fetuses7. Initially, the detection of a CHD on screening implied the determination of the fetal karyotype, but soon targeted fetal echocardiography was used as a tool in groups at high risk for aneuploidy. We should bear in mind the increasing risk of chromosomal abnormalities not only facing a CHD but also cardiac markers such as an echogenic focus or pericardial effusion, which are known to increase the background risk for aneuploidy. Recently, Huggon et al. suggested that a careful search for tricuspid regurgitation at an early stage of pregnancy was important, as this is frequently a marker for chromosomal defects

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even in the absence of structural heart disease [60]. Furthermore, in the past decade, molecular genetics of heart defects has developed, showing that complex cardiac defects involving the great vessels are strongly associated with a microdeleThis tion of chromosome 22q11.261. microdeletion was found to be the common genetic cause of a wide clinical spectrum of anomalies, and the acronym CATCH 22 was suggested for the following: cardiac defect, abnormal face, thymus hypoplasia or aplasia, cleft palate, hypocalcemia and deletion on chromosome 22. The detection of such a heart defect has important implications for counseling, owing to the association with mental retardation and immunological deficiency. This type of chromosomal aberration has been shown to be present in up to 30% of isolated conotruncal anomalies. Knowing that in these children the thymus is hypoplastic or absent, Chaoui et al. recently showed that the prenatal evaluation of the thymus during fetal echocardiography had a sensitivity of 85% in detecting such a microdeletion62. It is expected that in the future the defective genes for many cardiac defects will be localized and that targeted gene analysis will become routine when a CHD is prenatally detected.

Routes for examination of the fetal heart One of the limiting factors in ultrasound resolution is the depth of the region of interest and the extent of the tissue layers between the scan head and the region of interest. The transvaginal (TV) approach to evaluate the fetal heart has been recently described to avoid these problems. Since the first early diagnosis of a CHD in 1990 by this route63, a series of studies have shown the feasibility and reliability of this approach43,64–78. Recently, a new approach has been developed and tested in animals using a modified coronary ultrasound catheter to perform transesophageal echocardiography in the fetus79. Another new method is the transvaginal insertion of such a catheter into the maternal uterine cavity to examine embryological cardiac development80.

Early fetal echocardiography Recently, the finding of an increased nuchal translucency33,34 or an altered ductus venosus blood flow35,40 at 10–14 weeks’ gestation have been associated with a high risk for CHD and their prevalence increased exponentially with the thickness of the nuchal translucency regardless of the fetal karyotype. Since earlier diagnosis of congenital malformations is increasingly


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demanded, the option of an early fetal echocardiogram must be taken into account64,81,82. The use of high-frequency vaginal ultrasound probes along with substantial improvements in magnification and processing of the imaging, together with the introduction of color Doppler, have extensively contributed to the development of the technique, allowing better visualization of cardiac structures earlier in pregnancy. Although most groups perform early fetal echocardiography between 13 and 16 weeks’ gestation, we can name it as so when performed before the 18th week of gestation. Despite several studies that have stated that fetal heart examination could be incorporated in the first or early second trimester examinations, its use is currently still limited to a few specialized centers. The first diagnosis of a CHD by early echocardiography was reported by Gembruch et al. in 199063. A complete atrioventricular canal defect, with complete heart block and atrioventricular valve regurgitation was diagnosed at 11 weeks plus 4 days’ gestation using a 5-MHz transvaginal probe. The same year, Bronshtein et al.83 reported the diagnosis of a ventricular septal defect with overriding aorta and a further case of an isolated ventricular septal defect with pericardial effusion, both cases at 14 weeks’ gestation. Since then, an increasing number of case reports and series on the early diagnosis of CHD have been reported, in both high-risk and low-risk populations. Tables 1 and 2 summarize some of the largest and most significant studies on the detection of CHD using early fetal echocardiography in high-risk and low-risk pregnancies43,64–79. Obviously, studies in unselected populations report less encouraging results, with lower visualization rates and detection rates. The largest series to date is the one published by Bronshtein and Zimmer68. They report the diagnosis of 173 cases of CHD in 36 323 fetuses evaluated by transvaginal ultrasound at 11–17 weeks’ gestation over a 14-year period, with 99% of scans performed at 14–16 weeks’ gestation and 86% of them in a low-risk population. Recently, two institutions went further and reported their experience performing echocardiography as early as between 10 and 13 weeks’ gestation70,72. The most frequent fetal heart anomalies diagnosed at early echocardiography are summarized in Table 3 (true positive cases)43,64, 66–69,71–74,76,78 . Note that only the main anomaly for each fetus is presented in the table, even though some fetuses had several cardiac anomalies. It should be noted that defects such a small isolated ventricular septal defect or valvular stenosis are not reported in these studies. Table 4 summarizes the published cases of cardiac

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anomaly not detected in early pregnancy (falsenegative cases)43,64,67–69,71–76,78. The results of these studies support the use of early fetal echocardiography to detect the majority of major CHDs in both low-risk and high-risk populations, during the first and early second trimesters of pregnancy84. The cardiac anomalies detected at this early stage of pregnancy are mainly defects involving the four-chamber view, such as large ventricular septal defects, atrioventricular septal defects and malformations resulting in asymmetry of the ventricles, indicating that defects solely affecting the outflow tracts are difficult to diagnose in the first trimester of pregnancy. Heart defects diagnosed early in pregnancy tend to be more complex than those detected later, with a higher incidence of associated structural malformations, chromosomal abnormalities and spontaneous abortions. It is widely accepted that the spectrum of CHDs diagnosed during prenatal life is different from that observed in postnatal series, with a higher incidence of associated extracardiac lesions and a significant relationship with chromosomal abnormalities in comparison with postnatal life3,23,24,65. Furthermore, when the cardiac defects are detected during early pregnancy, they seem to be even more complex, probably corresponding to the most severe spectrum of the disease and causing more severe hemodynamic compromise in the developing fetus. A common finding is the presence of a hygroma or hydrops associated with CHD, whereas this is not found when the diagnosis is performed later in pregnancy. As a result, many of these fetuses will not survive long into the second trimester, but this does not argue against early diagnosis. Indeed, when the intrauterine demise of the fetus occurs days or weeks before delivery, the pathological examination is certainly more difficult to perform. All these considerations should be taken into account when counseling the parents about complex CHD.

Personal experience We have previously published our own institutional experience in early diagnosis of fetal congenital heart defects by the transvaginal approach, showing encouraging preliminary results85. Recently we have published our experience in the first multicenter trial in early fetal echocardiography performed in Spain69. Figure 8 shows several views of early fetal echocardiography by 2D in a structurally normal heart at 15 weeks’ gestation. Figure 9 illustrates the application of color Doppler. Figures 10–13 illustrate some examples of CHD detected early


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Table 1. Results of early fetal echocardiograpy to diagnose cardiac defects in high-risk populations (only series with at least 10 cardiac defects diagnosed) Author, year Gembruch, 199364 Zosmer, 199943 Simpson, 200071 Huggon, 200272 Haak, 200270 Bronshtein, 200268 Comas, 200269 Lopes, 200378

Route

GA (weeks)

TV TA TA TA TV TV TV TV

11–16 13–17 12–15 10–14 10–13 11–17 12–17 12–16

Success

Risk

N

Cases

11–16 weeks

20–22 weeks

90.3%

high high high high high high high high

114 323 229 478 45 6175 337 275

13 27 17 68 13 46 48 37

92% 89% 76% 94% 54% 4 90% 79% 89%

100% 96.3% 94%

98.7% 86.8% 95.5% 4 99% 94.6% 94.9%

96%

Route, main approach. TV, transvaginal; TA, transabdominal GA, range of gestational age at scan Success, visualization success rate for complete early fetal echocardiograpy N, total number of pregnancies scanned Cases, total number of cardiac defects (pre- and postnatal) 11–16 weeks, percentage of the cardiac defects identified at early echocardiograpy 20–22 weeks, percentage of the cardiac defects identified at mid-trimester echocardiograpy

Table 2. Detection rate of cardiac defects at the early ultrasound scan to screen for congenital malformations in a low-risk population Author, year

GA 66

Achiron, 1994 Hernadi, 199773 D’Ottavio, 199774 Yagel, 199765 Economides, 199875 Whitlow, 199976 Guariglia, 200077 Rustico, 200067 Bronshtein, 200268

13–15 12 13–15 13–16 12–13 11–14 10–16 13–15 11–17

Success

Risk

Normal

Cases

98%

low low low low low low low low low

660 3991 3490 6924 1632 6443 3592 4785 30148

6 3 8 66 3 10 11 41 127

99%

5 50% 99%

11–16 weeks 20–22 weeks 50% 33% 25% 64% 0% 40% 18% 10% 97%

50% 100% 80% 81% 33% 60% 56% 32% 99%

GA, range of gestational age at scan Success, visualization success rate for the extended cardiac examination (four chambers plus outflow tracts) Normal, total number of pregnancies screened Cases, total number of cardiac defects (pre- and postnatal) 11–16 weeks, percentage of the cardiac defects identified at early scan 20–22 weeks, percentage of the cardiac defects identified at mid-trimester scan

by fetal echocardiography. In accordance with other studies, this experience stresses the usefulness of early echocardiography when performed by expert operators on the fetus specifically at risk for cardiac defects. Our review of these additional 48 cases contributes to the expanding literature on the ability of TV ultrasonography to detect fetal heart defects in early pregnancy.

Indications Since most CHDs are detected in low-risk pregnancies, and knowing the high prevalence of heart defects in a non-selected population

(incidence of CHD in low-risk population 1/ 23868), some authors suggest that an early detailed cardiac examination should be performed in all pregnant women65,68. Indeed, very few cardiac defects have been identified in pregnancies in which a family history was the main indication for the early fetal echocardiography, which is consistent with the recurrence rate of 2–3% for siblings. The main value of the early scan in such family-risk cases lies in the reassurance that it gives to the parents. As we have previously stated, in most studies early echocardiography is somewhat less reliable and may result in higher false-negative and false-


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14

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64


4

4

A

2

1

1

B

2 21

3 5 4 4

3

C

6 71

6 3 2 2 29 13 8 2

D

5

1

2

2

E

11 46

1

12 9 10

1 1 1

F

2 1 2 5 54

9 25 4

1 4 1

G

A, abnormal atriovenous connections B, atrial septal defects C, tricuspid atresia or dysplasia D, atrioventricular septal defect E, single ventricle F, ventricular septal defects G, aortic atresia, aortic stenosis, hypoplastic left heart H, pulmonary atresia or stenosis I, tetralogy of Fallot J, transposition of the great arteries K, truncus L, double-outlet right ventricle M, aortic arch anomalies N, isomerism O, myocardiopathy P, ectopia cordis Q, complex cardiac defect, others R, vascular ring *This series included cases with tetralogy of Fallot and double-outlet right ventricle

Gembruch, 1993 Zosmer, 199943 Rustico, 200067 Simpson, 200071 Huggon, 200272 Bronshtein, 200268 Comas, 200269 Achiron, 199466 Hernadi, 199773 D’Ottavio, 199774 Whitlow, 199976 Rustico, 200067 Lopes, 200378 Overall

True +

1 9

1

2 1 3 1

H

2

3

1 1 43

31* 3 2

I

1 24

22

1

J

1 12

1 5 2 1

2

K

3 5

2

L

2 29

18 1

2

2 4

M

2

1 1

N

19

1

1 17

O

Table 3: Fetal heart anomalies diagnosed at early echocardiography (true positive cases at early fetal echocardiography)

9

1

1 3 3 1

P

6

2

1

2

1

Q

13

13

R

12 24 5 13 60 169 38 8 1 4 3 4 33 375

Overall

Fetal echocardiography C. Comas


C. Comas

ion

vers d e e t prinr onlin r o no f r fo Mo Colou

Figure 8. Early fetal echocardiography by two-dimensional (2D) ultrasound in a structurally normal heart (15 weeks’ gestation). (a) Early fetal echocardiography by 2D ultrasound in a structurally normal heart. The four-chamber view: normal situs solitus; normal size and axis of the heart in relation to the chest; both atria equal in size, with the foramen ovale flapping within the left atrium; both ventricles equal in size and contractility; atrial and ventricular septa are of normal appearance; tricuspid and mitral valves are normally inserted. RV, right ventricle; LV, left ventricle; RA, right atrium; LA, left atrium; FO, foramen ovale; DAo, descending aorta(b) Early fetal echocardiography by 2D ultrasound in a structurally normal heart. The five-chamber view: left ventricle outflow tract in the long axis view showing the continuity between the interventricular septum and the anterior wall of the ascending aorta. RV, right ventricle; LV, left ventricle; RA, right atrium; LA, left atrium; AAo, ascending aorta; DAo, descending aorta; IVS, interventricular septum. (c) Early fetal echocardiography by 2D ultrasound in a structurally normal heart. The three-vessel view: cross sections of the pulmonary artery, ascending aorta and superior vena cava in a transverse view of the upper mediastinum. In normal conditions, the structures in the three-vessel view are in descending order of size from left to right. PA, pulmonary artery; Ao, aorta; SVC, superior vena cava. (d) and (e) Early fetal echocardiography by 2D ultrasound in a structurally normal heart. The left sagittal view of ductal (d) and aortic arches (e). RV, right ventricle; LV, left ventricle; PA, pulmonary artery; DA, ductus arteriosus; DAo, descending aorta; AAo, ascending aorta.

positive results in comparison with transabdominal echocardiography at 20–22 weeks. Furthermore, early echocardiography is most time-consuming and requires a high level of expertise of the examiner. Therefore, it is difficult to offer this scan as a screening test to the general population. In this context, the identification of a high-risk population is of paramount importance. Currently, the importance of the aforementioned limitations of early fetal cardiac examination justifies restriction of its use to fetuses at high risk of having cardiac anomalies. Increased NT ( 4 95th or 99th centile) and/or abnormal blood flow in the DV are the main indications for referral in all recently reported studies.

Currently, as long as the sensitivity, specificity and predictive value of early echocardiography are still unclear, this examination should be generally reserved for patients at high risk for CHD. However, only the accumulation of results from careful collaborative studies such as the present series will clearly define the role of early transvaginal echocardiography.

Limitations However, there are certain disadvantages to early scanning which reduce its diagnostic accuracy compared with the conventional examination at 20–22 weeks’ gestation64,65,82. The transvaginal technique requires a substantial amount of operator experience, yet it cannot


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n rsio e v ed rint online p r r o no f lour fo o M Co

Figure 9. Early fetal echocardiography by two-dimensional (2D) ultrasound and color Doppler in a structurally normal heart (15 weeks’ gestation). (a) Early fetal echocardiography by 2D ultrasound and color Doppler in a structurally normal heart. Color Doppler in the four-chamber view is particularly useful to confirm normal inflow to the ventricles and to detect turbulent flow or jets suggesting valve regurgitation. RV, right ventricle; LV, left ventricle. (b) Early fetal echocardiography by 2D ultrasound and color Doppler in a structurally normal heart. Color Doppler is particularly useful to demonstrate the crossing of the great arteries. Ao, aorta; PA, pulmonary artery. (c) Early fetal echocardiography by 2D ultrasound and color Doppler in a structurally normal heart. Color Doppler is particularly useful to demonstrate the normal V-shaped confluence of the ductal and aortic arches (V sign). Note that normally the trachea is located behind the aortic arch. (d) Early fetal echocardiography by 2D ultrasound and color Doppler in a structurally normal heart. Color Doppler is particularly useful to demonstrate the aortic arch. DAo, descending aorta.

ion


Figure 10. Tetralogy of Fallot detected at 16 weeks’ gestation in a fetus affected by cystic hygroma and with a normal karyotype. Note the left cardiac deviation (a) and the dominance of the aorta compared with the small pulmonary artery at the three-vessel view in the upper mediastinum (b).

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on ersi v d e rint online p r r o no oflour fo o M C

Figure 11. Atrioventricular septal defect with unbalanced right ventricle dominance and double-outlet right ventricle at 15 weeks’ gestation. Note the abnormal reveresed A wave in the ductus venosus (a), the color Doppler flow through the atrioventricular septal defect with atrioventricular regurgitation (b) and the double-outlet right ventricle with unbalanced right ventricle dominance (c).

ion


Figure 12. Hypoplastic left heart and double-outlet right ventricle at 15 weeks’ gestation in a case of trisomy 18. Note the identification of multiple markers of chromosomal abnormality, increased nuchal translucency (a), abnormal ductus venosus flow (b), absent nasal bone (c) and single umbilical artery (d). (e) An anterior aorta in the three-vessel view. (f) An unbalanced right ventricle dominance with double-outlet right ventricle.


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C. Comas

ion

vers d e t rin online p r r o no flour fo o M Co

Figure 13. Hypoplastic left heart and aortic stenosis at 17 weeks’ gestation in a case of Turner syndrome. Note the left cardiac axis deviation (a), the severe reduction of the aortic outflow tract compared to the main pulmonary artery (b) and the opposite color flow in the V sign at the upper mediastinum level (c).

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be learned from the second-trimester examination as the early transabdominal scan. Unfavorable fetal position or limited angles of insonation due to the less mobile capacity of the transvaginal probe may not be overcome. Also, spatial orientation can be challenging for the transvaginal scan. In such cases, we recommend a transabdominal scan that will help us quickly asses the situs and obtain a good spatial orientation. The small size of the fetal heart is an important limiting factor to obtain an optimal sonographic visualization, and also to obtain a successful pathological examination, particularly before the 13th week of gestation. At 13–14 weeks of gestation the transverse diameter of the heart at the four-chamber view ranges between 5 and 8 mm, and the great artery diameter at the level of the semilunar valves ranges between 0.8 and 1.8 mm24. Moreover, this exploration is more time-consuming and requires a high level of training of the examiner. Finally, the greatest disadvantage of first-trimester echocardiography is the later manifestation of structural and functional changes in some CHDs. Some cardiac lesions are progressive in nature, such as mild pulmonary and aortic stenosis or coarctation and even hypoplastic left heart syndrome. Some obstructive lesions, as a result of a reduced blood flow, may increase the severity of the lesions, resulting

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in a restricted growth in chambers or arteries. This may be the greatest disadvantage of performing the early scan. Progression usually is towards a more severe form of lesion that may sometimes be discernible only in the second or even the third trimester, although in some rare cases a regression to a less severe form may be observed. In this sense, the false-negative cases published in the literature are particularly instructive in demonstrating these limitations (Table 4). Another disadvantage of early fetal echocardiography is the possible detection of defects that could resolve spontaneously in later pregnancy, such as muscular venticular septal defects, resulting in unnecessary anxiety for the parents. Therefore, a normal early examination does not preclude a subsequent abnormal heart development at the second trimester ultrasound examination, or even in the third trimester or the postnatal period. After normal early fetal echocardiography, conventional transabdominal echocardiography at 20–22 weeks of gestation is strongly recommended.

Advantages The first benefit of performing early fetal echocardiography would be an early reassurance of normality in order to relieve anxiety and


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Table 4. Fetal heart anomalies not detected at early echocardiography (false-negative cases at early fetal echocardiography) False -

A

B

C

D

64

Gembruch, 93 Hernadi, 9773 D’Ottavio 9774 Economides, 9875 Whitlow, 9976 Zosmer, 9943 Rustico, 0067 Simpson, 0071 Comas, 0269 Huggon, 0272 Bronshtein, 0268 Lopes, 0378 Overall

E

F

G

H

I

J

Overall

1 1 1 1 2 1 3 4 2 3 18

1 3 1 1 4

2 1 2 1 1

1 1 1

1 1 1

2

1 1

3

1

1

1 1 1

13

10

5

2

2

2

1

1 1 3

2 1 6

1

1 2 7 3 7 3 9 4 10 7 4 4 61

A, ventricular septal defects B, atrial septal defects C, abnormal atriovenous connections D, tricuspid atresia or dysplasia E, atrioventricular septal defect F, aortic atresia, aortic stenosis, hypoplastic left heart G, tetralogy of Fallot H, transposition of the great arteries I, aortic arch anomalies J, myocardiopathy

reduce emotional trauma to the parents at high risk for CHD. Early prenatal diagnosis of CHD will allow us to optimize genetic counseling to the parents by permitting further testing such as fetal karyotyping; in those cases with severe defects it may provide the parents with the option of an earlier and safer termination of pregnancy. In selected cases, there is the possibility of pharmacological therapy. Furthermore, the correct timing and place for delivery may be planned and arranged well in advance. Early fetal echocardiography is a promising technique which can be of considerable value for patients at risk of having offspring with a cardiac defect.

PRENATAL THERAPY Fetal arrhythmias and certain forms of severe structural CHDs have become increasingly amenable to successful in utero therapy.

Fetal arrhythmias Sustained fetal arrhythmias may lead to fetal congestive heart failure and fetal death. For this reason, sophisticated diagnostic and treatment modalities have been developed over many years, but they continue to evolve and to generate controversy. Generally, fetuses with a sctructur-

al CHD appear to be less tolerant of sustained arrhythmias than fetuses with a normally structured heart. While fetuses tend to tolerate sustained bradycardia relatively well, sustained tachycardia more typically results in fetal hydrops. Considerable controversy remains over which fetuses deserve treatment and with which antiarrhythmics. Given the absence of an adequate fetal electrocardiogram, efforts to improve the diagnosis of fetal arrhythmias continue to evolve. Additional modalities have been recently described, such as Doppler assessment of fetal PR interval for detecting delayed conduction across the atrioventricular node16, tissue velocity imaging in fetal kinetocardiograms86 or magnetocardiography applied to the fetal heart87. Related to treatment of bradyarrhythmias, early treatment of fetuses affected by atrioventricular delayed conduction or complete heart block with maternally administered dexamethasone or ritodrine may improve or prevent the loss of atrioventricular nodal conduction88,89. The treatment of fetal tachycardia remains controversial. Intermittent premature beats, couplets or short runs of supraventricular tachycardia do not usually require treatment, particularly in the absence of structural heart disease or hydrops. However, no consensus has been reached on which fetuses have to be treated


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or with which antiarrhythmics. Digoxin remains the drug of choice for sustained supraventricular tachyarrhythmias, but other new drugs have been emerging, such as sotalol or flecainide.

Fetal cardiac surgical intervention Endoscopic fetal heart surgery is no more than an experimental alternative to postnatal repair in the human at present. Potential indications for fetal cardiac surgery include heart defects that, after a progression, may evolve into oneventricle pathology. In a few select centers, isolated critical aortic or pulmonary valve stenosis has been successfully dilated during the second trimester, in order to prevent the development of hypoplastic heart syndromes90,91. Percutaneous ultrasound-guided balloon valvuloplasty has been successfully performed in a few cases. Even these experiences have demonstrated that they are technically possible, although perinatal results are still discouraging. At present, the selective cases of fetal cardiac interventions performed worldwide have shown that we are still at the experimental stage and that further research is needed. Further modifications and miniaturization of new materials combined with future improvement in transcatheter techniques, a better selection of candidates and timing of prenatal intervention, offer promise in reducing risks of intrauterine cardiac surgery techniques92. There has been an increasing ability to intevene successfully in prenatal fetal arrhythmias, heart failure and some severe forms of structural heart disease.

CONCLUSIONS Fetal echocardiography has made rapid strides in the past two decades from a combination of increased awareness and technologic support. The present challenges facing the field revolve around improving detection rates and resource allocation. Recent developments hold exciting opportunities for this field, such as new strategies to improve screening policies, ruling out fetal heart diseases, the identification of new early markers of congenital heart defects, early transvaginal echocardiography, three-dimensional technology and telemedicine.

References 1. Campbell S. Isolated major congenital heart disease. Ultrasound Obstet Gynecol 2001;17:370–379.

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2. Mitchell SC, Korones SB, Berendes HW. Congenital heart disease in 56,109 births. Incidence and natural history. Circulation 1971;43:323–332. 3. Allan L, Sharland G, Milburn A, et al. Prospective diagnosis of 1006 consecutive cases of congenital heart disease in the fetus. J Am Coll Cardiol 1994;23:1452–1458. 4. Garne E, Stoll C, Clementi M, and the EUROSCAN GROUP. Evaluation of prenatal diagnosis of congenital heart diseases by ultrasound: experience from 20 European registries. Ultrasound Obstet Gynecol 2001;17:386–391. 5. Sklansky M. New dimensions and directions in fetal cardiology. Curr Opin Pediatr 2003;15:463–471. 6. Bonnet D, Coltri A, Butera G, et al. Detection of transposition of the great arteries in fetuses reduces neonatal morbidity and mortality. Circulation 1999;99:916–918. 7. Chaoui R. Fetal echocardiography: state of art. Ultrasound Obstet Gynecol 2001;17:277–284. 8. Paladini D, Vasallo M, Tartaglione A, Lapadula C, Martinelli P. The role of tissue harmonic imaging in fetal echocardiography. Ultrasound Obstet Gynecol 2004;23:159–164. 9. 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;21:26–32. 10. Paladini D, Lamberti A, Teodoro A, Arienzo M, Tartaglione A, Martinelli P. Tissue Doppler imaging of the fetal heart. Ultrasound Obstet Gynecol 2000;16:530–535. 11. Sklansky M, Nelson T, Pretorius D. Usefulness of gated three-dimensional fetal echocardiography to reconstruct and display structures not visualized with two-dimensional imaging. Am Cardiol 1997;80:665–668. 12. Hejmadi A. Latest advances and topics in fetal echocardiography. Curr Opin Cardiol 2004;19:97– 103. 13. Michailidis GD, Simpson JM, Karidas C, Economides DL. Detailed three-dimensional fetal echocardiography facilitated by an Internet link. Ultrasound Obstet Gynecol 2001;18:325–328. 14. Bruining N, Lancee C, Roelandt JR, Bom N. Threedimensional echocardiography paves the way toward virtual reality. Ultrasound Med Biol 2000;26:1065–1074. 15. Chang FM, Hsu KF, Ko HC, et al. Fetal heart volume assessment by three-dimensional ultrasound. Ultrasound Obstet Gynecol 1997;9:42–48. 16. Rosenthal D, Friedman DM, Buyon J, Dubin A. Validation of the Doppler PR interval in the fetus. J Am Soc Echocardiogr 2002;15:1029–1030. 17. 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;380–387. 18. Vin ˜ als F, Poblete P, Giuliano A. Spatio-temporal image correlation (STIC): a new tool for the prenatal screening of congenital heart defects. Ultrasound Obstet Gynecol 2003;22;388–394.


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