Differential diagnosis and approach to a heart murmur in term infants (PCNA)

1. Pediatr Clin N Am 51 (2004) 1023 – 1032
Differential diagnosis and approach to a heart
murmur in term infants
Michele A. Frommelt, MD
Children’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 than
1% of all live births [1]. In contrast, as many as 90% of children will have an
audible heart murmur at some point in time [2], and Braudo and Rowe reported
a murmur in 60% of healthy newborn babies [3]. It therefore becomes the
clinician’s responsibility to screen infants and children and determine which
patients 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 a
heart murmur in the infant born at term but less than 6 months of postnatal age. It
is important to remember that a heart murmur in this age group more frequently
reflects structural heart disease, in contrast to a heart murmur in the toddler or
older child. The author focuses on the most common structural lesions presenting
with 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 the
term infant should include questions about the family, the pregnancy, the peri-
natal course, and early growth and development. Is there a sibling or first-degree
relative with structural heart disease? Are there any known heritable syndromes,
such as Marfan’s syndrome or hypertrophic cardiomyopathy? A maternal history
of diabetes mellitus, especially when poorly controlled during pregnancy, can be
E-mail address: mafrom@mcw.edu
0031-3955/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcl.2004.03.003

2. 1024 M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032
associated with significant heart disease in up to 30% of infants [4]. Was the fetus
exposed to alcohol or any maternal medications? Perhaps the most important
questions in the term infant with a heart murmur should focus on the perinatal
course, as well as on the early growth and development. Were there any problems
at the time of birth? Was there any cyanosis or tachypnea? What was the infant’s
birth weight, and has the infant grown appropriately? Although weight gain is
variable 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 [5]. An accurate feeding history
is 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 length
of time per feeding, and associated symptoms such as tachypnea or diaphoresis.
Although infants with a large ventricular septal defect may take four ounces per
feeding, it typically takes them much longer to complete the feeding, with
frequent 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 1
Malformation syndromes associated with congenital heart disease
Syndrome Cardiac defect
Alagille (arteriohepatic dysplasia) Peripheral pulmonary stenosis
Coloboma, 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 defect
DiGeorge Aortic arch anomalies, tetralogy of Fallot
Down Atrioventricular septal defects, ventricular septal defect
Fetal alcohol Ventricular septal defect, atrial septal defect, tetralogy
of Fallot
Goldenhar’s Tetralogy of Fallot
Holt-Oram Atrial or ventricular septal defect
Laurence-Moon-Biedl Tetralogy of Fallot, ventricular septal defect
Multiple lentigenes (leopard) Pulmonary stenosis
Noonan’s Pulmonic stenosis, atrial septal defect
Rubella Patent ductus arteriosus, peripheral pulmonary stenosis
Rubinstein-Taybi Patent ductus arteriosus
Scimitar Hypoplasia of the right lung, anomalous pulmonary
drainage
Smith-Lemli-Opitz Ventricular septal defect, patent ductus arteriosus
Thrombocytopenia-absent radius(TAR) Atrial septal defect, tetralogy of Fallot
Turner’s Coarctation of the aorta, bicuspid aortic valve
Velocardiofacial Ventricular septal defect, right aortic arch
Williams Supravalvular aortic stenosis, peripheral pulmonary
stenosis

3. M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032 1025
General examination
Any physical examination in the term infant should begin with a general
assessment of overall appearance. Does the infant appear robust, playful and
comfortable, or is the infant irritable, diaphoretic, and breathless? Are there any
dysmorphic features or extracardiac anomalies? Although structural congenital
heart disease can be an isolated abnormality, there are a great number of
malformation syndromes involving the cardiovascular system (Table 1). Growth
parameters should be plotted on appropriate growth charts, and vital signs should
be recorded. Heart rate, respiratory rate, and blood pressure should be measured.
Although it may require a team effort to measure an accurate blood pressure in
the infant, this is a critical but often neglected part of the infant examination. Are
there any signs of respiratory distress, such as tachypnea, retractions, grunting, or
nasal flaring? Is the infant pink, or is there subtle cyanosis of the mucous
membranes? Acrocyanosis (bluish discoloration of the skin related to vasospasm
of the subcutaneous blood vessels) should be differentiated from true central
cyanosis, because acrocyanosis is a normal phenomenon in the young infant.
Acrocyanosis is commonly noted on the hands and feet, and occurs on exposure
to cold, generally improving with activity. If there is any question, pulse oximetry
is indicated. Hepatomegaly is common in infants with congestive heart failure, so
a relaxed abdominal examination is very important. The typical signs of venous
congestion that are seen in the adult are rare in the infant. Jugular venous
distention is difficult to assess, and peripheral edema is usually secondary to renal
disease with hypoproteinemia, not cardiac disease.
Cardiac examination
The cardiac examination should be performed in a systematic manner, so that
one does not become unduly focused on a single finding; however, one needs to
be flexible enough to alter the approach, especially in the term infant, who is not
always quiet or sleeping. One general approach is to start with inspection and
palpation, and to do this appropriately, one needs to lay the hands directly on the
chest. Is there a left-sided precordial bulge, suggesting cardiac enlargement? Is
there a substernal heave, indicating right ventricular hypertension? Is there a
palpable precordial thrill? Any of these additional findings in the term infant with
a heart murmur suggest that the murmur is indeed pathologic. If the infant is
quiet, one may then go on to auscultation, again remembering to approach this in
a systematic manner. The first heart sound, reflective of mitral and tricuspid valve
closure, is typically single and is best heard at the left lower sternal border. The
second 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 heart
disease, making it perhaps the most important element of auscultation in the
pediatric patient. Third and fourth heart sounds can be normal in the child, are

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typically low in frequency, and are best heard at the cardiac apex. Systolic
ejection clicks are typically high in frequency, occur early in systole, and often
reflect semilunar valvar stenosis. Murmurs should be described by their intensity
and timing, as well as their location and radiation. Any variability that occurs
with a change in position or with a maneuver should be described. The Grade I
murmur is barely audible and often only heard in a quiet environment with a
cooperative child. The Grade II murmur is soft but easily audible, whereas the
Grade III murmur is loud and often recognized immediately when placing the
stethoscope on the chest. The Grades IV, V, and VI murmurs are associated with a
palpable precordial thrill, and are always pathologic. The ability to discern the
Grade V murmur (audible with the edge of the stethoscope on the chest wall) or
Grade VI murmur (audible with the stethoscope off the chest wall) adds little to
the diagnosis. After grading the murmur, one must define the timing of the
murmur, or when it occurs within the cardiac cycle. Is it systolic, diastolic, or
continuous (throughout the cardiac cycle)? The two major types of systolic
murmurs are the systolic ejection murmur and the systolic regurgitant murmur.
The systolic ejection murmur is harsh, starts beyond the first heart sound, and is
diamond-shaped. The systolic regurgitant murmur is blowing, starts with and
obscures the first heart sound, and plateaus throughout its course. The innocent
murmurs are soft (Grade I or II) and ejection in quality; the pathologic systolic
murmur 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 murmur
indicates that structural heart disease is present. Continuous precordial murmurs
in infants are also generally pathologic, with the exception of the cervical venous
hum. The venous hum, an innocent murmur related to turbulent flow at the
junction between the jugular vein and the superior vena cava, should resolve in
the supine position or with gentle compression of the jugular vein. After cardiac
auscultation 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 capillary
refill time. This is obtained by blanching the nail bed or digit, and observing the
time to reperfusion, typically less than 3 seconds.
Specific lesions
Peripheral pulmonary stenosis
Several studies in the literature have suggested that innocent heart murmurs in
healthy term infants are mostly related to pulmonary branch stenosis, which is
reduced in two thirds of cases by 6 weeks of age and in most others by 6 months
[6]. The etiology of the murmur is secondary to both relative hypoplasia of the
pulmonary artery branches and an associated angulation at their origin [7]. The

5. M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032 1027
murmur is soft (Grade I or II), ejection in quality, and best heard anteriorly
at the left upper sternal border; however, the murmur is clearly recognized
by its characteristic transmission to the axillae and back bilaterally, and by its
disappearance over time. There are no associated signs or symptoms of heart
disease, and the rest of the cardiac examination is normal. The pulmonary flow
murmur of an atrial septal defect may mimic this murmur, but is generally heard
in later infancy or childhood. Pulmonary valve stenosis is of louder intensity
and is associated with an early systolic ejection click; severe stenosis can re-
sult in a precordial thrill. Pathologic peripheral pulmonary stenosis is typically
more severe, generating a louder murmur, and does not regress over time.
Associated noncardiac anomalies and dysmorphic features are common with
pathologic branch stenosis. Coarctation of the aorta can result in a murmur at the
left upper sternal border and left back; however, a careful assessment of lower
extremity pulses should easily differentiate aortic coarctation from pulmonary
branch stenosis.
If peripheral pulmonary stenosis is suspected in the term infant with a heart
murmur, close follow-up by the clinician is indicated. If the murmur intensifies or
persists after 6 months of age, cardiology referral is indicated.
Ventricular septal defect
Excluding the bicuspid aortic valve, which may be difficult to recognize in
neonates, isolated ventricular septal defects are the most common congenital
heart defect identified through the first 3 decades of life, with an incidence from
1 to 7 per 1000 live births [8]. Certainly, in the experience of the author and
others [9], the term infant with a pathologic heart murmur is more likely to have
an isolated ventricular septal defect than any other form of congenital heart
disease. It is important to remember that these infants can present in different
ways, and that the presentation is determined by the size of the defect and the
status of the pulmonary vascular resistance.
Most commonly the murmur is detected at 2 to 6 weeks of age, when the
infant returns for the initial checkup after hospital discharge; however, in the
presence of a small defect associated with a normal fall in pulmonary vascular
resistance, the murmur can be heard during the first few days of life. The infant
with a small ventricular septal defect otherwise appears healthy, with normal
growth and no cardiac symptoms. The precordial activity is normal, and there
typically is not a palpable systolic thrill. The murmur of a small ventricular septal
defect can be quite loud, reflecting the normal drop in pulmonary vascular
resistance and resultant high-velocity, turbulent jet of flow between the higher-
pressured left ventricle and the lower-pressured right ventricle. Of note, if a small
muscular 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-

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cally fallen, the moderate defect allows a more significant volume left-to-right
shunt, leading to cardiomegaly and a hyperdynamic precordium. The murmur
is always loud, is frequently associated with a systolic thrill, and is harsh and
holosystolic, obscuring the first and second heart sounds. Because of the increased
pulmonary blood flow, which is often twice the systemic flow, a prominent third
heart sound or diastolic flow murmur can be heard at the cardiac apex. This
reflects the increased flow across the mitral valve, causing a relative mitral
stenosis murmur in mid-diastole. The infant with a large ventricular septal defect
can be more of a diagnostic dilemma, but should be recognized because of sig-
nificant clinical symptoms and failure to thrive. Feeding problems and irritability
are common, and infants may be misdiagnosed with colic or gastroesophageal
reflux. The large defect allows a significant volume left-to-right shunt and left
heart volume overload, leading to an increased left-ventricular precordial im-
pulse. Because the pulmonary vascular resistance remains moderately elevated
with resultant right ventricular and pulmonary artery hypertension, there is a
marked right ventricular heave, with a loud and single second heart sound. The
murmur is soft (Grade II), short and early systolic, again reflecting the significant
elevation in right ventricular and pulmonary artery pressures. A prominent third
heart sound and diastolic rumble are common. These infants will also have
hepatomegaly, and systemic perfusion can be compromised.
If a ventricular septal defect is suspected in the term infant with a heart
murmur, cardiology referral is indicated to confirm the diagnosis, but the
urgency of referral depends on the clinical symptoms. Patients with small
defects have an excellent prognosis, with spontaneous closure occurring in
75% to 80% of patients during the first 2 years of life [10]. There are no data
to suggest a decreased life expectancy; thus surgical closure is not indicated
[11]. Although these patients are at risk for endocarditis if the defect remains
patent, endocarditis is extremely rare in the infant. Patients with moderate to
large defects will likely benefit from medical or surgical therapy, with improved
growth potential and less risk of pulmonary vascular disease, so urgent referral
is warranted in these subgroups.
Tetralogy of Fallot
Tetralogy of Fallot refers to a spectrum of anatomic abnormalities that have a
large ventricular septal defect and right-ventricular outflow tract obstruction. This
was beautifully described by Fallot in 1888 and termed ‘‘maladie bleue.’’ It is the
most common form of cyanotic congenital heart disease, and accounts for about
6% of all infants born with congenital heart disease. The clinical presentation
depends on the severity of right-ventricular outflow tract obstruction; however,
most infants present with a murmur in the early neonatal period secondary to
turbulence through the right ventricular outflow tract. If the degree of right
ventricular outflow tract obstruction is severe, the infant can present with severe
cyanosis as the patent ductus arteriosus closes. At the time of presentation, the
infant often appears healthy, although there is a higher incidence of extracardiac

7. M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032 1029
anomalies and malformation syndromes in this group of patients. Subtle cyanosis
may be noted. The right ventricular impulse is increased, because the right
ventricle ejects at systemic pressure, and there may be a systolic thrill in infants
with 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 dilated
aortic root and a hypoplastic, less-mobile pulmonary valve. It is important to
remember that the systolic murmur in tetralogy of Fallot originates at the zone of
stenosis, and not across the ventricular septal defect. The murmur can be quite
loud, is ejection in quality, and diminishes in intensity and length when the degree
of obstruction increases. If a prominent diastolic murmur is also heard, one should
suspect pulmonary valve dysplasia, and in this setting, markedly-dilated branch
pulmonary arteries may cause airway obstruction and respiratory symptoms.
If tetralogy of Fallot is suspected in the term infant with a heart murmur, pulse
oximetry should be performed. Many infants with tetralogy who present with a
prominent murmur have only mild desaturation/cyanosis at rest, which is not
easily 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 is
found in approximately one third of patients with tetralogy of Fallot. Prompt
cardiology 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 in
the newborn nursery, because the anatomic and physiologic conditions for the
murmur are present at birth. The intensity of the murmur depends on the severity
of obstruction; soft murmurs of mild obstruction may be overlooked for many
years. The infant otherwise appears well with, at times, a cherubic facies. The
right ventricular impulse is prominent, and there may be a systolic thrill at the left
upper sternal border if the obstruction is severe. An ejection sound is character-
istic of pulmonary valve stenosis, and is easily recognized by its high-pitched
clicking quality, varying with respiration. The pulmonic component of the second
heart 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 upper
sternal border.
If pulmonary valve stenosis is suspected in the term infant with a heart
murmur, elective cardiology referral is indicated. These infants typically do well
for many years without intervention; however, balloon dilatation is indicated in
those with a moderate degree of obstruction.
Atrial septal defect
Secundum atrial defects are most common in females and are sometimes
familial, occurring through a number of generations [12]. Because the clinical

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findings are subtle and symptoms are rare, isolated atrial septal defects account
for fewer than 10% of cases of congenital heart disease in infants, but for more
than 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, because
they do become apparent during the first year of life. Also, when unrecognized in
childhood, the patient is at risk for pulmonary vascular disease, arrhythmias, and
a 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 ventricle
thins after the fall of the high fetal pulmonary vascular resistance. Clinical
symptoms are typically absent; however, on occasion the infant with a large
defect and a relatively small left ventricle presents with congestive heart failure.
Young children with atrial septal defects often have a thin habitus. Precordial
palpation is abnormal, with a prominent hyperdynamic right-ventricular impulse.
At times, one may actually palpate the dilated main pulmonary artery trunk in
the second left intercostal space. The auscultatory hallmark of the atrial septal
defect is wide, fixed splitting of the second heart sound. Wide splitting reflects
delayed closure of the pulmonary valve, and most practitioners feel that this is
related to increased pulmonary vascular capacitance [13]. The murmur accom-
panying the atrial defect is usually prominent (Grade II or III), systolic ejection in
quality, and heard best at the left upper sternal border. The murmur reflects
increased 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 the
term 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 spontaneous
closure over time [14]. Surgical or catheter closure of these defects is generally
not performed until 3 or 4 years of age, because of the lack of symptoms and the
possibility 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 [15]. It is much more
common in males, with a sex ratio of approximately 4:1. Many bicuspid valves
will function normally for many years until calcification occurs in adulthood;
however, the bicuspid aortic valve can be stenotic at birth. Just as in the infant
with valvar pulmonary stenosis, a helpful feature in the history is a murmur
noted in the newborn nursery, because the anatomic and physiologic conditions
are present to generate the heart murmur. Most infants with valvar aortic stenosis

9. M.A. Frommelt / Pediatr Clin N Am 51 (2004) 1023–1032 1031
are otherwise healthy, with appropriate growth and development. One notable
exception 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-ventricular
dysfunction, congestive heart failure, and low cardiac output. It is important
to remember that these neonates may not have a prominent murmur, because
there 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 the
suprasternal notch and over both carotid arteries. An ejection sound is also
characteristic 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 and
into 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 indicative
of more significant obstruction. Peripheral pulses and perfusion are generally
good, 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 or
young infant.
Coarctation of the aorta
Coarctation of the aorta is an obstruction in the descending aorta near
the insertion of the ductus arteriosus. It accounts for about 5% to 10% of all
congenital heart defects, and tends to be more common in males. The neonate
with severe obstruction will present early in life with low cardiac output, and is
not the focus of this discussion. The majority of patients with aortic coarctation
present in later childhood and are asymptomatic, and approximately 50% are
referred to the pediatric cardiologist with a heart murmur [16]. It is imperative
that we improve our diagnostic skills in this group of patients, because long-
term sequelae and survival are significantly better with early diagnosis and
repair [17].
It is critically important for clinicians to examine femoral pulses in all infants
and children, because the hallmark clinical feature of aortic coarctation at any age
is absent or weak femoral pulses. The diagnosis can be confirmed by the clinician
when a higher measured blood pressure is observed in the arm compared with the
leg. A systolic ejection click may be heard if there is an associated bicuspid aortic
valve. The murmur is generally soft (Grade II), ejection in quality, and audible at
the left upper sternal border as well as over the left back. The murmur can
resemble the murmur of peripheral pulmonary stenosis, but should be readily
differentiated 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 can
be assessed.

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Summary
In conclusion, heart murmurs in the term infant are frequently reflective of
structural congenital heart disease. A detailed history, physical examination, and
cardiac examination should help the clinician formulate a differential diagnosis.
Pediatric cardiology referral is indicated when the murmur is felt to be
pathologic, with more urgent referral in the symptomatic infant.
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