Differential diagnosis and approach to a heart murmur in term infants
Pediatr Clin N Am 51 (2004) 1023 – 1032 Differential diagnosis and approach to a heart murmur in term infants Michele A. Frommelt, MDChildren’s Hospital of Wisconsin, The Medical College of Wisconsin, 9000 West Wisconsin Avenue, P.O. Box 1997, Milwaukee, WI 53201, USA The incidence of structural congenital heart disease is estimated to be less than1% of all live births . In contrast, as many as 90% of children will have anaudible heart murmur at some point in time , and Braudo and Rowe reporteda murmur in 60% of healthy newborn babies . It therefore becomes theclinician’s responsibility to screen infants and children and determine whichpatients need further evaluation, because universal screening by echocardiogra-phy or pediatric cardiology consultation is not economically feasible. In this article, the author discusses the differential diagnosis and approach to aheart murmur in the infant born at term but less than 6 months of postnatal age. Itis important to remember that a heart murmur in this age group more frequentlyreflects structural heart disease, in contrast to a heart murmur in the toddler orolder child. The author focuses on the most common structural lesions presentingwith a murmur in this age group, reviewing important aspects of the history,physical examination, and cardiac examination.History Although there are many clinical and diagnostic tools that can help us dis-tinguish the innocent murmur from the pathologic murmur, the value of a com-plete medical history cannot be overestimated. The historical assessment of theterm infant should include questions about the family, the pregnancy, the peri-natal course, and early growth and development. Is there a sibling or first-degreerelative with structural heart disease? Are there any known heritable syndromes,such as Marfan’s syndrome or hypertrophic cardiomyopathy? A maternal historyof diabetes mellitus, especially when poorly controlled during pregnancy, can be E-mail address: email@example.com/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.doi:10.1016/j.pcl.2004.03.003
1024 M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032associated with significant heart disease in up to 30% of infants . Was the fetusexposed to alcohol or any maternal medications? Perhaps the most importantquestions in the term infant with a heart murmur should focus on the perinatalcourse, as well as on the early growth and development. Were there any problemsat the time of birth? Was there any cyanosis or tachypnea? What was the infant’sbirth weight, and has the infant grown appropriately? Although weight gain isvariable in the term infant, most will regain their birth weight by 2 weeks of age,and double their birth weight by 6 months of age . An accurate feeding historyis of the utmost importance, because feeding difficulties are common manifes-tations of congestive heart failure in the infant. When taking the feeding history,one must not only inquire about volume per feeding, but also inquire about lengthof time per feeding, and associated symptoms such as tachypnea or diaphoresis.Although infants with a large ventricular septal defect may take four ounces perfeeding, it typically takes them much longer to complete the feeding, withfrequent breaks, presumably from the combined effort of sucking and maintain-ing a rapid respiratory rate. Early developmental milestones can be delayed,especially gross motor milestones.Table 1Malformation syndromes associated with congenital heart diseaseSyndrome Cardiac defectAlagille (arteriohepatic dysplasia) Peripheral pulmonary stenosisColoboma, Heart defects, Atresia Ventricular, atrioventricular, and atrial septal defects of the choanae, Retardation of growth and development, Genital and urinary abnormalities, Ear abnormalities and/or hearing loss (CHARGE)De Lange’s Tetralogy of Fallot, ventricular septal defectDiGeorge Aortic arch anomalies, tetralogy of FallotDown Atrioventricular septal defects, ventricular septal defectFetal alcohol Ventricular septal defect, atrial septal defect, tetralogy of FallotGoldenhar’s Tetralogy of FallotHolt-Oram Atrial or ventricular septal defectLaurence-Moon-Biedl Tetralogy of Fallot, ventricular septal defectMultiple lentigenes (leopard) Pulmonary stenosisNoonan’s Pulmonic stenosis, atrial septal defectRubella Patent ductus arteriosus, peripheral pulmonary stenosisRubinstein-Taybi Patent ductus arteriosusScimitar Hypoplasia of the right lung, anomalous pulmonary drainageSmith-Lemli-Opitz Ventricular septal defect, patent ductus arteriosusThrombocytopenia-absent radius(TAR) Atrial septal defect, tetralogy of FallotTurner’s Coarctation of the aorta, bicuspid aortic valveVelocardiofacial Ventricular septal defect, right aortic archWilliams Supravalvular aortic stenosis, peripheral pulmonary stenosis
M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032 1025General examination Any physical examination in the term infant should begin with a generalassessment of overall appearance. Does the infant appear robust, playful andcomfortable, or is the infant irritable, diaphoretic, and breathless? Are there anydysmorphic features or extracardiac anomalies? Although structural congenitalheart disease can be an isolated abnormality, there are a great number ofmalformation syndromes involving the cardiovascular system (Table 1). Growthparameters should be plotted on appropriate growth charts, and vital signs shouldbe recorded. Heart rate, respiratory rate, and blood pressure should be measured.Although it may require a team effort to measure an accurate blood pressure inthe infant, this is a critical but often neglected part of the infant examination. Arethere any signs of respiratory distress, such as tachypnea, retractions, grunting, ornasal flaring? Is the infant pink, or is there subtle cyanosis of the mucousmembranes? Acrocyanosis (bluish discoloration of the skin related to vasospasmof the subcutaneous blood vessels) should be differentiated from true centralcyanosis, because acrocyanosis is a normal phenomenon in the young infant.Acrocyanosis is commonly noted on the hands and feet, and occurs on exposureto cold, generally improving with activity. If there is any question, pulse oximetryis indicated. Hepatomegaly is common in infants with congestive heart failure, soa relaxed abdominal examination is very important. The typical signs of venouscongestion that are seen in the adult are rare in the infant. Jugular venousdistention is difficult to assess, and peripheral edema is usually secondary to renaldisease with hypoproteinemia, not cardiac disease.Cardiac examination The cardiac examination should be performed in a systematic manner, so thatone does not become unduly focused on a single finding; however, one needs tobe flexible enough to alter the approach, especially in the term infant, who is notalways quiet or sleeping. One general approach is to start with inspection andpalpation, and to do this appropriately, one needs to lay the hands directly on thechest. Is there a left-sided precordial bulge, suggesting cardiac enlargement? Isthere a substernal heave, indicating right ventricular hypertension? Is there apalpable precordial thrill? Any of these additional findings in the term infant witha heart murmur suggest that the murmur is indeed pathologic. If the infant isquiet, one may then go on to auscultation, again remembering to approach this ina systematic manner. The first heart sound, reflective of mitral and tricuspid valveclosure, is typically single and is best heard at the left lower sternal border. Thesecond heart sound, reflective of aortic and pulmonary valve closure, is split,varies with respiration, and is best heard at the left upper sternal border.Abnormalities of the second heart sound are often seen in congenital heartdisease, making it perhaps the most important element of auscultation in thepediatric patient. Third and fourth heart sounds can be normal in the child, are
1026 M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032typically low in frequency, and are best heard at the cardiac apex. Systolicejection clicks are typically high in frequency, occur early in systole, and oftenreflect semilunar valvar stenosis. Murmurs should be described by their intensityand timing, as well as their location and radiation. Any variability that occurswith a change in position or with a maneuver should be described. The Grade Imurmur is barely audible and often only heard in a quiet environment with acooperative child. The Grade II murmur is soft but easily audible, whereas theGrade III murmur is loud and often recognized immediately when placing thestethoscope on the chest. The Grades IV, V, and VI murmurs are associated with apalpable precordial thrill, and are always pathologic. The ability to discern theGrade V murmur (audible with the edge of the stethoscope on the chest wall) orGrade VI murmur (audible with the stethoscope off the chest wall) adds little tothe diagnosis. After grading the murmur, one must define the timing of themurmur, or when it occurs within the cardiac cycle. Is it systolic, diastolic, orcontinuous (throughout the cardiac cycle)? The two major types of systolicmurmurs are the systolic ejection murmur and the systolic regurgitant murmur.The systolic ejection murmur is harsh, starts beyond the first heart sound, and isdiamond-shaped. The systolic regurgitant murmur is blowing, starts with andobscures the first heart sound, and plateaus throughout its course. The innocentmurmurs are soft (Grade I or II) and ejection in quality; the pathologic systolicmurmur occurs early in systole and can be quite loud. Although diastolic mur-murs are much less common in the child, the auscultation of a diastolic murmurindicates that structural heart disease is present. Continuous precordial murmursin infants are also generally pathologic, with the exception of the cervical venoushum. The venous hum, an innocent murmur related to turbulent flow at thejunction between the jugular vein and the superior vena cava, should resolve inthe supine position or with gentle compression of the jugular vein. After cardiacauscultation is performed, one should assess the peripheral pulses for rate,rhythm, and character. Are the pulses weak or bounding? Are the pulses sym-metric? Feeling the femoral pulses is a critical part of the cardiac examination,because weak or absent femoral pulses are the hallmarks of aortic coarctation.Last, a simple, noninvasive indicator of cardiac output is the measured capillaryrefill time. This is obtained by blanching the nail bed or digit, and observing thetime to reperfusion, typically less than 3 seconds.Specific lesionsPeripheral pulmonary stenosis Several studies in the literature have suggested that innocent heart murmurs inhealthy term infants are mostly related to pulmonary branch stenosis, which isreduced in two thirds of cases by 6 weeks of age and in most others by 6 months. The etiology of the murmur is secondary to both relative hypoplasia of thepulmonary artery branches and an associated angulation at their origin . The
M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032 1027murmur is soft (Grade I or II), ejection in quality, and best heard anteriorlyat the left upper sternal border; however, the murmur is clearly recognizedby its characteristic transmission to the axillae and back bilaterally, and by itsdisappearance over time. There are no associated signs or symptoms of heartdisease, and the rest of the cardiac examination is normal. The pulmonary flowmurmur of an atrial septal defect may mimic this murmur, but is generally heardin later infancy or childhood. Pulmonary valve stenosis is of louder intensityand is associated with an early systolic ejection click; severe stenosis can re-sult in a precordial thrill. Pathologic peripheral pulmonary stenosis is typicallymore severe, generating a louder murmur, and does not regress over time.Associated noncardiac anomalies and dysmorphic features are common withpathologic branch stenosis. Coarctation of the aorta can result in a murmur at theleft upper sternal border and left back; however, a careful assessment of lowerextremity pulses should easily differentiate aortic coarctation from pulmonarybranch stenosis. If peripheral pulmonary stenosis is suspected in the term infant with a heartmurmur, close follow-up by the clinician is indicated. If the murmur intensifies orpersists after 6 months of age, cardiology referral is indicated.Ventricular septal defect Excluding the bicuspid aortic valve, which may be difficult to recognize inneonates, isolated ventricular septal defects are the most common congenitalheart defect identified through the first 3 decades of life, with an incidence from1 to 7 per 1000 live births . Certainly, in the experience of the author andothers , the term infant with a pathologic heart murmur is more likely to havean isolated ventricular septal defect than any other form of congenital heartdisease. It is important to remember that these infants can present in differentways, and that the presentation is determined by the size of the defect and thestatus of the pulmonary vascular resistance. Most commonly the murmur is detected at 2 to 6 weeks of age, when theinfant returns for the initial checkup after hospital discharge; however, in thepresence of a small defect associated with a normal fall in pulmonary vascularresistance, the murmur can be heard during the first few days of life. The infantwith a small ventricular septal defect otherwise appears healthy, with normalgrowth and no cardiac symptoms. The precordial activity is normal, and theretypically is not a palpable systolic thrill. The murmur of a small ventricular septaldefect can be quite loud, reflecting the normal drop in pulmonary vascularresistance and resultant high-velocity, turbulent jet of flow between the higher-pressured left ventricle and the lower-pressured right ventricle. Of note, if a smallmuscular defect is present, the murmur is softer and confined to early systole,because these defects are obliterated in mid systole with ventricular contraction.The infant with a moderate-sized ventricular septal defect is often of small size,with decreased weight gain, and the parents may note dyspnea and diaphoresis,especially with feedings. Although the pulmonary vascular resistance has typi-
1028 M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032cally fallen, the moderate defect allows a more significant volume left-to-rightshunt, leading to cardiomegaly and a hyperdynamic precordium. The murmuris always loud, is frequently associated with a systolic thrill, and is harsh andholosystolic, obscuring the first and second heart sounds. Because of the increasedpulmonary blood flow, which is often twice the systemic flow, a prominent thirdheart sound or diastolic flow murmur can be heard at the cardiac apex. Thisreflects the increased flow across the mitral valve, causing a relative mitralstenosis murmur in mid-diastole. The infant with a large ventricular septal defectcan be more of a diagnostic dilemma, but should be recognized because of sig-nificant clinical symptoms and failure to thrive. Feeding problems and irritabilityare common, and infants may be misdiagnosed with colic or gastroesophagealreflux. The large defect allows a significant volume left-to-right shunt and leftheart volume overload, leading to an increased left-ventricular precordial im-pulse. Because the pulmonary vascular resistance remains moderately elevatedwith resultant right ventricular and pulmonary artery hypertension, there is amarked right ventricular heave, with a loud and single second heart sound. Themurmur is soft (Grade II), short and early systolic, again reflecting the significantelevation in right ventricular and pulmonary artery pressures. A prominent thirdheart sound and diastolic rumble are common. These infants will also havehepatomegaly, and systemic perfusion can be compromised. If a ventricular septal defect is suspected in the term infant with a heartmurmur, cardiology referral is indicated to confirm the diagnosis, but theurgency of referral depends on the clinical symptoms. Patients with smalldefects have an excellent prognosis, with spontaneous closure occurring in75% to 80% of patients during the first 2 years of life . There are no datato suggest a decreased life expectancy; thus surgical closure is not indicated. Although these patients are at risk for endocarditis if the defect remainspatent, endocarditis is extremely rare in the infant. Patients with moderate tolarge defects will likely benefit from medical or surgical therapy, with improvedgrowth potential and less risk of pulmonary vascular disease, so urgent referralis warranted in these subgroups.Tetralogy of Fallot Tetralogy of Fallot refers to a spectrum of anatomic abnormalities that have alarge ventricular septal defect and right-ventricular outflow tract obstruction. Thiswas beautifully described by Fallot in 1888 and termed ‘‘maladie bleue.’’ It is themost common form of cyanotic congenital heart disease, and accounts for about6% of all infants born with congenital heart disease. The clinical presentationdepends on the severity of right-ventricular outflow tract obstruction; however,most infants present with a murmur in the early neonatal period secondary toturbulence through the right ventricular outflow tract. If the degree of rightventricular outflow tract obstruction is severe, the infant can present with severecyanosis as the patent ductus arteriosus closes. At the time of presentation, theinfant often appears healthy, although there is a higher incidence of extracardiac
M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032 1029anomalies and malformation syndromes in this group of patients. Subtle cyanosismay be noted. The right ventricular impulse is increased, because the rightventricle ejects at systemic pressure, and there may be a systolic thrill in infantswith a moderate degree of obstruction. The second heart sound is typically single,because one does not hear the pulmonary component in the setting of a dilatedaortic root and a hypoplastic, less-mobile pulmonary valve. It is important toremember that the systolic murmur in tetralogy of Fallot originates at the zone ofstenosis, and not across the ventricular septal defect. The murmur can be quiteloud, is ejection in quality, and diminishes in intensity and length when the degreeof obstruction increases. If a prominent diastolic murmur is also heard, one shouldsuspect pulmonary valve dysplasia, and in this setting, markedly-dilated branchpulmonary arteries may cause airway obstruction and respiratory symptoms. If tetralogy of Fallot is suspected in the term infant with a heart murmur, pulseoximetry should be performed. Many infants with tetralogy who present with aprominent murmur have only mild desaturation/cyanosis at rest, which is noteasily recognized with the eye alone. A chest radiograph may demonstrate a boot-shaped heart, reflective of the associated right-ventricular hypertrophy. Identifi-cation of a right aortic arch should raise suspicion of this diagnosis, because it isfound in approximately one third of patients with tetralogy of Fallot. Promptcardiology referral is indicated in all patients.Pulmonary stenosis Isolated pulmonary valve stenosis is fairly common, accounting for about 10%of congenital heart disease. A useful feature is a prominent murmur detected inthe newborn nursery, because the anatomic and physiologic conditions for themurmur are present at birth. The intensity of the murmur depends on the severityof obstruction; soft murmurs of mild obstruction may be overlooked for manyyears. The infant otherwise appears well with, at times, a cherubic facies. Theright ventricular impulse is prominent, and there may be a systolic thrill at the leftupper sternal border if the obstruction is severe. An ejection sound is character-istic of pulmonary valve stenosis, and is easily recognized by its high-pitchedclicking quality, varying with respiration. The pulmonic component of the secondheart sound is delayed and soft, because right ventricular ejection is prolonged.The murmur is often loud, ejection in quality, and is best heard at the left uppersternal border. If pulmonary valve stenosis is suspected in the term infant with a heartmurmur, elective cardiology referral is indicated. These infants typically do wellfor many years without intervention; however, balloon dilatation is indicated inthose with a moderate degree of obstruction.Atrial septal defect Secundum atrial defects are most common in females and are sometimesfamilial, occurring through a number of generations . Because the clinical
1030 M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032findings are subtle and symptoms are rare, isolated atrial septal defects accountfor fewer than 10% of cases of congenital heart disease in infants, but for morethan 30% of cases of congenital heart disease in adults. Although it is less com-monly diagnosed in infancy, it is important to recognize the features, becausethey do become apparent during the first year of life. Also, when unrecognized inchildhood, the patient is at risk for pulmonary vascular disease, arrhythmias, anda decreased life span. Isolated atrial septal defects are rarely diagnosed in the neonate, because left-atrial to right-atrial shunting is established only gradually as the right ventriclethins after the fall of the high fetal pulmonary vascular resistance. Clinicalsymptoms are typically absent; however, on occasion the infant with a largedefect and a relatively small left ventricle presents with congestive heart failure.Young children with atrial septal defects often have a thin habitus. Precordialpalpation is abnormal, with a prominent hyperdynamic right-ventricular impulse.At times, one may actually palpate the dilated main pulmonary artery trunk inthe second left intercostal space. The auscultatory hallmark of the atrial septaldefect is wide, fixed splitting of the second heart sound. Wide splitting reflectsdelayed closure of the pulmonary valve, and most practitioners feel that this isrelated to increased pulmonary vascular capacitance . The murmur accom-panying the atrial defect is usually prominent (Grade II or III), systolic ejection inquality, and heard best at the left upper sternal border. The murmur reflectsincreased right-ventricular stroke volume across the pulmonary valve. This in-creased stroke volume also crosses the tricuspid valve in diastole, creating a mid-diastolic flow rumble. When a systolic ejection murmur is heard at the left upper sternal border in theterm infant, the differential diagnosis includes atrial septal defect, valvar pul-monary stenosis, branch pulmonary artery stenosis, and tetralogy of Fallot.Careful auscultation of the second heart sound should differentiate these lesions.Pulse oximetry should be normal in all of the lesions except tetralogy of Fallot.Although cardiology referral is certainly indicated when an atrial defect is sus-pected, most infants are asymptomatic and there are many reports of spontaneousclosure over time . Surgical or catheter closure of these defects is generallynot performed until 3 or 4 years of age, because of the lack of symptoms and thepossibility of spontaneous closure.Aortic stenosis The bicuspid aortic valve is the most prevalent congenital heart abnormality,estimated to be present in 1% to 2% of the population . It is much morecommon in males, with a sex ratio of approximately 4:1. Many bicuspid valveswill function normally for many years until calcification occurs in adulthood;however, the bicuspid aortic valve can be stenotic at birth. Just as in the infantwith valvar pulmonary stenosis, a helpful feature in the history is a murmurnoted in the newborn nursery, because the anatomic and physiologic conditionsare present to generate the heart murmur. Most infants with valvar aortic stenosis
M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032 1031are otherwise healthy, with appropriate growth and development. One notableexception is the neonate with such severe aortic stenosis at birth that left-ventricular output is compromised. These infants are characterized as having‘‘critical’’ aortic stenosis, and usually present with marked left-ventriculardysfunction, congestive heart failure, and low cardiac output. It is importantto remember that these neonates may not have a prominent murmur, becausethere is limited antegrade flow across the aortic valve. The left ventricular im-pulse can be normal in mild obstruction or increased in more moderate obstruc-tion. A systolic thrill is common in aortic stenosis, and is readily detected in thesuprasternal notch and over both carotid arteries. An ejection sound is alsocharacteristic of aortic stenosis and is best heard at the cardiac apex. The mur-mur is maximal in the second right interspace, with radiation to the right andinto the neck. The intensity of the murmur is variable, with an ejection quality.A general rule is that the louder, longer, late-peaking murmur is indicativeof more significant obstruction. Peripheral pulses and perfusion are generallygood, except in the neonate with critical obstruction, in whom pulses are dif-fusely diminished. If aortic stenosis is suspected in the term infant with a heart murmur,cardiology referral is indicated, with more urgent referral in the neonate oryoung infant.Coarctation of the aorta Coarctation of the aorta is an obstruction in the descending aorta nearthe insertion of the ductus arteriosus. It accounts for about 5% to 10% of allcongenital heart defects, and tends to be more common in males. The neonatewith severe obstruction will present early in life with low cardiac output, and isnot the focus of this discussion. The majority of patients with aortic coarctationpresent in later childhood and are asymptomatic, and approximately 50% arereferred to the pediatric cardiologist with a heart murmur . It is imperativethat we improve our diagnostic skills in this group of patients, because long-term sequelae and survival are significantly better with early diagnosis andrepair . It is critically important for clinicians to examine femoral pulses in all infantsand children, because the hallmark clinical feature of aortic coarctation at any ageis absent or weak femoral pulses. The diagnosis can be confirmed by the clinicianwhen a higher measured blood pressure is observed in the arm compared with theleg. A systolic ejection click may be heard if there is an associated bicuspid aorticvalve. The murmur is generally soft (Grade II), ejection in quality, and audible atthe left upper sternal border as well as over the left back. The murmur canresemble the murmur of peripheral pulmonary stenosis, but should be readilydifferentiated by the discrepancy in femoral pulses. If the term infant with a heart murmur is suspected to have aortic coarctation,urgent cardiology referral is indicated so that the severity of the obstruction canbe assessed.
1032 M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032Summary In conclusion, heart murmurs in the term infant are frequently reflective ofstructural congenital heart disease. A detailed history, physical examination, andcardiac examination should help the clinician formulate a differential diagnosis.Pediatric cardiology referral is indicated when the murmur is felt to bepathologic, with more urgent referral in the symptomatic infant.References  Hoffman JIE. Incidence of congenial heart disease: I. Postnatal incidence. Pediatr Cardiol 1995; 16:103 – 13.  Harris JP. Evaluation of heart murmurs. Pediatr Rev 1995;12:490 – 3.  Braudo M, Rowe RD. Auscultation of the heart—early neonatal period. Am J Dis Child 1961; 101:575 – 86.  Cooper JJ, Enderlein MA, Tarnoff H, Roge CL. Asymmetric septal hypertrophy in infants of diabetic mothers: Fetal echocardiography and the impact of maternal diabetic control. Am J Dis Child 1992;146:226 – 9.  Kaplan SL. Growth: normal and abnormal. In: Rudolph AM, Hoffman JIE, editors. Pediatrics. Norwalk (CT): Appleton-Century-Crofts; 1977. p. 83 – 104.  Arlettaz R, Archer N, Wilkinson AR. Natural history of innocent heart murmurs in newborn babies: controlled echocardiographic study. Arch Dis Child Fetal Neonatal Ed 1998;78:166 – 70.  Danilowicz DA, Rudolph AM, Hoffman JIE, Heymann M. Physiologic pressure differences between main and branch pulmonary arteries in infants. Circulation 1972;45:410 – 9.  Graham TP, Bender HW, Spach MS. Ventricular septal defect. In: Adams FH, Emmanouilides GC, Riemenschneider TA, editors. Moss’ heart disease in infants, children, and adolescents. Baltimore (MD): Williams & Wilkins; 1989. p. 189 – 209.  Ainsworth SB, Wyllie JP, Wren C. Prevalence and clinical significance of cardiac murmurs in neonates. Arch Dis Child Fetal Neonatal Ed 1999;80:43 – 5. Alpert BS, Cook DH, Varghese PJ, Rowe RD. Spontaneous closure of small ventricular septal defects: ten-year follow-up. Pediatrics 1979;63:204 – 6. Weidman WH, DuShane JW, Ellison RC. Clinical course in adults with ventricular septal defect. Circulation 1977;56:178. Howitt G. Arial septal defet in three generations. Br Heart J 1961;23:494. Atrial septal defect. In: Perloff JK, editor. The clinical recognition of congenital heart disease. Philadelphia: WB Saunders; 1972. p. 272 – 349. Senocak F, Karademir S, Cabuk F, Onat N, Koc S, Duman A. Spontaneous closure of interatrial septal opening in infants: an echocardiographic study. Int J Cardiol 1996;53:221 – 6. Roberts WC. The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol 1970;26:72. Ing FF, Starc TJ, Griffiths SP, Gersony WM. Early diagnosis of coarctation of the aorta in children: a continuing dilemma. Pediatrics 1996;98:378 – 82. Maron BJ, Humphries JO, Rowe RD, Mellitts ED. Prognosis of surgically corrected coarctation of the aorta: a 20-year post-operative appraisal. Circulation 1973;47:119 – 26.