Diagnosis, Natural History, and Outcome of Fetal Heart Disease

Diagnosis, Natural History, and Outcome of Fetal Heart Disease Lisa K. Hornberger and Catherine Barrea Advances in the prenatal diagnosis of heart disease have improved accuracy in the evaluation of structural heart lesions, dysrhythmia mechanisms, and functional pathology and will lead to better perinatal management and counseling. Additional technical advances will lead to earlier diagnosis, perhaps even during embryonic development. Newer developments, including the transumbilical and transuterine approaches, may make antenatal intervention possible and safer for a larger number of affected pregnancies. Copyright © 2001 by W.S. Saunders Company Key words: Fetal echocardiography, prenatal ultrasound, heart disease, congenital, fetus.

from Montreal's McGill University, first Idescribed imaging of the normal fetal heart

n 1972, Fred Winsberg, a radiologist

in utero using so-called B- or brightnessmode ultrasound. I Nearly a decade later the first reports of M-mode and two-dimensional imaging of the fetal heart were published. 2-s During this period there was a focus on defining normal ventricular and great artery dimensions and in establishing fetal echocardiography, particularly two-dimensional imaging, as a useful tool in the diagnosis of structural 6 and functionaI7 heart lesions and dysrhythmias B,9 in the fetus. With increasing experience in the prenatal detection of structural heart disease, it soon became clear that fetal heart disease represented a more severe spectrum of disease than encountered postnatally,6 and was associated with an increased incidence of extracardiac abnormalities, particularly aneuploidy,lO In the mid to From Ih( Dll'lJIon ofCardlOlogv and Cardioz'aJcular ReJearch, The Hospllal for S,ck Chzldrm, ['nil'ersl!), of Toronto; and Ihe UnweTsilE Cathohque de LoUl'aln, Clilllques L'niversitalTn Saint Lu(, Brussels, BelgIUm. This work was supported In part ~)' a PhyslClan-Inl'estlgator FellowshIp Award from the Amencan Heart AssociatIOn. Massachusetts .1ffilzate. Address reprint requesfr to LISa K. Hornberger, ,IfD, D1lllSlOn of CardlOlo.IO·, The HospItal for Sick Children, 555 L'lllz'em~)' Al'e, Toronlo, Ontano .U5G1XB. COp'mght © 2001 ~)' WB. Saunders Compan,v 1092-9126/01 /0401-0003135.00/0 dOl: JO.1053Ipcsu.2001.23731

late 1980s, assessment of fetal heart function, including pulsed Doppler flow patterns lI ,I2 and assessment of both diastolic l3 and systolic function parameters, H was of particular interest. Today, this area has continued to be important as we gain experience with primary and secondary causes of myocardial dysfunction and are searching for predictors of perinatal outcome,IS.If} Over the past 2 decades, enhancements in real-time, gray-scale imaging, with phased array technology, computerization of imaging techniques, advanced digital scan converters, dynamic focusing, and annular array technology have resulted in significant improvements in image quality, Further technical advances and clinical experience have resulted in more precise anatomic assessment of the fetal heart. Diagnosis of fetal heart disease as early as 10 to 14 weeks has become possible. 17 With serial evaluation, we also have begun to appreciate the natural history of fetal heart disease beyond the embryonic period, including the development of secondary lesions and more severe disease by term. I8-2I In the last few years of the millennium we also have sought to show the impact of fetal echocardiography, both in the incidence of certain cardiovascular defects observed among live births 22 ,23 and in the perioperative outcome of critical neonatal heart disease,u-26 The subsequent sections of this

Pedlatne Cardiac SurgeD' Annual of Ihe Seminars ill ThoraCIC and Cardiovascular Su~~e,:)'. Vol -I. 2001: pp 229-243

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chapter will focus on the current approach to prenatal diagnosis of congenital heart disease, the antenatal natural history, prenatal counseling, impact of fetal echocardiography, and future directions in fetal cardiology.

Prenatal Diagnosis of Heart Disease Indications for fetal echocardiography can be divided into three categories; maternal risks, fetal risks, and familial risks (Table I). Although the most common reason for referral in the majority of practices is for a family history of congenital heart disease and maternal metabolic disease, the reason for referral that results in the highest yield of fetal cardiac pathology by far is a suspected cardiovascular abnormality on a routine fetal Table 1. Indications for Fetal Echocardiography Maternal Indications

Metabolic disorders Insulin dependent diabetes (4%-5%) Phenylketonuria (15% if maternal phenylaline > 15%) Teratogen exposure Thalidomide (10% if 20-36 days post conception) Lithium (-7%) Alcohol (25% with fetal alcohol syndrome) Anticonvulsants Isotretinoin Maternal heart disease (5%-10%)

Fetal Indications

General ultrasound suggestive of fetal heart defect Fetal arrhythmia Extracardiac defects Chromosomal anomalies (includes abnormal maternal serum screen) Syndromes Structural lesions Nonimmune hydrops (20%-30%) Polyhydramnios

Familial Indications

Mendelian syndromes Tuberous sclerosis Noonan syndrome DiGeorge syndrome Holt-Oram syndrome Patemal heart disease Previously affected child

anatomic screen, typically performed in the midtrimester. 27 The second reason most likely to yield fetal cardiac abnormalities is the presence of an extracardiac abnormality in the fetus. Given this experience, efforts to improve screening of primarily low-risk pregnancies in general obstetrical and radiology practices are critical for the development of a successful fetal cardiac program. Fetal echocardiography is typically performed at 17 to 23 weeks of gestation in pregnancies at increased risk for fetal heart disease. Given the timing of routine fetal anatomic scans, referrals for suspected fetal cardiac disease in low-risk pregnancies are often performed in the same time period. However, many pregnancies continue to be referred later in gestation, frequently as a result of pathology missed on an earlier screen or lack of an earlier screen. Early recognition of pathology and referral for fetal echocardiography have major advantages in terms of providing time for fetal karyotyping, further anatomic assessment for extracardiac pathology, and the option of termination of pregnancy should the mother and her family so-desire. For most centers in North America, the latest gestational age that an elective termination of pregnancy can be offered is 22 to 23 weeks. However, under special circumstances some centers will offer pregnancy termination at S 32 weeks for more "lethal" conditions, often with the assistance of an ethics committee. Fetal echocardiography in the late first and early second trimester is only offered in certain programs with high-resolution ultrasound instruments and endovaginal transducers that provide improved image resolution for gestations of less than 16 weeks. The utility of early screening for fetal heart disease in a general population has not yet been shown. However, in conjunction with a finding of increased nuchal translucency in the 10- to 14-week fetus, with or without chromosomal abnormalities, it may play a very important role. 28

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There are several unique aspects of fetal echocardiography relative to postnatal echocardiography that are important to keep in mind, both for the individuals responsible for the assessment and for those involved in perinatal management. Imaging of the fetal heart requires orientation to the fetal position within the mother and imaging at a greater depth than is true for pediatric echocardiography. Fetal size may be a limiting factor, particularly at less than 17 weeks of gestation and at more than 35 weeks. Limited fetal movement, the vertex and prone position, and reduced amniotic fluid also restrict imaging. Nonstandard views relative to those obtained postnatally are almost always the rule. The presence of fetal circulation requires reliance on indirect findings to assess severity of disease, such as ventricular and great artery absolute size and discrepancy between the ventricles and great arteries. The foramen ovale, ventricular septal defects, and ductus arteriosus permit a redistribution of blood flow, such that detecting a significant gradient in the presence of ventricular inflow or outflow tract obstruction is unusual. One is entirely dependent on echocardiographic findings for clinical information. Finally, there must be immediate analysis of the findings for appropriate counseling of the mother and her family. Cardiovascular abnormalities detected in utero by fetal echocardiogtaphy can be di-

vided into three primary categories: structural heart lesions, dysrhythmias, and primary functional myocardial diseases. Of the three categories, the most common abnormalities detected are structural defects, which will be the primary focus of the remainder of this chapter. To date, the diagnosis of most forms of major and minor structural heart disease has been described. In our earlier experience, the types of lesions primarily identified were those associated with an abnormal four-chamber view. 29 Such lesions included atrioventricular septal defects (Fig I), single ventricles, tricuspid valve dysplasias and Ebstein's anomaly of the tricuspid valve (Fig 2, see Fig 2b on color plate on p 231), and severe left and right heart obstruction. With the incorporation of outflow tract and great artery images, detection of many other lesions has become more common, including transposition of the great arteries, conotruncal anomalies (Fig 3), and arch anomalies. In addition to making a primary diagnosis, a thorough assessment for cardiac lesions that will complicate the postnatal medical management and ultimate surgical repair or palliation of the infant is critical. For instance, in hypoplastic left heart syndrome, evaluation of the atrial septal communication and pulmonary venous flow pattern provides crucial information regarding the degree of foramen ovale restriction and left atrial hypertension (Fig 4). Assessment of

Figure 1. Two-dimensional images obtained in a 23-week gestational age fetus with a balanced atrioventricular septal defect (a,b) and in a 19-week fetus with an unbalanced defect and hypoplastic left ventricle and aortic arch (c,d). (a) The four chamber view in ventricular systole shows an absence of the crux of the heart, a common AV valve, and symmetry of the ventricles. (b) The short-axis view demonstrates both superior and inferior bridging leaflets with symmetric opening over both ventricles (arrowheads) . The superior bridging leaflet has attachments to the ventricular septum. (c) In the second fetus, there was obvious asymmetry in the four chamber view with moderate left ventricular hypoplasia. (d) The short-axis image of the same fetus further confirms the presence of an unbalanced atrioventricular septal defect with a free-floating superior bridging leaflet (arrowheads). A, anterior; P, posterior; L, left; R, right; S, superior; I, inferior; RVOT, right ventricular outflow tract; RV, right ventricle; LV, left ventricle; PA, pulmonary artery.

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detected but could impact outcome. Lesions including small- to moderate-sized atrial and ventricular septal defects, complex apical muscular ventricular septal defects, minor valve abnormalities, partial anomalous pulmonary veins (Fig 6), and coronary artery anomalies (Fig 5) may be difficult to exclude with very few exceptions (see color plate for Fig 6 on p 231). There are several structural heart defects thal also are more commonly encountered in the fetus, either because of high intrauterine loss or lack of symptoms postnatally. Such lesions include ductus arteriosus aneurysms,31 ectopia cordis,32 and ventricular aneurysms. 33

Antenatal Evolution of Heart Disease Figure 2. Echocardiographic images obtained in a 28-week gestational age fetus with Ebstein's anomaly of the tricuspid valve. (a) There is significant right atrial dilation in the four chamber view. The septal leaRet is tethered (arrowheads) and there is poor coaptation of the leaflets in ventricular systole. (b) Color flow imaging confirms the presence of significant tricuspid insufficiency with a jet that starts well within the body of the right ventricle (arrow). (See Fig 2b color plate on p 231.) RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.

the lorman ovale and ductus arteriosus?' ventricular outlets, semilunar and atrioventricular valves, and identification of ventricular septal defects is important in transposition of the great arteries (Fig 5). For more complex lesions associated \vith heterotaxy syndrome, the segmental anatomy must be defined, as well as the svstemic and pulmonary venous connections, ventricular size, the ventricular septal defect morphology, outflow tract arrangement, and presence or absence of outlct obstruction. In addition to considering what can be seen, it is critical 1hal one consider lesions that might not be

In addition to the detection of all obvious structural cardiovascular defects, the potential for antenatal progression of disease over the remaining weeks or months of gestation must always be considered. Fetal heart disease can progress toward more severe disease in five different ways: 1) development or progression in the degree of outftO\'\' tract obstruction; 2) development or progression in the degree of ventricular and great artery hypoplasia, particularly in the context of ventricular inAow or outflow tract obstruction; 3) development or progression in the degree of atrioventricular or semilunar valve regurgitation; 4) development or progression in the degree of dysrhythmia; and 5) development of congestive heart failure. Probably the most intriguing form of evolution that provides insight into the spectrum of lesions encountered postnatally is the development and progression in the degree of ventricular and great artery hypoplasia. Fetal life is characterized by very rapid growth that is most accelerated in the first half of gestation. Although the increase in grams per week is greatest in the third trimester, the magnitude of change in body size is in facl more dramatic in the earlier periods of gestation.

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Figure 3. Echocardiograms obtained in a 23-weck gestational age fetus with tnmcus arteriosus type I and 22.q 11.2 deletion. (a) The four-chamber view is not so abnormal as is typical for many conotruncallesions. (b) A parasternal short-axis equivalent shows the key pathology with a large subarterial \'e ntricular septal defect (arrow) and an overriding dysplastic truncal valve. The main pulmonary artery arises from the posterior and leftward aspect of the trunk as further demonstrated in (c), right at the sinotubular junction of the trunk. (b and c) Continued cross-sectional sweeps from (a) in a caudal to cephalad direction o\'er the fetal thorax. The trachea (d) and both bronchi (c) can be visualized just anterior to the spine. The truncal arch clearly descends initially to the left of the spine. Further assessment confIrmed normal branching of th e brachiocephalic n :sscls. RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle ; PA, pulmonary artery; 1'r, truncus arteriosus; LPA. left pulmonary artery; RPA, right pulmonary artery; SVC, superior \'ena cm'a; L~ , left aortic arch.

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Figure 4. Images obtained in a 20-week fetus with aortic and mitral atresia. (a) The four-chamber view confirmed the primary diagnosis; however, further assessment showed a thickened atrial septum (a) with a small high velocity jet from left to right (not seen in the planes shown). The left and right pulmonary veins were dilated (arrows), (in fact, anatomically larger than the branch pulmonary arteries) and by color How mapping (b and c) (see Figs 4b and c color plate on p 231) and pulsed Doppler (d) demonstrated forward How in ventricular diastole (b), and retrograde How during atrial contraction (c), consistent with significantly increased left atrial pressure. This is in contrast to the normal pulmonary vein flow pattern which is nearly continuous with only brief cessation of flow in atrial systole (sec Fig 6). LA, left atrium; RA, right atrium; RV, right ventricle. For instance, from 10 to 20 ,,,,eeks the fetus shO\,\,s a 10-fold increase in body weight (from 30 to 300 grams on average). From 20 to 30 weeks of gestation there is a nearly 5-fold increase in weight (from 300 to 1,500 grams on average), and in the last 10 weeks the magnitude of increase is only 2- to 3-fold (from 1,500 to 3,000 grams).:\! Growth of cardiovascular structures nearly parallels this general somatic grov.·th, with t he most accelerated growth occurring shortly after the heart is formed (Fig 7). If there is any disturbance in growth secondary usually to altered blood flow (eg, critical aortic stenosis or pulmonary stenosis), with a redistribution of blood flow towards

the unaffected heart, the fetus can still thrive, but growth of the obstructed heart or vessel will be reduced. 2(),3j With the patterns of cardiovascular growth that occur ante natally, the earlier in gestation the growth disturbance occurs, the more severe the degree of ventricular or great artery hypoplasia. For instance, critical aortic stenosis at 10 to 14 weeks with left ventricular dysfunction and reduced filling likely results in hypoplastic left heart syndrome by 20 to 24 weeks, with no visible left ventricular cavitv. If the aortic stenosis occurs more gradually and becomes critical only in the third trimester,211 the left ventricular size may be relatively normal. I

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Figure 5. Two-dimensional images obtained in a 30-week gestational age fetus with Dtransposition of the great arteries. In the short axis view, the aortic (a) and pulmonary valves (b) could be shown and appeared to be trileaftet and thin. (c) Sweeping further down into the ventricles, a tuft of mobile tissue was detected beneath the pulmonary valve in the left ventricular outflow tract (arrow). (See Fig 5c color plate on p 231.) (d) Rotating into an oblique sagittal plane we were convinced this tissue likely represented aneurysm of membranous septum, and further confirmed the presence of a perimembranows ventricular septal defect (*) by c) color flow mapping. The ventricular septal defect flow was primarily from right ventricle to left. Finally, coronary artery assessment showed usual coronary artery pattern for D- transposition of the great arteries with f) the left main arising from the left-anterior sinus, and the right coronary artery from the right-posterior sinus, and g) a bifurcation of the left main into the circumflex and the left anterior descending. Our prenatal observations were confirmed at postnatal echocardiography and surgery. Ao V-aortic valve, Pulm V-pulmonary valve, RA-right atrium, LA-left atrium, RV- right ventricle, LV-left ventricle, RCA-right coronary artery, LCA-Ieft coronary artery.

The potential for progression in the degre~ of outlet obstruction has been documented. This is particularly true for tetralogy of Fallot,19 lesions associated with severe tricuspid insufficicncy,:lti and even for semilunar valve obstructioll. 20 . 2 1. :1'l, 3 7 The development or progression in the degree of atrio-

ventricular and semilunar valve regurgitation would be particularly important in the context of single ventricle physiology and in lesions with outflmv tract obstruction. In these conditions, such regurgitation may be very poorly tolerated in utero and may impact postnatal management. Atrio\,cntriclI-

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Figure 6. (See color plate on p 231.) Echocardiograms obtained in a 23-week fetus with a diagnosis of partial anomalous pulmonary venous connection. (a) By color flow mapping in a four-chamber view, return from one left pulmonary vein can be seen entering the left atrium (arrow). The rightward posterior aspect of the left atrium had no obvious pulmonary venous flow (lie). On further assessment, at least one right pulmonary vein could be seen connecting to the right atrium (arrow) to the right of the inferior vena cava-right atrial junction (suspected right lower pulmonary vein) as demonstrated by (b) color flow mapping and by (c) spectral Doppler tracing obtained in this vessel with a typical pulmonary venous flow pattern. RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; LPV, left pulmonary vein; RPV, right pulmonary vem.

lar conduction problems may develop in isolation in the presence of maternal autoantibodies, but also must be considered in the presence of heterotaxy syndrome (eg, left atrial isomerism), L-ventricular looping, and even atrioventricular septal defects. 38 The development of heart block in the presence of complex heart disease associated with polysplenia has a grim prognosis with a very high perinatal 108s.38 Supraventricular tachyarrhythmia and atrial flutter may develop in the presence of significant atrial enlargement (eg, Ebstein's anomaly of the tricuspid valve), which also may lead to rapid decompensation. 36 Finally, any structural, functional, or rhythm-related abnormality that results in increased systemic venous pressures can lead to the development of congestive (right) heart failure which, in its most severe state, is manifested as hydrops fetalis. Much like Fontan circulation, the fetal circulation relies on very low downstream pressures. Any cause for increase in ventricular filling, atrial filling, and systemic venous pressures leads to a reduction in umbilical

venous flow with development of placental edema, serosal fluid collections, and skin edema in the fetus. Of the primary cardiac causes of fetal congestive heart failure, truly effective antenatal treatment strategies are currently only available for tachyarrhythmias. 39,4o

Prenatal Counseling All fetal echocardiographers have their own unique approach to counseling, and although we try to not provide a bias, this can be challenging at times. Clearly it is one of the more difficult aspects of prenatal diagnosis, even for the most experienced individual. One must describe for the family the cardiovascular defect, taking into consideration their level of education and ability to comprehend. Information regarding the anticipated prenatal and postnatal course must be presented. An algorithm of management, depending on the clinical status of the infant after birth, may be provided when the postnatal severity of disease is not entirely clear (especially with pulmonary outflow tract obstruction). It is critical that the counselor is aware of the current mortality and morbidity risks for any given procedure in his or her own institution, in addition to the risks published in the literature, taking into consideration any unusual or additional lesion that may worsen the prognosis (which mayor may not be detected). Information regarding long-term outcome, particularly the impact of a cardiovascular defect on general quality of life, cognitive function, and physical abilities is often requested by parents. Extracardiac abnormalities associated with the defect postnatally which mayor may not be antenatally detected must be considered, with appropriate referral for fetal anatomic assessment, fetal karyotyping, and genetic counseling. Potential for progression of the defect also must be considered, including the need for serial antenatal assessment. Excellent communication with obstetrical and neonatal colleagues regarding the timing, location, and route of delivery improves peri-

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Figure 7. (Top) Photograph showing normal human hearts obtained from 8- to 19-week gestational age fetuses. Note the rapid change in heart and great artery size over this very brief period of gestation (scale represents I mm for smaller bars and 5 mm for larger bars). (Bottom left) Left and right ventricle short-axis growth. (Bottom right) Aortic and pulmonary artery growth. Growth curves obtained in normal fetuses from 10 weeks to term. Again, note the rapid growth particularly in the 10- to 20-week gestational age period relative to the latter half of gestation.

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natal management of an affected fetus. Furthermore, early discussion with cardiovascular surgical colleagues, particularly when an earlier delivery is being entertained, is necessary, again to ensure the most appropriate management of the mother and fetus.

Perinatal Outcome of Fetal Heart Disease An increased incidence of chromosomal abnormalities, genetic syndromes, and major extracardiac pathology significantly contribute to the worse outlook of antenatally detected congenital heart disease. Certain cardiac lesions are poorly tolerated in utero. For example, Ebstein's anomaly of the tricuspid valve and other causes of significant tricuspid regurgitation are associated with 48% intrauterine loss when the pregnancy is continued. 36 Other lesions such as atrioventricular septal defects and tetralogy of Fallot have a very high incidence of chromosomal anomalies and extracardiac lesions occurring in approximately 60% to 70%.41,42 Excluding cases with severe extracardiac pathology and chromosomal anomalies, several groups have begun to assess the impact of fetal echocardiography on the perioperative morbidity and mortality of structural heart lesions in particular. As has been shown for hypoplastic left heart syndrome 25 ,43 and transposition of the great arteries 25 among other lesions, prenatal diagnosis does result in an improved preoperative condition and decreased morbidity. It may reduce hospital stay and costs. 24 More recent data suggest it also may have an impact on neonatal mortality for critical neonatal heart disease,26 although limited numbers from any single center restrict this assessment.

Future Directions in Fetal Cardiology The field of fetal and perinatal cardiology is expanding in many exciting directions. In the future, we will no doubt continue to strive for improved diagnostic accuracy in

the evaluation of structural heart lesions, dysrhythmia mechanisms, and functional pathology, which will ultimately lead to better perinatal management and counseling. Further technical advances will likely lead to even earlier diagnoses, perhaps even during embryonic development. To date, attempts at antenatal intervention for structural heart disease, particularly semilunar valve obstruction, in the human fetus has been limited to isolated case reports. 44 However, newer directions, including the transumbilical and transuterine approaches, may make antenatal intervention possible and safer for a larger number of affected pregnancies.45 ,46 We will continue to expand our role in the assessment of secondary causes of ventricular dysfunction before and after intervention, and in the evaluation of lesions associated with lung hypoplasia. As our exposure to many pathologic conditions of pregnancy is broadened, we will likely playa larger role in defining fetal physiology in health and maternal, placental, and fetal disease. There is a growing interest in the investigation of hemodynamic, cellular, and molecular causes of fetal heart disease and its progressionY Finally, in addition to seeking improved genetic screening for fetal heart disease, we look toward the long-term prospects of fetal gene therapy to prevent and palliate congenital heart disease in utero. Fetal echocardiography will remain an established arm of pediatric cardiovascular medicine, and the prenatal detection of structural heart disease, in particular, will indubiously continue to impact our pediatric cardiology and cardiovascular surgical practices.

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3. Lange LW, Sahn D], Allen HD, et al: Qualitative real-time cross-sectional echocardiographic imaging of the human fetus during the second half of pregnancy. Circulation 62: 799-805, 1980 4. Sahn D], Lange LW, Allen HD, et al: Quantitative real-time cross-sectional echocardiography in the developing normal human fetus and newborn. Circulation 62:588-603, 1980 5. Huhta ]C, Hagler D], Hill LM: Twodimensional echocardiographic assessment of normal fetal cardiac anatomy.] Reprod Med 29: 162-165, 1984 6. Allan D, Crawford DC, Anderson RH, et al: Spectrum of congenital heart disease detected echocardiographically in prenatal life. Br Heart] 54:523-526, 1985 7. Kleinman CS, Donnerstein RL, DeVore GR, et al: Fetal echocardiography for evaluation of in utero congestive heart failure. N Engl] Med 306:568-571, 1982 8. Kleinman CS, Donnerstein RL, Jaffe CC, et al: Fetal echocardiography: A tool for evaluation of in utero cardiac arrhythmias and monitoring of in utero therapy: Analysis of 71 patients. Am] Cardiol 51:237-242,1983 9. Allan LD, Anderson RH, Sullivan ID, et al: Evaluation of fetal arrhythmias by echocardiography. Br Heart ] 50: 240-245, 1983 10. Cope I ]A, Pilu G, Kleinman CS: Congenital heart disease and extracardiac anomalies: Associations and indications for fetal echocardiography. Am] Obstet Gynecol 154:1121-1124, 1986 11. Huhta]C, Strasburger ]F, Carpenter R], et al: Pulsed doppler fetal echocardiography. ] Clin Ultrasound 13 :247 -251, 1985 12. Reed KL, l\leijboom E], Sahn D], et al: Cardiac doppler flow velocities in human fetuses. Circulation 73:41-46, 1986 13. Reed KL, Sahn D], Scagnelli S, et al: Doppler echocardiographic studies of diastolic function in the human fetal

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tricular septum: Impact of fetal echocardiography on incidence at birth and postnatal outcome. UK and Eire Collaborative Study of Pulmonary Atresia with Intact Ventricular Septum. Circulation 98:562-566, 1998 24. CopellA, Tan AS, Kleinman CS: Does a prenatal diagnosis of congenital heart disease alter short-term outcome? Ultrasound Obstet Gynecol 10:237-241, 1997 25. Kumar K, Newburger lW, Gauvreau K, et al: Comparison of the outcome when hypoplastic left heart syndrome and transposition of the great arteries are diagnosed prenatally versus when diagnosis of these two conditions is made only postnatally. Am] Cardiol 83: 16491653, 1999 26. Bonnet D, Coltri A, Butera G, et al: Prenatal diagnosis of transposition of great vessels reduces neonatal morbidity and mortality. Arch Mal Coeur Vaiss 92: 637-640, 1999 27. Cullen S, Sharland GK, Allan LD, et al: Potential impact of population screening for prenatal diagnosis of congenital heart disease. Arch Dis Child 67:775778, 1992 28. Hyett lA, Perdu M, Sharland GK, et al: Increased nuchal translucency at 10-14 weeks of gestation as a marker for major cardiac defects. Ultrasound Obstet Gynecol 10:242-246, 1997 29. Copel ]A, Pilu G, Green], et al: Fetal echocardiographic screening for congenital heart disease: The importance of the four-chamber view. Am] Obstet Gynecol 157:648-655, 1987 30. Maeno YV, Kamenir SA, Sinclair B, et al: Prenatal features of ductus arteriosus constriction and foramen ovale restriction in d-transposition of the great arteries. Circulation 99:1209-1214,1999 31. Dyamenahalli U, Smallhorn ]F, Geva T, et al: Isolated ductus arteriosus aneurysm in the fetus and infant: A multiinstitutional experience.] Am Coil Cardiol 36:262-269, 2000

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