Disclosures: Carolyn A Altman, MD Nothing to disclose. David R Fulton, MD Nothing to disclose. Leonard E Weisman, MD Consultant/Advisory Boards: Glaxo-Smith Kline [Malaria vaccine]; NIAID [Staphylococcus aureus (Mupirocin)]. Patent Holder: Baylor College of Medicine [Ureaplasma diagnosis/vaccines/antibodies, process for preparing biological samples]. Equity Ownership/Stock Options: Vax-Immune [Ureaplasma diagnosis, vaccines and antibodies]. Carrie Armsby, MD, MPH Nothing to disclose.
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INTRODUCTION — Congenital heart disease (CHD) is the most common congenital disorder in newborns [1-3]. Critical CHD, defined as requiring surgery or catheter-based intervention in the first year of life, occurs in approximately 25 percent of those with CHD . Although many newborns with critical CHD are symptomatic and identified soon after birth, others are not diagnosed until after discharge from the birth hospitalization [5-8]. In infants with critical cardiac lesions, the risk of morbidity and mortality increases when there is a delay in diagnosis and timely referral to a tertiary center with expertise in treating these patients [9,10].
Factors that should lead clinicians to suspect critical congenital heart lesions in neonates will be reviewed here. Pulse oximetry screening and the diagnosis and management of cyanotic CHD are discussed separately . (See "Diagnosis and initial management of cyanotic heart disease in the newborn".)
TERMINOLOGY — The following terms are used to characterize congenital heart disease (CHD) in this discussion:
●Cyanotic CHD − Cyanotic CHD includes lesions that allow circulation of deoxygenated blood in the systemic circulation via intracardiac or extracardiac shunting (table 1). (See "Cardiac causes of cyanosis in the newborn" and "Diagnosis and initial management of cyanotic heart disease in the newborn".)
●Ductal-dependent CHD − Ductal-dependent congenital heart lesions are dependent upon a patent ductus arteriosus (PDA) to supply pulmonary or systemic blood flow or to allow adequate mixing between parallel circulations (figure 1). In critical right heart obstructive lesions, the PDA is necessary to supply blood flow to the lungs; in critical left heart lesions, the PDA supplies systemic circulation; and in parallel circulations (eg, transposition of the great arteries), bidirectional flow in the PDA allows mixing between oxygenated and deoxygenated circuits (table 1). Many, but not all, cyanotic congenital heart defects are ductal-dependent.
●Critical CHD − Critical CHD refers to lesions requiring surgery or catheter-based intervention in the first year of life (table 1). This category includes ductal-dependent and cyanotic lesions as well as less severe forms of CHD that are not dependent on the PDA. Critical CHD accounts for approximately 25 percent of all CHD .
EPIDEMIOLOGY — The reported prevalence of congenital heart disease (CHD) at birth ranges from 6 to 13 per 1000 live births [13-19]. Variation is primarily due to the use of different methods to detect CHD (ie, fetal echocardiography versus postnatal referral to a cardiac center) [17,20].
The most common congenital heart defect is a bicuspid aortic valve (BAV), with a prevalence estimated between 0.5 and 2 percent, but as an isolated lesion it is rarely diagnosed in infancy [21-23]. The next most common defects are ventricular septal defects (VSDs) and secundum atrial septal defects (ASDs) (prevalence of 4 and 2 per 1000 live births, respectively) [11,15,24,25]. Tetralogy of Fallot (TOF) is the most common cyanotic CHD (0.5 per 1000 births) [15,26].
CHD is the leading cause of perinatal and infant death from a congenital birth defect, although outcomes have significantly improved with the advancement of corrective or palliative interventions [1,16,27-29].
Critical CHD accounts for approximately 25 percent of all CHD . In infants with critical CHD, the risk of morbidity and mortality increases when there is a delay in diagnosis and timely referral to a tertiary center with expertise in treating these patients .
●Prematurity − The risk of CHD (excluding isolated patent ductus arteriosus [PDA]) is two- to threefold higher in preterm (gestational age <37 weeks) compared with term infants .
●Family history − There is an overall threefold increased risk for CHD when a first-degree relative has CHD [31,32].
●Genetic syndromes − Genetic and extracardiac abnormalities are common in patients with CHD: in a population-based study, chromosomal defects were detected in 7 percent of patients with CHD, and extracardiac anomalies in 22 percent . Many genetic syndromes are associated with an increased risk of CHD (table 3) .
●Maternal factors − Maternal conditions that increase the risk of CHD include diabetes mellitus, hypertension, obesity, phenylketonuria, thyroid disorders, systemic connective tissue disorders, and epilepsy . In addition, drugs taken during pregnancy (eg, phenytoin and retinoic acid) as well as smoking and/or alcohol use can be associated with cardiac defects [34-37]. (See "Fetal cardiac abnormalities: Screening, evaluation, and pregnancy management", section on 'Indications for echocardiography'.)
●Assisted reproductive technology (ART) – (See "Pregnancy outcome after assisted reproductive technology", section on 'Congenital anomalies'.)
●In utero infection − CHD may result from congenital infections (eg, rubella). Maternal influenza or flu-like illness during pregnancy is also associated with increased risk of CHD . Congenital cardiomyopathy may result from infection with cytomegalovirus, coxsackie, herpes virus 6, parvovirus B19, herpes simplex, toxoplasmosis gondii, and possibly human immunodeficiency virus (HIV). (See "Influenza and pregnancy" and "Overview of TORCH infections".)
TIMING OF DIAGNOSIS
Prenatal diagnosis — Clinicians skilled at fetal echocardiography are able to identify most congenital heart defects. However, clinical suspicion or a risk factor for congenital heart disease (CHD) must be identified to prompt referral for fetal echocardiography. Routine antenatal ultrasound traditionally included assessment of the fetal heart using the four chamber view; however, the most recent practice guidelines of the International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) published in 2013 now recommend expanded views for screening, including assessment of the outflow tracts . Studies performed in the era prior to publication of these guidelines indicate that less than half of patients with critical congenital heart defects were routinely identified [10,40-42]. CHD lesions involving abnormal outflow tracts (including tetralogy of Fallot, double outlet right ventricle [DORV], and transposition of the great arteries [TGA]) are particularly at risk for not being identified. The expanded prenatal screening recommendations of the ISUOG may lead to improved detection rates in the future. One study found that the rate of prenatal detection of critical CHD increased from 44 percent in 2007 to 69 percent in 2013 .
Prenatal sonographic screening for CHD is discussed in detail separately. (See "Fetal cardiac abnormalities: Screening, evaluation, and pregnancy management".)
Postnatal diagnosis — Infants with critical CHD may present during the birth hospitalization, often with serious and life-threatening clinical findings that require immediate intervention . However, some infants with CHD may appear normal on routine examination and signs of critical CHD may not be apparent until after discharge . The timing of presentation varies with the underlying lesion and its dependence upon a patent ductus arteriosus (PDA) (table 1). Prior to the routine use of pulse oximetry screening, approximately 30 percent of patients with critical CHD were discharged from the birth hospitalization undiagnosed .
The most commonly reported delayed diagnoses are coarctation of the aorta, interrupted aortic arch, aortic stenosis, hypoplastic left heart syndrome (HLHS), transposition of the great arteries, pulmonary valve stenosis, and tetralogy of Fallot (TOF) [43,44]. Pulse oximetry screening can identify infants with some, but not all, of these lesions. (See 'Targeted lesions' below.)
In patients with ductal-dependent lesions, closure of the PDA within the first few days of life can precipitate rapid clinical deterioration with potentially life-threatening consequences (ie, severe metabolic acidosis, cardiogenic shock, cardiac arrest, seizures, other end-organ injury) . For infants with critical CHD who are not diagnosed during the birth hospitalization, the risk of mortality is as high as 30 percent [9,10,46].
CLINICAL FEATURES — Neonates with critical congenital heart disease (CHD) can present during their birth hospitalization with serious and life-threatening manifestations including shock, cyanosis, tachypnea, and/or symptoms of pulmonary edema. However, some infants with CHD may appear normal on routine examination and signs of critical CHD may not be apparent.
Urgent consultation/referral to a pediatric cardiologist should be made when CHD is suspected in neonates who present with shock, cyanosis, or pulmonary edema .
Infants with ductal-dependent lesions are at increased risk for death and significant morbidity unless interventions are initiated to maintain patency of the ductus arteriosus (ie, prostaglandin therapy), ensure adequate mixing of deoxygenated and oxygenated blood, and/or relieve obstructed blood flow. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Initial management'.)
Shock — Some infants with critical CHD will present during the neonatal hospitalization in shock. Most commonly, this is seen in infants with unsuspected critically obstructive left heart lesions (table 1), including:
●Critical aortic valve stenosis (see "Valvar aortic stenosis in children", section on 'Critical AS')
●Critical coarctation of the aorta (figure 3) (see "Clinical manifestations and diagnosis of coarctation of the aorta")
●Interrupted aortic arch
Infants with these lesions may present in cardiogenic shock as the ductus arterious closes and systemic perfusion decreases. In these patients, initiation of prostaglandin E1 (generic drug name, alprostadil) to re-open or maintain the ductus arteriosus is imperative. The use of prostaglandin E1 is discussed separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.)
Infants with total anomalous pulmonary venous return (TAPVR) (figure 4) most commonly present with cyanosis and tachypnea. However, if there is significant obstruction at the atrial communication, systemic perfusion will be impaired as all pulmonary venous return must traverse the atrial communication to reach the left heart and supply the systemic circulation. This is the rare instance when these lesions might benefit from ductal patency (ie, prostaglandin therapy) until urgent surgical intervention can be achieved. If obstruction occurs within the pulmonary venous pathway itself, such as occurs commonly in TAPVR below the diaphragm, ductal patency is not of utility and the only effective management strategy is urgent surgical intervention. (See "Total anomalous pulmonary venous connection", section on 'Initial medical management'.)
Cardiogenic shock must be differentiated from other causes of shock, such as sepsis. In newborns who present with shock, cardiomegaly and lack of response to volume resuscitation suggest a cardiac etiology . (See "Etiology, clinical manifestations, and evaluation of neonatal shock".)
Cyanosis — Cyanosis is an important sign of critical CHD. Cyanosis is the bluish skin tone caused by the presence of ~3 to 5 g/dL of deoxygenated hemoglobin. However, cyanosis may not be readily clinically apparent in patients with mild desaturation (>80 percent saturation) or anemia . Cyanosis can be especially difficult to appreciate in darkly pigmented infants. Pulse oximetry is helpful to detect mild desaturation in patients with cyanotic CHD. (See "Diagnosis and initial management of cyanotic heart disease in the newborn" and 'Pulse oximetry screening' below.)
Ductal-dependent lesions — In patients with ductal-dependent lesions (table 1), closure of the patent ductus arteriosus (PDA) in the first days of life can precipitate profound cyanosis by the following mechanisms:
●In patients with critically obstructive right heart lesions (eg, critical pulmonary valve stenosis, pulmonary atresia with intact ventricular septum (figure 5)), pulmonary blood flow is supplied retrograde from the aorta via the PDA. Therefore, progressively severe cyanosis occurs as the ductus closes and blood flow to the lungs decreases. (See "Pulmonary atresia with intact ventricular septum (PA/IVS)", section on 'Postnatal presentation' and "Pulmonic stenosis (PS) in neonates, infants, and children", section on 'Severe and critical PS'.)
●Patients with critically obstructive left heart lesions (eg, HLHS (figure 2), critical aortic valve stenosis) who have an adequate atrial septal communication and a patent ductus will typically exhibit only minimal desaturation. For those with sufficient prograde flow across the aortic valve to supply the right subclavian artery fully, the preductal saturations can be normal. However, postductal saturations will be lower as right to left shunting at the PDA supplies the lower body circulation. However, upon closure of the ductus, systemic circulation is compromised, resulting in poor peripheral perfusion (ie, cardiogenic shock) and cyanosis. (See "Hypoplastic left heart syndrome" and "Valvar aortic stenosis in children", section on 'Critical AS'.)
Patients with critical left heart obstruction and a restrictive atrial communication will exhibit more profound cyanosis even with ductal patency . A restrictive atrial communication results in decreased shunting of the oxygenated pulmonary venous return into the right heart, severe pulmonary edema, and pulmonary hypertension, all of which contribute to decreased systemic oxygenation.
●Patients with parallel pulmonary and systemic circulations (eg, transposition of the great arteries (figure 6)) depend upon the PDA and atrial communications for mixing of oxygenated and deoxygenated blood. With ductal closure in the absence of an adequate atrial septal defect, profound cyanosis ensues. (See "Pathophysiology, clinical manifestations, and diagnosis of D-transposition of the great arteries", section on 'Postnatal presentation'.)
●Neonates with Ebstein's anomaly of the tricuspid valve may be cyanotic and ductal dependent for pulmonary blood flow in the situation where there is a functional pulmonary atresia (figure 7). (See "Ebstein's anomaly of the tricuspid valve".)
In patients with ductal-dependent lesions who present with severe cyanosis or shock, rapid initiation of prostaglandin E1 (generic drug name, alprostadil) to reopen and maintain the patency of the ductus arteriosus is imperative. The use of prostaglandin E1 is discussed separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.)
Nonductal-dependent lesions — Nonductal-dependent congenital heart defects that cause cyanosis include (table 1):
●Tetralogy of Fallot (TOF) (figure 9) and tricuspid atresia (figure 10) may or may not be ductal-dependent depending upon the degree of right ventricular outflow tract obstruction and presence and size of a ventricular septal defect (VSD) (in tricuspid atresia). (See "Pathophysiology, clinical features, and diagnosis of tetralogy of Fallot" and "Tricuspid valve (TV) atresia".)
Differential cyanosis — In infants with critical coarctation of the aorta (figure 3), interrupted arch, or critical aortic stenosis, differential cyanosis occurs, wherein the flow of deoxygenated blood through the ductus arteriosus supplies the lower half of the body's circulation, but oxygenated blood flow from the left heart supplies the upper body via the vessels proximal to the site of arch obstruction. A difference of >3 percent in the oxygen saturation measured in the right hand (preductal) and either foot (postductal) identifies infants with differential cyanosis. Differential cyanosis also occurs in infants with structurally normal hearts who have persistent pulmonary hypertension of the newborn. (See "Persistent pulmonary hypertension of the newborn" and "Clinical manifestations and diagnosis of coarctation of the aorta".)
Reversed differential cyanosis is a rare finding that may occur in patients with transposition of the great arteries (TGA) associated with either coarctation or pulmonary hypertension. In these infants, oxygen saturation is higher in the lower, rather than the upper, extremity as the most oxygenated flow is pumped by the left ventricular out the pulmonary artery and thus across the PDA.
Noncardiac causes — Noncardiac conditions also can cause cyanosis and are differentiated from CHD by the history, cardiovascular examination, and/or results of hyperoxia test, chest radiograph, echocardiography, and other laboratory testing. (See 'Diagnostic approach' below.)
●Pulmonary disorders are the most common cause of cyanosis and include structural abnormalities of the lung, ventilation-perfusion mismatching due to respiratory distress syndrome, congenital or acquired airway obstruction, pneumothorax, and hypoventilation. (See "Overview of neonatal respiratory distress: Disorders of transition".)
●Abnormal forms of hemoglobin (eg, methemoglobin) can result in cyanosis, and polycythemic infants may appear cyanotic even if they are adequately oxygenated. (See "Genetic disorders of hemoglobin oxygen affinity" and "Neonatal polycythemia".)
●Poor peripheral perfusion with cyanosis may result from sepsis, hypoglycemia, dehydration, and hypoadrenalism.
●Right-to-left shunting through the ductus arteriosus, resulting in differences in oxygen saturation measured in the arm (preductal) and leg (postductal), can occur with primary or persistent pulmonary hypertension . (See "Persistent pulmonary hypertension of the newborn".)
●Acrocyanosis refers to bluish color in the hands and feet and around the mouth (circumoral cyanosis). The mucus membranes generally remain pink. Acrocyanosis usually reflects benign vasomotor changes in the diffuse venous structures in the affected areas. It does not indicate pathology unless cardiac output is extremely low, resulting in cutaneous vasoconstriction .
Respiratory symptoms — Tachypnea, increased work of breathing, and feeding difficulties can occur due to pulmonary edema from a rapid, massive increase in pulmonary blood flow as pulmonary vascular resistance falls shortly after delivery. This may occur in the following conditions:
●TAPVC − TAPVC without obstruction generally results in mild to moderate symptoms of pulmonary overcirculation. In patients with obstruction within the extracardiac pulmonary venous channel or at a restrictive atrial septum, pulmonary venous edema predominates and generates more severe symptoms (figure 4) . (See "Total anomalous pulmonary venous connection", section on 'Obstructed forms'.)
●PDA in premature infants (figure 11). (See "Pathophysiology, clinical manifestations, and diagnosis of patent ductus arteriosus in premature infants".)
In patients with large VSDs, tachypnea, increased work of breathing, and feeding difficulties can occur due to pulmonary overcirculation from left to right shunting. This typically develops over the first four to six weeks of life as pulmonary vascular resistance falls. (See "Pathophysiology and clinical features of isolated ventricular septal defects in infants and children".)
Respiratory signs and symptoms must be distinguished from those due to pulmonary disease. Persistently elevated respiratory rate (normal is 45 to 60 breaths per minute), increased respiratory effort at rest, or distress during feeding merit further investigation including careful physical examination, chest radiography, and hyperoxia test, with subsequent consultation or referral to a pediatric cardiologist for echocardiography. (See "Overview of neonatal respiratory distress: Disorders of transition", section on 'Diagnosis'.)
Cardiac neonatal tachypnea may reflect increased pulmonary venous pressure or volume secondary to a large left-to-right shunt, pulmonary venous obstruction, or increased left ventricular end-diastolic pressure . Tachypnea in heart failure is also thought to have a neurohormonal basis.
Infants with CHD and mild to moderate pulmonary overcirculation frequently have tachypnea without significant increased work of breathing at rest, sometimes referred to as "happy" tachypnea. Infants may become more tachypneic with increasing pulmonary edema or during feeding, and exhibit grunting, nasal flaring, retractions, and head bobbing.
Cough and wheeze are more likely to be of pulmonary etiology, but they can occur with cardiac malformations. As an example, a tight vascular ring can compress the trachea, leading to wheezing, coughing, or stridor [54,55]. Lesions that cause elevated pulmonary venous pressure result in bronchial edema and bronchial compression by a distended left atrium and large left pulmonary artery [52,54,56]. These include large left-to-right shunts, mitral stenosis, left ventricular dysfunction (eg, from myocarditis), or pulmonary venous obstruction [52,54,56,57].
During the birth hospitalization — The presence or absence of symptoms in the neonate determines the extent of evaluation that should be performed during the birth hospitalization.
Symptomatic neonates — Urgent consultation/referral to a pediatric cardiologist should be made when congenital heart disease (CHD) is suspected in symptomatic neonates. The diagnostic evaluation includes the following:
●Physical examination − A thorough physical examination should be performed with attention to findings suggestive of CHD (table 4), including abnormal precordial activity, abnormal heart sounds (eg, S3 gallop, click, or single S2), pathologic murmurs (loud, harsh, pansystolic, diastolic, or loudest at upper left or right sternal border or apex), diminished or absent lower extremity pulses, and abnormal four extremity blood pressure (ie, blood pressure ≥10 mmHg higher in the arms than legs). (See 'Physical examination' below.).
●Pulse oximetry − Pre- and postductal pulse oximetry to assess for cyanosis and differential cyanosis.
●Chest radiograph − A chest radiograph can be helpful in differentiating between cardiac and pulmonary disorders and should be obtained in neonates with cyanosis and/or respiratory symptoms (table 4).
Chest radiograph is also useful in assessing for noncardiac causes of cyanosis, including pneumothorax, pulmonary hypoplasia, diaphragmatic hernia, pleural effusion, or airway disease.
Cardiomegaly, dextrocardia, or an abnormal cardiac silhouette (eg, boot-shaped (image 1) in tetralogy of Fallot [TOF] or egg-on-a-string pattern in D-transposition of the great arteries [d-TGA]) may point towards the presence of CHD. Abnormal pulmonary vascular markings or side of the aortic arch may also suggest CHD. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Chest radiograph'.)
●Electrocardiogram (ECG) − Although the ECG may be normal in many cyanotic heart lesions during the neonatal period, some lesions are associated with specific patterns (table 4). (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Electrocardiogram'.)
●Hyperoxia test − The hyperoxia test is useful in distinguishing cardiac from noncardiac causes of cyanosis, especially pulmonary disease, in cases where it is otherwise unclear. In this test, arterial oxygen tension (PaO2) is measured in the right radial artery (preductal) and in a lower extremity artery (postductal) during the administration of room air and 100 percent oxygen. The relative changes in PaO2 are used to differentiate the various cardiac and noncardiac causes of neonatal cyanosis (table 5 and table 6). This test and its interpretation are discussed in detail separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Hyperoxia test'.)
●Echocardiography — Echocardiography provides a definitive diagnosis of CHD with information on cardiac anatomy and function. Echocardiography should be performed in consultation with a pediatric cardiologist if any of the following are present :
•Signs or symptoms concerning for critical CHD, including shock unresponsive to volume resuscitation, cyanosis or differential cyanosis, failed hyperoxia test, unexplained respiratory symptoms, or pulmonary edema (see 'Shock' above and 'Cyanosis' above and 'Respiratory symptoms' above)
•ECG and/or chest radiograph findings suggestive of CHD (table 4)
•Physical exam findings suggestive of CHD (table 4), including abnormal heart sounds (eg, S3 gallop, single S2, click), pathologic murmur, diminished or absent lower extremity pulses, abnormal four extremity blood pressures (see 'Physical examination' below)
•Positive pulse oximetry screening (algorithm 1)
•Genetic disorder or extracardiac malformation associated with cardiovascular malformations (table 3)
Echocardiography can also be valuable in the diagnosis of some noncardiac causes of cyanosis (eg, persistent pulmonary hypertension of the newborn). (See "Persistent pulmonary hypertension of the newborn", section on 'Diagnosis'.)
Asymptomatic neonates — Early detection of neonatal CHD remains challenging because clinical findings may be subtle or absent immediately after birth. Studies have shown that pulse oximetry is an effective, though not infallible, screening measure. Thus, the American Academy of Pediatrics (AAP), the American Heart Association (AHA), and the American College of Cardiology Foundation (ACCF) have recommended universal screening of all newborns with pulse oximetry to improve the recognition of CHD . In addition to pulse oximetry screening, careful review of the history and examination of the infant remain imperative. (See 'Pulse oximetry screening' below.)
In addition to inquiring about CHD among family members, parents should be questioned about familial occurrence of cardiomyopathies, sudden death, or unexpected death in infancy or childhood that could potentially uncover genetic preponderance of potential congenital cardiac abnormalities within the family. (See "Clinical features of congenital long QT syndrome".)
Physical examination — Several studies have shown that the newborn examination alone fails to detect more than half of infants with heart disease [46,60,61]. However, subtle clinical findings may be detected that indicate underlying cardiac disease. The following discussion reviews the physical findings that may be seen in an infant with CHD; however, as noted above, findings may be absent in infants with ductal-dependent lesions if the ductus arteriosus remains patent during their birth hospitalization.
The following cardiovascular findings suggestive of CHD merit further evaluation and/or referral to clinicians with expertise in caring for neonates with CHD:
●Abnormal heart rate − In infants with heart rates that are higher or lower than the normal range of 90 to 160 beats per minute for neonates up to six days of age, electrocardiography is initially performed to determine whether there is an arrhythmia, and to guide further assessment and management . (See "Irregular heart rate (arrhythmias) in children" and "Approach to the child with tachycardia" and "Bradycardia in children" and "Supraventricular tachycardia in children: AV reentrant tachycardia (including WPW) and AV nodal reentrant tachycardia".)
●Abnormal precordial activity − Precordial palpation ascertains whether the heart is normally located on the left side of the chest. Dextrocardia is often associated with complex CHD. In addition, palpation may detect the following:
•Cardiac enlargement, which, in a newborn with respiratory symptoms, is more suggestive of cardiac than pulmonary disease .
•Ventricular impulse in the lower left parasternal area suggestive of right ventricular volume or pressure overload.
•Increased apical activity suggestive of left ventricular volume or pressure overload.
•Thrill due to outflow tract obstruction or a restrictive ventricular septal defect (VSD).
●Abnormal S2 splitting − The second heart sound (S2) normally splits physiologically with inspiration, and becomes single during expiration. The presence of S2 splitting reduces the likelihood of severe CHD; however, the newborn's rapid heart rate often makes it challenging to detect S2 splitting. Splitting is audible in 80 percent of normal newborns by 48 hours of age, usually when the heart rate is less than 150 beats per minute [52,64]. As an infant's heart is positioned more horizontally, splitting may be easier to hear along the mid to lower sternal border than in children or adults. Listening may be facilitated by a gentle breath into the baby's face that may temporarily slow the heart rate. (See "Assessment of the newborn infant" and "Auscultation of heart sounds".)
A single second heart sound occurs in the following conditions:
•Pulmonary atresia (PA)
•Truncus arteriosus (TAC)
•Conditions with pulmonary hypertension, as increased impedance in the pulmonary circuit causes early closure of the pulmonary valve, resulting in a single S2
In the great arteries (TGA), the pulmonary artery is located posterior and directly behind the aorta; thus, the softer pulmonary component of the second heart sound is often inaudible.
A widely or fixed split S2 occurs with atrial septal defect (ASD) and other lesions associated with right ventricular volume overload or right-sided conduction delays. However, the absence of a widely split S2 in an infant does not rule out an ASD. The abnormal splitting may develop later with increasing volume of flow crossing the defect after pulmonary resistance has fallen.
●Abnormal extra heart sounds — The following additional heart sounds may be associated with cardiac abnormalities. If any of these are heard, the infant should be evaluated by a pediatric cardiologist.
•Early systolic clicks, which occur with semilunar valve stenosis, bicuspid aortic valve, and TAC.
•Midsystolic clicks, which are heard with mitral valve prolapse and with Ebstein's anomaly of the tricuspid valve.
•An S3 gallop, which, in infants, can result from ventricular dysfunction or left ventricular volume overload.
•Pericardial friction rubs occur with small to moderate pericardial effusions and pericarditis. Purulent pericarditis is an unusual complication of neonatal sepsis [65,66]. Pericarditis is also seen in neonatal lupus that may occur in infants of mothers with connective tissue disorders and anti-Ro/SSA and/or anti-La/SSB bodies . (See "Neonatal lupus".)
●Pathologic murmurs − The presence of a murmur is often associated with CHD. However, not all CHD lesions are associated with murmurs, and many infants with murmurs do not have structural heart disease [68,69].
Murmurs associated with heart disease can be distinguished from innocent murmurs based upon the intensity and quality of the murmur and associated findings [70-72]. The following features of murmurs are associated with structural heart disease :
•Murmur intensity grade 3 or higher
•Loudest at upper left, upper right sternal border, or apex
In addition, murmurs that are associated with other abnormal findings (eg, diminished femoral pulses or noncardiac abnormalities) should raise suspicion for CHD.
Lesion-specific qualities of murmurs associated with CHD are discussed separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Murmur'.)
Many infants with CHD do not have a murmur [68,73], and therefore the absence of a murmur does not rule out CHD. The following factors may account for the absence of a murmur:
•The velocity of turbulent blood flow may not be high enough to generate a murmur. This typically occurs in hypoplastic left heart syndrome (HLHS), simple TGA, total anomalous pulmonary venous connections (TAPVC), PA, and cardiomyopathy.
•Decreased ventricular function can limit the generation of a murmur. As an example, if the left ventricular myocardium cannot generate enough contraction to create sufficient flow across a critically obstructed aortic valve, a murmur of aortic stenosis will not be heard.
•Elevated pulmonary resistance may limit flow. The volume or velocity of flow across a VSD may not be sufficient to be audible until the resistance has fallen .
A substantial proportion of murmurs heard in the newborn period are innocent. In studies of neonates undergoing echocardiography for evaluation of murmurs, 13 to 23 percent were found to have no structural heart disease [68,69].
The majority of innocent murmurs in term infants are due to benign pulmonary branch stenosis (PBS), also known as peripheral pulmonary stenosis. This condition is usually detected as a grade 1-2/6, midsystolic, high-pitched or blowing ejection murmur heard best in the pulmonary area with radiation to the axilla and back after the infant is 24 hours of age, when most patent ductus arteriosus (PDAs) have closed . The murmur may be due to the relative hypoplasia at birth of the branch pulmonary arteries compared with the main pulmonary artery (which is large because it feeds the PDA and systemic circulation in utero) and its sharp angle of origin [75-79].
Another innocent finding on auscultation in infants is a Still's murmur thought to arise from the vibrations of the attachments of the pulmonic valve leaflets. These low-pitched, vibratory, musical, grade 1-2/6 systolic ejection murmurs are usually best heard between the lower left sternal border and apex. They typically decrease in intensity or resolve with a Valsalva maneuver, which can be induced in infants by gentle pressure on the abdomen. Still's murmurs tend to vary with heart rate, becoming more evident as the heart rate slows; however, they are relatively uncommon in the newborn.
The natural history of neonatal innocent murmurs was investigated with serial two-dimensional and pulsed Doppler echocardiograms in 50 healthy term infants with a clinical diagnosis of an innocent murmur and 50 controls without a murmur . Cardiac findings were more frequent in the murmur group than in controls, including PBS (50 versus 12 percent) and PDA (30 versus 12 percent). The murmur had disappeared in 64 and 98 percent of babies by six weeks and six months of age, respectively. Structural heart disease (pulmonary stenosis) was diagnosed in only one patient by six months of age.
●Diminished pulses in the lower extremities − Assessment of symmetric peripheral arterial pulses is an essential part of the neonatal evaluation. The diagnosis of coarctation of the aorta (COA) or other aortic arch obstruction is strongly suggested in the infant with decreased or absent pulses in the lower extremities with strong upper extremity pulses, or blood pressure ≥10 mmHg higher in the arms than legs. (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Manifestations according to age'.)
Infants with significant COA may have cool and/or mottled lower extremities that must be distinguished from cutis marmorata (picture 1), a purplish, marble-like mottling that appears with exposure to cold . Cutis marmorata is probably caused by constriction of the small cutaneous arterioles, causing the small venules to appear prominent. It is not usually limited to the lower extremities, and disappears once the infant is warm. COA should also be considered in the differential diagnosis of neonatal hypertension .
Some cases of COA escape early diagnosis . In the study of the utility of routine exams to detect CHD cited above, 19 of 95 (20 percent) infants diagnosed with COA by 12 months of age were not diagnosed before 12 weeks of age .
●Extracardiac abnormalities − Extracardiac abnormalities are frequently detected in children with CHD. Skeletal abnormalities, especially those of the hand and arm, are often associated with cardiac malformations. CHD may be a component of many specific syndromes and chromosomal disorders . In a review of the population-based surveillance data from the Metropolitan Atlanta Congenital Defects Program (MACDP), 12.3 percent of infants with CHD had a chromosomal abnormality . Infants with genetic disorders associated with cardiovascular malformations (table 3) should be evaluated for possible cardiac abnormalities.
The frequency of extracardiac abnormalities was demonstrated in a retrospective study of 1058 children with CHD evaluated during a 10-year period at a tertiary center in Belgium . About 20 percent of patients (n = 224) had noncardiac abnormalities. Eleven percent (n =118) had an identifiable syndrome or chromosomal disorder. In the previously mentioned Danish population-based study, chromosomal defects were detected in 7 percent of patients with CHD, and extracardiac anomalies in 22 percent .
Pulse oximetry screening — Universal neonatal screening with pulse oximetry (algorithm 1) improves the identification of patients with critical CHD compared with physical examination alone [8,61,84-88]. The strategy of universal newborn screening is endorsed by the AAP, AHA, Health and Human Services (HHS), and ACCF [59,89,90]. Most states in the United States require mandatory newborn pulse oximetry screening to detect critical CHD (the Centers for Disease Control and Prevention [CDC] provides a map with information on legislation on newborn pulse oximetry screening for each state) . Pulse oximetry screening and the diagnosis and management of cyanotic CHD are discussed separately . (See "Diagnosis and initial management of cyanotic heart disease in the newborn".)
Targeted lesions — The seven primary targets for which newborn pulse oximetry screening was developed are :
Other lesions which may have desaturation and thus might be identified by pulse oximetry screening include :
●Double-outlet right ventricle
Universal pulse oximetry screening has an additional benefit of identifying term infants with low oxygen saturation resulting from noncardiac disorders [88,92]. These include pneumonia, sepsis, pulmonary hypertension of the newborn, meconium aspiration syndrome, pneumothorax, and hemoglobinopathies with low oxygen affinity.
Screening procedure — The procedure for pulse oximetry screening in newborns includes the following elements (algorithm 1):
●Timing − Screening should be performed after 24 hours of life or as late as possible if early discharge is planned.
●Instrumentation − The screening should be performed using a motion-tolerant pulse oximeter. Either disposable or reusable probes can be used. Reusable probes reduce the cost of screening, but must be appropriately cleaned to minimize the risk of infection.
●Probe placement − Oxygen saturation (SpO2) should be measured in the right hand (preductal) and either foot (postductal). Screening at both locations can occur simultaneously or in direct sequence.
●Personnel − Screening is performed by qualified and trained personnel.
Positive screen — Criteria for a positive screening test include any of the following:
•SpO2 measurement <90 percent
•SpO2 measurement <95 percent in both upper and lower extremities on three measurements, each separated by one hour
•SpO2 difference >3 percent between the upper and lower extremities
Assessment of infants with positive pulse oximetry screening test includes the performance of high-quality echocardiography and interpretation by a pediatric cardiologist. Patients should have access to these diagnostic services at the birth center, via telemedicine, or via short-distance transport. Each birthing institution should establish a protocol to ensure a timely evaluation for newborns with a positive screening test.
At the first outpatient visit, primary care providers should ascertain whether screening was performed during the birth hospitalization, and if not, develop strategies for appropriate screening.
Limitations of screening — The following limitations are important to consider when performing pulse oximetry screening:
●False negative results − Pulse oximetry screening fails to identify some patients with obstructive left-sided lesions and will not detect noncyanotic congenital heart lesions, such as ventricular septal defect. Both care providers and parents must be aware that a negative result does not exclude the possibility of potentially significant CHD.
●High altitude − The pulse oximetry screening guidelines recommended by the AAP are feasible up to an elevation of 2643 ft (806 m) without any needed adjustments [93,94]. However, criteria have not been validated for newborns cared for at centers at higher altitudes.
Late presentation — Clinicians should be alert to clinical manifestations of CHD that may be detected in the course of initial routine newborn visits because some neonates with critical CHD are asymptomatic during the birth hospitalization and then develop signs and symptoms after discharge, typically by two weeks of age [46,60,68].
Prior to the initiation of routine pulse oximetry screening, the most commonly missed diagnoses during the birth hospitalization included [43,44,46]:
●HLHS (figure 2)
●COA (figure 3)
●Interrupted aortic arch
●TGA (figure 6)
●TOF (figure 9)
Pulse oximetry screening targets several of these lesions (TGA, TOF, HLHS) and so the frequency of missed diagnoses is likely to drop as pulse oximetry screening becomes widespread. However, it is important to recognize that infants with noncyanotic heart defects (including those with "pink" TOF [ie, those with minimal pulmonary stenosis]), and some left heart obstructive lesions will not be identified by pulse oximetry screening .
Clinical manifestations — In affected newborn infants, parents most commonly notice difficulty with feeding. This may be manifested by intake of a limited volume of milk, or feedings that are taking too long or are frequently interrupted by sleeping or resting, choking, gagging, and/or vomiting. Infants may have respiratory distress that is reported by parents as fast or hard breathing, worse with feedings, or a persistent cough or wheeze.
Other manifestations include:
●Color changes, such as central cyanosis or persistent pallor
●Excessive, unexplained irritability
●Excessive sweating that is increased with feeding and may occur during sleep
●Poor weight gain
●Decreased activity or excessive sleeping
●Delay in motor milestones 
Evaluation — The evaluation for CHD in an infant includes (see 'Physical examination' above):
●General assessment (including weight).
●Measurement of heart rate and upper and lower extremity blood pressure.
●Detailed cardiac examination (including auscultation for murmurs and/or abnormal heart sounds) − In some infants with CHD, murmurs may not be heard during the initial exam but may be detected at or beyond the age of six weeks .
●Assessment of peripheral pulses.
In addition, primary care providers should ascertain whether pulse oximetry screening was performed during the birth hospitalization, and if not, perform screening in the office setting. (See 'Pulse oximetry screening' above.)
Measurement of upper and lower extremity blood pressure and assessment of peripheral pulses are particularly important. Diminished and absent peripheral pulses are findings consistent with the diagnosis of COA, which is frequently delayed. In the regional study from the United Kingdom of all infants with CHD diagnosed before 12 months of age, 27 and 20 percent of infants with coarctation remained undiagnosed by six weeks and three months, respectively . In a retrospective review of patients older than one year who had repair of COA, pulses were decreased but not absent in the majority of patients . (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Manifestations according to age'.)
When to refer — For infants seen in the office setting by primary care providers, consultation or referral to a pediatric cardiologist should be made if any of the following are noted:
●Physical exam findings suggestive of CHD (table 4), including abnormal precordial activity, abnormal heart sounds (eg, S3 gallop, click, or single S2), pathologic murmur, abnormal four extremity blood pressure (ie, blood pressure ≥10 mmHg higher in the arms than legs), or diminished or absent lower extremity pulses. (See 'Physical examination' above.)
●Positive pulse oximetry screening. (See 'Pulse oximetry screening' above.)
●Genetic disorder or extracardiac abnormality associated with cardiovascular malformations (table 3).
●Abnormal chest radiograph or ECG (table 4).
SUMMARY AND RECOMMENDATIONS
●Congenital heart disease (CHD) is the most common congenital disorder in newborns.
●Critical CHD, defined as lesions requiring surgery or catheter-based intervention in the first year of life, occurs in approximately 25 percent of neonates with CHD and is one of the leading causes of infant mortality. The risk of morbidity and mortality increases when there is a delay in diagnosis and treatment. (See 'Introduction' above.)
●The risk of CHD is increased in infants who have a history of maternal medical conditions or prenatal disorders associated with CHD, or a positive family history (table 2). When present, these factors should increase the vigilance of the clinician for the possibility of CHD in the newborn infant. (See 'Risk factors' above and 'History' above.)
●In patients with ductal-dependent lesions (table 1), closure of the ductus arteriosus within the first few days of life can precipitate rapid clinical deterioration with potentially life-threatening consequences. Initiation of prostaglandin E1 to reopen or maintain the ductus arteriosus can be life-saving in these patients and should be initiated as soon as CHD is suspected in symptomatic neonates. (See 'Clinical features' above and "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.)
●Neonates with critical CHD can present during their birth hospitalization with serious and life-threatening manifestations, including shock, cyanosis, or respiratory distress. However, some infants with critical CHD, particularly those with ductal-dependent lesions (table 1), may appear normal with either no or very subtle signs and symptoms. (See 'Postnatal diagnosis' above and 'Clinical features' above and 'Asymptomatic neonates' above.)
●Diagnostic evaluation of symptomatic neonates includes physical examination, pulse oximetry, chest radiograph, electrocardiogram (ECG), hyperoxia test (table 5), and echocardiography. (See 'Symptomatic neonates' above.)
●In otherwise asymptomatic infants, physical findings that are suggestive of CHD include abnormal cardiovascular examination (ie, abnormal heart rate, precordial activity, or heart sounds; pathologic murmurs; diminished/absent peripheral pulses or blood pressure ≥10 mmHg higher in the arms than legs) and noncardiac anomalies. (See 'Physical examination' above.)
●Routine pulse oximetry (algorithm 1) is an effective screening test to detect critical CHD in asymptomatic newborns. However, providers and families must recognize that it does not identify all CHD, particularly noncyanotic lesions and some left heart obstructive lesions. Infants with positive pulse oximetry screening tests should be evaluated with echocardiography interpreted by a pediatric cardiologist. (See 'Pulse oximetry screening' above.)
●Consultation or referral to a pediatric cardiologist should be made for infants with any of the following:
•Signs and symptoms concerning for critical CHD, including shock unresponsive to volume resuscitation, cardiomegaly, cyanosis, pulmonary edema, otherwise unexplained respiratory symptoms, or failed hyperoxia test. (See 'Shock' above and 'Cyanosis' above and 'Respiratory symptoms' above.)
•ECG, and/or chest radiograph findings suggestive of CHD (table 4). (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Electrocardiogram' and "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Chest radiograph'.)
•Physical exam findings suggestive of CHD (table 4), including abnormal heart sounds (eg, S3 gallop, click, or single S2), pathologic murmur (loud, holosystolic, diastolic, or loudest at apex or upper left or right sternal border), diminished or absent lower extremity pulses, or blood pressure ≥10 mmHg higher in the arms than legs. (See 'Physical examination' above.)
•Genetic disorder or extracardiac malformation associated with cardiovascular malformations. (table 3).
●Because the diagnosis of critical CHD may be missed during the birth hospitalization, clinicians should be aware and look for clinical manifestations of CHD during the first discharge visit at three to five days of age. Symptoms are nonspecific and include difficulty in feeding, poor weight gain, cyanosis, respiratory findings, decreased activity, irritability, and excessive sweating. The routine examination should include global assessment (including weight); measurement of heart rate and upper and lower extremity blood pressure; a detailed cardiac examination (including auscultation for murmurs and/or abnormal heart sounds); and assessment of peripheral pulses. (See 'Late presentation' above.)
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