Evaluation of suspected critical congenital heart disease (CHD) in the newborn

INTRODUCTION — 

Congenital heart disease (CHD) is the most common type of congenital anomaly. Critical CHD, defined as lesions requiring surgery or catheter-based intervention in the first year of life (table 1), accounts for approximately 25 percent of CHD [1]. Many newborns with critical CHD are diagnosed prenatally or are identified soon after birth (eg, due to symptoms or positive pulse oximetry screening). However, some affected infants are not diagnosed until after discharge from the birth hospitalization. For newborns 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 [2-4].

The clinical presentation and initial diagnostic evaluation of suspected critical CHD in the newborn will be reviewed here.

Related topics include:

●(See "Newborn screening for critical congenital heart disease using pulse oximetry".)

●(See "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management".)

●(See "Suspected heart disease in infants and children: Criteria for referral".)

TERMINOLOGY — 

The following terms are used to characterize 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 "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management".)

●Ductal-dependent CHD – Ductal-dependent congenital heart lesions are dependent upon a patent ductus arteriosus (PDA) (figure 1) to supply pulmonary or systemic blood flow or to allow adequate mixing between parallel circulations. In critical right-sided obstructive lesions, the PDA is necessary to supply blood flow to the lungs; in critical left-sided obstructive 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 forms of CHD that may not require surgery in the neonatal period but still require intervention in the first year of life, such as a large ventricular septal defect or an atrioventricular canal defect (or atrioventricular septal defect).

EPIDEMIOLOGY

Prevalence — Critical CHD accounts for approximately 25 percent of all CHD [1]. Reported combined prevalence rates for any critical CHD lesion vary from region to region, ranging from 1 to 3 per 1000 live births (median 1.9 per 1000 live births) [5].

The most common cyanotic critical CHD defects are tetralogy of Fallot (TOF) (figure 2) and D-transposition of the great arteries (D-TGA) (figure 3), each with a prevalence of approximately 0.2 to 0.5 per 1000 births, [5-7]. (See "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis", section on 'Epidemiology' and "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis", section on 'Epidemiology'.)

The most common noncyanotic critical CHD defect is coarctation of the aorta (COA) (figure 4), with a prevalence of approximately 0.2 to 0.6 per 1000 births [5]. (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Epidemiology'.)

Ventricular septal defects (VSDs) are among the most common CHD defects; however, relatively few VSDs are characterized as critical CHD (ie, requiring surgery in the first year of life). (See "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis", section on 'Prevalence'.)

Risk factors — The following factors are associated with an increased risk of CHD and should heighten the clinician's suspicion for CHD (table 2) [8]:

●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 [9].

●Family history – The risk of CHD in infants with first-degree relatives (ie, parents or siblings) who have nonsyndromic isolated CHD is estimated to be three- to fourfold higher than that of the general population [10-12]. The risk varies considerably depending on the type of CHD and whether the mother, father, sibling, or multiple family members are affected [12-15]. Left heart obstructive lesions carry a higher risk of recurrence; whereas D-transposition of the great arteries carries a low risk of recurrence (table 2).

●Genetic syndromes and extracardiac abnormalities – Genetic syndromes 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 [11]. Many genetic syndromes are associated with an increased risk of CHD (table 3) [16,17]. Some genetic conditions may only be identified after the diagnosis of CHD is made upon further investigation. Consultation with a cardiac geneticist and genetic counselor is extremely helpful in these cases. Cardiac genetics is a rapidly evolving field, and advances in genomic sequencing have led to a better understanding of the genetic basis of CHD [18].

●Maternal factors – Maternal conditions that increase the risk of CHD include diabetes mellitus, hypertension, obesity, phenylketonuria, thyroid disorders, systemic connective tissue disorders, and epilepsy (table 2) [19-21]. 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 [22-24]. (See "Congenital heart disease: Prenatal screening, diagnosis, and management", section on 'Indications for echocardiography'.)

●Fertility treatment – Assisted reproductive technology (ART) has been linked to increased risk of CHD [25-27]. In a meta-analysis of 24 observational studies reporting outcomes of offspring conceived via in vitro fertilization, the pooled incidence of major CHD was 1 percent [27]. While the increased risk of CHD in this population may be related to ART itself, other confounding factors (maternal age, male infertility, and twinning) may also play a role. (See "Assisted reproductive technology: Infant and child outcomes".)

●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 [28]. Congenital cardiomyopathy may result from infection with cytomegalovirus, coxsackie, herpes virus 6, parvovirus B19, herpes simplex, toxoplasmosis, and possibly human immunodeficiency virus. (See "Seasonal influenza and pregnancy" and "Overview of TORCH infections".)

Timing of diagnosis — For infants with critical CHD, the risk of morbidity and mortality increases when there are delays in diagnosis and timely referral to a tertiary center with expertise in treating these patients [2-4,29]. CHD is the leading cause of perinatal and infant death from a congenital anomaly, although outcomes have improved substantially with advances in corrective or palliative interventions [30-32].

Prenatal diagnosis — In the contemporary era, approximately 50 to 60 percent of cases of critical CHD are detected prenatally, though detection rates vary depending on the specific lesion [5,33-35]. A standard obstetric ultrasound examination includes assessment of the four chambers and ventricular outflow tracts of the fetal heart. (See "Congenital heart disease: Prenatal screening, diagnosis, and management", section on 'Standard cardiac evaluation'.)

While prenatal screening detects many cases of CHD, its sensitivity depends on operator expertise, gestational age, fetal position, and type of defect. As a result, some patients with critical CHD will not be detected through prenatal ultrasonography screening. In particular, coarctation of the aorta (COA) (figure 4) can be challenging to definitively diagnose prenatally. (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Prenatal diagnosis'.)

Clinicians skilled at fetal echocardiography are able to identify most critical congenital heart defects. Fetal echocardiography is indicated if there are cardiac abnormalities on the routine obstetrical ultrasound or if there are certain antenatal risk factors [36]. Fetal echocardiography is typically performed in the second trimester. (See "Congenital heart disease: Prenatal screening, diagnosis, and management", section on 'Indications for echocardiography'.)

Social determinants of health appear to impact prenatal diagnosis rates for critical CHD [37]. In one study, lower economic status, rural residence, and Hispanic ethnicity were associated with lower prenatal detection of two critical CHD lesions (transposition of the great arteries and hypoplastic left heart syndrome) [38]. These studies highlight the importance of remaining vigilant for postnatal diagnoses.

Postnatal presentation — Infants with critical CHD may present during the birth hospitalization, often with serious and life-threatening clinical findings that require immediate intervention [39]. However, some infants with CHD may appear healthy on routine examination, and signs of critical CHD may not be apparent until after discharge [29,39]. The timing of presentation varies with the underlying lesion and its dependence upon a PDA (figure 1 and table 1). (See 'Early presentation' below and 'Late presentation' below.)

Prior to the routine use of pulse oximetry screening, approximately 15 to 30 percent of patients with critical CHD were discharged from the birth hospitalization undiagnosed [40,41]. In low- and middle-income countries, a substantially higher number of patients have late diagnosis (50 percent in one study) [42]. In settings where newborn pulse oximetry screening has been adopted into routine practice, this rate has decreased to approximately 7 to 10 percent [29,43].  

The most commonly reported delayed diagnoses are COA (figure 4), interrupted aortic arch (figure 5), aortic stenosis, hypoplastic left heart syndrome (figure 6), transposition of the great arteries (figure 3), pulmonary valve stenosis, and TOF (figure 2) [40,44]. Pulse oximetry screening can identify infants with some, but not all, of these lesions. (See "Newborn screening for critical congenital heart disease using pulse oximetry", section on 'Definition and targeted lesions'.)

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) [45]. For infants with critical CHD who are not diagnosed during the birth hospitalization, the risk of mortality is as high as 30 percent [3].

CLINICAL FEATURES — 

Neonates with critical CHD can present during their birth hospitalization with serious and life-threatening manifestations including:

●Shock (see 'Shock' below)

●Cyanosis (see 'Cyanosis' below)

●Tachypnea and other signs of pulmonary edema (see 'Respiratory abnormalities' below)

However, some infants with CHD may appear healthy 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 a newborn [46].

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 "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management", section on 'Initial management'.)

Early presentation — Neonates who present with symptomatic CHD in the early newborn period typically present with shock, cyanosis, or respiratory signs (or a combination of these).

Shock — Some infants with critical CHD will present during the neonatal hospitalization with shock. Most commonly, this is seen in infants with unsuspected critically obstructive left heart lesions (table 1), including:

●Hypoplastic left heart syndrome (HLHS) (figure 6) (see "Hypoplastic left heart syndrome: Anatomy, clinical features, and diagnosis")

●Critical aortic valve stenosis (see "Valvar aortic stenosis in children", section on 'Critical aortic stenosis')

●Critical coarctation of the aorta (COA) (figure 4) (see "Clinical manifestations and diagnosis of coarctation of the aorta")

●Interrupted aortic arch (IAA) (figure 5)

Infants with these lesions may present with cardiogenic shock as the ductus arteriosus closes and systemic perfusion decreases. In these patients, initiation of prostaglandin E1 (alprostadil) to reopen or maintain the ductus arteriosus is imperative. The use of prostaglandin E1 is summarized in the table (table 4) and discussed in detail separately. (See "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management", section on 'Prostaglandin E1'.)

Infants with total anomalous pulmonary venous connection (TAPVC) (figure 7) most commonly present with mild cyanosis and tachypnea. However, patients may present with cyanosis and shock if there is significant obstruction with a restrictive atrial communication. In these cases, systemic perfusion is impaired because all pulmonary venous return must traverse the restrictive atrial communication to reach the left heart and supply the systemic circulation. This is the rare instance in which 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 total anomalous pulmonary venous return below the diaphragm, ductal patency is not of utility and the only effective management strategy is urgent surgical intervention. These patients present with severe cyanosis and marked pulmonary venous edema. (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 presenting with shock, features that suggest a cardiac etiology include cardiomegaly on chest radiograph, differential pulses, and lack of improvement or clinical deterioration in response to volume resuscitation [47]. (See 'Differential diagnosis' below and "Neonatal shock: Etiology, clinical manifestations, and evaluation".)

Cyanosis — Cyanotic forms of CHD are associated with intracardiac and/or ductal right-to-left shunting. Cyanosis can be appreciated on examination when the level of deoxygenated hemoglobin exceeds 3 g/dL. However, cyanosis may not be readily apparent in patients with mild desaturation (>80 percent saturation), anemia, or dark skin pigmentation. Pulse oximetry is helpful to detect mild desaturation in patients with cyanotic CHD. (See "Newborn screening for critical congenital heart disease using pulse oximetry".)

Many, but not all, forms of cyanotic CHD are ductal-dependent (table 1). Ductal-dependent CHD lesions rely upon a patent ductus arteriosus (PDA) (figure 1) to supply pulmonary or systemic blood flow or to allow adequate mixing between parallel circulations.

●Cyanotic CHD lesions – Cyanotic CHD lesions include:

•Right-sided obstructive lesions (eg, tetralogy of Fallot [TOF] (figure 2), pulmonary atresia with intact ventricular septum (figure 8), critical pulmonic stenosis, tricuspid atresia (figure 9), severe Ebstein anomaly (figure 10)) (see "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management", section on 'Right-sided obstructive lesions')

•Left-sided obstructive lesions (eg, HLHS (figure 6), critical COA (figure 4), IAA (figure 5), crucial aortic stenosis) (see "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management", section on 'Left-sided obstructive lesions')

•Parallel pulmonary and systemic circulations (D-transposition of the great arteries (figure 3)) (see "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis")

•TAPVC (figure 7) (see "Total anomalous pulmonary venous connection")

•Truncus arteriosus (figure 11) (see "Truncus arteriosus")

●Differential cyanosis – Ductal-dependent CHD lesions that are associated with right-to-left shunting across the PDA are characterized by differential cyanosis, in which the upper body is pink and the lower body is cyanotic. (See "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management", section on 'Differential cyanosis'.)

Differential cyanosis can also occur in newborns with structurally normal hearts who have persistent pulmonary hypertension (PPHN). (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Pre- and postductal oxygen saturation'.)

Reversed differential cyanosis is a rare finding that may occur in patients with transposition of the great arteries (figure 3) associated with either coarctation or pulmonary hypertension. (See "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis", section on 'Clinical features'.)

●Noncardiac causes of cyanosis – Noncardiac conditions (eg, respiratory disorders, PPHN) also can cause cyanosis and are differentiated from CHD by the history, cardiovascular examination, chest radiograph, and echocardiography. (See 'Diagnostic approach' below and 'Differential diagnosis' below.)

Respiratory abnormalities — 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.

The following CHD defects commonly present with tachypnea and respiratory distress:

●Truncus arteriosus (figure 11) [46]. (See "Truncus arteriosus".)

●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 7) [48]. (See "Total anomalous pulmonary venous connection".)

●PDA in preterm infants (figure 1). (See "Patent ductus arteriosus (PDA) in preterm infants: Clinical features and diagnosis".)

●Large ventricular septal defect (VSD) – Respiratory signs of congestive heart failure typically develop over the first four to six week after birth as pulmonary vascular resistance falls. (See "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis".)

Infants with mild to moderate pulmonary overcirculation frequently have tachypnea without appearing distressed, sometimes referred to as "happy" or "comfortable" tachypnea. The infant may become more tachypneic during feeding or if pulmonary edema worsens. Signs of distress can include grunting, nasal flaring, retractions, and head bobbing. Cardiac tachypnea in neonates can occur due to a large left-to-right shunt, pulmonary venous obstruction, or increased left ventricular end-diastolic pressure [49]. Tachypnea in heart failure is also thought to have a neurohormonal basis.

For newborns presenting with respiratory signs, primary pulmonary causes are more common than CHD and are usually considered first in the differential diagnosis (see 'Differential diagnosis' below). Concern for a cardiac cause may arise due to findings on examination (eg, pathologic murmur) or findings on chest radiography (eg, cardiomegaly, pulmonary edema). (See 'Physical examination' below and 'Chest radiograph' below.)

If there are findings suggestive of a cardiac etiology or if no clear pulmonary cause is identified on the initial evaluation, consultation or referral should be made to a pediatric cardiologist for echocardiography. (See 'Referral' below and 'Echocardiography' below.)

Late presentation — 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 [50-52].

Defects that may present late — Prior to the introduction of routine pulse oximetry screening, the CHD defects that most frequently escaped diagnosis during the birth hospitalization included [40,44,50]:

●HLHS (figure 6)

●COA (figure 4)

●IAA (figure 5)

●Aortic stenosis

●D-TGA (figure 3)

●Pulmonic stenosis

●TOF (figure 2)

Pulse oximetry screening targets several of these lesions (D-TGA, TOF, HLHS). However, it is important to recognize that pulse oximetry screening will not identify newborns with noncyanotic heart defects (including those with "pink" TOF [ie, those with minimal pulmonary stenosis]) and some left heart obstructive lesions (eg, some patients with COA). This is discussed in detail separately. (See "Newborn screening for critical congenital heart disease using pulse oximetry", section on 'Negative screen'.)

Clinical manifestations — For infants with a late presentation, clinical manifestations may include:

●Feeding difficulties (lethargy and tiring with early stopping of feeding)

●Respiratory distress and tachypnea

●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

●Delays in achieving motor milestones

DIAGNOSTIC APPROACH — 

The diagnostic evaluation of neonates with suspected CHD includes:

●History and physical examination (see 'History' below and 'Physical examination' below)

●Measurement of upper and lower extremity blood pressure (see 'Upper and lower extremity blood pressure' below)

●Pulse oximetry (see 'Pulse oximetry' below)

●Electrocardiogram (ECG) (see 'Electrocardiogram' below)

●Chest radiograph (see 'Chest radiograph' below)

●Echocardiography (see 'Echocardiography' below)

For newborns presenting with cardiorespiratory instability that is suspected to be due to critical CHD, urgent consultation with a pediatric cardiologist is warranted. (See 'Referral' below.)

In addition to the cardiac evaluation outlined below, newborns with concerning cardiorespiratory findings should undergo evaluation for other potential causes (see 'Differential diagnosis' below). The approach to evaluating neonates with these findings is discussed separately:

●Shock (see "Neonatal shock: Etiology, clinical manifestations, and evaluation", section on 'Diagnostic evaluation')

●Cyanosis (see "Approach to cyanosis in the newborn", section on 'Evaluation')

●Respiratory distress (see "Overview of neonatal respiratory distress and disorders of transition", section on 'Diagnostic approach')

In many cases, it is appropriate to perform a sepsis evaluation and administer empiric antibiotics pending culture results. The evaluation and empiric treatment of sepsis in neonates are discussed separately. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at or after 35 weeks gestation", section on 'Evaluation and initial management'.)

History — The maternal history, prenatal history, and family history should be reviewed to identify possible risk factors that increase the likelihood of CHD (table 2). (See 'Risk factors' above.)

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.

Physical examination — A thorough physical examination should be performed with attention to findings suggestive of CHD (table 5), including abnormal precordial activity, abnormal heart sounds (eg, third heart sound [S3] gallop, click, or single second heart sound [S2]), pathologic murmurs (loud, harsh, pansystolic, diastolic, or loudest at upper left or right sternal border or apex), hepatomegaly, diminished or absent lower extremity pulses, and abnormal four extremity blood pressure (ie, blood pressure ≥10 mmHg higher in the arms than legs).

Several studies have shown that the newborn examination alone fails to detect a substantial subset of newborns with heart disease [43,50,51]. However, subtle clinical findings can be detected that indicate underlying cardiac disease. The following discussion reviews the physical findings that may be seen in a newborn with CHD; however, findings may be absent in infants with ductal-dependent lesions if the ductus arteriosus remains patent.

The following cardiovascular findings suggestive of CHD merit further evaluation and/or referral to clinicians with expertise in caring for neonates with CHD. (See 'Referral' below.)

●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, ECG is initially performed to determine whether there is an arrhythmia and to guide further assessment and management [53]. (See "Irregular heart rhythm (arrhythmias) in children" and "Approach to the child with tachycardia" and "Bradycardia in children" and "Clinical features and diagnosis of supraventricular tachycardia (SVT) in children".)

●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 [54]

•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

●Abnormal S2 splitting – The S2 normally splits physiologically with inspiration and becomes single during expiration (movie 1). 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 <150 beats per minute [49,55]. 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 "Approach to the infant or child with a cardiac murmur", section on 'Second heart sound'.)

A single S2 occurs in the following conditions (table 5):

•Aortic atresia

•Pulmonary atresia

•Truncus arteriosus (figure 11)

•Severe pulmonary stenosis

•Tetralogy of Fallot (TOF) (figure 2)

•Conditions with pulmonary hypertension, as increased impedance in the pulmonary circuit causes early closure of the pulmonary valve, resulting in a single S2 (movie 2)

In the dextro transposition of the great arteries (D-TGA) (figure 3), the pulmonary artery is located posterior and directly behind the aorta; thus, the softer pulmonary component of the S2 is often inaudible.

A widely or fixed split S2 occurs with atrial septal defect (ASD) (movie 3) and other lesions associated with right ventricular volume overload or right-sided conduction delays (movie 4).

●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. (See "Approach to the infant or child with a cardiac murmur", section on 'Third and fourth heart sounds' and "Approach to the infant or child with a cardiac murmur", section on 'Other sounds'.)

•Early systolic clicks, which occur with semilunar valve stenosis (movie 5), bicuspid aortic valve (movie 6), and truncus arteriosus.

•Midsystolic clicks, which are heard with mitral valve prolapse and with Ebstein anomaly of the tricuspid valve.

•An S3 gallop (movie 7), which, in infants, can result from ventricular dysfunction or left ventricular volume overload.

•Pericardial friction rubs (movie 8) occur with small to moderate pericardial effusions and pericarditis. Purulent pericarditis is an unusual complication of neonatal sepsis [56,57]. 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 [58]. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

●Pathologic murmurs – The presence of a murmur is often associated with CHD (table 5). However, not all CHD lesions are associated with murmurs, and many infants with murmurs do not have structural heart disease [52,59].

Murmurs associated with heart disease may be distinguished from innocent murmurs based upon the intensity (table 6), location, and quality of the murmur and associated findings [60-62]. Features that are associated with heart disease are summarized in the table (table 7). If the murmur cannot confidently be ascertained as innocent, echocardiography should be performed.

The approach to evaluating cardiac murmurs in infants and children is discussed separately. (See "Approach to the infant or child with a cardiac murmur".)

Many infants with CHD do not have a murmur [52,63], 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 (figure 6), simple transposition of the great arteries (figure 3), total anomalous pulmonary venous connections (TAPVC) (figure 7), pulmonary atresia, 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 ventricular septal defect may not be sufficient to be audible until the resistance has fallen [59].

●Hepatomegaly – In newborns, the liver edge normally is palpated 1 to 3 cm below the right costal margin. An enlarged liver is a nonspecific finding that may be seen in infants with heart failure and increased central venous pressure. (See "Assessment of the newborn infant", section on 'Palpation'.)

●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) (figure 4) or interrupted aortic arch (IAA) (figure 5) is strongly suggested in the infant with decreased or absent pulses in the lower extremities with strong upper extremity pulses. (See "Clinical manifestations and diagnosis of coarctation of the aorta".)

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 [49]. 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 [64]. (See "Etiology, clinical features, and diagnosis of neonatal hypertension".)

●Extracardiac abnormalities – Extracardiac abnormalities are frequently detected in children with CHD, and CHD may be a component of many specific genetic syndromes (table 3) [16]. Infants with genetic disorders associated with cardiovascular malformations (table 3) should be evaluated for possible cardiac abnormalities. Skeletal abnormalities, especially those of the hand and arm, are often associated with cardiac malformations.

In the available reports, approximately 20 percent of children with CHD had noncardiac abnormalities and 7 to 12 percent had an identifiable syndrome or chromosomal disorder [11,65,66].

Upper and lower extremity blood pressure — Blood pressure (BP) should be measured in the upper and lower extremities. BP ≥10 mmHg higher in the arms than legs suggests COA (figure 4). (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Manifestations according to age'.)

When measuring BP in neonates, it is important to ensure that the cuff size is appropriate and that the infant is in the same state (ideally, sleeping or in a quiet awake state) during all measurements. (See "Etiology, clinical features, and diagnosis of neonatal hypertension", section on 'Measurement'.)

Measurement of upper and lower extremity BP and assessment of peripheral pulses are particularly important in infants presenting after discharge from the birth hospitalization since the presentation of COA can be delayed [67].

Pulse oximetry — All neonates with suspected CHD should have their peripheral oxygen saturation (SpO₂) measured. The SpO₂ should be measured in both preductal (right hand) and postductal (either foot) locations to assess for cyanosis and differential cyanosis. Many birthing centers routinely perform pulse oximetry screening in all newborns.

Universal newborn pulse oximetry screening improves the identification of patients with critical CHD compared with physical examination alone [41,43,68-72]. The approach is summarized in the figure and is discussed in detail separately (algorithm 1). (See "Newborn screening for critical congenital heart disease using pulse oximetry".)

For infants presenting after discharge from the birth hospitalization, the clinician should ascertain whether pulse oximetry screening was performed during the birth hospitalization and, if not, perform screening in the office setting.

Electrocardiogram — The normal neonatal ECG has right-axis deviation (QRS axis +90 to +180 degrees) and a precordial pattern of right ventricular hypertrophy (RVH).

In many CHD lesions, the ECG may be normal during the neonatal period or it may show only subtle nonspecific abnormalities. However, some CHD lesions are associated with specific ECG patterns (table 5):

●Lesions associated with a small right ventricle have the following:

•Left-axis deviation for age (for pulmonary atresia intact, ventricular septum typically +30 to +90 degrees; for tricuspid atresia with normally related great arteries, typically -30 to -90 degrees)

•Right atrial enlargement – Tall, peaked P waves most easily identified in lead II

•Left ventricular hypertrophy

●HLHS often has marked RVH (increased QRS voltage in the right and anterior lead) and decreased left ventricular forces in the lateral precordial leads.

●Ebstein anomaly has right atrial enlargement and, occasionally, a delta wave of Wolff-Parkinson-White syndrome.

Chest radiograph — A chest radiograph can be helpful in differentiating between cardiac (table 5) and pulmonary disorders and should be obtained in neonates with cyanosis and/or respiratory symptoms.

When evaluating the chest radiograph in a newborn with suspected cardiac disease, the following features should be assessed:

●Heart size – Patients with left-sided obstructive lesions (eg, critical aortic stenosis, aortic coarctation) may have cardiomegaly due to heart failure. (See "Valvar aortic stenosis in children".)

Extreme cardiomegaly suggests lesions associated with a dilated right atrium since this chamber is very compliant. These include pulmonary atresia with intact ventricular septum or Ebstein anomaly. (See "Pulmonary atresia with intact ventricular septum (PA/IVS)" and "Ebstein anomaly: Clinical manifestations and diagnosis".)

●Heart shape – Characteristic abnormalities of heart shape are associated with specific lesions:

•TOF – Boot-shaped (coeur en sabot) contour (image 1). (See "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis".)

•D-TGA – Egg-on-a-string pattern caused by a narrow mediastinal shadow produced by the anterior-posterior rather than right-left relationship of the great arteries. (See "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis".)

●Pulmonary vascular markings – The pattern of pulmonary blood flow depends upon the specific cardiac lesion. In right-sided obstructive lesions (eg, TOF, PA/IVS, pulmonic stenosis), pulmonary vascular markings are usually decreased. Whereas, increased pulmonary vascular markings can be seen in truncus arteriosus as pulmonary vascular resistance falls after delivery.

Pulmonary venous congestion and pulmonary edema due to heart failure is characterized by indistinct vascular markings spreading in a butterfly distribution from the central region of the chest. This is often seen in obstructed total anomalous pulmonary venous connection (TAPVC) (image 2). It can also be seen in patients with heart failure due to left-sided obstructive lesions (HLHS or severe coarctation of the aorta) or cardiomyopathy. (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Chest radiography'.)

●Situs of aortic arch – A right aortic arch can be seen in D-TGA, some patients with TOF (image 1), truncus arteriosus, and various other lesions.

Echocardiography — The definitive diagnosis of CHD is made with transthoracic echocardiography, including two-dimensional imaging, and pulsed and color Doppler interrogation of flow patterns. Echocardiography provides detailed information on cardiac anatomy and function.

Echocardiography should be performed in consultation with a pediatric cardiologist if any of the following are present [73]:

●Signs or symptoms concerning for critical CHD, including shock unresponsive to volume resuscitation, cyanosis or differential cyanosis, unexplained respiratory symptoms, or pulmonary edema. (See 'Shock' above and 'Cyanosis' above and 'Respiratory abnormalities' above.)

●ECG and/or chest radiograph findings suggestive of CHD (table 5).

●Physical examination findings suggestive of CHD (table 5), 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' above.)

●Positive pulse oximetry screening (algorithm 1).

●Genetic disorder or extracardiac malformation associated with cardiovascular malformations (table 3).

Echocardiographic findings of specific critical CHD lesions are described in separate topic reviews:

●COA (see "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Echocardiography')

●Critical aortic stenosis (see "Valvar aortic stenosis in children", section on 'Echocardiography')

●HLHS (see "Hypoplastic left heart syndrome: Anatomy, clinical features, and diagnosis", section on 'Echocardiography')

●TOF (see "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis", section on 'Echocardiography')

●TOF with pulmonary atresia (see "Tetralogy of Fallot with pulmonary atresia and major aortopulmonary collateral arteries (TOF/PA/MAPCAs)", section on 'Echocardiography')

●Pulmonary atresia with intact ventricular septum (see "Pulmonary atresia with intact ventricular septum (PA/IVS)", section on 'Echocardiography')

●Critical pulmonic stenosis (see "Pulmonic stenosis in infants and children: Clinical manifestations and diagnosis", section on 'Echocardiography')

●Tricuspid atresia (see "Tricuspid valve atresia", section on 'Echocardiography')

●Ebstein anomaly (see "Ebstein anomaly: Clinical manifestations and diagnosis", section on 'Echocardiography')

●D- transposition of the great arteries (see "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis", section on 'Echocardiography')

●TAPVC (see "Total anomalous pulmonary venous connection", section on 'Echocardiography')

●Truncus arteriosus (see "Truncus arteriosus", section on 'Postnatal diagnosis')

●Ventricular septal defects (VSDs) (see "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis", section on 'Diagnosis')

●Atrioventricular canal defect (see "Clinical manifestations and diagnosis of atrioventricular (AV) canal defects", section on 'Echocardiography')

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 (PPHN): Clinical features and diagnosis", section on 'Echocardiography'.)

Hyperoxia test — The hyperoxia test historically was used to help distinguish cardiac from pulmonary causes of cyanosis. With the advent of routine pulse oximetry screening for critical CHD and improved access to echocardiography, the hyperoxia test is usually not necessary.

However, hyperoxia testing may be useful in some settings, particularly if echocardiography is not readily available.

Hyperoxia testing can be performed formally, using arterial blood gases (ABGs), or informally, using a pulse oximeter:

●Formal hyperoxia testing (using ABGs) – Testing is performed by measuring the partial pressure of oxygen (PaO₂) in the right radial artery (preductal) before and after administration of 100 percent inspired oxygen for 10 minutes. An increase in the PaO₂ to a level >150 mmHg during the hyperoxia test suggests pulmonary disease (table 8). An increase to a value <150 mmHg or no increase is suggestive of cyanotic CHD. PaO₂ levels differ somewhat depending on the type of CHD lesion.

●Informal hyperoxia testing (using pulse oximetry) – The hyperoxia response can be assessed informally using a pulse oximeter, thereby avoiding arterial puncture for blood sampling. However, this method is less reliable than measuring the PaO₂. An increase in the SpO₂ by ≥10 percent with administration of 100 percent inspired oxygen suggests a pulmonary cause of cyanosis. This finding by itself is generally not sufficient to forego additional evaluation with echocardiography. However, it may be helpful when added to other findings that suggest pulmonary disease (eg, history, examination, and chest radiograph findings).

Hyperoxia testing is not definitive. An abnormal or equivocal response should generally prompt further evaluation with echocardiography. While a rise in oxygen saturation and PaO₂ during the challenge suggests a pulmonary cause of cyanosis, it does not exclude CHD and echocardiography should still be performed if clinical suspicion for CHD remains high based upon other findings. (See "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management", section on 'Echocardiography'.)

In addition, it is important to recognize that the response to hyperoxia testing in patients with severe forms of lung disease or persistent pulmonary hypertension may be falsely suggestive of CHD (ie, little or no increase in SpO₂ or PaO₂ during the challenge). (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

The physiologic basis for the hyperoxia test is as follows:

●In cyanotic CHD due to right-to-left shunting, blood in the pulmonary veins is fully saturated with oxygen in ambient air. Administering higher concentrations of inspired oxygen increases the amount of dissolved oxygen but has minimal effect on oxygen tension levels because there is no effect on the deoxygenated blood that is shunted to the systemic circulation.

●In contrast, patients with pulmonary disease have pulmonary venous desaturation. Supplemental oxygen administration in pulmonary disease typically increases pulmonary venous oxygen levels and improves systemic oxygenation.

REFERRAL — 

Consultation with or referral to a pediatric cardiologist should be made if any of the following are noted:

●Clinical signs that are concerning for CHD – For neonates presenting during the birth hospitalization, concerning findings that warrant consultation include shock unresponsive to volume resuscitation, cyanosis or differential cyanosis, unexplained respiratory symptoms, or pulmonary edema. For infants presenting in the outpatient setting after discharge, suggestive findings include cyanosis, respiratory distress, difficulty feeding, or poor weight gain, especially if these occur in conjunction with concerning examination findings (eg, pathologic murmur, abnormal hear sounds) or radiographic findings (eg, pulmonary edema, abnormal cardiac silhouette) or if noncardiac causes for these findings have been excluded. (See 'Early presentation' above and 'Late presentation' above.)

●Physical examination findings suggestive of CHD (table 5 and table 7), including 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' above and "Newborn screening for critical congenital heart disease using pulse oximetry".)

●Abnormal chest radiograph or ECG with findings that suggest heart disease (table 5).

●Genetic disorder or extracardiac abnormality associated with cardiovascular malformations (table 3).

DIFFERENTIAL DIAGNOSIS — 

There are many other diagnostic considerations when evaluating a neonate with suspected CHD. The differential diagnosis varies depending on the chief clinical findings (shock, cyanosis, or respiratory distress). The history, cardiovascular examination, chest radiograph, laboratory testing, and, ultimately, echocardiography distinguish CHD from noncardiac conditions. (See 'Diagnostic approach' above.)

●Shock – Sepsis is the most common cause of neonatal shock. Other important causes are summarized in the table (table 9). A cardiac etiology of shock may be suggested based on a finding of pre to postductal oxygen saturation difference, cardiomegaly on chest radiograph, and/or lack of improvement or clinical deterioration in response to volume resuscitation. Causes of neonatal shock and the diagnostic evaluation are discussed in greater detail separately. (See "Neonatal shock: Etiology, clinical manifestations, and evaluation".)

●Cyanosis – Noncardiac conditions that can cause cyanosis include (table 10) (see "Approach to cyanosis in the newborn"):

•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 and 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 "Hemoglobin variants that alter 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 [74]. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

•Acrocyanosis refers to bluish color in the hands, 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 [49]. (See "Approach to cyanosis in the newborn", section on 'Peripheral versus central cyanosis'.)

●Respiratory symptoms – Tachypnea in a newborn is most commonly due to disorders of transition (eg, transient tachypnea of the newborn, respiratory distress syndrome). Other pulmonary etiologies include infection (sepsis, pneumonia) and noninfectious causes (table 11). Neonates with cardiac tachypnea frequently lack increased work of breathing at rest (sometimes referred to as "happy" or "comfortable" tachypnea), and they become more distressed with feeding. In contrast, neonates with primary pulmonary disorders often appear distressed both at rest and with activity. Cough and wheeze are also more likely to be of pulmonary etiology, though they can occur with CHD. While these findings may suggest a cardiac or pulmonary etiology, further investigation including physical examination, pulse oximetry, chest radiography, and, ultimately, echocardiography are required to make the distinction. (See 'Diagnostic approach' above and "Overview of neonatal respiratory distress and disorders of transition".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Congenital heart disease in infants and children".)

SUMMARY AND RECOMMENDATIONS

●Prevalence – Critical congenital heart disease (CHD), defined as lesions requiring surgery or catheter-based intervention in the first year of life, accounts for approximately 25 percent of all CHD with an estimated prevalence of 1 to 3 per 1000 births. Critical CHD is an important contributor to infant mortality. The risk of morbidity and mortality increases when there are delays in diagnosis and treatment. (See 'Epidemiology' above and 'Terminology' above.)

●Risk factors – Risk factors for CHD include (see 'Risk factors' above):

•History of maternal medical conditions or prenatal disorders associated with CHD (table 2)

•Family history of CHD in a first- or second-degree relative (table 2)

•Genetic syndromes or extracardiac anomalies (table 3)

●Screening

•Prenatal screening – Routine prenatal ultrasonography detects many cases of critical CHD, as discussed separately. (See "Congenital heart disease: Prenatal screening, diagnosis, and management".)

•Postnatal pulse oximetry screening – Pulse oximetry screening for critical CHD is suggested for all newborns, as summarized in the algorithm (algorithm 1) and discussed in detail separately. (See "Newborn screening for critical congenital heart disease using pulse oximetry".)

However, screening does not detect all critical CHD lesions, particularly noncyanotic lesions and some left heart obstructive lesions.

●Clinical features of critical CHD

•Early presentation – Neonates can present during the birth hospitalization with serious and life-threatening manifestations, including (see 'Early presentation' above):

-Shock (see 'Shock' above)

-Cyanosis, or (see 'Cyanosis' above)

-Respiratory distress (see 'Respiratory abnormalities' above)

However, some newborns with critical CHD, particularly those with ductal-dependent lesions (table 1), may initially have no or very subtle signs.

•Closure of the ductus arteriosus – In patients with ductal-dependent lesions (table 1), closure of the ductus arteriosus (figure 1) within the first few days after birth can precipitate rapid clinical deterioration with potentially life-threatening consequences. Initiation of prostaglandin E1 to reopen or maintain the ductus can be lifesaving in these patients, as discussed separately. (See "Cyanotic congenital heart disease (CHD) in the newborn: Causes, evaluation, and initial management", section on 'Prostaglandin E1'.)

•Late presentation – Because some neonates with critical CHD may not be identified during the birth hospitalization, clinicians should be aware and look for clinical manifestations of CHD during the first postdischarge visit. Symptoms are nonspecific and include (see 'Late presentation' above):

-Feeding difficulties

-Poor weight gain

-Cyanosis

-Respiratory distress

-Decreased activity

-Irritability

-Excessive sweating

•Physical examination findings – Physical findings that are suggestive of CHD include (table 7) (see 'Physical examination' above):

-Abnormal heart rate or rhythm

-Pathologic murmurs

-Diminished/absent peripheral pulses or blood pressure ≥10 mmHg higher in the arms than legs

-Abnormal heart sounds (eg, third heart sound [S3] gallop, click, or single second heart sound [S2])

-Extracardiac anomalies

●Initial evaluation – The diagnostic evaluation of neonates with suspected CHD includes (see 'Diagnostic approach' above):

•Measurement of upper and lower extremity blood pressure (see 'Upper and lower extremity blood pressure' above)

•Pulse oximetry (see 'Pulse oximetry' above)

•Chest radiograph (see 'Chest radiograph' above)

•Electrocardiogram (ECG) (see 'Electrocardiogram' above)

●Referral and echocardiography – The definitive diagnosis of CHD is made with echocardiography. Echocardiography should be performed in consultation with a pediatric cardiologist if any of the following are noted (see 'Echocardiography' above and 'Referral' above):

•Clinical signs or examination findings suggestive of CHD (table 5 and table 7). (See 'Clinical features' above and 'Physical examination' above.)

•Positive pulse oximetry screening (algorithm 1). (See 'Pulse oximetry' above and "Newborn screening for critical congenital heart disease using pulse oximetry".)

•Abnormal chest radiograph or ECG with findings that suggest heart disease (table 5). (See 'Chest radiograph' above and 'Electrocardiogram' above.)

•Genetic disorder or extracardiac abnormality associated with high likelihood of cardiovascular malformations (table 3).