Cardiac causes of cyanosis in the newborn

INTRODUCTION — For neonates with cyanotic congenital heart disease (CHD), early recognition, emergency stabilization, and transport to a cardiac care center with expertise in the management of cyanotic CHD are important to ensure an optimal outcome.

The causes of cyanotic CHD in the newborn are presented here. The presentation and screening of critical CHD and initial management of infants with cyanotic CHD are reviewed separately:

●(See "Identifying newborns with critical congenital heart disease".)

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

●(See "Diagnosis and initial management of cyanotic heart disease in the newborn".)

DEFINITION OF CYANOSIS — Cyanosis is a bluish discoloration of the tissues that results when the absolute level of reduced hemoglobin in the capillary bed exceeds 3 g/dL [1-3]. The appearance of cyanosis depends upon the total amount of reduced hemoglobin rather than the ratio of reduced-to-oxygenated hemoglobin.

Several factors can affect the detection of cyanosis:

●Hemoglobin concentration (cyanosis may not be apparent in patients with anemia) (figure 1)

●Skin pigmentation (cyanosis can be especially difficult to appreciate in infants with darkly pigmented skin)

●Physiologic factors that affect the oxygen dissociation curve such as alkalosis, acidosis, cold temperature, low levels of 2,3-diphosphoglycerate, and high levels of fetal hemoglobin (figure 2)

A more detailed description of how these factors affect the detection of cyanosis is presented separately. (See "Approach to cyanosis in the newborn".)

Routine pulse oximetry screening improves detection of cyanotic CHD, particularly in patients with mild desaturation. Newborn screening for critical CHD using pulse oximetry is discussed in detail separately. (See "Newborn screening for critical congenital heart disease using pulse oximetry".)

EPIDEMIOLOGY — Congenital heart disease (CHD) is the most common group of congenital disorders, with a reported prevalence ranging from 6 to 13 per 1000 live births [4-9]. Cyanotic cardiac lesions account for approximately 15 percent of all CHD cases [4] and one-third of potentially fatal forms of CHD (critical CHD) (table 1) [10,11]. (See "Identifying newborns with critical congenital heart disease", section on 'Epidemiology'.)

NONCARDIAC CAUSES OF CYANOSIS — Hypoxemia, with decreased arterial oxygen saturation leading to central cyanosis, can result from many different mechanisms (table 2). (See "Measures of oxygenation and mechanisms of hypoxemia", section on 'Mechanisms of hypoxemia'.)

Common noncardiac causes of neonatal cyanosis include:

●Pulmonary disorders – Pulmonary disorders are the most common causes of central cyanosis and include transient tachypnea of the newborn; respiratory distress syndrome; meconium aspiration; neonatal pneumonia; pneumothorax; hypoventilation; and structural abnormalities of the airway, lung, or diaphragm. (See "Overview of neonatal respiratory distress and disorders of transition" and "Approach to cyanosis in the newborn", section on 'Pulmonary disorders'.)

●Persistent pulmonary hypertension of the newborn (PPHN) – In PPHN, central cyanosis is caused by right-to-left shunting through the ductus arteriosus, resulting in differential cyanosis (ie, oxygen saturation measured in the arm [preductal] is higher than that in the leg [postductal]). (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

●Poor peripheral perfusion/shock – Shock states are often characterized by poor peripheral perfusion and cyanosis. Noncardiac causes of neonatal shock include sepsis, hypovolemia, fetomaternal hemorrhage, and adrenal insufficiency (table 3). (See "Neonatal shock: Etiology, clinical manifestations, and evaluation".)

●Acrocyanosis – Acrocyanosis is often seen in healthy newborns and refers to the peripheral cyanosis around the mouth and extremities (hands and feet) (picture 1).

Noncardiac causes of cyanosis in newborns are discussed in greater detail separately. (See "Approach to cyanosis in the newborn", section on 'Causes of central cyanosis'.)

CARDIAC CAUSES OF CYANOSIS — A frequently used mnemonic to identify five of the more common cyanotic lesions is the "five T's" of cyanotic congenital heart disease (CHD):

●Transposition of the great arteries, dextro type (D-TGA) (figure 3)

●Tetralogy of Fallot (TOF) (figure 4)

●Truncus arteriosus (figure 5)

●Total anomalous pulmonary venous connection (TAPVC) (figure 6)

●Tricuspid valve abnormalities (figure 7 and figure 8)

A sixth "T" is often added for "Tons of other lesions," such as double-outlet right ventricle, pulmonary atresia, multiple variations of single ventricle, hypoplastic left heart syndrome (HLHS), complex conditions associated with heterotaxy syndromes, or anomalous systemic venous connection (left superior vena cava connected to the left atrium).

Overview of physiology — In cyanotic CHD, central cyanosis results from right-to-left shunting. Cyanotic cardiac lesions can be categorized according to the underlying physiology as follows:

●Decreased pulmonary blood flow

●Increased pulmonary blood flow

●Severe heart failure

CHD lesions can also be categorized according to whether or not they are ductal-dependent. Ductal-dependent congenital heart lesions rely upon a patent ductus arteriosus (PDA) (figure 9) to supply pulmonary or systemic blood flow or to allow adequate mixing between parallel circulations. Many, but not all, cyanotic congenital heart defects are ductal-dependent (table 1).

Congenital heart defects that are associated with right-to-left shunting across the PDA create differential cyanosis, in which the upper one-half of the body is pink and the lower one-half cyanotic. Differential cyanosis can occur in patients with severe coarctation of the aorta (CoA), interrupted aortic arch, or critical aortic stenosis. It may also occur in patients with structurally normal hearts who have persistent pulmonary hypertension of the newborn (PPHN). (See "Identifying newborns with critical congenital heart disease", section on 'Differential cyanosis'.)

Reversed differential cyanosis is a rare finding that may occur in patients with TGA associated with either coarctation or pulmonary hypertension. In these infants, oxygen saturation is higher in the lower than upper extremity. (See "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis".)

Decreased pulmonary blood flow — Cyanotic lesions with decreased pulmonary blood flow include TOF, tricuspid valve anomalies, pulmonary valve atresia, and critical valvar pulmonary stenosis.

Tetralogy of Fallot — TOF is a constellation of four anatomic defects, consisting of an overriding aorta, right ventricular hypertrophy, pulmonary stenosis, and ventricular septal defect (figure 4 and image 1). The clinical presentation depends upon the degree of pulmonary stenosis. More severe stenosis leads to greater reduction of pulmonary blood flow and increased cyanosis. The clinical features, diagnosis, and management of TOF are discussed separately. (See "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis" and "Tetralogy of Fallot (TOF): Management and outcome".)

Pulmonary atresia with intact ventricular septum — Pulmonary atresia with intact ventricular septum (PA/IVS) is characterized by complete obstruction of right ventricular outflow with varying degrees of right ventricular and tricuspid valve hypoplasia (figure 10). Blood is thus unable to flow from the right ventricle to the pulmonary artery and lungs, and an alternative source of pulmonary blood flow (ie, a PDA) is required for survival. The clinical features, diagnosis, and management of PA/IVS are discussed separately. (See "Pulmonary atresia with intact ventricular septum (PA/IVS)".)

Critical pulmonic stenosis — Neonates with critical valvular pulmonic stenosis are also dependent on a PDA for adequate pulmonary perfusion. The clinical features, diagnosis, and management of critical pulmonic stenosis are discussed separately. (See "Pulmonic stenosis in infants and children: Clinical manifestations and diagnosis" and "Pulmonic stenosis in infants and children: Management and outcome".)

Tricuspid valve anomalies — Tricuspid valve anomalies include:

●Tricuspid atresia – In tricuspid atresia, there is no communication between the right atrium and right ventricle, which results in a total and obligatory right-to-left atrial shunt (figure 8). Other abnormalities may be present including ventricular septal defect, pulmonary stenosis, or TGA. The clinical features, diagnosis, and management of tricuspid atresia are discussed separately. (See "Tricuspid valve atresia".)

●Tricuspid stenosis – Tricuspid stenosis is usually seen with hypoplastic right ventricle and atrial septal defect. This also results in an atrial-level right-to-left shunt.

●Ebstein anomaly – Ebstein anomaly is a malformation of the tricuspid valve (figure 7). The variation in clinical severity is related to the extent of the inferior displacement of the tricuspid leaflets from the tricuspid annulus. In the most serious form of this defect, the tricuspid valve is severely deformed, displaced into the right ventricular outflow tract, and becomes increasingly insufficient. As a result, the right ventricular cavity size is reduced and right ventricular outflow obstruction may result. Tricuspid regurgitation increases right atrial size and the diameter of a patent foramen ovale. Cyanosis results from right-to-left shunting at the atrial level but typically improves as pulmonary vascular resistance decreases in the neonatal transition period. The clinical features, diagnosis, and management of Ebstein anomaly are discussed separately. (See "Ebstein anomaly: Clinical manifestations and diagnosis" and "Ebstein anomaly: Management and prognosis".)

Increased pulmonary blood flow — Defects that present with cyanosis with increased pulmonary blood flow include D-TGA (figure 3), truncus arteriosus (figure 5), and TAPVC (figure 6).

D-transposition of the great arteries — TGA is a ventriculo-arterial discordant lesion in which the aorta arises from the right ventricle and the pulmonary artery from the left ventricle (figure 3). The most common form of TGA is D-TGA, in which the origin of the aorta is anterior and rightward to the pulmonary artery origin. This creates two parallel circulations that result in cyanotic heart disease. The first sends deoxygenated systemic venous blood to the right atrium and back to the systemic circulation via the right ventricle and aorta, and the second sends oxygenated pulmonary venous blood to the left atrium and back to the pulmonary circulation via the left ventricle and pulmonary artery. In infants with D-TGA, survival depends upon mixing of these two circulations, which occurs at the level of the atria (patent foramen ovale), ventricles (approximately one-third of patients also have a ventricular septal defect), or great vessels (via the PDA). The clinical features, diagnosis, and management of D-TGA are discussed separately. (See "D-transposition of the great arteries (D-TGA): Anatomy, clinical features, and diagnosis" and "D-transposition of the great arteries (D-TGA): Management and outcome".)

Truncus arteriosus — Truncus arteriosus is a condition in which a single great vessel arises from the heart (figure 5). The aorta, pulmonary arteries, and coronary arteries all originate from the ascending portion of this single vessel. There is always an associated ventricular septal defect. The single semilunar valve contains three to six cusps and may be regurgitant. The various subtypes of truncus arteriosus relate to the branching pattern of the pulmonary arteries. The aorta contains combined output from the left and right ventricles, resulting in cyanosis, which may be mild if pulmonary vascular resistance is low and pulmonary blood flow is excessive. In that case, cyanosis may not be visible. The clinical features, diagnosis, and management of truncus arteriosus are discussed separately. (See "Truncus arteriosus".)

Total anomalous pulmonary venous connection — TAPVC, also referred to as total anomalous pulmonary venous return (TAPVR), is a cyanotic congenital defect in which all four pulmonary veins fail to make their normal connection to the left atrium (figure 6). This results in drainage of all pulmonary venous return into the systematic venous circulation. The clinical manifestations, diagnosis, and management of TAPVC and its variants are discussed separately. (See "Total anomalous pulmonary venous connection".)

Left-sided obstructive lesions — Severe left-sided obstructive lesions can present in the newborn period with heart failure or cardiogenic shock accompanied by cyanosis. Left-sided obstructive lesions include HLHS (figure 11), severe CoA (figure 12), interrupted aortic arch (figure 13), and critical valvular aortic stenosis. These lesions depend upon a PDA to supply systemic blood flow. As the ductus closes, cyanosis, pulmonary edema, metabolic acidosis, and hypotension develop (cardiogenic shock).

Hypoplastic left heart syndrome — HLHS consists of a number of defects involving underdevelopment of the left-sided chambers and valves (figure 11). Most commonly, there is aortic valve atresia, severe mitral valve stenosis, and marked hypoplasia of the left ventricle. In HLHS, right-to-left shunting via the PDA provides retrograde perfusion of the ascending and transverse portions of the aorta, so that the subclavian, carotid, and coronary arteries are supplied. If untreated, HLHS is almost always fatal within the first few weeks of life. With modern medical therapy and surgical interventions, approximately 60 to 70 of affected infants survive past the age of five years. However, there is considerable morbidity. The clinical features, diagnosis, and management of HLHS are discussed separately. (See "Hypoplastic left heart syndrome: Anatomy, clinical features, and diagnosis" and "Hypoplastic left heart syndrome: Management and outcome".)

Coarctation of the aorta — CoA is a discrete narrowing of the aorta, which typically involves a thoracic preductal location distal to the left subclavian artery (figure 12). Infants with a severe CoA may present with heart failure when the ductus arteriosus closes. The clinical manifestations, diagnosis, and management of CoA are discussed separately. (See "Clinical manifestations and diagnosis of coarctation of the aorta" and "Management of coarctation of the aorta".)

Interrupted aortic arch — The most extreme form of coarctation is an interrupted aortic arch (figure 13). Complete interruption usually occurs between the left common carotid and left subclavian arteries, but can occur distal to the left subclavian artery or between the innominate artery and left common carotid artery, and is usually associated with a large, nonrestrictive ventricular septal defect. Surgical correction is required for both the arch obstruction and the ventricular septal defect.

Critical aortic stenosis — Severe left ventricular outflow tract obstruction due to critical valvular aortic stenosis results in cyanosis and heart failure or even cardiogenic shock. Affected infants may not have an appreciable ejection murmur and may have minimal gradient across the valve as measured by Doppler echocardiography because of severe LV dysfunction and poor cardiac output. The clinical features, diagnosis, and management of aortic stenosis are discussed separately. (See "Valvar aortic stenosis in children" and "Subvalvar aortic stenosis (subaortic stenosis)".)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Tetralogy of Fallot (The Basics)")

●Basics topic (see "Patient education: Aortic coarctation in children (The Basics)")

●Basics topic (see "Patient education: Total anomalous pulmonary venous connection in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

●In cyanotic congenital heart disease (CHD), central cyanosis results from right-to-left shunting. Several factors can affect the detection of cyanosis, including hemoglobin concentration (figure 1), skin pigmentation, and physiologic factors that affect the oxygen dissociation curve. Routine pulse oximetry screening improves detection of cyanotic CHD, particularly in patients with mild desaturation. (See 'Definition of cyanosis' above and "Newborn screening for critical congenital heart disease using pulse oximetry".)

●Cyanotic cardiac lesions account for approximately 15 percent of all CHD and one-third of potentially fatal cases of CHD (ie, critical CHD (table 1)). (See 'Epidemiology' above.)

●Ductal-dependent congenital heart lesions are dependent upon a patent ductus arteriosus (PDA) (figure 9) to supply pulmonary or systemic blood flow or to allow adequate mixing between parallel circulations. Many, but not all, cyanotic congenital heart defects are ductal-dependent (table 1).

●Cyanotic CHD lesions can be classified based on their physiology as follows:

•Decreased pulmonary blood flow – Tetralogy of Fallot (figure 4), pulmonary atresia with intact ventricular septum (PA/IVS) (figure 10), critical valvar pulmonic stenosis, and tricuspid valve anomalies (figure 8 and figure 7). (See 'Decreased pulmonary blood flow' above.)

•Increased pulmonary blood flow – Transposition of the great arteries (figure 3), truncus arteriosus (figure 5), and total anomalous pulmonary venous connection (figure 6). (See 'Increased pulmonary blood flow' above.)

•Left-sided obstructive lesions – As the ductus arteriosus closes, severe obstructive left-sided heart lesions may present with heart failure or cardiogenic shock, accompanied by cyanosis. These lesions include hypoplastic left heart syndrome (HLHS) (figure 11), coarctation of the aorta (CoA) (figure 12), interrupted aortic arch (figure 13), and critical aortic stenosis. (See 'Left-sided obstructive lesions' above.)

●A frequently used mnemonic to identify five of the more common cyanotic diseases is the "five T's" of cyanotic CHD (see 'Cardiac causes of cyanosis' above):

•Transposition of the great arteries (TGA) (figure 3)

•Tetralogy of Fallot (TOF) (figure 4)

•Truncus arteriosus (figure 5)

•Total anomalous pulmonary venous connection (TAPVC) (figure 6)

•Tricuspid valve abnormalities (figure 8 and figure 7)

A sixth "T" is often added for "Tons of other lesions" (eg, double-outlet right ventricle, pulmonary atresia, HLHS and other variants of single ventricle, heterotaxy, anomalous systemic venous connection).

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Laurie B Armsby, MD, who contributed to an earlier version of this topic review.