Identifying newborns with critical congenital heart disease

INTRODUCTION — Congenital heart disease (CHD) is the most common type of congenital anomaly, with an overall prevalence of approximately 1 percent [1-3]. 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 [4]. 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 [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 [9-12].

The clinical presentation and initial diagnostic evaluation of suspected critical CHD in the newborn will be reviewed here. Pulse oximetry screening and its role in the diagnosis and management of cyanotic CHD are discussed in greater detail separately [13]. (See "Newborn screening for critical congenital heart disease using pulse oximetry" and "Diagnosis and initial management of cyanotic heart disease in the newborn".)

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 "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) (figure 1) to supply pulmonary or systemic blood flow or to allow adequate mixing between parallel circulations. 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 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). Critical CHD accounts for approximately 25 percent of all CHD [4].

EPIDEMIOLOGY

Prevalence — The reported prevalence of CHD ranges from 6 to 13 per 1000 live births [14-20]. The variability in these estimates is primarily due to the methods to detect CHD in the different studies (ie, fetal echocardiography versus postnatal referral to a cardiac center) [18,21].

Critical CHD accounts for approximately 25 percent of all CHD [4]. 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 [10,11]. CHD is the leading cause of perinatal and infant death from a congenital anomaly, although outcomes have significantly improved with the advancement of corrective or palliative interventions [1,17,22-24].

The most common congenital cardiac defect is a bicuspid aortic valve, with a prevalence estimated between 0.5 and 2 percent; however, as an isolated lesion, it is rarely diagnosed in infancy [25-27]. The next most common defects are ventricular septal defects and secundum atrial septal defects (ASDs), with a prevalence of 4 and 2 per 1000 live births, respectively [13,16,28,29]. Tetralogy of Fallot (figure 2) is the most common cyanotic CHD (0.5 per 1000 births) [16,30].

Risk factors — The following factors are associated with an increased risk of CHD and should heighten the clinician's suspicion for CHD (table 2) [31]:

●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 [15].

●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 [32-34]. The risk varies considerably depending on the type of CHD and whether the mother, father, sibling, or multiple family members are affected [34-37]. 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 [33]. Many genetic syndromes are associated with an increased risk of CHD (table 3) [38,39]. Some genetic conditions may only be identified after the diagnosis of CHD is made upon further investigation under the direction of a cardiac geneticist and genetic counselor.

●Maternal factors – Maternal conditions that increase the risk of CHD include diabetes mellitus, hypertension, obesity, phenylketonuria, thyroid disorders, systemic connective tissue disorders, and epilepsy [20,40]. 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 [41-45]. (See "Congenital heart disease: Prenatal screening, diagnosis, and management", section on 'Indications for echocardiography'.)

●Fertility treatment – Assisted reproductive technology (ART) and non-ART fertility treatments have been linked to increased risk of septal defects and cyanotic CHD [46,47]. (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 [48]. Congenital cardiomyopathy may result from infection with cytomegalovirus, coxsackie, herpes virus 6, parvovirus B19, herpes simplex, toxoplasmosis, and possibly HIV. (See "Seasonal influenza and pregnancy" and "Overview of TORCH infections".)

TIMING OF DIAGNOSIS

Prenatal diagnosis — Clinicians skilled at fetal echocardiography are able to identify most critical congenital heart defects. Referrals for fetal echocardiography are typically prompted by the presence of risk factors or suspicion on obstetrical anatomy ultrasounds, typically performed in the second trimester. The International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) in 2013 recommended that antenatal ultrasound include assessment of the outflow tracts in addition to the four-chamber views to assist in better recognition of CHD [49]. CHD lesions involving abnormal outflow tracts (including tetralogy of Fallot (figure 2), double-outlet right ventricle, and transposition of the great arteries (figure 3)) are particularly at risk for not being identified. Coarctation of the aorta (COA) (figure 4) can be difficult to definitively diagnose prenatally, regardless of the technique. (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Prenatal diagnosis'.)

Whether the expanded prenatal screening recommendations of the ISUOG have improved prenatal detection of critical CHD is uncertain. Studies performed in the era prior to publication of these guidelines indicate that less than one-half of patients with critical congenital heart defects were routinely identified [11,50-52]. One study found that the rate of prenatal detection of critical CHD increased from 44 percent in 2007 to 69 percent in 2013 [51]. However, other studies have shown more mixed results, with detection rates of only 50 to 60 percent in the era following the 2013 ISUOG guidelines [53-55].

In addition, social determinants of health impact prenatal diagnosis rates [56]. 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) [57].

These studies highlight the importance of remaining vigilant for postnatal diagnoses.

Prenatal sonographic screening for CHD is discussed in greater detail separately. (See "Congenital heart disease: Prenatal screening, diagnosis, and 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 [19]. However, some infants with CHD may appear normal on routine examination and signs of critical CHD may not be apparent until after discharge [19]. The timing of presentation varies with the underlying lesion and its dependence upon a patent ductus arteriosus (PDA) (figure 1 and 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 [58].

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 tetralogy of Fallot (figure 2) [58,59]. 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) [60]. For infants with critical CHD who are not diagnosed during the birth hospitalization, the risk of mortality is as high as 30 percent [10,11,61].

CLINICAL FEATURES — Neonates with critical 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 [62].

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'.)

Early presentation — Neonates who present with symptomatic CHD in the early newborn period typically present with shock, cyanosis, or respiratory symptoms (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 (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 (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 (generic drug name: alprostadil) to reopen 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 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 TAPVR 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 [63]. (See 'Differential diagnosis' below and "Neonatal shock: Etiology, clinical manifestations, and evaluation".)

Cyanosis — Cyanosis is an important sign of critical CHD. Cyanosis is the bluish skin tone caused by the presence of approximately 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 [64]. 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 "Newborn screening for critical congenital heart disease using pulse oximetry" and 'Pulse oximetry screening' below.)

Ductal-dependent lesions — In patients with ductal-dependent lesions (table 1), closure of the patent ductus arteriosus (PDA) (figure 1) 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 8)), 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 in infants and children: Clinical manifestations and diagnosis", section on 'Severe and critical pulmonic stenosis'.)

●Patients with critically obstructive left heart lesions (eg, hypoplastic left heart syndrome (figure 6), 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: Anatomy, clinical features, and diagnosis" and "Valvar aortic stenosis in children", section on 'Critical aortic stenosis'.)

Patients with critical left heart obstruction and a restrictive atrial communication will exhibit more profound cyanosis even with ductal patency [65]. 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 3)) 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 "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis", section on 'Presentation'.)

●Neonates with Ebstein anomaly of the tricuspid valve may be cyanotic and ductal-dependent for pulmonary blood flow when there is a functional pulmonary atresia (figure 9). (See "Ebstein anomaly: Clinical manifestations and diagnosis".)

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):

●Total anomalous pulmonary venous connection (TAPVC) (figure 7). (See "Total anomalous pulmonary venous connection".)

●Truncus arteriosus (figure 10). (See "Truncus arteriosus".)

●Tetralogy of Fallot (figure 2) and tricuspid atresia (figure 11) 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 (in tricuspid atresia). (See "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis" and "Tricuspid valve atresia".)

Differential cyanosis — In differential cyanosis, the upper one-half of the body is pink and the lower one-half cyanotic. This can occur in infants with critical COA (figure 4), interrupted arch (figure 5), or critical aortic stenosis. In these lesions, the flow of deoxygenated blood through the ductus arteriosus supplies the lower one-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. It also occurs in newborns with structurally normal hearts who have persistent pulmonary hypertension. (See "Clinical manifestations and diagnosis of coarctation of the aorta" and "Valvar aortic stenosis in children" and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

To detect differential cyanosis, oxygen saturation should be measured in both the right hand (preductal) and either foot (postductal). It is preferable to use the right hand rather than left because the left subclavian artery arises close to the ductus arteriosus and some of its flow may come from the ductus and thus not accurately reflect preductal values. An oxygen saturation difference of >3 percent is considered clinically meaningful. The differential effect may be reduced if there is also right-to-left shunting at the level of the foramen ovale or if there is left-to-right shunting across a coexisting ventricular septal defect. (See "Newborn screening for critical congenital heart disease using pulse oximetry", section on 'Approach to screening'.)

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. 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 ventricle out to the pulmonary artery and thus across the PDA. (See "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis".)

Noncardiac causes — Noncardiac conditions (eg, respiratory disorders, persistent pulmonary hypertension of the newborn) also can cause cyanosis and are differentiated from CHD by the history, cardiovascular examination, chest radiograph, echocardiography, and other laboratory testing. (See 'Diagnostic approach' below and 'Differential diagnosis' below.)

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 CHD defects:

●Truncus arteriosus (figure 10) [62]. (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) [66]. (See "Total anomalous pulmonary venous connection".)

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

In patients with large ventricular septal defects, 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 "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis".)

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" or "comfortable" tachypnea. Infants may become more tachypneic with increasing pulmonary edema or during feeding, and they may exhibit grunting, nasal flaring, retractions, and head bobbing. Cardiac tachypnea in neonates 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 [67]. Tachypnea in heart failure is also thought to have a neurohormonal basis.

Respiratory signs and symptoms must be distinguished from those due to pulmonary disease. Cough and wheeze are more likely to be of pulmonary etiology, but they can occur with cardiovascular malformations. As an example, a tight vascular ring can compress the trachea, leading to wheezing, coughing, or stridor [68,69]. Lesions that cause elevated pulmonary venous pressure result in bronchial edema and bronchial compression by a distended left atrium and large left pulmonary artery [67,68,70]. These include large left-to-right shunts, mitral stenosis, left ventricular dysfunction (eg, from myocarditis), or pulmonary venous obstruction [67,68,70,71]. (See 'Differential diagnosis' below.)

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, pulse oximetry, and chest radiography, as discussed below (see 'Diagnostic approach' below). If there are findings suggestive of CHD or if no clear pulmonary cause is identified on the initial evaluation, consultation or referral should be made to a pediatric cardiologist for echocardiography.

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 [61,72,73].

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 [58,59,61]:

●Hypoplastic left heart syndrome (figure 6)

●COA (figure 4)

●Interrupted aortic arch (figure 5)

●Aortic stenosis

●Transposition of the great arteries (figure 3)

●Pulmonic stenosis

●Tetralogy of Fallot (figure 2)

Pulse oximetry screening targets several of these lesions (transposition of the great arteries, tetralogy of Fallot, hypoplastic left heart syndrome), 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" tetralogy of Fallot [ie, those with minimal pulmonary stenosis]) and some left heart obstructive lesions will not be identified by pulse oximetry screening [74]. (See "Newborn screening for critical congenital heart disease using pulse oximetry".)

Signs and symptoms — In affected newborn infants, parents/caregivers most commonly notice difficulty with feeding. This may be manifested by intake of a limited volume of milk or by 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, breathing that is 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 [75]

DIAGNOSTIC APPROACH

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 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, 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). (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 (table 4) and pulmonary disorders and should be obtained in neonates with cyanosis and/or respiratory symptoms.

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 or egg-on-a-string pattern in D-transposition of the great arteries) 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 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.

In the hyperoxia test, arterial oxygen tension (PaO₂) is measured in the right radial artery (preductal) 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 [76]:

•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 symptoms' above.)

•ECG and/or chest radiograph findings suggestive of CHD (table 4).

•Physical examination 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 (PPHN): Clinical features and diagnosis", 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 [77]. In addition to pulse oximetry screening, careful review of the history and examination of the infant remain imperative. (See 'Pulse oximetry screening' below and "Newborn screening for critical congenital heart disease using pulse oximetry".)

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. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations".)

Physical examination — Several studies have shown that the newborn examination alone fails to detect more than one-half of infants with heart disease [61,72,78]. 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, ECG is initially performed to determine whether there is an arrhythmia and to guide further assessment and management [79]. (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 [80]

•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 less than 150 beats per minute [67,81]. 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 4):

•Aortic atresia

•Pulmonary atresia

•Truncus arteriosus (figure 10)

•Severe pulmonary stenosis

•Tetralogy of Fallot (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 great arteries (transposition of the great arteries) (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). 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. (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 [82,83]. 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 [84]. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

●Pathologic murmurs – The presence of a murmur is often associated with CHD (table 4). However, not all CHD lesions are associated with murmurs and many infants with murmurs do not have structural heart disease [73,85].

Murmurs associated with heart disease may be distinguished from innocent murmurs based upon the intensity (table 7), location, and quality of the murmur and associated findings [86-88]. Features that are associated with heart disease are summarized in the table (table 8). 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 [73,89], 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 [85].

●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 other aortic arch obstruction (figure 5) 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'.)

When measuring upper and lower extremity blood pressure 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'.)

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 [67]. 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 [90]. (See "Etiology, clinical features, and diagnosis of neonatal hypertension".)

Some cases of COA escape early diagnosis [91]. In the study of the utility of routine examinations 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 [72]. (See 'Late presentation' below.)

●Extracardiac abnormalities – Extracardiac abnormalities are frequently detected in children with CHD, and CHD may be a component of many specific syndromes and chromosomal disorders (table 3) [38]. 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 [33,92,93].

Pulse oximetry screening — Universal newborn screening with pulse oximetry improves the identification of patients with critical CHD compared with physical examination alone [8,78,94-98]. The strategy of universal newborn screening is endorsed by the AAP, AHA, Health and Human Services (HHS), and ACCF [77,99,100]. In the United States, nearly all states require mandatory newborn screening for critical CHD [101].

The approach to newborn screening for critical CHD using pulse oximetry is summarized in the figure and is discussed in detail separately (algorithm 1). (See "Newborn screening for critical congenital heart disease using pulse oximetry".)

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 [61,72,73]. (See 'Late presentation' above.)

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 examination but may be detected at or beyond the age of six weeks [6].

●Palpation of the liver edge (to assess for hepatomegaly).

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

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 (figure 4), which is frequently delayed. The importance of physical examination findings in detecting newborns with COA was highlighted in a study of 90 infants with critical COA, 19 (21 percent) of whom were born at centers with pulse oximetry screening [74]. One-half of the neonates were discharged from the birth hospital undiagnosed, and nearly one-half of the discharged infants were later readmitted for circulatory failure (one infant died at home). Clinical findings suggestive of COA (ie, systolic cardiac murmur and/or weak femoral pulses) had been noted in 17 (37 percent) of the discharged infants. In a 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 [72]. (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:

●Signs or symptoms concerning for CHD, including cyanosis, respiratory symptoms, difficulty feeding, or poor weight gain. (See 'Cyanosis' above and 'Respiratory symptoms' above.)

●Physical examination findings suggestive of CHD (table 4 and table 8), 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 and "Newborn screening for critical congenital heart disease using pulse oximetry".)

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

●Abnormal chest radiograph or ECG (table 4).

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 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 [102]. (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 [67]. (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 pneumonia, pneumothorax, congenital diaphragmatic hernia, tracheoesophageal fistula, and congenital pulmonary airway malformation. 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, but 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 – Congenital heart disease (CHD) is the most common type of congenital anomaly, with an overall prevalence of approximately 1 percent. Critical CHD, defined as lesions requiring surgery or catheter-based intervention in the first year of life, accounts for approximately 25 percent of CHD and is a leading causes of infant mortality. The risk of morbidity and mortality increases when there is a delay in diagnosis and treatment. (See 'Epidemiology' above and 'Terminology' above.)

●Risk factors – The risk of CHD is increased in infants who have a history of maternal medical conditions or prenatal disorders associated with CHD, positive family history (table 2), or extracardiac anomalies (table 3). 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.)

●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 symptoms' above)

However, some newborns with critical CHD, particularly those with ductal-dependent lesions (table 1), may initially have no or very subtle signs and symptoms. (See 'Postnatal diagnosis' above and 'Asymptomatic neonates' above.)

•Ductal-dependent lesions – In patients with ductal-dependent lesions (table 1), closure of the ductus arteriosus (figure 1) 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 lifesaving in these patients and should be initiated as soon as CHD is suspected, as discussed separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", 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:

-Feeding difficulties

-Poor weight gain

-Cyanosis

-Respiratory distress

-Decreased activity

-Irritability

-Excessive sweating

The routine examination should include global 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), palpation of the liver, and assessment of peripheral pulses. (See 'Late presentation' above.)

•Physical examination findings – Physical findings that are suggestive of CHD include (table 8) (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

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

•Physical examination

•Pulse oximetry

•Chest radiograph

•Electrocardiogram (ECG)

•Echocardiography

●Referral – Urgent referral to a pediatric cardiologist for consultation and echocardiography should be made for infants with any of the following (see 'When to refer' above):

•Signs and symptoms concerning for critical CHD, including shock unresponsive to volume resuscitation, cardiomegaly, cyanosis, pulmonary edema, or otherwise unexplained respiratory symptoms. (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 examination findings suggestive of CHD (table 4 and table 8), including abnormal heart sounds (eg, third heart sound [S3] gallop, click, or single second heart sound [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.)

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

•Genetic disorder or extracardiac malformation associated with cardiovascular malformations. Abnormal findings on echocardiogram (table 3).