Tetralogy of Fallot with pulmonary atresia and major aortopulmonary collateral arteries (TOF/PA/MAPCAs)

INTRODUCTION — Tetralogy of Fallot with pulmonary valve atresia and major aortopulmonary collateral arteries (TOF/PA/MAPCAs) is the most extreme variant of TOF, in which complete atresia of the pulmonary valve replaces pulmonary stenosis, and pulmonary blood flow is supplied by collateral vessels from the systemic circulation.

The definition, anatomy, physiology, clinical presentation, management, and outcome of TOF/PA/MAPCAs will be reviewed here.

TOF without PA, which is the more common defect, is discussed in detail separately. (See "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis" and "Tetralogy of Fallot (TOF): Management and outcome" and "Tetralogy of Fallot (TOF): Long-term complications and follow-up after repair".)

INCIDENCE — TOF/PA is a rare form congenital heart disease (CHD), with an estimated incidence of 0.7 per 10,000 live births [1]. While TOF is the most common cyanotic CHD lesion, TOF/PA/MAPCAs is the most extreme form of TOF and accounts for a small subset of cases (ie, 20 percent of TOF cases have TOF/PA, and approximately 30 to 65 percent of these have MAPCAs) [1,2].

ANATOMY — TOF/PA is a complex lesion that includes characteristic features of TOF (anterior malaligned ventricular septal defect [VSD] and overriding aorta) with PA. PA may be limited to the valve itself (membranous PA) or involve the subpulmonary infundibulum (muscular PA) and results in no antegrade flow from the right ventricle (RV) to the pulmonary artery. (See "Pulmonary atresia with intact ventricular septum (PA/IVS)", section on 'Anatomy'.)

The lack of antegrade pulmonary blood flow in utero leads to a range of morphologic findings in the pulmonary artery vasculature. If the ductus arteriosus is present, confluent true pulmonary arteries of variable size may develop. Without flow through the ductus arteriosus or one or more MAPCAs, fetal vessels derived from the splanchnic vascular plexus may persist after birth [3]. These vessels connect the systemic and pulmonary arterial vasculature, thereby supplying pulmonary blood flow. MAPCAs are tortuous vessels that arise directly from the aorta or its branches. MAPCAs vary in number and origin; follow circuitous routes to reach central, lobar, and segmental pulmonary arteries; and have variable areas and locations of stenosis. Their arborization pattern is unpredictable and often incomplete, leaving some lung segments with either excessive or insufficient flow, and they can become narrow over time [4,5]. As a result, a given segment of the lung may be supplied solely from the true pulmonary arteries, solely from the MAPCAs, or both. The morphology of the pulmonary vasculature and MAPCAs plays a critical role in determining management decisions. (See 'Surgical intervention' below.)

A right-sided aortic arch and left-sided lesions, such as dilation of the ascending aorta and aortic valve abnormalities, are more common in patients with TOF/PA/MAPCAs than in those with other TOF variants [6].

GENETICS — Several genetic variants have been associated with TOF/PA/MAPCAs, including the following [7-9]:

●22q11.2 deletion – Approximately one-third of patients with TOF/PA/MAPCAs have documented 22q11.2 deletion [10]. Deletions of chromosome 22q11.2 are associated with conotruncal defects including TOF/PA due to involvement of three genes identified in this locus: TBX1, CRKL, and ERK2 [9]. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

●Alagille syndrome – TOF/PA/MAPCAs can occur in patients with Alagille syndrome. These patients tend to have anatomy on the more severe end of the spectrum. (See "Alagille syndrome", section on 'Congenital heart disease'.)

●Copy number variants – In a study using high-resolution microarrays, patients with TOF without 22q11.2 deletion, including those with TOF/PA, had a larger burden of large, rare copy number variants compared with control subjects [7]. After 22q11.2 deletions, the most common copy number variant identified in patients with TOF was 1q21.1 duplications, occurring in approximately 1 percent of cases.

●One case report demonstrated a duplication of 9p13 and deletion of 9q34.3 in a patient with TOF/PA [11].

●One case report demonstrated an interstitial deletion of 16q21-q22.1 in a newborn infant with TOF/PA and MAPCAs [12].

PATHOPHYSIOLOGY — Children with unrepaired TOF/PA/MAPCAs are cyanotic due to the right-to-left intracardiac shunt. The degree of cyanosis depends on the amount of pulmonary blood flow supplied by the MAPCAs and, in occasional cases, the ductus arteriosus. Some patients may have torrential pulmonary blood flow with high oxygen saturations and, if left unrepaired for a prolonged period of time, are at risk for developing pulmonary hypertension. In these patients, there is a large volume load to the left ventricle (LV), which may lead to the development of heart failure. In contrast, other patients may have very little pulmonary blood flow and present with cyanosis, which can progress over time if the MAPCAs become narrower. (See 'Postnatal presentation' below.)

CLINICAL PRESENTATION

Fetal presentation — Advances in ultrasound technology have enabled routine antenatal screening around 18 to 22 weeks gestation to establish a fetal diagnosis of TOF/PA/MAPCAs. In one case series of 6587 scanned fetuses by a tertiary service for fetal cardiology between 1997 and 2006, 11 cases of TOF/PA/MAPCAs were identified by detecting systemic-to-pulmonary arterial connections other than a patent ductus arteriosus for pulmonary blood flow. Of the latter six pregnancies in this series, four were electively terminated [13]. The presence of systemic-to-pulmonary collateral arteries was confirmed postmortem in three fetuses and in two delivered infants. Prenatal screening and diagnosis of congenital heart disease (CHD) are discussed separately. (See "Congenital heart disease: Prenatal screening, diagnosis, and management".)

Postnatal presentation — Although most patients with TOF/PA/MAPCAs present as neonates, the range of symptoms and clinical manifestations vary. The clinical presentation and management decisions depend on the anatomy of the MAPCAs and whether or not pulmonary blood flow is dependent on the presence of a patent ductus arteriosus.

●If the MAPCAs are large with relatively few areas of stenosis, blood flow to the pulmonary vascular bed is typically unrestricted and patients may have mild or no evidence of cyanosis (ie, they appear pink). In some patients with unrestricted flow, heart failure may develop as their pulmonary vascular resistance decreases after birth with an increased left ventricular (LV) volume load, and these patients may require medical therapy.

●Patients with restrictive MAPCAs may have insufficient pulmonary blood flow and require intervention in the neonatal period. These patients have severe cyanosis.

●Some newborns may have a patent ductus arteriosus supplying blood flow to one or both lungs. These patients typically have moderate degrees of cyanosis with true, confluent pulmonary arteries and may not have extensive MAPCAs. Prostaglandin E1 infusion is required to maintain ductal patency and pulmonary blood flow; otherwise, they become increasingly cyanotic and hypoxic as the patent ductus arteriosus closes.

Cardiac examination — The cardiac examination generally reveals a single second heart sound (S2) and a loud, continuous murmur heard throughout the precordium, with radiation to the back and axillae.

Tests — Most newborns with suspected cyanotic CHD undergo initial testing, including pulse oximetry, chest radiography, and electrocardiogram (ECG). The findings on these tests are nonspecific, and the diagnosis of TOF/PA/MAPCAs is typically made by echocardiography and confirmed with computed tomographic angiography (CTA) and/or cardiac catheterization. (See "Identifying newborns with critical congenital heart disease", section on 'Diagnostic approach'.)

●Pulse oximetry – Pulse oximetry reveals desaturation consistent with the physical findings of cyanosis. The systemic oxygen saturation depends on the amount of left-to-right shunt from the aorta to the pulmonary arteries via systemic-to-pulmonary arterial connections. There is no difference between pre- and postductal arterial saturations, since flow across a patent ductus arteriosus (if present) is left to right. (See "Newborn screening for critical congenital heart disease using pulse oximetry".)

●Chest radiography – The chest radiograph of a patient with TOF/PA/MAPCAs typically demonstrates the characteristic boot-shaped heart of patients with TOF. The lung fields findings vary depending on the pulmonary blood flow through the MAPCAs. If flow through the MAPCAs is restrictive, the lung fields appear hypoperfused; in contrast, findings of pulmonary edema may be present if flow is unrestricted through the MAPCAs (image 1).

●ECG – The ECG in patients with TOF/PA/MAPCAs typically demonstrates normal sinus rhythm and right ventricular (RV) hypertrophy, which is a normal finding in the first days after birth.

●Hyperoxia testing – With improved access to echocardiography, the hyperoxia test is usually not necessary for identifying infants with cyanotic CHD. When performed, hyperoxia testing in an infant with TOF/PA/MAPCAs usually reveals a partial pressure of oxygen (PaO₂) <100 mmHg. (See "Identifying newborns with critical congenital heart disease".)

DIAGNOSIS — The diagnosis of TOF/PA/MAPCAs is initially made by echocardiography. However, echocardiography is limited in its ability to delineate the anatomy of the MAPCAs needed for surgical management. Therefore, patients at our institution undergo diagnostic angiography and cardiac catheterization to obtain detailed anatomic and hemodynamic data needed for decisions regarding intervention. (See 'Angiography' below.)

Echocardiography — The diagnosis of TOF/PA/MAPCAs is made by two-dimensional echocardiography and Doppler examination that demonstrate the following features (see "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis", section on 'Echocardiography'):

●Anterior malaligned ventricular septal defect (VSD)

●Overriding aortic valve

●PA with absence of blood flow from the right ventricle (RV) to the pulmonary artery

●MAPCAs are detected by their characteristic continuous flow pattern on color-flow Doppler mapping; however, smaller collateral arteries and branch pulmonary arteries may not be detected

Angiography — Diagnostic angiography is required to identify all sources of pulmonary blood flow, the presence and arborization of true pulmonary arteries, and the origins and contributions of all MAPCAs. All communications between MAPCAs and the true pulmonary artery system must be identified since surgical planning depends on whether each lung segment receives blood flow from MAPCAs, true pulmonary arteries (isolated supply), or both (dual supply). In addition, all areas of stenosis in each MAPCA need to be identified. (See 'Surgical intervention' below.)

Computed tomographic angiography — Computed tomographic angiography (CTA) can provide accurate, detailed images of the pulmonary architecture (image 2) [14,15]. CTA is performed routinely in the neonatal period. If the CTA demonstrates anatomy that may require neonatal surgery, cardiac catheterization is performed. If the patient is clinically stable and the CTA confirms that the patient can wait for surgery, cardiac catheterization is deferred until the patient is four to six months old prior to surgery. Magnetic resonance imaging is not routinely utilized to evaluate pulmonary arterial anatomy.

Cardiac catheterization — Cardiac catheterization measures pressures in each MAPCA, providing information about vessel stenosis and health of the distal pulmonary vascular bed that is needed for surgical decision-making [16]. Our standard of care is therefore to catheterize every patient before surgical intervention to obtain hemodynamic data and angiography.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of TOF/PA includes other cyanotic congenital heart defects with right ventricular outflow tract (RVOT) obstruction. TOF/PA is distinguished from these conditions by echocardiography.

●Tricuspid atresia (see "Tricuspid valve atresia")

●PA with intact ventricular septum (see "Pulmonary atresia with intact ventricular septum (PA/IVS)")

●Double-outlet RV with PA

●Double-inlet left ventricle (LV) with PA

●Congenitally corrected transposition of the great arteries with ventricular septal defect (VSD) and PA (see "L-transposition of the great arteries (L-TGA): Anatomy, clinical features, and diagnosis")

MANAGEMENT

Overview — The management of patients with TOF/PA/MAPCAs is challenging, given the wide spectrum of pulmonary artery architecture.

Neonates should be cared for at a medical center with experience in managing complex congenital heart disease (CHD). When an antenatal diagnosis is made, maternal transfer should be performed so that neonatal care can be provided immediately after birth by a cardiac team with this expertise. (See "Congenital heart disease: Prenatal screening, diagnosis, and management", section on 'Delivery planning'.)

Management of TOF/PA/MAPCAs includes:

●Initial medical management to maintain sufficient pulmonary blood flow for survival.

●Subsequent management focused on complete separation of the pulmonary and systemic circulations. This is accomplished by restructuring pulmonary blood flow to create a low-pressure system, establishing antegrade pulmonary blood flow from the right ventricle (RV), and closing the ventricular septal defect (VSD).

Initial medical treatment — Initial management is focused on stabilizing cardiac and pulmonary function and ensuring adequate pulmonary blood flow and systemic oxygenation. However, the range of interventions varies depending on the initial oxygen saturation.

●In patients with inadequate pulmonary blood flow (low oxygen saturation), therapy is focused on increasing the ratio of pulmonary blood flow to systemic blood flow (Qp/Qs). Prostaglandin E1 (alprostadil) is initiated to maintain patency of the ductus arteriosus if it is present. (See "Diagnosis and initial management of cyanotic heart disease (CHD) in the newborn", section on 'Prostaglandin E1'.)

Other supportive measures include volume administration to increase preload and maintaining the hematocrit above 40 percent with red blood cell transfusion to maximize oxygen-carrying capacity. Occasionally, vasopressor therapy with phenylephrine or norepinephrine is used to increase systemic vascular resistance and promote shunting through narrow MAPCAs.

●Some patients with excessive pulmonary blood flow due to unrestricted MAPCAs may develop pulmonary congestion and heart failure, especially as pulmonary vascular resistance declines in the days to weeks after birth. Medical intervention depends on the severity of symptoms and may include use of angiotensin-converting enzyme (ACE) inhibitors and diuretics. Medical management of heart failure is discussed in greater detail separately. (See "Heart failure in children: Management", section on 'Pharmacologic therapy'.)

●In patients with sufficient, but not excessive, pulmonary blood flow, no intervention may be necessary in the neonatal period, since these patients may maintain acceptable oxygen saturations in the 75 to 85 percent range without intervention.

Surgical intervention

Goals of surgery — The goal of surgical management of TOF/PA/MAPCAs is to construct completely separate, in-series pulmonary and systemic circulations. Surgical management is tailored to the anatomy of each individual patient and depends on the presence and caliber of true pulmonary arteries and the anatomy of the MAPCAs.

A key goal is to avoid high RV pressure post-repair since elevated RV pressure is associated with increased mortality risk [17]. The general goal is to achieve postoperative RV pressure that is less than half of left ventricular (LV) pressure (ie, RV:LV pressure ratio <0.5). It is therefore of utmost importance to maximize the pulmonary vascular cross-sectional area by recruiting as many lung segments as possible and relieving any significant obstruction to blood flow from the RV to the pulmonary microvasculature. Establishing antegrade flow as early as possible is also important to facilitate the postnatal growth of the underdeveloped pulmonary arterial tree, thereby allowing access for future interventional procedures, if needed.

Components of surgical repair — The surgical steps include:

●Unifocalization – Unifocalization involves detachment of collateral vessels from their systemic arterial origins and anastomosis to the central pulmonary arteries, resulting in creation of a low-pressure pulmonary arterial system.

●RV outflow tract (RVOT) reconstruction – The RVOT is reconstructed with an allograft valved conduit from the RV to pulmonary artery, resulting in antegrade pulmonary blood flow from the RV into the pulmonary vascular system.

●VSD closure – The timing of VSD closure is important, especially as it relates to RVOT reconstruction. Closing the VSD too early may result in pulmonary hypertension and RV failure. However, delay in closing the VSD after unifocalization may result in excessive pulmonary blood flow, causing pulmonary congestion, left-sided heart failure, and, if this physiology persists, pulmonary hypertension. In our center, we make the decision to close the VSD based on intraoperative measurements of pulmonary artery pressure (PAP) since these measurements predict postoperative PAP and RV:LV pressure ratio [18]. If the intraoperative mean PAP stays consistently <25 mmHg at a pulmonary blood flow of 2.5 L/min/m², the VSD can be closed, as this predicts a postoperative RV:LV pressure ratio <0.5, which is associated with a good long-term outcome [17]. However, if PAP is >25 mmHg, the VSD is not closed and the reconstruction of the RVOT is not performed.

Our approach — In our center, the management approach is based on the individual morphology of individual patients, which can be categorized into the following four groups [16,19]:

●Large-caliber MAPCAs without segmental-level stenosis – For patients with large-caliber MAPCAs without significant segmental-level stenosis, a single-stage repair is generally performed. This includes one-stage unifocalization and intracardiac repair with VSD closure and RV outflow reconstruction.

●Small- to moderate-caliber MAPCAs without segmental-level stenosis – For patients with small- to moderate-caliber MAPCAs without significant segmental-level stenosis, unifocalization procedure and creation of a shunt between the central aorta and a neopulmonary artery are initially performed. The aortopulmonary shunt promotes pulmonary arterial growth. Intracardiac repair with VSD closure and RVOT reconstruction is performed at a later date, pending reevaluation of the pulmonary vascular bed by catheterization.

●Dual pulmonary blood supply – A small subgroup of patients have dual pulmonary blood supply with true, small-caliber pulmonary arteries that are confluent and arborize to all segments as well as multiple small collaterals that are connected peripherally into the true pulmonary arterial system. Because the collateral vessels are small in caliber, there is little material for unifocalization. In this setting, an initial palliative procedure is performed in the neonatal period in order to stimulate native pulmonary artery growth. The palliative procedure consists of creating an aortopulmonary window, which is an end-to-side anastomosis of the small main pulmonary trunk to the ascending aorta. The patient then undergoes cardiac catheterization three to six months postoperatively to evaluate whether there has been suitable pulmonary artery growth to permit unifocalization. In a study of 35 patients who underwent aortopulmonary window at the authors' institution, 87 percent were able to achieve complete intracardiac repair by three years following placement of the window [20].

●Extensive segmental-level stenoses – For patients with extensive segmental-level stenoses, multiple-stage unifocalization procedures are required. For each unifocalization, a modified Blalock-Thomas-Taussig shunt (also commonly called a modified Blalock-Taussig shunt) is created from a major systemic artery to the newly unifocalized pulmonary arterial tree. Subsequent intracardiac repair is performed based on results from cardiac catheterization and the intraoperative flow study that demonstrates low mean pulmonary artery pressure.

The success of this strategy was demonstrated by a retrospective study from the authors' institution describing outcomes of 780 patients managed with this approach over 20 years [16,19]. Approximately 90 percent of patients ultimately underwent complete repair, either as the initial surgery in a single-stage procedure (43 percent) or after prior surgery or palliation (57 percent). Most patients achieved acceptably low RV pressures postrepair (mean RV:LV pressure ratio 0.34). At median follow-up of 3.8 years, the overall survival rate for the cohort was 88 percent. (See 'Prognosis' below.)

Postoperative complications — Postoperative complications in patients with TOF/PA/MAPCAs include:

●Tracheobronchial airway obstruction – Many infants and children experience signs and symptoms of airway obstruction (ie, wheezing, increased ventilator requirement) in the postoperative period after unifocalization surgery. This is thought to be caused by the extensive dissection and disruption of lymphatics and blood vessels around the bronchopulmonary tree, resulting in obstructive airway secretions [21].

●Reperfusion pulmonary edema – Children with significant preoperative stenosis of their collateral vessels are at risk for the development of reperfusion pulmonary edema following unifocalization procedures (image 3) [22].

●Other pulmonary complications including pneumonia, large airway compression, and pulmonary hemorrhage.

Because of these respiratory complications, patients undergoing unifocalization procedures are at risk for prolonged postoperative respiratory failure. In a study of 780 patients managed at the authors' center, the median duration of mechanical ventilation after surgery was 5 days and 25 percent of patients required mechanical ventilation for ≥7 days [19].

PROGNOSIS — Without treatment, mortality for patients with TOF/PA/MAPCAs is high. Less than 50 percent of untreated patients survive beyond the age of two years, with continued attrition beyond then [23].

However, surgical intervention has markedly improved mortality. In studies reporting outcomes over median follow-up of three to four years, reported survival rates range from 84 to 88 percent [19,24]. Reported risk factors for mortality in these studies include:

●22q11 deletion syndrome

●Alagille syndrome

●Need for preoperative respiratory support

●Need for initial palliative surgery

●Young age or small size at the time of unifocalization (ie, ≤30 days old or weight <3 kg)

Most survivors require repeated percutaneous and/or surgical interventions [16,24]. These are primarily for conduit enlargement or replacement or to address subsequent pulmonary artery stenosis.

LONG-TERM MANAGEMENT — As for all patients with repaired or palliated congenital heart disease (CHD), long-term health care maintenance is a collaborative effort between primary care and pediatric cardiology clinicians. Guidelines for long-term management of patients with repaired and palliated CHD exist [25,26], although not specifically for TOF/PA/MAPCAs. There are instances when patients present in adolescence/adulthood with chronic, unrepaired cyanotic heart disease, including patients who may have been palliated with systemic-to-pulmonary artery shunts. These patients require specialty care with adult congenital cardiologists.

Follow-up care — Follow-up care depends on the timing and type of surgery that the patient has undergone:

●Infants awaiting surgical intervention are particularly vulnerable and require close monitoring for worsening cyanosis. They should be seen at regular, frequent intervals to monitor weight gain and systemic oxygen saturation. Any significant worsening in oxygen saturation should prompt earlier surgical intervention.

●Patients who have undergone unifocalization surgery without intracardiac repair have aortopulmonary shunts providing pulmonary blood flow. They are therefore susceptible to complications from the aortopulmonary shunt, including shunt stenosis, thrombosis, or pulmonary overcirculation. These patients must be monitored closely for any changes in their oxygen saturation or ventricular volume overload. Patients are maintained on aspirin for platelet inhibition to prevent shunt thrombosis at a dose of 10 mg/kg/day.

●Patients who have undergone complete intracardiac repair should be monitored for recurrent pulmonary artery stenosis, right ventricle (RV)-to-pulmonary artery conduit stenosis or insufficiency, and RV hypertension and dilation.

●After unifocalization surgery, lung perfusion scans are performed on all patients prior to hospital discharge and before undergoing subsequent surgical interventions. All patients also undergo a complete surveillance cardiac catheterization in six months to one year to assess the anatomy and physiology of the pulmonary vasculature. Echocardiograms should be performed routinely to monitor RV function.

Endocarditis prophylaxis — To reduce the risk of endocarditis, patients with repaired TOF/PA/MAPCAs should maintain good oral hygiene and receive timely treatment of infections. Antibiotic prophylaxis may be required before certain dental, oral, or invasive airway procedures (eg, routine dental cleaning, tooth extraction, adenotonsillectomy, cleft lip, or palate repair) to reduce the risk of infective endocarditis. Prophylaxis is not necessary prior to gastrointestinal procedures (eg, endoscopy, colonoscopy) or genitourinary procedures (eg, cystoscopy, voiding cystourethrogram) unless the patient has an active infection.

Antibiotic prophylaxis prior to relevant procedures is recommended during the first six months after repair. Prophylaxis is also recommended in patients who have prosthetic heart valves, in whom prosthetic material was used for cardiac valve surgery, if there are residual defects at or adjacent to the site of a prosthetic device or material, or if there was a prior episode of endocarditis.

The approach to determining the need for prophylaxis is summarized in the figure (algorithm 1) and discussed in detail separately. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

Pregnancy — A comprehensive cardiovascular evaluation by a congenital cardiac specialist is recommended prior to pregnancy to confirm that there are no cardiovascular features that would be best treated before pregnancy or that make pregnancy unadvisable. Patients who have undergone unifocalization surgery with complete intracardiac repair and who have no residual pulmonary artery stenosis plus a normal RV:left ventricle (LV) pressure ratio should be able to tolerate pregnancy; however, there have been few reported cases [24].

SUMMARY AND RECOMMENDATIONS

●Anatomy and genetics – Tetralogy of Fallot with pulmonary atresia and major aortopulmonary collateral arteries (TOF/PA/MAPCAs) is a rare form of congenital heart disease (CHD). It is the most extreme variant of TOF and has the characteristic features of TOF (anterior malaligned ventricular septal defect [VSD] and overriding aorta) with complete atresia of the pulmonary valve. Blood flow to the pulmonary vasculature is provided via one or more MAPCAs. Several genetic variants have been associated with TOF/PA. In particular, 22q11.2 deletions are seen in approximately one-third of cases. (See 'Anatomy' above and 'Genetics' above.)

●Presentation – TOF/PA/MAPCAs may be detected antenatally on routine obstetric ultrasound. Patients who present postnatally can have variable presentations depending on the amount of pulmonary blood flow through the systemic-to-pulmonary artery connections. The degree of cyanosis is dependent on the restriction of blood flow through the systemic-to-pulmonary artery connections. The left-to-right shunt decreases in patients with narrow MAPCAs, resulting in more severe cyanosis. In contrast, unrestricted pulmonary blood flow may lead to pulmonary congestion and heart failure as the neonate's pulmonary vascular resistance decreases. (See 'Clinical presentation' above.)

●Diagnosis – Most infants with suspected cyanotic CHD undergo initial testing with pulse oximetry, chest radiography, and electrocardiogram (ECG). The characteristic chest radiograph finding in all forms of TOF is a boot-shaped heart (image 1). Other findings on initial testing are generally nonspecific. (See 'Tests' above.)

The definitive diagnosis of TOF/PA/MAPCAs is made by echocardiography, with the characteristic findings of an anterior malaligned VSD, overriding aortic valve, PA, and one or more aortopulmonary collaterals. (See 'Echocardiography' above.)

Computed tomographic angiography (CTA) (image 2) and cardiac catheterization are required prior to cardiovascular surgery to provide detailed anatomic and hemodynamic information that helps guide management decisions. (See 'Cardiac catheterization' above and 'Computed tomographic angiography' above.)

The differential diagnosis includes other cyanotic CHD defects with right ventricular outflow tract (RVOT) obstruction. TOF/PA/MAPCAs is distinguished from these conditions by echocardiography. (See 'Differential diagnosis' above.)

●Management – Neonates with PA, including TOF/PA and its variants, should be managed in a medical center with experience and expertise in managing complex CHD. (See 'Management' above.)

•Initial management focuses on stabilizing cardiac and pulmonary function and ensuring adequate pulmonary blood flow and systemic oxygenation. The need for and type of intervention is dependent on the amount of pulmonary blood flow and degree of cyanosis (see 'Initial medical treatment' above):

-Patients with inadequate pulmonary blood flow (low oxygen saturation), require prostaglandin E1 (alprostadil) therapy to maintain patency of the ductus arteriosus, if present, which is discussed in detail separately. (See "Diagnosis and initial management of cyanotic heart disease (CHD) in the newborn", section on 'Prostaglandin E1'.)

-Patients with excessive pulmonary blood flow due to unrestricted MAPCAs may require medical therapy for heart failure, which is discussed in greater detail separately. (See "Heart failure in children: Management".)

•Surgical management is aimed at constructing completely separate, in-series pulmonary and systemic circulations. The surgical steps include unifocalization (ie, detachment of collateral vessels from their aortic origins and anastomosis to the central pulmonary arteries), reconstruction of the RVOT with a valved conduit, and VSD closure. The specific approach depends on the size and morphology of MAPCAs (see 'Surgical intervention' above):

-Large-caliber MAPCAs without stenosis – For patients with large-caliber MAPCAs without significant segmental-level stenosis, we suggest a single-stage repair (Grade 2C). Repair consists of unifocalization and intracardiac repair with VSD closure and RV outflow reconstruction.

-Small to moderate-caliber MAPCAs without stenosis – For patients with small- to moderate-caliber MAPCAs without significant segmental-level stenosis, we suggest a staged repair (Grade 2C). This first stage consists of unifocalization and creation of a shunt between the central aorta and a neopulmonary artery. The aortopulmonary shunt promotes pulmonary arterial growth. Intracardiac repair with VSD closure and RVOT reconstruction is performed later, pending reevaluation of the pulmonary vascular bed by catheterization.

-Extensive segmental-level stenoses – Patients with extensive segmental-level stenoses generally require multiple staged unifocalization procedures. For each unifocalization, a modified Blalock-Thomas-Taussig shunt is created from a major systemic artery to the newly unifocalized pulmonary arterial tree. Subsequent intracardiac repair is performed based on results from cardiac catheterization and the intraoperative flow study that demonstrates low mean pulmonary artery pressure.

-Other patients – For the small subset for patients with dual pulmonary blood supply with true, small-caliber pulmonary arteries that are confluent and arborize to all lung segments as well as multiple small collaterals that are connected peripherally into the true pulmonary arterial system, we suggest an initial palliative procedure in the neonatal period (ie, creation of an aortopulmonary window) (Grade 2C). This approach is preferred because there is little material for unifocalization, and creation of an aortopulmonary window stimulates native pulmonary artery growth. The patient undergoes cardiac catheterization three to six months postoperatively to assess suitability for unifocalization.

●Prognosis – Without treatment, there is a 50 percent mortality rate by two years of age. With the surgical interventions described above, approximately 85 percent of patients survive to age five years. Most survivors require reintervention primarily for conduit enlargement or replacement or to address subsequent pulmonary artery stenosis. (See 'Prognosis' above.)

●Long-term management – Providing health care maintenance is a collaborative effort between primary care and pediatric cardiology clinicians. The specifics of follow-up care are dependent on the timing and type of surgery that the patient has undergone. Tests used to monitor patients following unifocalization surgery include lung perfusion scans, cardiac catheterization, and echocardiography. (See 'Long-term management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stanton Perry, MD, who contributed to an earlier version of this topic review.