Chapter 6: PRENATAL DIAGNOSIS OF CONGENITAL HEART DISEASE

The cardiovascular system provides a large volume of information about the well-being of the fetus. It is accessible because of rapid developments in the technology of noninvasive techniques, particularly ultrasonography. The fetus has become the new patient of the decade due to the rapid changes in ultrasonic technologies and other fetal assessment techniques. The fetal biophysical profile is useful to detect changes in fetal well-being, and assesses mainly changes in brain function.^1,2 The decision to deliver a fetus prematurely due to cardiac changes must be made in the context of the risks both pre- and postnatally. Most associations of how cardiovascular changes correlate with other organ function in the fetus have yet to be defined. Therefore, any assessment demands a coordinated team approach between obstetricians, perinatologists, cardiologists, and neonatologists.^3,4

Cardiac defects are the most common cause of infant death in United States.⁵ They occur in approximately 0.8% of liveborn children, but in a much higher percentage of those aborted spontaneously, stillborn, or those diagnosed early in gestation.⁶ Although the etiology of heart defects is not known, population studies have suggested a number of factors that may increase the risk of heart defects. Approximately 8 in 1000 live births are affected by congenital heart disease. The incidence of severe congenital heart disease that will require heart surgery in the first year after birth is about 2.5 to 3 per 1000 live births. The moderately severe forms of congenital heart disease probably account for another 3 per 1000 live births.⁷

Several factors, like maternal folate deficiency, have been linked to an increased rate of spontaneous abortion as well as conotruncal defects, neural tube defects, orofacial defects, and limb defects.^{8,9,10, and 11} Any strategy to prevent congenital heart disease should include preconceptional supplementation of folic acid and a balanced diet.^12,13 Structural malformations such as diaphragmatic hernia, cystic adenomatoid malformation, omphalocele, and atrioventricular malformations, as well as pathophysiological conditions such as intrauterine growth restriction, hydrops, indometacin tocolytic therapy, and fetal anemia, all can be associated with decreased effective cardiac output.¹⁴ We use the cardiovascular profile score to assess the presence and severity of fetal congestive heart failure in these entities as well.¹⁵

An understanding of cardiac anatomy is fundamental for the proper interpretation of clinical echocardiography. In the normal heart, the morphologic right atrium forms the right front part of the cardiac mass. The external wall of the atrium consists of the venous component (into which the superior and inferior vena caval veins as well as the coronary sinus open) and an anterior part, the appendage that has a triangular shape and extends forward surrounding the right wall of the aorta. Internally it is connected with the smooth-walled venous component of the atrium. Numerous pectinate muscles arise from the terminal crest and travel as parallel ridges along the anterior aspect of the free wall of the right atrium.¹⁶

The atrial septum has an interatrial component (between the right and left atria) and an atrioventricular component (between the right atrium and left ventricle). The interatrial portion is relatively small, and its most prominent feature is the fossa ovalis (oval fossa). During fetal and neonatal life, the valve of the fossa ovalis represents a paper-thin, delicate, translucent membrane. In contrast to the fossa ovalis, the foramen ovale (oval foramen) represents a passageway between the 2 atria. It courses between the anterosuperior aspect of the limbus and the valve of the fossa ovalis and then through a natural valvular perforation, the ostium secundum, and into the left atrium.¹⁶

The left atrium is a midline posterosuperior chamber that receives pulmonary venous blood and expels it across the mitral valve and into the left ventricle. When a left superior vena cava persists, the coronary sinus into which it drains is generally quite dilated, in some cases indenting the left atrial wall, and should not be mistaken for the descending thoracic aorta. As on the right side, the left atrium consists of a free wall and a septum. The free wall includes a dome-shaped body, which receives the pulmonary veins, and a fingerlike appendage. The body of the left atrium contains no pectinate muscles, and there is no crista terminalis.¹⁶

The atrioventricular valves serve to maintain unidirectional blood flow and to electrically separate the atria and ventricles. Each valve has 5 components. The annulus, leaflets, and commissures form the valvular apparatus, and the chordae tendineae (tendinous cords) and papillary muscles form the tensor apparatus. The annulus of each valve is somewhat saddle shaped rather than being truly planar and represents an ill-defined ring of fibrous tissue from which the leaflets arise.¹⁶

Anatomically, the right ventricle can be divided into inlet, trabecular, and outlet regions. This concept of a tripartite chamber correlates well with the embryologic development of the right ventricle. The inlet portion is associated with the tricuspid valve, and its border is defined by the cordal insertions. Anteroapically, prominent muscle bundles traverse the chamber from septum to free wall and demarcate the trabecular region. The septal band is a Y-shaped structure with a long, broad stem and smaller inferior and anterior limbs. The 2 limbs, in turn, cradle the outlet septum and give rise to the medial tricuspid papillary muscle. Apically, the septal band merges with the apical trabeculations and gives rise to the moderator band, which inserts at the base of the anterior tricuspid papillary muscle.

The left ventricle is a left posterior chamber consisting of septal and free-wall components, and its entrance and exit are guarded by the mitral and aortic valves, respectively. The ventricular apex is characterized by small, shallow trabeculations, and the apical one-half to two-thirds of the septal surface is also finely trabeculated.¹⁶

Because of hemodynamic streaming within the right atrium during intrauterine life, poorly oxygenated blood from the superior vena cava is directed toward the tricuspid orifice, whereas well-oxygenated placental blood within the inferior vena cava is directed by the eustachian valve toward the foramen ovale and into the left atrium. Consequently, the most oxygenated blood in the fetal circulation travels, via the left side of the heart, to the coronary arteries, upper extremities, and the rapidly developing central nervous system (Figure 6-1).

During fetal life, the presence of a patent ductus arteriosus is associated with equalization of aortic and pulmonary artery pressures and a state of physiologic pulmonary hypertension. Thus, during fetal and neonatal life, right ventricular hypertrophy is evident and the thickness of the right ventricle is similar to that of the left. The fetal ventricular pressures are equal except in rare cases such as with fetal ductal constriction where the right ventricle and pulmonary artery pressures exceed the left ventricle pressure. Because the pulmonary and systemic circulations are separate in the fetus, each ventricle has a stroke volume determined by the individual preload, afterload, and contractility of that chamber. Both ventricles are linked by a common heart rate and by the atrial pressures, which are similar due to the presence of the foramen ovale. They are also linked by the ventricular septum, which is shared by each ventricle, and by the common arterial pressure, which is the result of the widely patent ductus arteriosus. Right and left atrial pressures are almost equal because of the presence of the foramen ovale, and right and left ventricular pressures are equal due to the ductus arteriosus. The left ventricle ejects into the upper body and cerebral circulation, and the right ventricle ejects into the pulmonary arteries and through the ductus arteriosus into the lower body and the placental circulation. The vascular beds of upper and lower body are connected via the aortic isthmus.¹⁷

The unique feature of the parallel nature of the ventricular ejection is that if there is increased afterload of one ventricle, the output of that ventricle will fall and the output of the contralateral ventricle will increase in a compensatory manner. This leads to the commonly observed feature associated with congenital heart disease of disproportionate growth of the normal side of the heart. As a further consequence of the parallel arrangement of these circulations, ventricular outputs can be different, and in the case of obstruction on one side of the heart, the other side is able to increase its work or even completely supply the whole circulation alone (see Figure 6-1).¹⁷

The effect of heart rate on fetal combined cardiac output is much more pronounced than postnatally. The fetus has a range of heart rates between 50 and 200 at which the stroke volume of the ventricular chambers can adapt to maintain adequate combined cardiac output and tissue perfusion. Outside of this range, heart failure will often result. The major determinant of cardiac output is the afterload of the fetal ventricle. Any influence that raises the impedance to ejection will inversely lower the ventricular stroke volume by the effect on both the systolic and diastolic functions of the heart.

The fetal echocardiogram should not be mistaken for the fetal heart screen. The major differences between fetal heart screen and fetal echocardiogram are highlighted in Table 6-1. Consideration should be given to follow the guidelines of the International Society of Ultrasound in Obstetrics & Gynecology.^18,19

Fetal Heart Screening

The "basic" and "extended basic" fetal cardiac screening examination is the general fetal anatomical ultrasound scan that is performed in the majority of low-risk pregnancies at 18 to 22 weeks of gestation to screen for congenital anomalies. The "basic" cardiac screening examination relies on a 4-chamber view of the fetal heart involving a careful evaluation of specific criteria. An "extended basic" cardiac examination requires the views of the outflow tracts.¹⁸ The personnel responsible include obstetricians, radiologists, and sonographers.

Fetal echocardiography is focused on fetal anatomical details and is performed by health care providers with additional expertise in the prenatal detection and interpretation of congenital heart disease. It is performed when an anomaly is suspected on the basis of history, biochemical abnormalities, or the results of either the limited or standard scan suggesting the presence of fetal pathology.

The fetal heart screen relies on evaluation of the cardiac situs, axis and position, 4-chamber view, and atrioventricular valves. Key components of the normal 4-chamber view include an intact interventricular septum and atrial septum primum. Usually, there is no disproportion between the left and right ventricles. A moderator band helps to identify the morphologic right ventricle (Figure 6-2).

A normal heart is no larger than one-third the area of the chest. The ratio of the size of the chest is a useful prognostic tool in structural and functional heart disease at risk to develop heart failure. The circumference of the heart and thorax can be measured and express as a ratio. This can be achieved in a cross-sectional view when the entire thorax is seen and includes a 4-chamber view, at least 1 complete rib, and no abdominal content. The cardiothoracic circumference ratio has a mean value of 0.45 at 17 weeks and 0.5 at term.²⁰ The ratio of the cardiac and thoracic area can also be calculated and is rather constant throughout pregnancy, with a normal value of 0.35 or less (Figure 6-3). These methods to calculate heart size use only screen data, and are a simple tool to evaluate fetal heart cardiomegaly.²¹

The heart is normally deviated about 45 ± 20 degrees (2 standard deviations) toward the left side of the fetus.²² Careful attention should be given to cardiac axis and position. Situs abnormalities should be suspected when the fetal heart and/or stomach is not found on the left side as well. Abnormal axis increases the risk of cardiac malformations, especially involving the outflow tracts. Some hearts are abnormally displaced from their usual position in the anterior left central chest. Abnormal cardiac position in the anterior left central chest can be caused by a diaphragmatic hernia or space-occupying lesion, such as cystic adenomatoid malformation. Position abnormalities can also be secondary to fetal lung hypoplasia.

Both atrial chambers normally appear similar in size, and the foramen ovale flap should open into the left atrium. Pulmonary veins can often be seen entering the left atrium. The lower rim of atrial septal tissue, septum primum, should be present. The moderator band helps to identify the morphologic right ventricle. Both ventricles should appear similar in size without evidence for thickened walls. Disproportion is the best sign of fetal congenital heart disease.²³ Although mild ventricular disproportion with right-sided enlargement can occur as a normal variant, with more severe disproportion, hypoplastic left heart syndrome and aortic coarctation are important causes of this disparity.^{23,24, and 25}

The ventricular septum should be carefully examined for cardiac wall defects. A septal wall defect may be difficult to detect when the transducer's angle of insonation is directly parallel to the ventricular wall. Under these circumstances, a defect may be falsely suspected because of acoustic "drop-out" artifact.

Two distinct atrioventricular valves should be seen to open separately and freely. The septal leaflet of the tricuspid valve is inserted to the septum closer to the apex when compared to the mitral valve. Abnormal alignment of the atrioventricular valves can be a key sonographic finding for cardiac anomalies such as atrioventricular septal defect.

The aortic and pulmonary artery size should be evaluated and if there is disproportion of chamber sizes, or if a structure appears abnormal in size, appropriate measurements should be made for comparison with normal ranges. Measurements in two-dimensional images should be made of the internal dimensions (inner to inner walls) in a standard fashion. For normal values, consider the appendix of The Perinatal Cardiology Handbook.²⁶

A normal extended basic examination requires that normal great vessels are approximately equal in size and they cross each other at right angles from their origins as they exit from their respective ventricular chambers. Failure to confirm these findings in a well-visualized study warrants further evaluation. Evaluation of the outflow tracts can increase the detection rates for major cardiac malformations like conotruncal anomalies such as tetralogy of Fallot, transposition of great arteries, double outlet right ventricle, and truncus arteriosus.¹⁸

Fetal Echocardiogram

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. Fetal echocardiography is for pregnancies at risk for structural, functional, and rhythm-related fetal heart disease. Indications for fetal echocardiography can be classified as maternal, fetal, and familial. The indication with the greatest positive yield is a finding of suspected fetal heart disease at routine obstetrical screening examination. Routine obstetrical ultrasound screening is critical in the prenatal detection of fetal/congenital heart disease. Unfortunately, a high proportion of prenatally detectable cases of congenital heart disease occur in patients without any risk factors or extracardiac anomalies.²⁷

Indications for Fetal Echocardiogram

Maternal Indications

Maternal Metabolic Disorders

• Type 1 or 2 diabetes mellitus (preconception)—The incidence is reported to be 2- to 5-fold higher than that of the general population. Major structural defects identified include D-transposition of the great arteries, hypoplastic left heart syndrome, tetralogy of Fallot, and pulmonary and tricuspid atresia. Diabetic hypertrophic cardiomyopathy, which typically does not evolve until late in gestation, is an indication for fetal echocardiography, although the majority of affected infants are clinically well after birth and the pathology regresses spontaneously after birth, but rare neonates will have severe ventricular outflow obstruction.

• Phenylketonuria—Fourteen percent risk particularly with phenylalanine levels of greater than 600 μmol/L at 0 to 8 weeks, and specific lesions include left heart obstruction and tetralogy of Fallot

Maternal Congenital (or Familial) Heart Disease

• Maternal congenital heart disease—The risk is dependent upon the specific lesion. If the mother has aortic stenosis the risk of affected offspring is 13% to 18%, for atrioventricular canal 14%, for tetralogy of Fallot 6% to 10%, for pulmonary stenosis 4% to 6.5%, for ventricular septal defect 6%, for atrial septal defect 4% to 4.5%, and for coarctation of the aorta 4%.^{28,29, and 30}

• Cardiomyopathy—Dependent upon the type of inheritance and age at presentation (most present in adolescence and as such would not be expected to be identified prenatally).

Maternal Autoimmune Disease

Specifically those associated with anti-Ro and/or anti-La autoantibodies. Fetal atrioventricular heart block (typically presence after 17 weeks in mother with autoantibodies with or without clinical autoimmune disease) may result and late fetal cardiomyopathy with endocardial fibroelastosis can occur in childhood.

Teratogen Exposure

• Alcohol—Atrial and ventricular septal defects³⁰

• Valproic acid—Atrial and ventricular septal defects, aortic and pulmonary valve obstruction, coarctation of the aorta

• Vitamin A derivatives—Conotruncal abnormalities

• Lithium—Ebstein anomaly of the tricuspid valve

Fetal Indications

Obstetrical Ultrasound Examination Suggesting Fetal Heart Disease

• Structural cardiac pathology—The indication that has been shown to provide the highest yield for true fetal structural cardiac pathology, which provides support for the critical importance of obstetrical ultrasound screening

• Hyperechogenic foci

• Functional pathology

• Pregnancies at risk for fetal cardiovascular compromise such as twin–twin transfusion syndrome (recipient twin); maternal viral infection associated with fetal myocarditis or cardiomyopathy due to coxsackie, cytomegalovirus, and parvovirus; high output states including fetal arteriovenous malformations (eg, sacrococcygeal teratoma, vein of Galen aneurysm, placental chorioangioma); agenesis of the ductus venosus; fetal anemia; and hydrops fetalis or polyhydramnios (the latter is a relative risk given that it can be associated with increased atrial pressures and atrial dilation)

• Fetal dysrhythmia (ectopy, bradycardia, tachycardia)

Obstetrical Ultrasound Scan Suggesting Extracardiac Disease in the Fetus

• Structural pathology involving other organ systems such as renal dysgenesis, central nervous system pathology (eg, Dandy-Walker syndrome, hydrocephalus, agenesis of the corpus callosum), omphalocele (risk for both cardiac pathology and aneuploidy) 20% to 30% risk, diaphragmatic hernia (15% to 25%), duodenal atresia, esophageal atresia, or tracheo-esophageal fistula

• Increased nuchal translucency in the first trimester

• Findings suggestive of chromosomal abnormality or aneuploidy or documented abnormal fetal karyotype

• Trisomy 21—Risk of ventricular and atrial septal defect, atrioventricular septal defect (50%)

• Trisomy 18—Risk of atrial and ventricular septal defects, dysplastic atrioventricular and semilunar valves, tetralogy of Fallot, double-outlet right ventricle with mitral atresia or stenosis

• Trisomy 13—Risk of atrial and ventricular septal defects, atrioventricular septal defect, and tetralogy of Fallot

• Turner syndrome—Risk of left heart obstructive lesions including bicuspid aortic valve coarctation of the aorta, aortic valve stenosis, and hypoplastic left heart syndrome

Familial Indications

• Paternal congenital heart disease

• Sibling with congenital heart disease—The recurrence risks for future siblings are 2% to 6%.⁷

• Mendelian syndromes

  • Holt-Oram syndrome—Autosomal dominant; risk of atrial and ventricular septal defects; recently TBX5 gene also associated with hypoplastic left heart syndrome.

  • DiGeorge syndrome (22q11.2 deletion)—Risk of conotruncal cardiovascular pathology. Deletions were found in 50.0% with interrupted aortic arch, 34.5% of patients with truncus arteriosus, and 15.9% with tetralogy of Fallot.³¹

  • Noonan syndrome—Autosomal dominant; risk of dysplastic pulmonary valve, pulmonary stenosis, and hypertrophic cardiomyopathy.

  • Williams syndrome—Autosomal dominant; supravalvar aortic stenosis, peripheral pulmonary artery stenosis.

  • Ellis-van Creveld syndrome—Autosomal recessive; risk of atrial and ventricular septal defects and atrioventricular septal defect.

  • Familial cardiomyopathy—Most common autosomal dominant inheritance for both hypertrophic and dilated forms.

Responsible Personnel for Fetal Echocardiogram

Responsible personnel include (1) pediatric cardiologists and their sonographers with expertise in fetal and pediatric echocardiography and knowledge about the nuances of congenital heart disease including the medical and surgical outcomes, and knowledge about structural, functional, and rhythm-related fetal heart disease; and (2) obstetrical or radiology personnel with training in fetal echocardiography but with assistance from pediatric cardiologists for interpretation of the findings and prenatal counseling.

Fetal Heart Echocardiographic Technique

The fetal echocardiogram relies on two-dimensional ultrasonography that includes Doppler echocardiography as well. This includes detailed assessment of the cardiac anatomy, blood flows, heart rate and rhythm, and function, and is performed in pregnancies at risk for or with suspected structural, functional, or rhythm-related fetal heart disease. Fetal echocardiography relies on the assessment of the heart using key cardiac views that include apical 4-chamber, parasternal long axis, parasternal short axis, subcostal, and arch views. It is important to establish the situs to confirm that the inferior vena cava and aorta are in correct relationship. The aorta should originate from the left ventricle and is in continuity with the mitral valve. By comparision, the pulmonary artery arises from the right ventricle and branches into its pulmonary branches. Aortic and ductal arches with the head and neck vessels arising from the aorta should be identified. Dimensions of the aortic and pulmonary branches are important. as it is to identify left- or right-sidedness of the aortic arch and patency of the ductus arteriosus, and pulmonary venous connections to the left atrium, inferior vena cava, and superior vena cava connecting to the right atrium, and tricuspid, and mitral valves of similar size, with the tricuspid inserting slightly more apical than the mitral.^23,25,32 The integrity of interventricular and interatrial septa should be evaluated, as well as the foramen ovale bulging to the left atrium with flow from right to left. Effusions, ascites, or hydrops should be assessed. Two-dimensional imaging should include visceral and atrial situs, 4-chamber view assessment, evaluation of the outflow tracts, and the 3-vessel view.

The outflow tracts are usually obtained by angling the transducer toward the fetal head from a 4-chamber view when the interventricular septum is tangential to the ultrasound beam. Another method for evaluating the outflow tracts has also been described for the fetus when the interventricular septum is perpendicular to the ultrasound beam. This approach requires a 4-chamber view of the heart where the probe is rotated until the left ventricular outflow tract is seen. Once this view is obtained, the transducer is rocked cephalad until the right ventricle arterial outflow tract is observed in a plane that is perpendicular to the aorta.^33,34

Moving cranial to the aortic valve, the pulmonary valve can be seen lying anterior, leftward, and cranial to the aortic valve. The ductal connection to the descending aorta, aorta in cross-section, and superior vena cava are seen in this view, which has been termed the 3-vessel view (Figure 6-4).^35,36

The left ventricular outflow tract view confirms the presence of a great vessel originating from the left ventricle (Figure 6-5). Continuity should be documented between the anterior aortic wall and ventricular septum. The aortic valve moves freely and should not be thickened. When the left ventricular outflow tract is truly the aorta, it should even be possible to trace the vessel into its arch, from which 3 arteries originate into the neck. The left ventricular outflow tract view may help to identify ventricular septal defects and conotruncal abnormalities that are not seen during the basic cardiac examination alone.

A view of the right ventricular outflow tract documents the presence of a great vessel from a morphologic right ventricle with a moderator band (Figure 6-6). The pulmonary artery normally arises from the right ventricle and courses toward the left of the more posterior ascending aorta.

The pulmonary arterial valve moves freely and should not be thickened. Pulmonary valve stenosis, for example, may be associated with right ventricular wall hypertrophy, with decreased chamber volume secondary to increased right-to-left shunting across the foramen ovale, with right ventricular hypertrophy or with increased chamber volume if tricuspid regurgitation occurs.³⁷ The distal pulmonary artery normally divides toward the left side into a ductus arteriosus that continues into the descending aorta. The right side is the right pulmonary artery.

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, foramen ovale mechanism, atrioventricular connections, ventriculoarterial connections, great arteries relationships, and sagittal views of the aortic and ductal arches.^18,25,38

Today, no fetal echocardiogram exam would be complete without the use of color flow Doppler sonography. The addition of color flow Doppler sonography adds further information concerning the function of the atrioventricular and semilunar valves, inferior vena cava, and ductus venosus (Figure 6-7), exclusion of abnormal flows (particularly atrioventricular valve regurgitation), as well as flows within important fetal flow pathways such as the ductus venosus, foramen ovale, ductus arteriosus, and umbilical venous pulsations (Figure 6-8).³⁹

The principle of color Doppler echocardiography is that information on blood flow velocity is computed, color encoded, and simultaneously superimposed on the two-dimensional echocardiographic image (Figure 6-9). The two-dimensional echocardiographic system assigns different colors to the blood flow, depending on the direction and velocity of the blood flow. Most commonly, flow moving toward the transducer probe is displayed in shades of red and flow moving away from the transducer is in shades of blue. Color Doppler echocardiography provides a display of mean flow velocities with higher velocities being shown in brighter shades and the lower velocities in darker shades. Turbulent blood flow can be displayed as a mosaic with green superimposed on the other colors. Thus, color Doppler sonography gives information regarding direction, velocity, and turbulence of blood flow to provide visualization of blood flow patterns in the fetus. Color Doppler sonography is an important adjunct to cross-sectional scanning. The correct direction of flow throughout the cardiac chambers and arch vessels can be demonstrated. It can be used to exclude regurgitation at any valve. Unaliased color flow throughout the heart indicates that the flow is at normal velocities. If color shows aliasing at any point in the heart, pulsed Doppler sonography should be used to obtain an accurate velocity. The peak velocity at the atrioventricular valves is 30 to 60 cm/s and is fairly constant throughout gestation (Figure 6-10). The peak velocity of flow at the arterial valves is approximately 25 cm/s at 12 weeks, increasing to 60 to 100 cm/s by term. Turning on color flow Doppler sonography helps to exclude a significant ventricular septal defect when the ultrasound beam is perpendicular to the ventricular septum. Color Doppler sonography is essential to confirm normal pulmonary venous connections. The ultrasound beam must be positioned "in-line" with the flow under observation when using pulsed or color-flow mapping.³⁵

The fetal aortic arch is seen on a sagittal section as a narrow curvature arch passing to the descending aorta with a "candy-cane" appearance. The most specific feature of the aortic arch is the origin of the head and neck vessels including the left carotid artery and left subclavian artery from the aortic arch (Figure 6-11).

In the normal fetus, the ductus arteriosus arises in a more anterior position in the chest compared with the aortic arch, as it is connected with the right ventricle, the heart's most anterior structure. The ductus arteriosus has a wider curvature than the aortic arch, having the appearance of a "hockey-stick" on fetal echocardiography. The peak velocity of this vessel reaches the highest value of the entire fetal circulation and increases towards the end of pregnancy. The pulsatility index is more constant throughout gestation, varying between 1.9 and 3.0.

Ductus arteriosus patency is fundamental for fetal survival. Premature ductal constriction or closure is associated with cyclooxygenase inhibitors like indomethacin, used frequently to stop preterm labor, or other anti-inflammatory agents that inhibit the production of prostaglandins. Suspicion of ductal constriction on two-dimensional images, should be confirmed with pulsed or continuous Doppler assessment. With ductal constriction the systolic velocity is greater than 1.40 m/s, the diastolic velocity is greater than 0.35 m/s, and the pulsatility index is less than 1.9 (Figure 6-12). Prenatal ductal constriction can lead to progressive right ventricle dysfunction, with secondary tricuspid regurgitation (Figure 6-13), congestive heart failure, and fetal death.

Cardiac rate and regular rhythm should be confirmed (Figure 6-14). The normal rates range from 120 to 160 beats per minute. Mild bradycardia is transiently observed in normal second trimester fetuses. Fixed bradycardia, especially heart rates that remain below 110 beats per minute, requires timely evaluation for possible heart block (Figure 6-15). Repetitive heart rate decelerations during the third trimester can be caused by fetal distress.⁴⁰ Occasional skipped beats are typically not associated with an increased risk of structural fetal heart disease. However, this finding may occur with clinically significant cardiac rate or rhythm disturbances as an indication for fetal echocardiography.⁴¹

Mild tachycardia (>160 beats per minute) can occur as a normal variant during fetal movement. Persistent tachycardia, however, should be further evaluated for possible fetal distress or more serious tachydysrhythmias.

Rhythm Abnormalities

1. Intermittent (<12/24 hours) supraventricular tachycardia or atrial flutter: In several series, intermittent tachycardia did not progress to sustained tachycardia during fetal life. Continued follow-up is recommended, as some may become sustained after birth.

2. Intermittent accelerated ventricular rhythm at rates less than 200 beats per minute: A benign rhythm, usually seen in the neonate, that responds to short-term postnatal beta-blocker therapy.

3. Isolated atrial or ventricular ectopy: Only 0.5% to 1% develop sustained supraventricular tachycardia or atrial flutter. We recommend checking fetal heart tones weekly until ectopy resolves, and obtaining a postnatal 12-lead electrocardiogram (ECG).

4. Atrioventricular block with a structurally normal heart and negative maternal Sjögren (SSA/SSB, Ro/La) antibodies: This is rare. If the fetus has type 2, 2-degree atrioventricular block without SSA/SSB antibodies, monitor closely for ventricular tachycardia as this presentation and sinus bradycardia are consistent with congenital long QT syndrome. Postnatal follow-up is essential to exclude long QT syndrome. Long QT syndrome has been associated with infant and childhood sudden cardiac death.

5. If the fetus has sustained arrhythmia (other than ectopy) and is 35 weeks of gestation or more with minimal or no hydrops, delivery and postnatal therapy may be the best option. Slower than normal heart rate or persistent rapid heart rate leads to cardiomegaly. The time frame of the onset of the arrhythmia may therefore be estimated by the effect on the cardiac size. For example, an intermittent arrhythmia that has appeared recently would not be expected to cause cardiac enlargement.

Significance and Effectiveness of Prenatal Cardiac Diagnosis

Prenatal cardiac diagnosis, by facilitating anticipatory use of prostaglandin E₁ to prevent closure of the ductus arteriosus in neonates with critical impairment of systemic or pulmonary blood flow, allows affected fetuses to avoid neonatal acidemia.⁴²

Fetuses with lesions reparable into 2 ventricular systems appeared to enjoy a significant enhancement of survival prospects. Among the individual cardiac lesions for which prenatal diagnosis has been suggested to impart a survival advantage are transposition of the great arteries,⁴³ coarctation of the aorta,⁴⁴ and hypoplastic left heart syndrome.⁴⁵

Prenatal diagnosis, by providing time, may alter survival through alteration of the site of delivery and subsequent surgery. It is possible, if not likely, that the latter will exert a profound impact of prenatal cardiac diagnosis on postnatal survival.

Cesarean delivery may be indicated in rare situations in which the coordinated care of the neonate requires the skills of multiple specialists who are assembled specifically at the time of delivery, and in fetuses with cardiac rhythm disturbances that preclude effective intrapartum fetal heart rate monitoring. Such arrhythmias may include chaotic rhythms that confound the logic of external fetal heart rate monitors that calculate heart rate from instantaneous measurement of R-R intervals or regular tachyarrhythmias or bradyarrhythmias such as atrial flutter or complete heart block, where the heart rate may not vary with the alterations in sympathetic and parasympathetic tone that are associated with uterine contraction.⁴⁶

Limitations of Fetal Echocardiography

Fetal position and fetal size are critical factors. As the gestational age increases, the ossification increases, making it harder to see intrathoracic structures (Figure 6-16). Image resolution is also an important factor. As a result of such limitations, ventricular septal defects, even atrioventricular septal defects and more subtle conditions such as tetralogy of Fallot, with milder right ventricle outflow obstruction may be missed.

Acquired cardiac lesions that become apparent later in life, even those of genetic origin such as Marfan syndrome and hypertrophic subaortic stenosis, are not generally detectable by prenatal ultrasonography.¹⁸

Safety Issues

Diagnostic ultrasound studies of the fetus are generally considered safe during pregnancy. The lowest possible ultrasonic exposure setting should be used to gain the necessary diagnostic information under the as low as reasonably achievable (ALARA) principle.⁴⁷ The operator must be aware of the acoustic output of instruments used, and the thermal and mechanical indices must be within recommended levels. These indices provide information on the relative risk of producing thermal or cavitation effects. Risks may be greater during embryogenesis (<10 weeks conceptual gestational age). For late first trimester assessments, use short duration of scans and limited duration of Doppler interrogation. Reassessment is recommended in the midtrimester given the image resolution issues in the later first trimester and potential for progression.

The ability to diagnose prenatal cardiovascular disease has improved dramatically due to education and improved ultrasound technology. As our ability to image increases, so does the potential for generation of new knowledge concerning the fetal cardiovascular state. Sophisticated imaging techniques allow us to assess previously puzzling physiologies at earlier and earlier points in gestation. It is crucial that the natural history of congenital cardiac disease be mapped out accurately before we can appropriately undertake a strategy of perinatal cardiac intervention for specific lesions.⁴⁸

The color Doppler sonographic findings in specific heart defects⁴⁹ are summarized in Table 6-2.

Left Heart Defects

Hypoplastic Left Heart Syndrome

Incidence

Hypoplastic left heart syndrome makes up to 4.8% to 9% of congenital heart disease. The incidence is between 0.1 and 2.7 per 1000 live births. It is considered to be the most common cause of cardiac death during the first week of life.^45,50

Embryology/Pathophysiology/Genetics

The fetal left ventricle is predominantly filled with oxygenated blood that returns from the placenta and traverses the foramen ovale.⁵¹ If blood flow across the foramen ovale is diminished or reversed, the combined cardiac output is redistributed to the right ventricle and pulmonary artery, resulting in enlargement of the right heart structures and creating less impetus for normal growth of left heart structures, possibly evolving into hypoplastic left heart syndrome. Perhaps the most well-recognized mechanism for decreased flow or reversal of flow through the foramen ovale in utero is the presence of severe aortic valve disease.^45,52,53 With significant aortic valve stenosis, alterations in left ventricular compliance may occur, either secondary to the development of left ventricular hypertrophy or secondary to the development of left ventricular dilation and dysfunction. Endocardial fibroelastosis, a poorly understood phenomenon where the endocardial lining of the left ventricle becomes fibrotic, may also be present. As the disease state progresses, with subsequent elevation in left atrial pressure, flow across the foramen ovale becomes bidirectional and eventually left to right, the result of which may be the cessation of left ventricular growth.⁵⁴

Although a multifactorial mode of inheritance is likely, the recurrence risk among siblings suggests transmission via an autosomal recessive mode. In addition, pedigree analyses have demonstrated a 12% prevalence of cardiac abnormalities involving the left ventricular outflow tract in first-degree relatives of patients with hypoplastic left heart syndrome.⁵⁵

Hypoplastic left heart syndrome is associated with chromosomal anomalies in about 2% of cases, particularly Turner syndrome (XO), trisomies 13 and 18, and rarely microdeletion of chromosome 22q11.³¹

Diagnostic Features

Recent advances in two-dimensional and Doppler echocardiography have made it feasible to diagnose all forms of congenital heart disease in the fetus. Hypoplastic left heart syndrome is one of the most common structural lesions diagnosed prenatally, as a screening obstetric ultrasound will preferentially identify lesions that dramatically alter the 4-chamber view (Figure 6-17).^49,56,57 The prenatal diagnosis of hypoplastic left heart syndrome is made when a small, muscle-bound left ventricular chamber is identified.

Clues to fetal sonographic diagnosis are a small echogenic left ventricle or absent left ventricle (Figure 6-18), a small left atrium, and left-right atrial shunt (Figure 6-19). There is a hypoplastic ascending aorta and enlarged pulmonary artery with retrograde flow in the aortic arch (Figure 6-20). Left ventricle to coronary fistulous connections may be present.

Pregnancy Course

Most commonly, aortic atresia is associated with an underdeveloped left ventricle, but it can start with a normal-sized left ventricle, progressing to a severely hypoplastic ventricle with gestation. The degree of endocardial fibroelastosis can progress depending on left ventricle outflow tract obstruction.

Serial echocardiographic follow-up is indicated in these fetuses, paying particular attention to growth of left heart structures and patterns of blood flow across the foramen ovale and transverse aortic arch. Importantly, it now seems feasible to reliably select fetuses for prenatal intervention, using both anatomic and physiologic markers.⁴⁶

The challenge for the fetal echocardiographer today is to recognize the potential for the evolution of hypoplastic left heart syndrome and to diagnose the severely restrictive or intact atrial septum in this patient group prior to birth, as these patients may benefit from prenatal intervention.

What to Expect after Delivery

If the fetus remains well compensated and the lesion is isolated, delivery can be at term in a tertiary care center. Following delivery, prostaglandins are initiated to maintain ductal patency, and an echocardiogram is performed to confirm the diagnosis. If severe atrial septal restriction is suspected on the prenatal ultrasound, interventional cardiology, and/or cardiothoracic surgery should be immediately available.

Prognosis

Early studies that focused on the impact of prenatal diagnosis of hypoplastic left heart syndrome appeared to suggest that prenatal diagnosis had a negative influence on short-term survival. This may be related to a weighting toward prenatal diagnosis in a sicker subpopulation of fetuses. More recently it has been demonstrated that fetal echocardiography has a positive impact on survival. Infants with a prenatal diagnosis of hypoplastic left heart syndrome were found to have less preoperative acidosis than those diagnosed after birth as well as an improved preoperative status and postoperative survival.^45,56,57 Today, stage I Norwood operation in a term newborn has a greater than 85% survival rate.

Prenatal diagnosis may improve the outcome of the fetuses with hypoplastic left heart syndrome at highest risk by identifying those who will need urgent balloon atrial septostomy. It will also help to separate others that are able to continue their prenatal course with less severe disease. The influences of these factors on outcome of hypoplastic left heart syndrome have not been evaluated. In rare cases of critical aortic stenosis with intact septum there may be mitral regurgitation (Figure 6-21) and enlarged left atrium and left ventricle (Figure 6-22).

Coarctation of the Aorta

Epidemiology

Coarctation of the aorta occurs in approximately 8% to 10% of patients with congenital heart disease, with a male preponderance (2:1). Aortic arch anomalies accounted for 6.1% of all cardiovascular lesions detected antenatally in the combined series of Allan and colleagues. In this series, out of a total of 138 fetuses with arch anomalies, there were 46 survivors of 79 continuing pregnancies (59%).⁵⁸

Embryology/Pathophysiology/Genetics

The aortic arch and its branches develop during the sixth to eighth week of human gestation. The embryologic third aortic arches persist as the common carotid arteries. The left fourth aortic arch forms the thoracic aortic arch and isthmus, and the right fourth arch normally involutes. The embryologic sixth aortic arches persist as the proximal pulmonary arteries, with the left sixth aortic arch developing distally into the ductus arteriosus. A thoracic coarctation, therefore, is a manifestation of an abnormality in development of the embryologic left fourth and sixth aortic arches.⁵⁹ The underlying cause of the abnormal arch development is not well understood.

The pathophysiology of coarctation varies with the severity of the stenosis and is also affected by the presence of associated lesions, such as patent ductus arteriosus, ventricular septal defect, and aortic or mitral stenosis. The clinical presentation of coarctation also varies widely, ranging from heart failure in the newborn to asymptomatic hypertension or a murmur in an older child.

The genetic component to coarctation has long been recognized in the Turner XO syndrome, in which about 35% of patients are affected. Recent data suggest that there is a more important genetic influence on the development of left-sided obstructive lesions, including coarctation, than previously recognized.⁶⁰

Left-sided obstructive lesions account for approximately 14% of congenital heart diseases. There is a relatively consistent excess in males compared to females (3:1.5). The observed sibling recurrence risk for these defects is approximately 2% and the risk if the mother is affected is about 4%.³⁰

Diagnostic Features

Prenatal diagnosis of coarctation of the aorta can be difficult. However, the diagnosis can be inferred from dilatation of the right atrium, right ventricle, and pulmonary artery when these structures are compared with those of the left heart (Figure 6-23A). On direct echocardiographic examination of the aortic arch, arch hypoplasia or interruption of the aortic arch can be recognizable prenatally. Typically, the arch in coarctation is hypoplastic and elongated between the left carotid and left subclavian arteries. Doppler shows increased velocity in the aortic isthmus in some cases (Figure 6-23B).

Pregnancy Course

Follow-up includes serial antenatal fetal echocardiography studies at 4-week intervals. If the fetus remains well compensated and the lesion is isolated, delivery can be at term vaginally in a tertiary care center.

What to Expect after Delivery

Once the baby is delivered, an echocardiogram should be performed to determine arch size and ductal dependency. Following delivery, prostaglandin E₁ (PGE₁) may be initiated if the coarctation is severe. Otherwise, some cases of prenatally diagnosed coarctation of the aorta may not be ductus dependent and may not require surgical correction in the neonatal period.

Prognosis

A retrospective review of infants with normal karyotype with coarctation of the aorta diagnosed between 1994 and 1998 showed a higher likelihood of cardiovascular collapse or death in those infants diagnosed after birth. In this group, 30% died before surgery could be performed. Conversely, both pre- and postoperative mortality was 0% in the infants diagnosed by fetal echocardiography.⁴⁴

Right Heart Defects

Pulmonary Valve Stenosis

Epidemiology

Isolated pulmonary stenosis represented 0.8% of cases of structural cardiac malformation diagnosed in fetal life. Pulmonary stenosis, with and without other associated lesions, occurs in 25% to 30% of all patients with congenital heart disease.

Embryology/Pathophysiology/Genetics

The exact embryologic process resulting in pulmonary valve stenosis is not well understood. Maldevelopment of the distal part of the bulbus cordis has been proposed.

When the degree of valvular pulmonary stenosis is severe enough to cause a decrease in fetal right ventricular output, a larger-than-normal atrial right-to-left shunt is established in utero. This condition has been termed critical pulmonary stenosis. The right ventricle is often hypoplastic because of severe hypertrophy and the effects of reduced flow through the right ventricle during development.

Pulmonary stenosis can occur as part of Noonan, Alagille, or Williams syndrome. It is very rare for isolated pulmonary stenosis to be associated with chromosomal anomalies. Familial occurrence of pulmonary stenosis has been reported. In the Second Natural History Study of Congenital Heart Defects, the occurrence of definite and possible congenital cardiac defects in 1356 siblings of 449 patients with valvar pulmonary stenosis was 1.1% and 2.1%, respectively.⁶¹

Diagnostic Features

The echocardiographic findings depend on the degree of pulmonary obstruction. The right ventricle may show hypertrophy (usually), dilatation (occasionally), or hypoplasia (depending on the degree of pulmonary obstruction). Right ventricle function may be decreased and this might decrease the Doppler velocities across the stenotic valve. The pulmonary artery is usually smaller than the aorta with thickened and restrictive leaflets. There is turbulence at the pulmonary valve with color Doppler and increased blood velocity (Figure 6-24). Frequently, there is systolic reversal of the pulmonary blood velocity with valvar or infundibular pulmonary stenosis. Pulmonary stenosis gradient in utero may not reflect the severity of the stenosis depending on the size of the patent ductus and right ventricle function.

The tricuspid valve will show restricted opening because of the decreased inflow. In critical pulmonary stenosis, there will be reverse flow across the ductus arteriosus.

Pregnancy Course

The pregnancy course depends on the severity of the lesion and the gestational age at which the diagnosis is made. The intrauterine prognosis of critical pulmonary valve stenosis depends on the size of the foramen ovale and left ventricle function to support the combined cardiac output.

Pulmonary regurgitation in a structurally normal valve could be a sign of increased right ventricular afterload and heart failure. Failure of growth of the right ventricle and the pulmonary trunk may occur as the pregnancy advances. This is important in counseling, especially with regard to the possibility of biventricular surgical repair at birth.

What to Expect after Delivery

Central cyanosis may be present at birth, but while the arterial ductus is open may not be obvious. As the ductus constricts, pulmonary blood flow decreases and cyanosis becomes more apparent, typically within 48 hours, and may be severe enough to be life threatening. Although the right ventricular cavity is often relatively hypoplastic, the atrial communication is usually large enough to maintain cardiac output and prevent right heart failure at the expense of cyanosis. Symptoms of right-sided heart failure may be seen in some newborns with significant tricuspid insufficiency or may develop in untreated infants if the atrial communication becomes inadequate with growth.

Prognosis

The prognosis is dependent on the degree of pulmonary obstruction. Most patients with mild or moderate stenosis remain stable, and pressure gradients recorded early in life often decrease with growth. This is particularly true in patients with associated syndromes, such as Williams, Noonan, or congenital rubella; however, multiple peripheral pulmonary stenosis of severe degree may be progressive, and the prognosis is poor unless angioplasty, stent placement, or surgery is successful. Long-term prognosis after treatment is reasonably good, except for the high rate of reinterventions for residual pulmonary stenosis and pulmonary valve insufficiency. Complications include right ventricular failure, pulmonary artery thrombosis, and poststenotic aneurysmal dilation with pulmonary artery hemorrhage.

Pulmonary Atresia With Intact Ventricular Septum

Epidemiology

Pulmonary valve stenosis or atresia with intact ventricular septum represents a spectrum of severity.

Pulmonary atresia with intact ventricular septum accounts for 2.5% to 4% of congenital heart disease and occurs in 1 in 2200 live births.

Embryology/Pathophysiology/Genetics

Kutsche and Van Mierop suggested that pulmonary atresia and ventricular septal defect occur early in cardiac morphogenesis, at or shortly after partitioning of the truncoconal part of the heart but before closure of the ventricular septum. Conversely, they suggest that pulmonary atresia and intact ventricular septum probably occur after cardiac septation.⁶²

An interatrial communication (either atrial septal defect or patent foramen ovale) and patent ductus arteriosus are necessary for survival. The high pressure in the right ventricle is often decompressed through dilated coronary fistulous connections into the left or right coronary artery. The obstruction of the proximal coronary arteries, which is often present, can cause high surgical mortality. Right atrium dilatation and hypertrophy may be one of the earliest clues to right ventricle outflow tract obstruction. With redistribution of flow to the left atrium and left ventricle, the left heart chambers dilate to accommodate the preload that is critical to sustain the equivalent of a combined ventricular output. Tricuspid regurgitation is commonly present. The tricuspid valve orifice is usually hypoplastic and the tricuspid valve opening appears restricted.

When there is a previous baby with the same condition, this congenital heart disease may be an autosomal recessive trait. In the absence of positive family history and normal karyotype, including fluorescence in situ hybridization (FISH) for 22q11.2, we may assume a multifactorial inheritance, and hence the estimated recurrence risk is around 2%.³⁰

Diagnostic Features

The condition is usually associated with an abnormal 4-chamber view, hypoplastic right ventricle, poorly contracting thick-walled ventricle, small tricuspid valve annulus (compare to mitral valve annulus and get a Z score value of the annulus), tricuspid regurgitation (usually at high Doppler velocity), variable size of main pulmonary artery and branches, absence of forward flow across pulmonary valve or main pulmonary artery, no antegrade flow across the pulmonary valve (in systole), reverse flow in the ductus arteriosus (aorta-pulmonary), and fistulous connections from the right ventricle to the coronary arteries, which may result in bidirectional, high velocity flow in the coronary arteries.

Not infrequently, the ductus venosus Doppler signal is abnormal, with increased pulsatility index and reversal of flow during atrial contraction. Being able to visualize coronary flow prenatally points toward associated ventriculo-coronary fistulous connections.⁶³ However, it is difficult to predict echocardiographically those who may have a right-ventricle-dependent circulation.

Pregnancy Course

The intrauterine prognosis depends on both the size of the foramen ovale and the left ventricle function to support the combined cardiac output. Follow-up includes serial antenatal studies at 4-week intervals, looking for right ventricle size and function, endocardial fibroelastosis, congestive heart failure, left ventricle function, and growth of pulmonary arteries and branches.

Fetal pulmonary valvuloplasty has been performed in an attempt to preserve right ventricle growth in the hope this will maximize the chances of a biventricular repair. However, at this point, the numbers are small, and there are no long-term follow up data and no clear-cut selection criteria as to which cases may benefit from prenatal intervention. Progressive signs of heart failure on cardiovascular profile score of seven or less may indicate a poor prognosis.

The mode of delivery is decided according to the functional condition of the left ventricle. Usually vaginal delivery is possible and should be at term or near term in a tertiary care center. Conditions for cesarean delivery are left ventricle dysfunction, such as fractional shortening of less than 25%, evidence of progressive flow restriction through the foramen ovale, and fluid accumulation in either the pleural or peritoneal cavities.

What to Expect after Delivery

After delivery, PGE₁ should be administrated to keep the ductus open, increasing pulmonary blood flow and raising the arterial oxygen saturation. Therapeutic balloon valvuloplasty of the pulmonary valve is being performed in some centers. Therapeutic balloon atrial septostomy must be performed in the rare situation of tiny right ventricle and restrictive patent foramen ovale.

Prognosis

Pulmonary atresia with intact ventricular septum lies at the severe end of the spectrum of congenital heart disease. Factors that affect the outcome include size of the right ventricle, ventriculo-coronary fistulous connections, coronary artery stenosis, and chromosomal abnormalities (relatively uncommon).

Management strategies for pulmonary atresia with intact ventricular septum continue to evolve and must include assessment of the coronary circulation. The presence of ventriculo-coronary fistulous connections may promote coronary artery stenosis and interruption, and aortic diastolic pressure may not be sufficient to drive coronary blood flow when obstructive lesions are present within the coronary circulation. Clinically, significant coronary artery stenosis is not detectable before birth with current technology. However, this finding can certainly impact the management options and long-term outcome of an affected infant.

The presence of right-ventricle-dependent coronary arteries is a contraindication to a biventricular repair. In a coronary circulation that is wholly or partially right ventricular dependent, it is the blood that gets into the right ventricle at systemic or above-systemic right ventricular systolic pressure that supplies the myocardium in a retrograde fashion. Interference with blood flow into the right ventricle or reduction of right ventricular systolic pressure in situations in which the coronary circulation is right ventricular dependent may result in myocardial ischemia, infarction, and sudden death.

Ebstein's Anomaly of the Tricuspid Valve or Tricuspid Dysplasia

Epidemiology

Ebstein anomaly occurs in about 1 to 5 per 200,000 births and represents less than 1% of all congenital heart disease.⁶⁴ Lithium exposure at the time of conception has been implicated as a cause for this defect.⁶⁵

Embryology/Pathophysiology/Genetics

Characteristic pathologic findings include displacement of the septal and posterior leaflets of the tricuspid valve into the right ventricle, so that a proportion of the right ventricle is incorporated into the right atrium (atrialized right ventricle), resulting in functional hypoplasia of the right ventricle and tricuspid regurgitation. The septal leaflet is typically rudimentary in more severe forms, but may be thickened only at its edges with minimal displacement from the true annulus in milder forms. The posterior leaflet may be thickened with abnormal chordal attachments tethering it to the ventricular myocardium in more severe forms of the lesion. The anterior leaflet is often large and quite redundant, resembling a sail. Abnormal chordal attachments to this and the posterior leaflet are often the cause of severe insufficiency. Although the atrialized portion of the right ventricular anterior wall may be thin, the distal unaffected portion of the right ventricular wall is usually normal in thickness.

Most cases of Ebstein anomaly occur sporadically, although familial cases have been reported. Associated lesions are not uncommon. In most cases, an interatrial communication is present either in the form of a patent foramen ovale or a true atrial septal defect. Ventricular septal defects and pulmonary stenosis or atresia are also occasionally found. The incidence of this lesion is higher than expected in infants born to women who have ingested lithium early during the pregnancy.⁶⁶

Diagnostic Features

Fetal echocardiography has provided the ability to determine the presence of Ebstein anomaly, because the distinctive tricuspid valve displacement can be detected as well as the marked right heart enlargement (Figure 6-25). Two-dimensional echocardiogram also gives the degree of displacement of the valve into the right ventricular cavity and prognostic features can be assessed. The presence of associated lesions also can be well demonstrated. With the addition of Doppler and color flow techniques, the degree of tricuspid insufficiency or stenosis can be assessed accurately along with intracardiac shunting patterns.

Pregnancy Course

Tricuspid valve abnormalities in the fetus range from mild displacement of the septal leaflet with mild insufficiency to severe displacement, absent valve coaptation with severe insufficiency, atrialization of the right ventricle, and functional pulmonary atresia.⁶⁷ Because of the truly massive proportions assumed by the right ventricle, severe forms of tricuspid insufficiency that present early may restrict growth of functional lung tissue, further decreasing the likelihood of postnatal survival. Even with anticipatory care and more novel approaches to postnatal management, it was recently shown that 27% died in utero and only 21% survived beyond the neonatal period. Factors indicating severity include the absence of anterograde flow across the pulmonary valve due to severe tricuspid regurgitation, ratio of the combined area of the right atrium and atrialized right ventricle to that of the functional right ventricle and left heart in 4-chamber view at end-diastole greater than 1.5, and in extreme cases fetal hydrops. If they appear, an elective delivery should be performed.⁶⁴

What to Expect after Delivery

An additional problem exists in the neonatal period, that of increased pulmonary vascular resistance. In more severe cases of Ebstein anomaly, the ability of the right ventricle to propel blood in an antegrade direction is compromised. Therefore, the right ventricle may not be able to generate adequate pressure to open an otherwise normal pulmonary valve. This results in functional pulmonary atresia. In this case, the neonate may be extremely cyanotic and dependent on patency of the ductus arteriosus for pulmonary blood flow. As pulmonary vascular resistance diminishes, the right ventricle may be able to pump blood in an anterograde direction across the right ventricular outflow tract. The degree of tricuspid insufficiency and right-to-left atrial level shunt then diminishes, and the infant becomes less cyanotic.

Prognosis

The prognosis for the fetus diagnosed in utero with significant tricuspid valve disease is extremely poor.⁶⁴ Survival rates described are 49% at birth in fetuses with Ebstein anomaly or tricuspid valve dysplasia, but approximately 20% beyond 1 month of age.⁶⁴

Although there are reports of patients with Ebstein anomaly living many decades, most authors describe a mean age of death at about 20 years, with about one-third dying before the age of 10 years.⁶⁸ Surgical repair of Ebstein anomaly, especially in infants, remains a major challenge. Patients with milder forms of the disease can live well into adulthood, and women can become pregnant and deliver normal-term infants in most cases.⁶⁹

Septal Defects

Ventricular Septal Defects

Epidemiology

Ventricular septal defects are the most common form of congenital heart disease detected in infancy, accounting for more than 30% of the total cases of congenital heart diseases. The incidence of ventricular septal defects is approximately 2 per 1000 live births. The spectrum of ventricular septal defects seen in prenatal life is very different from that manifesting postnatally. Isolated ventricular septal defects constituted only 6% of a large series of congenital heart diseases identified prenatally. Ventricular septal defects are commonly associated with other cardiac defects as part of more complex disease. Ventricular septal defects can vary in location and are divided into inlet, outlet, perimembranous, and muscular defects. Perimembranous ventricular septal defects account for 80% of ventricular septal defects. Outlet ventricular septal defects account for 5% of ventricular septal defects worldwide but 20% in East Asia. Inlet ventricular septal defects account for 5%, and muscular ventricular septal defects account for 10% to 20% of ventricular septal defects.⁷ Outlet defects are associated with aortic valve dysfunction and require surgery.⁷⁰

mbryology/Pathophysiology/Genetics

In the fetus, the right and left ventricular pressures are equal or similar. Small dynamic differences cause systolic left-to-right and diastolic right-to-left shunting through a large ventricular septal defect. After birth, the pulmonary artery pressure drops, and the shunt through a large ventricular septal defect increases in magnitude. Pulmonary resistances continue to fall postnatally reaching its nadir at 3 to 4 months of age, when the worst symptoms of cardiac heart failure can be expected.

Ventricular septal defects are the most common lesion in many chromosomal syndromes, including trisomy 13, trisomy 18, and trisomy 21 groups, as well as in more rare syndromes. A multifactorial cause has been proposed in which interaction between hereditary predisposition and environment results in the defect.

Diagnostic Features

Ventricular septal defects are the most common type of congenital heart malformation to be overlooked in the fetus; however, most of the overlooked defects tend to be small. Their detection prenatally depends on the image quality, the size, and the site of the defect, and the color Doppler capabilities of the ultrasound machine. Ventricular septal defects are commonly found as a part of complex cardiac anomalies, some of which are not obvious when the study is performed during pregnancy. Important associated defects with ventricular septal defect are coarctation of the aorta, atrial septal defects, aortic stenosis, mitral valve anomalies, pulmonary stenosis, anomalous muscle bundle of right ventricle, and anomalies of pulmonary venous return. In the 4-chamber view of a normal heart, the ventricular septum should appear intact. However, if the ultrasound beam is parallel to the ventricular septum, dropout can often be seen at the crux of the heart where the septum is thin and membranous. A real defect has edges, a so-called "T artifact," ie, bright spots delineating the borders of the defect, whereas in dropout, the ventricular septum "fades" toward the crux of the heart. Ventricular septal defects are commonly associated with other cardiac defects as part of more complex disease.

In the color flow image, a "smear" across the septum may give a false-positive diagnosis of a ventricular septal defect. Color flow projection must be seen to breech the septum to confirm a real ventricular septal defect. Bidirectional color flow across the defect (unless there is right or left ventricular outflow obstruction) confirms the presence of a real defect (Figure 6-26). Color flow mapping does not "highlight" a small ventricular septal defect by showing turbulent flow in the same way as it does postnatally, because of equal ventricular pressures in the fetus.

Pregnancy Course

Serial antenatal fetal echocardiography studies should be performed at 6- to 8-week intervals to assess the size of the defect and compare it with the aortic root size serially. At each visit, a renewed search is made for possible developing associated cardiac lesions, such as coarctation of the aorta. In an outlet ventricular septal defect, pulmonary stenosis can appear later in pregnancy, as evidenced by a pulmonary artery smaller than the aorta, thus evolving into tetralogy of Fallot or pulmonary valve stenosis. The size of the ascending aorta and transverse aortic arch should be monitored because hypoplasia of the aortic arch can develop in association with a ventricular septal defect as pregnancy advances. Size and function of both ventricles and the size of the aortic valve annulus should be evaluated. Development of heart failure would not be expected in this condition.

What to Expect after Delivery

If the fetus remains well compensated and the lesion is isolated, delivery can be normal at term in a secondary care center. Once the baby is delivered, an echocardiogram should be performed, within the first 2 weeks of delivery, to determine the size, number, and hemodynamics of the ventricular septal defects and to exclude additional pathology.

Prognosis

There have been some reports of ventricular septal defects closing spontaneously in prenatal life. The majority of ventricular septal defects usually close in the first year of life or before school age, although later closure has been reported. Smaller defects and perimembranous or muscular defects are more likely to close spontaneously.

Children with small ventricular septal defects are asymptomatic and have excellent long-term prognosis. Neither medical therapy nor surgery is indicated.

Surgical repair of ventricular septal defects is usually performed if there is failure to thrive, congestive heart failure resistant to medical therapy, pulmonary hypertension at 6 to 12 months, or cardiomegaly at school age, suggesting significant shunt. Long-term survival following repair of isolated ventricular septal defect is 86% to 93% at 12 to 15 years following repair.⁷¹

Atrial Septal Defects

Epidemiology

An atrial septal defect occurs in about 1 in 1500 live births. It is a common component of complex disease. In fetal life there is always a defect in the secundum portion of the atrial septum, the foramen ovale. The foramen ovale represents a normal interatrial communication that is present throughout fetal life. Functional closure of the foramen ovale occurs during the first year of life, as pressure in the left atrium exceeds that in the right atrium. In 25% to 30% of people, however, anatomic closure does not occur, and a potential interatrial channel persists through which blood or air may shunt whenever pressure in the right atrium exceeds that in the left atrium.⁷²

Embryology/Pathophysiology/Genetics

The septum primum, which is the first septum to develop, is an incomplete thin-walled partition in which the anteroinferior free edge is above the atrioventricular canal and becomes lined by tissue derived from the superior and inferior endocardial cushions. Before the resultant interatrial opening (ostium primum) becomes sealed by endocardial cushion tissue, programmed cell death in an area near the anterosuperior aspect of the septum primum creates small cribriform perforations. These perforations coalesce to form a large, second interatrial communication (ostium secundum) maintaining interatrial blood flow.

At this time, to the right of the first septum, an anterosuperior infolding of the atrial roof occurs and forms a second septal structure (septum secundum). It expands posteroinferiorly as a thick-walled muscular ridge to form an incomplete partition that overlies the ostium secundum. As atrial septation is accomplished, septum secundum forms the limbus of the fossa ovalis and septum primum forms the valve of the fossa ovalis. There are essentially 4 types of atrial septal defects, with different mechanisms underlying their formation: secundum atrial septal defect, sinus venosus atrial septal defect, coronary sinus venosus, and primum atrial septal defect. It is usually sporadic, but it can occur as part of genetic syndromes such as Holt-Oram syndrome (autosomal dominant). In 1997, Li et al⁷³ reported that Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Further understanding of genetic abnormalities causing atrial septal defects is still in its early stages. To date, heterozygous mutations in 2 genes, NKX2.5 and GATA4, have been identified to be causative for a subset of familial atrial septal defect through genetic linkage analysis of pedigrees with nonsyndromic congenital cardiovascular diseases.^74,75 Most recently, a missense mutation in myosin heavy chain 6 (on chromosome 14q12) has been found to cause familial atrial septal defect.⁷⁶

Diagnostic Features

Normally, the foramen ovale defect occupies about the middle one-third of the atrial septum. A true secundum atrial defect is larger than the normal foramen for gestational age (3 mm in size at 20 weeks to 8 mm at term). In a true secundum defect, the atrial defect should be above this normal range. This is a rare diagnosis in the fetus. The primum atrial septal defect is characterized by a defect in the lower atrial septum with a cleft mitral valve; the sinus venosus atrial septal defect by a deficiency in the posterosuperior atrial septum; and the coronary sinus atrial septal defect by a communication at the level of the orifice of the coronary sinus. Absence of septum primum and atrial septum primum aneurism in the fetus is consistent with a secundum atrial septum defect (defect at fossa ovalis).

Color-flow imaging allows the blood traversing an atrial septal defect to be demonstrated.

Pregnancy Course

In cases of isolated atrial defect, delivery should be at term and does not require a tertiary care center.

Amniocentesis should be recommended with the diagnosis of primum atrial septal defect because of the possible association with trisomy 21, followed by DiGeorge syndrome and Ellis-van Creveld syndrome. For primum atrial septal defect, spontaneous intrauterine death and neonatal death have been reported, especially with left atrial isomerism.

What to Expect after Delivery

A prospective echocardiographic study suggested that as many as 24% of newborns have evidence of an opening (3 to 8 mm) in the atrial septum in the first week of life.⁷⁷ However, by a little more than 1 year of age, 92% of the patients were found to have spontaneous closure of the opening, and in most patients there was evidence of a valvelike opening of the atrial septum that was believed to contribute to closure.

Prognosis

In the absence of atrial isomerism, the prognosis for all forms of atrial septal defect is good.

Small secundum defects commonly close spontaneously in the first 2 years of life.⁷⁷ Most of the larger defects can be closed using the transcatheter closure device by 2 to 3 years of life. Otherwise, open-heart surgery is performed around 3 to 5 years of age. It appears that spontaneous closure, or a decrease in size, is most likely to occur in atrial septal defects less than 7 to 8 mm and with younger age at diagnosis. Ostium primum and sinus venosus defects do not close spontaneously. The presence and severity of functional limitation among patients with atrial septal defects seem to increase with age. Congestive heart failure is found rarely in the first decades of life, but it can become common once the patient is older than 40 years of age. The onset of atrial fibrillation or, less commonly, atrial flutter can be a hallmark in the course of patients with atrial septal defects. The incidence of atrial arrhythmias increases with advancing age. Pulmonary vascular disease can occur in 5% to 10% of patients with untreated atrial septal defects, predominantly in females, and usually it occurs after 20 years of age.⁷⁸

Atrioventricular Septal Defect

Epidemiology

Atrioventricular canal accounts for 4% to 5% of congenital heart disease, an estimated occurrence of 0.19 in 1000 live births.⁷⁹ In a large fetal echocardiography experience, atrioventricular septal defects were the most common anomaly detected, constituting 18% of abnormal fetal hearts.⁵⁸

Embryology/Pathophysiology/Genetics

Failure of the endocardial cushions to fuse creates a defect in the atrioventricular septum. The primum atrial septal component of this defect is usually large. This results in downward displacement of the anterior mitral leaflet to the level of the septal tricuspid leaflet. In atrioventricular septal defects, the atrioventricular valves have the same septal insertion level in contrast to the leaflet arrangement in the normal heart. The distance from the cardiac crux to the left ventricular apex is foreshortened, and the distance from the apex to the aortic valve is increased.

Because the dextrodorsal conus cushion contributes to the development of the right atrioventricular valve and the outflow tracts lie adjacent to their respective inflow tracts, atrioventricular septal defects may be associated with conotruncal anomalies. In addition, shift of the atrioventricular valve orifice may result in connection of the valve primarily to only 1 ventricle, creating disproportionate or unbalanced ventricles. Berg et al⁸⁰ found an association of atrioventricular septal defects with chromosomal anomalies in 52.4% (mainly trisomy 21), heterotaxy syndromes in 29.3%, nonchromosomal malformation syndromes in 6.9%, isolated complex cardiac malformations in 6.5%, singular extracardiac malformations in 2.0%, and 2.8% were isolated atrioventricular septal defects.

With isolated atrioventricular septal defects the recurrence risk is approximately 5%. The recurrence risk following a baby with trisomy 21 depends on the mother's age. If the mother is older than 35 years, the recurrence risk is the mother's age-related risk, whereas if the mother is younger than 30 years, the recurrence risk is about 1%.³⁰

Diagnostic Features

In utero diagnosis of an atrioventricular septal defect is readily made on routine fetal 4-chamber imaging. Dropout in the lower atrial septum or upper ventricular septum may be suggestive of the diagnosis. The septum primum is absent. There is inferior displacement of the atrioventricular valves, and attachment of a portion of the left atrioventricular (mitral) valve to the septum; therefore, the 2 separate atrioventricular valve orifices are equidistant from the cardiac apex. The distance from the cardiac crux to the left ventricular apex is foreshortened, and the distance from the apex to the aortic valve is increased. In atrioventricular septal defects, the disproportion between the 2 distances causes anterior displacement of the left ventricular outflow tract. As a result, the left ventricular outflow tract is longer and narrower than normal and produces the "gooseneck" deformity.

Pregnancy Course

Follow-up is required at 4- to 6-week intervals because outflow tract obstruction can develop later in pregnancy (atrioventricular canal with tetralogy of Fallot) and atrioventricular valve regurgitation may increase in severity, increasing the risk of congestive heart failure.

Given the high possibility of chromosomal anomalies, amniocentesis should be offered.

What to Expect after Delivery

If the fetus remains well compensated and the lesion is isolated, delivery can be at term in a secondary-level center, but if there is any size discrepancy between the ventricles and the great arteries, delivery should be in a tertiary care center.

Usually heart failure develops progressively over the first 4 to 8 weeks of postnatal life, so medical treatment should be initiated. The timing of surgery ranges from 8 weeks to 3 years, depending on hemodynamic severity.

Prognosis

Huggon et al,⁸¹ in a series of 301 fetuses, noticed that despite some improvements in the outlook for atrioventricular septal defects diagnosed prenatally, the overall prognosis remains considerably poorer than that implied from surgical series. In this series, parents opted for termination of pregnancy in 58.5%. For the continuing pregnancies, Kaplan-Meier estimates for live birth, survival past the neonatal period, and survival to 3 years were 82% (confidence interval [CI] = 75.3% to 88.9%), 55% (CI = 46.0% to 64.3%), and 38% (CI = 27.1% to 48.6%), respectively. Fetal hydrops, earlier year of diagnosis, and atrioventricular block, as well as the presence of an atypical form of the lesion, are associated with adverse survival.^{82,83, and 84}

Conotruncal Defects

Tetralogy of Fallot

Epidemiology

Tetralogy of Fallot comprises a constellation of cardiac findings that share the following common anatomic abnormalities: a large malaligned ventricular septal defect, overriding of the aorta over the septal defect, right ventricular outflow obstruction, and right ventricular hypertrophy.⁸ Incidence of tetralogy of Fallot ranges from 0.26 to 0.8 per 1000 live births. The proportion of patients with congenital heart disease who have tetralogy of Fallot ranges from 3.5% to 9%.⁸⁵

Embryology/Pathophysiology/Genetics

Normal development of the conotruncus involves proper septation and alignment of the pulmonary and left ventricle outflow tracts above their respective ventricles. The embryologic precursors to the ventricular outflow tracts and great arteries are distal to the bulbus cordis and truncus arteriosus, respectively. The anatomic transition point, between the bulbus cordis and truncus arteriosus, coincides with the level at which the semilunar valves form from the growth and fusion of the truncal–bulbar cushions.

The anatomy seen in tetralogy of Fallot is believed to result from incomplete rotation and faulty partitioning of the conotruncus during septation. This process normally occurs by proper spatial growth and rotation of the truncal-bulbar ridges. Malrotation of these ridges results in misalignment of the outlet and trabecular septum, and consequent straddling of the aorta over the malaligned ventricular septal defect. The subpulmonic obstruction, then, is created by abnormally anterior septation of the conotruncus by the bulbotruncal ridges.

The sibling recurrence rate appears to range from 2.5% to 3% if only 1 sibling is affected, but it is likely to increase substantially if more than 1 sibling is affected. The recurrence risk may also increase if familial disease or syndromic features are present in the affected proband or relatives. The estimated recurrence risk to offspring of parents with tetralogy of Fallot is generally higher than that for siblings and ranges from 1.2% to 8.3%.^11,28

Extra cardiac abnormalities in tetralogy of Fallot may occur in as many as 30% of affected infants and children. In fetal tetralogy of Fallot the incidence of extra cardiac lesions may be 50% to 60% with 25% having chromosomal abnormalities. Chromosomal abnormalities includes aneuploidy such as trisomies 21, 18, and 13, and single gene disorders, specifically microdeletion of chromosome 22 (up to 20% of infants with tetralogy of Fallot). It may also be seen in other less common syndromes and associations. Down syndrome is present in approximately 75% to 80% of those with the combination of atrioventricular septal defect and tetralogy of Fallot. Midline defects (eg, pentalogy of Cantrell, omphalocele), renal, skeletal and gastrointestinal, and central nervous system abnormalities may be found in fetal tetralogy of Fallot.²⁹

Diagnostic Features

In tetralogy of Fallot the 4-chamber view is typically normal, but often with a more leftward axis than normal. Usually a subaortic ventricular septal defect is seen in the long-axis view of the left ventricle (also known as 5-chamber view) with sweeps to the outflow tracts. There is anterior displacement of the ascending aorta resulting in the aorta overriding the ventricular septal defect (Figure 6-27A). The ascending aorta diameter is greater than the pulmonary artery with forward flow in the pulmonary artery. The ascending aorta tends to be larger than normal in size for gestation, particularly later in gestation, and blood flow onto the ascending aorta from both ventricles on color flow mapping can be seen. A gradient across the right ventricular outflow tract is usually not present as a result of the ventricular septal defect and due to fetal physiology. Absence of flow gradient in utero does not rule out pulmonary stenosis, and infundibular or subpulmonary narrowing caused by anterior ventricular septal deviation tends to be more appreciated later in gestation. With pulmonary atresia, the pulmonary arteries may rise from the reversed flow patent ductus arteriosus or from aorto-pulmonary collaterals from the aorta (Figure 6-27B).

Pregnancy Course

Prenatal diagnosis is common and can document the important hemodynamic burden of pulmonary regurgitation in utero including the presence of hydrops in up to 20% of fetuses.

What to Expect after Delivery

In tetralogy of Fallot with pulmonary stenosis, delivery should be at term in a tertiary center in order to evaluate the degree of right ventricle outflow obstruction at birth and the risk of cyanotic spells.

Prognosis

In medical follow-up, considerations should be given to progressive right ventricle dilation related to pulmonary regurgitation and/or abnormal distal arterial impedance, because these hemodynamic issues may have an impact on long-term myocardial health. Children with tetralogy have some risk of important malignant rhythm disorders/ventricular tachycardia and/or sudden cardiac death after cardiac surgical repair.

In a 30-year follow-up study, excellent clinical results of surgical repair of tetralogy of Fallot have been reported.⁸⁶ However, the nature of the repair leaves each patient with some degree of excessive hemodynamic burden because of residual defects, valvular abnormalities, or myocardial factors. For most patients, these abnormalities cause no clinical symptoms, although careful assessment of exercise capacity may reveal abnormal function. Furthermore, most large series include a few late deaths attributed to congestive heart failure.

Other Defects

Heterotaxy Syndromes

Epidemiology

Heterotaxia is the term used to describe an anomalous position of the viscera. The prevalence of heterotaxy syndromes is 1% of the neonates with symptomatic congenital heart disease.

Embryology/Pathophysiology/Genetics

Both right and left atrial isomerism comprise the heterotaxy syndromes. Right atrial isomerism or asplenia syndrome is associated with absence of the spleen and a tendency to bilateral right-sidedness. In left atrial isomerism or polysplenia syndrome, multiple splenic tissues with a tendency for bilateral left-sidedness are present along with interrupted inferior vena cava with azygous continuation of the inferior vena cava. Although the type and severity of cardiovascular malformations are somewhat different between the 2 syndromes, the same types of defects may be present in both conditions. In general, right atrial isomerism has more severe abnormalities of the structures. A normal heart or only minimal malformations of the heart is present in up to 25% of the patients with left atrial isomerism. Bilateral superior venae cavae is common, and anomalies of the pulmonary venous return are usually present. Single atrium, secundum atrial septal defect, and primum atrial septal defect are common. A single atrioventricular valve is common. Either a single ventricle or ventricular septal defect is usually present. Transposition of great arteries is usually present in right atrial isomerism and occasionally in polysplenia syndrome.

An X-linked recessive trait associated with the inability of the developing embryo to establish normal left-right asymmetry has been noted in right atrial isomerism. Familial heterotaxy occurs with autosomal dominant, recessive, and X-linked inheritance.⁸⁷ Genes implicated in human heterotaxy include Zic3, LeftyA, Cryptic, and Acvr2B.⁸⁸

Diagnostic Features

In right atrial isomerism, there are noninverted ventricles with the right ventricle to the right (D-ventricular loop) and a right anterior aorta, and multiple anomalies of systemic and pulmonary venous connections. Bilateral superior venae cavae with direct connections to the atria, bilateral pulmonary venous connections (direct right and left pulmonary venous connections to the ipsilateral atrium), anomalous supracardiac pulmonary venous connections, and absent coronary sinus are typical in left atrial isomerism. Most patients have some atrioventricular valve abnormality, such as common atrioventricular inlet, but right or left atrioventricular valve atresia is also recognized. Many have an unbalanced form of ventricular septal defect, most often with left ventricular hypoplasia, but they may have tricuspid valve atresia and right ventricular hypoplasia. Some may have a single ventricle of uncertain or indeterminate morphology with a common atrioventricular inlet. Most patients with asplenia have pulmonary stenosis or atresia.

In left atrial isomerism, bilateral hepatic venous connections to the ipsilateral atrium, azygous or hemiazygous continuation of the inferior vena cava to the superior vena cava, common-inlet ventricle of right ventricular morphology, and double-outlet right ventricle are all typical anomalies. Some outstanding differences are noteworthy, including a lower incidence of associated pulmonary stenosis and a more frequent occurrence of bilateral pulmonary venous connections to the ipsilateral atria.

Pregnancy Course

In right atrial isomerism, evaluations should be done every 4 to 6 weeks to monitor heart size and ventricular function, evidence of hydrops fetalis, progressive common atrioventricular valve regurgitation, size of left ventricle and pulmonary arteries, pulmonary vein growth, and flow patterns that could suggest progressive obstruction.

In left atrial isomerism, evaluations should be performed every week initially to check for heart rate; heart size and ventricular function; evidence of hydrops fetalis, eg, pericardial effusion; atrioventricular valve regurgitation; progressive aortic valve regurgitation; and bilateral outflow tract obstruction. Reassessment of the right ventricular outflow and direction of ductal and main pulmonary arterial flow is necessary.

The risk of amniocentesis is probably higher than the risk of abnormal karyotype in isomerism. Aneuploidy is extremely rare and reportable in atrial isomerism.

What to Expect after Delivery

In right atrial isomerism with complex congenital heart disease, delivery should be at term or as much as possible near term in a tertiary care center given the risk of pulmonary stenosis/ atresia and pulmonary vein obstruction. It is a ductal-dependent lesion so early initiation of PGE₁ is mandatory. However, if obstruction of the pulmonary veins coexists, then increasing pulmonary perfusion may cause pulmonary edema.

In left atrial isomerism with complete heart block and complex congenital heart disease, delivery should be at term or as much as possible near term in a tertiary care center. However, if the baby is developing fetal hydrops, earlier delivery may be necessary, as long as it is possible to improve the hemodynamic condition of the fetus with delivery and intervention. Cesarean section delivery may be considered given the difficulties with fetal monitoring in fetal bradycardia.

Prognosis

In general, the mortality of right atrial isomerism is high, due to the complexity of the structural defects, and specifically the association with asplenia and right atrial isomerism, and spongiform cardiomyopathy. Fetal patients with left atrial isomerism have a high proportion of atrioventricular block. Long-term survival with right atrial isomerism is 13% to 40%, and with left atrial isomerism it is 14% to 52%. Nonsurvival correlates with atrioventricular block and hydrops. Many (33% to 45%) of these pregnancies are interrupted. Prenatal diagnosis conferred no survival advantage for either left atrial isomerism or right atrial isomerism.⁸⁸

Common Arterial Trunk

Epidemiology

Persistent common arterial trunk or truncus arteriosus is an uncommon congenital cardiovascular malformation. There is not a striking gender difference in frequency, although most series contained more male than female subjects.

Embryology/Pathophysiology/Genetics

The embryonic truncus arteriosus lies between the conus cordis proximally and the aortic sac and aortic arch system distally. Partitioning of the truncus arteriosus is intimately associated with conal and aortopulmonary septation. When conotruncal or truncoaortic septation does not proceed normally, truncus arteriosus may result and is characterized by a single arterial vessel that arises from the base of the heart and gives origin to the coronary, pulmonary, and systemic arteries. Also, either deficiency or absence of the conal (infundibular) septum produces a large ventricular septal defect. Because the conal septum also contributes to the development of the anterior tricuspid leaflet and the medial tricuspid papillary muscle, these structures may be malformed. The single truncal valve may be deformed and functionally insufficient or, less commonly, stenotic.

Truncus arteriosus usually occurs as an isolated cardiovascular malformation, although it has been reported in association with anomalies of other systems, particularly the DiGeorge or velocardiofacial syndrome.³¹ Maternal diabetes has been implicated as a risk factor for truncus arteriosus. The anomaly has occurred in dizygotic twins and siblings, and there is an increased incidence of cardiac malformations in relatives of children with this lesion.⁸⁹

Diagnostic Features

Two-dimensional echocardiogram demonstrates a large ventricular septal defect directly under the truncal valve, which may be regurgitant, stenotic, or both. The pulmonary valve is not present. A large single great artery arises from the heart—truncus (Figure 6-28)—from which the brachiocephalic vessels and branch pulmonary arteries arise. Leftward cardiac axis is suggestive. Associated cardiac defects include right-sided aortic arch (30%), absence of arterial duct (50% to 75%), and less commonly aortic arch interruption, coronary anomalies, mitral valve obstruction, and atrioventricular septal defect.

Pregnancy Course

Progression of the lesion during pregnancy with truncal stenosis or regurgitation can cause hydrops fetalis and fetal demise and also contributes to the mortality and morbidity of affected infants after birth. In 2 series of 17⁹⁰ and 23 fetuses⁹¹ each, in utero demise was 0 or 9%, pregnancy interruption 24 or 35%, and neonatal deaths 25% or 22%, respectively.

Serial antenatal studies at 4-week intervals to assess the degree of truncal valve stenosis and regurgitation and reassess the ventricular function are indicated.

In classic truncus without any signs of heart failure, aortic interruption, or other associated malformation, delivery should be as close to term as possible and at least in an institution with neonatal intensive care support. This is because such babies are at risk for significant transient hypocalcemia and also heart failure with or without myocardial ischemia (after birth the pulmonary vascular resistance falls and steals from the coronaries).

What to Expect after Delivery

Truncus usually presents in the neonatal period. Symptoms depend on the degree of left-right shunt and the truncal valve regurgitation. Mild cyanosis (88% to 92% saturation) with a single second heart sound and a systolic ejection click should suggest truncus. Onset of symptoms of cardiac heart failure is determined by the rate with which the pulmonary vascular resistance falls and the degree of pulmonary shunting tolerated by the left heart. The presence of significant truncal valve regurgitation and/or stenosis (Figure 6-29) usually worsens the degree of heart failure as it contributes to the ventricular volume load and potentially causes coronary artery steal.

Prognosis

The actuarial survival rates were 81.7% ± 3.1%, 79.7% ± 3.2%, and 79.1% ± 3.3% at 6 months, and 1 and 18 years, respectively.⁹² Integrity of the truncal valve influences long-term survival. It is unknown if other factors frequent in truncus arteriosus, such as the 22q11 deletion, branch pulmonary artery stenosis, and interrupted aortic arch, affect either pre- or postnatal outcomes. Death in infancy most commonly is caused by heart failure. Without surgery, most infants die within 6 to 12 months, so surgical treatment of truncus arteriosus during infancy with a right ventricle to pulmonary artery conduit has become routine. Patients who had surgery need continued follow-up care throughout life.

D-Transposition of the Great Arteries

Epidemiology

D-transposition of the great arteries is a lethal and relatively frequent malformation, accounting for 5% to 7% of all congenital cardiac malformations. The incidence is reported to range from 20.1 to 30.5 per 100,000 live births with a strong (60% to 70%) male preponderance.

Embryology/Pathophysiology/Genetics

The morphogenesis of D-transposition of the great arteries can be hypothesized to result from the abnormal growth and development of the subaortic infundibulum and the absence of growth of the subpulmonary infundibulum. The aortic valve is protruded superiorly and anteriorly by the development of the subaortic infundibulum, placing it above the anterior right ventricle. Failure of development of the subpulmonary infundibulum prevents the normal morphogenetic movement of the pulmonary valve from posterior to anterior and further results in abnormal pulmonary to mitral valve ring fibrous continuity.

The course of the fetal circulation is modified because the right side of the heart ejects blood directly into the ascending aorta, in contrast to the sequence in the normal fetus, where the right ventricle ejects essentially into the descending aorta via the patent ductus arteriosus.

Extracardiac anomalies are less frequent in infants with D-transposition of the great arteries (<10%) compared with other forms of congenital heart disease, such as truncus arteriosus (48%), ventricular septal defect (34%), or tetralogy of Fallot (31%).

Diagnostic Features

The outflow assessment reveals transposition of great arteries with the aorta anterior and to the right of the pulmonary artery (Figure 6-30). There is unrestricted patent foramen ovale flow with a bidirectional shunt and a normal pulmonary venous flow pattern.

Perhaps the greatest advantage of prenatal diagnosis is the ability to deliver the infant in an obstetric facility with the expectation of cardiac disease, institution of PGE₁ therapy, and prompt transfer to a specialized cardiac facility before clinical deterioration may take place.

Pregnancy Course

Follow-up should occur every 4 to 6 weeks to check for the size of the left ventricle and progressive right ventricle outflow tract obstruction, as well as progressive main and branch pulmonary arteries and change in direction of ductus arteriosus flow, progressive foramen ovale restriction, and progressive ductus arteriosus constriction or spontaneous closure of the ventricular septal defect.

Both transposition of great arteries physiology and anatomy are compatible with normal fetal survival and relatively normal gestational development. The risk of amniocentesis is probably higher than the risk of abnormal karyotype in simple transposition.

In transposition of great arteries with pulmonary stenosis, delivery should be at term or as much as possible near term in a tertiary care center given the risk of foramen ovale restriction and ductus arteriosus constriction. In addition, the real degree of pulmonary stenosis after birth and after ductus arteriosus closure may be difficult to predict.

What to Expect after Delivery

After birth, the pulmonary vascular resistance falls with expansion of the lungs, and pulmonary blood flow and left atrial pressures increase in accordance with the more or less normal neonatal transitional physiology. The systemic vascular resistance increases because of removal of the low-resistance placental circulation. With transposition of great arteries, the right atrial pressures are increased, and the similarity of atrial pressures tends to keep the foramen ovale open, with resulting bidirectional shunting. A patent ductus arteriosus and unrestricted patent foramen ovale are essential for immediate neonatal survival prior to surgical correction of D-transposition of the great arteries.

Prognosis

Surgical correction of D-transposition of the great vessels is a procedure that at the best centers has less than 2% mortality. If the foramen ovale is recognized to be restrictive, the cardiology team can be prepared for a lifesaving immediate postnatal balloon septostomy. Bonnet's group studied a series of 130 fetuses with transposition of the great arteries and concluded that prenatal diagnosis of transposition of the great arteries reduces neonatal mortality but does not eliminate the risk of death. Assessment of the restriction of the foramen ovale and of the ductus arteriosus shortly before delivery detects a subgroup of fetuses that will need early balloon atrioseptostomy. The specificity and sensitivity of the fetal echocardiogram in predicting neonatal emergency was 84% and 54%, respectively. The specificity and sensitivity of a combination of restrictive foramen ovale and ductus arteriosus constriction were 100% and 31%, respectively.⁴³

Outcomes of the fetus diagnosed with congenital heart disease have improved somewhat in more recent studies, with overall survival ranging from 45% to 60%.^93,94

The 4-chamber view alone can detect up to 60% of congenital cardiac defects, including single ventricle (hypoplastic right and left heart syndromes); heterotaxy syndromes, which have a poor prognosis; and endocardial cushion defects, which have a high association with chromosome abnormalities.⁸⁵ Incorporating views of the left and right outflow tracts can further increase the detection of cardiac defects to 85% to 90% including ductal-dependent lesions such as transposition of the great vessels, coarctation of the aorta, and tetralogy of Fallot with severe pulmonary stenosis or pulmonary atresia.

The overall outcome of 1006 fetuses diagnosed with congenital heart diseases between 1980 and 1993 was fairly bleak with a high proportion (55%) of interrupted pregnancies. About 17% had associated chromosomal anomalies. Survivors of continuing pregnancies ranged from 92% with D-transposition of the great vessels to 0% with common arterial trunk, tetralogy of Fallot with absent pulmonary valve, or L-transposition of the great vessels with Ebstein malformation of the tricuspid valve.^58,93 Prenatal cardiac diagnosis, by facilitating anticipatory use of PGE₁ to prevent closure of the ductus arteriosus in neonates with critical impairment of systemic or pulmonary blood flow, allows affected fetuses to avoid neonatal acidemia, preventing neurodevelopmental damage.⁷¹ Among the individual cardiac lesions for which prenatal diagnosis has been suggested to impart a survival advantage are transposition of the great arteries, coarctation of the aorta, and hypoplastic left heart syndrome.

Cardiac Failure in the Fetus

There are several physiologic factors that can contribute to decreased cardiac reserve in response to stress and to a higher susceptibility of the fetus for cardiac failure.¹⁵ These factors include a reduced ability of the fetal heart to contract and generate force, a lower myocardial compliance with diminished Frank-Starling mechanism, a higher dependence of cardiac output on heart rate, and a lack of adrenoceptors.

Several features are responsible for fluid accumulation in fetal tissue. The final common pathway of many different conditions compromising the cardiovascular system is elevation of ventricular end-diastolic pressure, atrial pressure, and central venous pressure. In the fetus even small increases in venous pressure have been shown to alter fetal organ function. The younger the fetus, the higher its extracellular water content and the lower its tissue pressure.⁹⁵ Evaluation of the venous compartment of hemodynamically disturbed preterm fetuses along with right ventricular filling appears to be a useful model for investigating the physiopathology of fetal deterioration, and therefore may yield indirect discriminatory signs of severe compromise.⁹⁶

Faced with the fetus with hydrops fetalis, one must first determine if the hydrops is cardiac, inflammatory, or metabolic. Immune hydrops must always be considered in the differential diagnosis, but other causes of anemia can cause hydrops such as hemoglobinopathies. Many cases of hydrops are now being attributed to fetal systemic infection. New markers are identifying etiologic agents such as parvovirus or adenovirus. The associated hepatitis with these infections can compromise the protein-producing capability of the fetus, thereby decreasing the fetal oncotic pressure in the vascular space and resulting in fluid loss out of the circulation. Infections can cause hemolytic anemia, which can be treated by fetal transfusion. High central venous pressure may exceed the oncotic pressure of the interstitial space, causing fluid to pass into spaces such as the abdominal cavity (ascites), pleural or pericardial spaces (effusions), or any of the vital organs. Multiple mechanisms of hydrops may coexist and the primary cause may not be immediately obvious. Of more importance is the determination of the prognosis of hydrops. This task is aided by a semiquantitative measure of fetal heart failure—the cardiovascular profile score.⁹⁷

Prognosis of Fetal Heart Failure—Markers of Fetal Mortality

The most useful predictor of perinatal death in fetal hydrops is the presence of umbilical venous pulsations.⁹⁸ This is true because the most common pathway of perinatal demise is compromised fetal cardiac output—fetal congestive heart failure. What follows is a method to detect this entity and to attempt to decide which fetus should be referred to a fetal center. Initially, data are collected during fetal echocardiography:

1. Cardiac size/thoracic size: Cardiac divided by thoracic area ratio (normal 0.25–0.35) or cardiothoracic circumference ratio (normal <0.5)

2. Venous Doppler: Inferior caval or hepatic venous (increased atrial reversal) and umbilical cord vein (pulsations)

3. Four-valve Doppler: Any leak of the valve should be evaluated further

4. M-mode of the ventricular wall shortening

If there are abnormalities in any of these measurements, then a cardiac cause or associated physiological problem may be present and detailed study is indicated to rule out serious cardiovascular involvement.

The Cardiovascular Profile Score

Heart failure in the fetus can be characterized by findings in at least 5 categories, which are obtained during the ultrasonographic examination. The following 5 categories are each worth 2 points in a 10-point scoring system to assess the cardiovascular system. Abnormalities in the cardiovascular profile score may occur prior to the clinical state of hydrops fetalis. The five categories are:

• Hydrops: Ascites, pleural or pericardial effusion (Figure 6-31)

• Venous Doppler: Umbilical vein and ductus venosus (Figure 6-32)

• Heart size (Figure 6-33)

• Abnormal myocardial function: Holosystolic tricuspid regurgitation (Figure 6-34),⁹⁹ right ventricle/left ventricle shortening fraction less than 0.28, holosystolic mitral regurgitation, tricuspid regurgitation dP/dt less than 400, or monophasic filling

• Arterial Doppler: Absent or reversed end-diastolic velocity in umbilical artery (Figure 6-35)¹⁰⁰

Within specific disease entities, more emphasis is placed on certain areas by the attending physician to predict the prognosis. As always, this information can only comprise a portion of the total picture and must be integrated by the attending physician into the diagnostic and treatment plan for the patient.

The cardiovascular profile score gives a semiquantitative score of the fetal cardiac well-being and uses known markers by ultrasound that have been correlated with poor fetal outcome (Table 6-3). This profile is normal if the score is 10 and signs of cardiac abnormalities result in a decrease of the score from normal. For example, if there is hydrops with ascites and no other abnormalities, there would be a deduction of 1 point for hydrops (ascites but no skin edema) and no deductions for the other categories for a score of 9 out of 10.

Treatment

Digoxin is known to decrease the catecholamine response to congestive heart failure and, if there is diastolic dysfunction in the fetus, this may improve filling and lower filling pressures. If the afterload is high, then an increase in oxygen consumption could result from increased inotropy without improved myocardial perfusion. Digoxin may improve peripheral resistances by blocking the vasoconstricting effects of catecholamines. Terbutaline appears to have promise as an inotropic and chronotropic agent, but studies of the possible negative effects on the fetal myocardium are needed.^101,102 At the present time, we use digoxin for fetal cardiac failure due to arrhythmias and high output states such as fistula and anemia.¹⁰³

The rapidity of progression of a disease determines the urgency of treatment. This is due to the fact that the myocardial response to increased wall stress will be either adequate or inadequate depending on the severity and timing and duration of the insult, the coronary perfusion, the nutritional state of the fetus, and the other problems in the pregnancy.

Tei Index

Cardiac function can be estimated using the Tei index, a myocardial performance index. The Tei index is calculated using the filling time of the atrioventricular valve and the ejection time of the ventricle (Figure 6-36). The atrioventricular and semilunar valve movements (clicks) seen on the Doppler velocity waveform patterns are used as the reference points while measuring the cardiac cycle time intervals (the components of Tei index). The Tei index equals (a − b)/b, where a equals the sum of isovolumic contraction time, isovolumic relaxation time, and ejection time, and b equals the ejection time of a cardiac cycle. To calculate the left ventricle Tei index, pulsed-wave Doppler blood velocity waveforms are obtained simultaneously from the inflow and outflow of the left ventricle, and measurements of the a and b components are made. The component a is measured as the time interval from the closure click to the subsequent opening click of the mitral valve. The b component is measured from the opening to the closure of aortic valve. The right ventricle Tei index is calculated by measuring a and b components of the cardiac cycle from the pulsed-wave Doppler blood velocity wave forms of right ventricle inflow and outflow. The component a is measured as the time interval from closure click to the subsequent opening click of tricuspid valve, and the b component from the opening to the closure of the pulmonary valve.¹⁰⁴

The results are independent of ventricular shape, gestational age, and heart rate. The normal value is less than 0.45 and increases with decreased function. Using the Tei index (myocardial function index) in the fetus can aid in assessing the severity of cardiac compromise in the presence of hydrops. The Tei index is abnormal for the right ventricle and left ventricle with fetal hydrops. The severity of fetal congestive heart failure correlates with an abnormal Tei index.¹⁰⁵

Tissue Doppler Imaging in the Fetus

Tissue Doppler is a new technique that uses myocardial velocities as a way to assess fetal ventricular function. The movements of the myocardium are much slower than the flow of blood into and out of the ventricles. Although the inflow and outflow velocities in the human fetus are in the range of 0.5 to 1.0 m/s (50 to 100 cm/s), the myocardial velocities average about one-tenth of these velocities, ranging from 0.05 to 0.1 m/s (5 to 10 cm/s). These low velocity signals are complex in their orientation due to the three-dimensional (3-D) nature of the ventricular contraction.

Early results in examining normal changes of longitudinal myocardial velocities with increasing gestational age have appeared recently. In both ventricles, there were significant correlations between tissue Doppler E′/A′ and pulsed Doppler E/A (Figure 6-37).

Aoki and colleagues studied fetuses with and without heart failure. When compared with control fetuses, the mean E′ was significantly lower and the mean E was significantly higher in fetuses with heart failure, although these parameters did overlap between the 2 groups. The mean right ventricle myocardial wall-motion velocity during atrial contraction, ratio E′/A′ for right ventricle myocardial wall motion velocity during atrial contraction, and right ventricle myocardial wall motion velocity during systole did not differ between the 2 groups. In fetuses with heart failure compared with control fetuses, the mean E/E′ was significantly higher in the heart failure group (9.71 ± 0.91 vs 6.20 ± 0.97; P <.0001).¹⁰⁶ Animal validation has shown decreasing E′ with acidosis.¹⁰⁷

Assessment of myocardial tissue velocities in fetuses is feasible with tissue Doppler imaging. Age-related alterations in tissue Doppler velocities might suggest age-related maturational changes in diastolic function. Fetal tissue Doppler is a promising new technology; however, validating experimental work is needed to assess these ventricular wall changes by other techniques and to calibrate ultrasound machines.

Volume Sonography of the Fetal Heart

Using three- and four-dimensional data acquisition, the fetal heart study can be collected in a short period of time. It is likely that further attempts to improve this technology will result in a more available ability to share data sets with parents, colleagues, and consultants.

Fetal cardiac findings should be integrated into the clinical management of the fetus by a multidisciplinary health care team. The cardiovascular profile score can be used to communicate between visits and specialists to assess the urgency of abnormalities and the prognosis. Serial studies using the cardiovascular profile score are necessary to obtain the value from this test, and this information can be used to develop uniform treatment strategies.

Focused centers of excellence in fetal cardiac assessment are needed to investigate and achieve effective fetal treatment. However, the prenatal diagnosis of congenital heart disease will be difficult to achieve unless providers of obstetrical ultrasonography are able to effectively identify these abnormalities during the screening process. Therefore, each center of excellence in perinatal cardiology must accept the responsibility of education in the surrounding region. Good communication between heart screening sites and perinatal cardiology centers will benefit all involved and will allow progress to occur in this exciting field.

Highlighted References