Continuing Education Activity

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, representing 5% to 7% of all congenital heart defects. TOF is a conotruncal cardiac defect characterized by a large and anteriorly malaligned ventricular septal defect, an overriding aortic root, and narrowing of the subpulmonary and pulmonary valves. Right ventricular hypertrophy is secondary to the obstruction in the right ventricular outflow tract and pulmonary valve. Clinical presentation varies based on the severity of the right ventricular outflow tract obstruction (RVOTO), most commonly presenting as a cyanotic neonate. With the advent of fetal echocardiography, the diagnosis can be made prenatally, and in infants who present with severe RVOTO, prompt stabilization can avoid profound cyanosis and rapid deterioration. This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, managing TOF, and fostering effective interprofessional teamwork to improve outcomes.

Objectives:

• Identify the anatomy and interpret the pathophysiology of TOF.

• Identify the known genetic risk factors associated with TOF.

• Select the appropriate treatment for patients with TOF.

• Coordinate with interprofessional healthcare team members caring for patients with TOF, including maternal-fetal care, neonatal cardiac surgery, cardiac neurodevelopmental programs, outpatient care programs, and adult congenital programs.

Introduction

Classic tetralogy of Fallot (TOF) is a congenital heart defect (CHD) that is comprised of 4 anatomical alterations: a large, anteriorly malaligned ventricular septal defect (VSD), an overriding aorta which results in infundibular (ie, sub-pulmonary) right ventricular outflow tract obstruction (RVOTO), and consequent right ventricular hypertrophy secondary to chronic systemic pressures. The pulmonary valve annulus is often hypoplastic, with a pulmonary valve that is dysplastic and stenotic. The VSD is most frequently located in the perimembranous septum; however, the defect can extend to the muscular septum, and infrequently, there might be additional muscular VSDs.[1] A right aortic arch is observed in 20% to 25% of TOF.[2]

The clinical presentation will also depend on the associated cardiovascular anomalies in roughly 40% of patients with TOF. These may include atrial septal defects, patent ductus arteriosus, supravalvar pulmonary stenosis, branch pulmonary artery stenoses, hypoplastic branch pulmonary arteries, pulmonary valve atresia which may develop during fetal life as the subpulmonary infundibular narrowing progresses, a disconnected left pulmonary artery that originates from the ascending aorta formerly known as hemitruncus, a left pulmonary artery arising from the ductus arteriosus, absent left pulmonary artery, absent pulmonary valve, anomalous coronary arteries, anomalous pulmonary venous return, aortic incompetence, aortopulmonary window, and atrioventricular septal defect (AVSD).[3] 

Patients with TOF and pulmonary atresia may have a remnant of a pulmonary artery trunk with different calibers of the central pulmonary arteries and variable pulmonary tree anatomy. In approximately 50% of these patients, the right and left pulmonary arteries are confluent, and blood flow is ductal-dependent. In the other 50%, pulmonary flow is from multiple collateral vessels, usually from the descending thoracic aorta, and is not ductal-dependent. Occasionally, collateral arteries might arise from the head and neck, abdominal aorta, or coronary arteries. Surgical repair requires unifocalization of the many aortopulmonary collaterals, which can be quite challenging.[2]

TOF associated with rudimentary pulmonary valve leaflets, which occurs in 3% to 6% of cases, is known as “TOF with absent pulmonary valve.” In these patients, the main and branch pulmonary arteries are aneurysmal. Some degree of RVOTO is due to the presence of a small pulmonary annulus. The ductus arteriosus is usually absent, and approximately 50% have a right-sided aortic arch. Occasionally, one of the branch pulmonary arteries may arise from the aorta or may be absent.[2] Approximately 2% of patients with TOF have an associated atrioventricular septal defect (AVSD). Because the RVOTO limits pulmonary overcirculation, these patients usually do not display symptoms of congestive heart failure. Therefore, primary surgical repair can be performed within the first few months of life.[2] 

Etiology

TOF is the most frequently occurring conotruncal or outflow tract malformation, sharing this classification with other CHD (eg, truncus arteriosus, interrupted aortic arch, transposition of the great arteries, and double outlet right ventricle). In conotruncal malformations, suppression of developmental networks such as the NOTCH and WNT pathways during early embryogenesis produces malfunction of downstream regulatory pathways that lead to faulty structural cardiac development.[4] 

Approximately 75% to 80% of TOF cases are nonsyndromic, meaning that the patient has an isolated cardiac defect. Of these, 7% have a loss of function gene mutation, including NOTCH1, FLT4, and TBX1, a transcription factor involved in cardiac development that is affected in those with 22q11.2 microdeletion.[5] Mutations in certain transcription factors involved in cardiac morphogenesis (eg, NKX2.5, GATA-6, GATA-4, HAND1, HAND2, ZFPM2, and NF-ATC) have also been associated with nonsyndromic TOF.[6][7] In general, mutations in the NKX2.5 gene are commonly observed in familial CHD. Not surprisingly, CHDs reoccur in approximately 3% of affected families, though not necessarily TOF, when compared to the general population.[8]

The remaining 20% to 25% of patients with TOF have an associated syndrome or a chromosomal abnormality, with the most frequent being trisomy 21 (ie, Down syndrome) and the 22q11.2 deletion syndromes, which range from the more severe DiGeorge syndrome that is accompanied by dysmorphic facies, palatal abnormalities, immune deficiencies, hypocalcemia, and learning disabilities, to the less severe Sprintzen or velocardiofacial syndrome which does not have the immune deficiency and hypocalcemia. Because 22% to 48% of patients with a 22q11.2 microdeletion have an interrupted aortic arch, and 24% have a right-sided aortic arch, TOF is not infrequently associated with aortic arch malformations. When a patient with TOF presents with pulmonary valve atresia, the association with 22q11.2 microdeletion increases to 40%. Thus, genetic testing is currently recommended in fetuses with TOF to assess for the 22q11.2 microdeletion, especially since outcomes are worse than in those who do not carry the microdeletion.[8]

TOF can also occur in patients with known genetic mutations, including JAG1 and NOTCH2 genes (ie, Alagille syndrome), KMT2D and KDM6A genes (ie, Kabuki syndrome), CHD7 gene (ie, CHARGE syndrome), and the PTPN11, SOS1 or RAF1 genes (ie, Noonan syndrome). TOF may also be present in patients with unknown mutations (eg, VACTERL association and Goldenhar syndrome).[9] 

Epidemiology

CHD is found in approximately 1% to 1.2% of live births.[10] TOF is the most common cyanotic CHD, with a nearly equal sex distribution, a prevalence of 1 out of 3,000 births, and an incidence of 5 to 7 out of 10,000 live births. TOF represents 5% to 7% of all CHD.[4][1][6][4] Medical and surgical advances have allowed an increased prevalence of CHD among older children and adults, with a current estimated adult CHD patient US population of approximately 1 million, of which an estimated 15% are TOF patients.[11] In contrast, without surgical intervention, survival decreases as the patient ages. Patients with unrepaired TOF have an estimated survival rate of 66% at 1 year of age, 40% at 3 years, 11% at 20 years, 6% at 30 years, and 3% at 40 years.[12]

Pathophysiology

The VSD in TOF is typically large or nonrestrictive, allowing pressure equalization within the ventricles. Therefore, whether the shunting is left to right or vice versa will depend on the degree of downstream pressure the blood flow encounters. With significant RVOTO, most of the blood will shunt toward the aorta, thereby bypassing the pulmonary bed with consequent cyanosis. Conversely, if the resistance across the RVOT is less than the systemic vascular resistance, most of the blood will be directed to the pulmonary vascular bed, and the patient will be minimally cyanotic or acyanotic (see Image. Tetralogy of Fallot).[13] 

Different factors can contribute to RVOTO, including a stenotic pulmonary valve, a hypoplastic pulmonary valve annulus, the deviation of the infundibular septum that causes subvalvular obstruction, and the hypertrophy of the muscular bands of the RVOT. The obstruction across the RVOT can also be dynamic with sudden increases in cyanosis, a phenomenon known as “Tet or hypoxic spells.” The physiological process surrounding these hypercyanotic episodes is yet to be fully understood but appears to involve a decrease in systemic vascular resistance or an increase in pulmonary vascular resistance. The result is an increase in the right-to-left shunting across the ventricular septal defect, which produces marked desaturation. These episodes can be triggered by agitation, pain, anemia, fever, hypovolemia, or peripheral vasodilatation. These hypoxic spells occur in infants or children but do not occur in adults.[14][13]

Patients with TOF and pulmonary atresia are usually cyanotic in the newborn period, with worsening cyanosis as the ductus arteriosus closes. This becomes a lethal condition in the absence of sufficient blood flow from aortopulmonary collaterals. Patients with an absent pulmonary valve do not typically have cyanosis. However, these patients have aneurysmal branch pulmonary arteries that usually cause external compression of the airways, leading to tracheobronchomalacia with air trapping.[2] Approximately 10% to 35% of adult patients with TOF may have atrial arrhythmias (eg, reentrant atrial tachycardia and atrial fibrillation).[11] Ventricular arrhythmias can occur in up to 10% of patients, and sudden death is estimated to occur in 0.2% of patients each year of follow-up.[8] Life-threatening arrhythmias occur more frequently in those with moderate to severe pulmonary valve insufficiency with RV dilatation and fibrosis and in those with biventricular dysfunction with congestive heart failure. Therefore, life-long monitoring is recommended.[15] Progressive aortic root dilatation in repaired TOF with progressive aortic valve regurgitation is less common but warrants follow-up, as this may require aortic root replacement.[16]

History and Physical

Clinical Symptoms

Clinical presentation varies based on the severity of the RVOTO, most commonly presenting as a cyanotic neonate. Adult patients with TOF may have dyspnea and exercise intolerance. With the advent of fetal echocardiography, the diagnosis can be made prenatally, and in infants who present with severe RVOTO, prompt stabilization can avoid profound cyanosis and rapid deterioration.[17] 

In those undiagnosed before birth, presentation depends on the degree of obstruction to the RV outflow. Those with moderate RVOTO may be asymptomatic at presentation, except for the presence of a loud murmur, and may be referred to as "pink Tets." Those with minimal RVOTO behave as those who have a large VSD and will present with symptoms of pulmonary overcirculation as the pulmonary vascular resistance falls after a few weeks of life. Because RVOTO usually increases with time, pink Tets can later develop cyanosis and hypercyanotic spells when crying or in hypovolemia.[17] Patients with TOF and absent pulmonary valves can present primarily with respiratory distress from tracheobronchial compression from the dilated pulmonary arteries; cyanosis in these patients is usually mild.[18] 

"Tet spells" or hypercyanotic episodes can occur in infants or toddlers with unrepaired TOF, characterized by tachypnea and hyperpnea and a decrease in the intensity of the cardiac murmur. Some patients will be inconsolable in addition to worsening cyanosis. These episodes can either subside spontaneously or can cause syncope with or without cardiac arrest. Thus, rapid intervention should be provided with a referral for prompt primary repair or palliation. If the patient survives such episodes but remains unrepaired, "Tet spells" tend to become rare and may disappear by 4 to 5 years of age. Presently, patients with TOF presenting with cyanosis and severe, longstanding cyanosis are rare in developed countries with adequate pediatric cardiac services.[19][20]

The clinical manifestations of patients with TOF and absent pulmonary valves depend on the severity of respiratory distress, ranging from those with no respiratory distress to those with severe respiratory distress due to trachea and main stem bronchi compression by the massive pulmonary artery branches.[21] The degree of obstructive airway disease among these patients varies markedly. Some patients will improve with prone positioning. Otherwise, intubation and positive pressure ventilation are required.[18] Patients with TOF and absent pulmonary valves usually have to-and-fro systolic and diastolic murmurs and a single-second heart sound. As newborns, these patients are typically cyanotic; however, the cyanosis improves by the first week of life. Due to a lesser degree of RVOTO, as pulmonary vascular resistance naturally decreases during the first days of life, these patients may exhibit signs and symptoms of pulmonary overcirculation with tachypnea, excessive diaphoresis with feeds, and failure to thrive.[22]

Physical Exam Findings

Patients with TOF may have a typical first heart sound with a single-second heart sound because the pulmonic component is usually inaudible. The greater the degree of obstruction, the more prominent the murmur, usually described as crescendo-decrescendo with a harsh systolic ejection quality and best heard at the left mid to upper sternal border with posterior radiation. Sometimes, the murmur can have a regurgitant quality, and an early systolic click may be auscultated along the left sternal border attributed to the flow through a dilated ascending aorta. A prominent ventricular impulse and a systolic thrill may be palpable. A continuous murmur can be heard over the back and axillary regions in patients with pulmonary atresia and aortopulmonary collaterals.[13]

Adult patients with TOF may have findings that include severe or free pulmonary insufficiency with RV dilatation, severe tricuspid valve regurgitation, and RV dyssynchrony from right bundle branch block (RBBB) with prolonged QRS duration from TOF repair. These factors increase the incidence of atrial and ventricular arrhythmias, which are a major risk for mortality.[23] Those rarely encountered patients who did not undergo surgical repair may have complications of chronic hypoxemia such as hyperviscosity, abnormal hemostasis, stroke, cerebral abscess, and endocarditis.[13][24] 

Evaluation

Chest radiography, electrocardiogram, and an echocardiogram are the primary imaging studies utilized to diagnose TOF. Typical findings on chest radiography include a normal-size heart silhouette with an upturned apex and a concave or "boot-shaped" main pulmonary artery segment (see Image. Chest X-ray of Tetralogy of Fallot). Right axis deviation, prominent R or qR waves in V1, and upright T waves in V1, characteristic of right atrial enlargement and right ventricular hypertrophy, are common on the electrocardiogram. 

The echocardiogram is the gold standard for the diagnosis of TOF. This noninvasive modality is used at the patient's bedside to accurately assess the anatomy and severity of the RVOTO, the location and number of VSDs, associated anomalies, aortic arch, and coronary artery variants since RVOT crossing of coronary arteries will complicate the surgical approach. The major limitation of the transesophageal echocardiogram in patients with TOF is visualizing the distal pulmonary arteries.[19]

Cardiac magnetic resonance imaging (MRI) or cardiac computed tomography (CT) can be used, particularly in adults with repaired TOF. These noninvasive imaging modalities have made diagnostic cardiac catheterization no longer a routine for patients with classic TOF anatomy. However, cardiac catheterization can still be used to assess the level and degree of RVOTO, pulmonary stenosis or hypoplasia, distal branch pulmonary artery anatomy, and coronary artery anatomy. It can delineate aortopulmonary collaterals when present and show accessory septal defects best seen with a left ventricular injection. Cardiac catheterization can also be used in selected patients for ductal and RVOT stenting. Knowing that catheter manipulation can trigger a hypercyanotic or "tet spell" and should thus be used when strictly necessary is essential.[19]

Treatment / Management

Neonates with severe RVOTO who present with profound hypoxemia and cyanosis will require prostaglandin therapy to maintain ductal patency and adequate pulmonary blood flow before a transcatheter intervention or surgical repair. Tet spells require a rapid and aggressive approach, including knee-chest positioning to increase systemic vascular resistance and "force" more blood into the pulmonary artery, oxygen therapy to cause pulmonary vasodilation, and decrease pulmonary vascular resistance. Patients may require intravenous fluid boluses to improve RV filling and increase pulmonary blood flow. They may also need intravenous beta-blockers to decrease heart rate to aid RV filling further and, sometimes, intravenous phenylephrine to increase systemic afterload. Morphine can also be given as a sedative during a tet spell, alleviating pain and anxiety and helping decrease heart and respiratory rates. A tet spell, left untreated, may lead to loss of consciousness and, ultimately, death.[25][26][27] 

Without surgical treatment, the survival rate of patients with TOF without additional cardiac defects is approximately 66% at 1 year of age, 40% at 3 years, 11% at 20 years, 6% at 30 years, and 3% at 40 years.[13] Surgical or transcatheter palliation and surgical repair aim to provide adequate and stable pulmonary blood flow. The timing of TOF repair is still in debate, with some centers advocating neonatal repair with better results than systemic-to-pulmonary artery shunting, deferring the complete surgical repair to after the first 3 months of life. The technique involves placing a "modified" Blalock-Taussig shunt graft between the subclavian artery and the ipsilateral branch pulmonary artery.[8]

Reasons for an initial surgical palliative shunting include technical difficulties in the systemic-to-pulmonary shunt placement due to the smaller pulmonary arteries of the newborn, decreased postoperative mortality after the neonatal period, unfavorable coronary artery anatomy with a large branch crossing the RVOT that will require a right ventricle to pulmonary artery conduit, which is safer to operate in the larger heart of an older infant, and the surgeon's preference.[19][28] Stenting of the ductus arteriosus with or without RVOT stenting with pulmonary artery banding is a less invasive alternative to surgical palliation, as it does not require cardiopulmonary bypass with the additional advantage of not requiring a sternotomy or thoracotomy.[29] 

When possible, earlier techniques of transannular patching and ventriculotomy are being replaced by right atrial atriotomy and operation through the tricuspid valve, limiting the transannular incision.[1] During the VSD closure, care is taken to avoid injuring the His bundle, which would produce an atrioventricular conduction block. Reduced RV compliance may require leaving or creating a minor atrial septal defect to allow right atrial decompression at the expense of residual cyanosis.[19]

An RV to pulmonary artery conduit is used in patients with TOF and pulmonary atresia in the presence of a markedly hypoplastic or atretic RVOT or a sizeable conal branch coronary artery crossing the RVOT. Pulmonary artery conduits are also used in those requiring reoperation for severe pulmonary insufficiency or recurrent stenosis. These conduits include pulmonary or aortic homografts, heterografts (ie, bovine jugular vein grafts), or autologous pericardial valved conduits. However, they have a limited lifespan, requiring reoperation within a few years.[30] 

Patients with TOF and pulmonary atresia with major aortopulmonary collaterals (MAPCAs) might require prostaglandin E1 in the early neonatal period if these collaterals are not sufficiently developed. These patients can undergo early complete repair with segmental pulmonary artery reconstruction in the neonatal period incorporating all lung segments, or they can undergo a staged repair with initial unifocalization of the MAPCAs followed by intracardiac TOF repair at 4 to 7 months of age.[31]

Patients with TOF and absent pulmonary valves require plication and reduction of the size of the pulmonary arteries with or without suspension of the left pulmonary artery to the anterior chest wall to relieve bronchial compression, in addition to the intracardiac patch closure of the VSD. Another surgical technique is to transect the ascending aorta and anteriorly move the right pulmonary artery. Some undergo placement of a valved RV to pulmonary artery conduit to place a functioning pulmonary valve. Airway stenting is rarely indicated and reserved for those with severe airway obstruction despite surgery.[32] Early extubation will improve cardiac preload and RV filling, improving cardiac output.[19]

Differential Diagnosis

“Tet spells” can present with respiratory distress and worsening cyanosis. This clinical scenario can also be observed with other cardiac malformations with right-to-left shunting, including complete transposition of the great arteries (d-TGA) with pulmonary stenosis, double outlet right ventricle with severe pulmonary stenosis, tricuspid atresia, and Ebstein anomaly. Isolated severe pulmonic or aortic stenosis can produce a similar clinical picture. Viral or bacterial infections such as bronchiolitis or pneumonia can also be included as a differential diagnosis and pneumothorax. 

Prognosis

Although current surgical mortality can be as low as 2%, with 20-year survival exceeding 90%, most patients will develop residual hemodynamic and electrophysiologic abnormalities, especially after the third decade of life.[33] Pulmonary regurgitation, which results from the reconstruction of the RVOT, produces RV dilatation, dysfunction, and diffuse interstitial fibrosis that perpetuates the dysfunction.[34][35][36][37][34] The RV dysfunction affects the left ventricle via abnormal ventricular interaction from shared myofibers, creating electromechanical dyssynchrony.[38][39] 

Conventional practice has been that a QRS duration greater than 180 msec, sustained ventricular tachycardia, and a history of syncope are associated with exercise intolerance, cardiac failure, and death in these patients.[23][34][40] However, a very recent study in adults with repaired TOF observed that the highest mortality risk appears to be related to any of the following:

• Age younger than 50 years
• Findings on cardiac magnetic resonance imaging (MRI)
  • Extensive RV and LV late gadolinium enhancement, which confirms the presence of extensive collagen deposition or fibrosis
  • RV ejection fraction of ≤35%
  • LV ejection fraction ≤35%
• Peak oxygen uptake ≤17 mL/kg/m²
• B-type natriuretic peptide ≥127 ng/L
• Sustained atrial arrhythmias [41]

Atrial tachyarrhythmias, usually intra-atrial reentrant tachycardia and cavotricuspid isthmus-dependent atrial flutter, can be observed with advancing age after TOF repair and comprise up to 20% of the arrhythmias observed in these patients. Large right atrial size, sinus node dysfunction, and at least moderate tricuspid regurgitation are associated with atrial arrhythmias. Atrial fibrillation is more commonly associated with older patient age, decreased left ventricular function, left atrial dilatation, hypertension, and multiple cardiac surgeries.[42] Atrial arrhythmias have been recently recognized to be associated with severe adverse events in adult patients who had TOF repair.[43]

The prognosis of these patients is also affected by the need for pulmonary valve replacement due to progressive pulmonary insufficiency, which places them at risk of bacterial endocarditis.[24] Very recently, a multinational, multicenter study demonstrated for the first time that pulmonary valve replacement (PVR) in patients with repaired TOF is associated with a lower probability of sustained ventricular tachycardia (VT) and death, especially in those patients with more severe RV volume overload from pulmonary insufficiency, who are at high risk of developing mechanoelectrical cardiomyopathy. The study, however, did not determine the best timing for PVR or whether surgery or transcatheter pulmonary valve placement yields better results.[44]

Complications

Short Term Complications

Palliative surgery to place a modified Blalock-Taussig shunt poses the risk of recurrent laryngeal and phrenic nerve damage. In addition, shunt size might create inadequate or excessive pulmonary blood flow, leading to either pulmonary overcirculation/congestive heart failure (CHF) and failure to thrive or cyanosis, respectively.[19] Shunt thrombosis can be life-threatening and will require urgent reoperation, interventional catheterization for direct thrombolysis, or, if all fail, extracorporeal membrane oxygenation (ECMO).[45] 

Complications within the immediate postoperative period after complete TOF repair include pericardial and pleural effusion requiring drainage, chylothorax, bleeding requiring reoperation, superficial wound infection, moderate pulmonary regurgitation in up to 14% of patients, residual ventricular septal defects with persistent hypoxemia, and RVOTO.[46]

Junctional ectopic tachycardia (JET) can occur in approximately 15% to 20% of patients in the immediate postoperative period, causing a low cardiac output with profound hypotension and hemodynamic instability. Treatment may include correction of any electrolyte imbalance, cooling the patient (hypothermia), decreasing vasoactive drugs such as dopamine, atrial pacing over the ventricular rate to restore atrioventricular synchrony, increasing sedation to control pain (ie, dexmedetomidine infusion), magnesium sulfate, and antiarrhythmics such as amiodarone, procainamide, or esmolol. Nonresponders may require ECMO until the arrhythmia subsides and cardiac output can be maintained.[47][48][47] Significant predictors for the development of postoperative JET include a patient younger than 6 months of age and postoperative use of inotropes such as dopamine.[49]

Patients undergoing a transatrial-transpulmonary approach appear to have fewer tachyarrhythmias and virtually no permanent pacemaker requirement for postoperative conduction abnormalities in the early postoperative period compared to those receiving a right ventriculotomy.[46] Damage to the conduction system can occur, with RBBB occurring frequently, bifascicular block in 8% to 12% of patients, and complete atrioventricular block in 3% to 5%. Poor RV compliance is another postoperative complication, resulting from the combination of RV hypertrophy and diastolic dysfunction with uncoordinated RV contraction from damage to the conduction system and the creation of a transannular patch with resection of contractile muscle fibers that a non-contractile patch on the RV free wall has replaced. Management of RV dysfunction in the immediate postoperative period may require beta-agonist avoidance, beta-blocker use, and monitoring fluid balance.[19]

Arrhythmias can occur after TOF repair, including ventricular tachycardia, atrial fibrillation or flutter, and intra-atrial reentrant tachycardia. Risk factors for ventricular arrhythmias and sudden cardiac death include older age at repair, male gender, transient complete heart block beyond postoperative day 3, and QRS duration greater than 180 milliseconds.[50] Prematurity is associated with higher postoperative mortality risk.[46] The incidence of postoperative moderate to severe pulmonary regurgitation has decreased due to valve-sparing techniques.[46] 

Long-Term Complications

Adult patients with CHD are increasing in prevalence by an approximate estimate of 5% per year, surpassing the pediatric population. Thus, long-term complications from the surgical repair or CHD must be acknowledged. The progressive nature of pulmonary regurgitation despite valve-sparing techniques is well recognized, with a cumulative incidence of 40% at 35 years of age after TOF repair.[51][46][51] The most common indication for reoperation is pulmonary insufficiency. Long-term consequences include RV volume overload from pulmonary insufficiency and right and left ventricular dysfunction.[39] Pulmonary valve replacement can be achieved surgically or by a transcatheter approach.[52] 

Other long-term complications include RV aneurysm from the outflow patch or the ventriculotomy, distal pulmonary artery obstruction, ventricular hypertrophy, and aortic root dilation and insufficiency. Patients can have exercise intolerance, which can be aggravated by concomitant ventricular dyssynchrony and signs and symptoms of CHF.[23] An aortic root dilatation >55 cm with aortic insufficiency warrants aortic root surgery.[20] Patients with TOF, repaired or unrepaired, are at risk of endocarditis and should receive SBE prophylaxis before any dental or elective surgical procedure.[13]

Leading causes of mortality in patients with repaired TOF include late arrhythmias (ventricular and atrial), heart failure, and complications from reoperations. Forty to 50% of adults with repaired TOF can have ventricular arrhythmias, including sustained ventricular tachycardia with syncope. The risk of sudden death ranges between 6% to 9% 30 years after the surgical procedure. Some factors associated with this risk are QRS duration greater than 180 milliseconds, older age at repair, especially older than 3 years, significant pulmonary valve or tricuspid valve regurgitation, history of syncope, multifocal premature ventricular contractions, and presence of ventricular tachycardia.[11] 

Atrial flutter and fibrillation become increasingly prevalent with advancing age in the TOF population, causing substantial morbidity.[13] Larger right atrial size and at least moderate tricuspid regurgitation are associated with such atrial tachyarrhythmias. Additionally, atrial tachyarrhythmias frequently occur concomitantly with sinus node dysfunction and may perpetuate each other.[42] Those with RV to pulmonary artery conduits who reach adulthood are also at increased risk of death or sustained ventricular tachycardia.[33]  Among adults with CHD, acquired cardiac disease secondary to metabolic syndrome, hypertension, obesity, and diabetes type 2 are leading causes of morbidity and mortality.[53]

Patients with CHD, in general, are known to be at risk for neurodevelopmental disability from underlying syndromes, genetic or developmental disorders, and medical and surgical therapies. These patients usually present mild cognitive impairment, impaired communication skills and social interaction, inattention, impulsivity, and impaired executive function. Tutoring, special education, and physical, occupational, and speech therapy are frequently required, with a significant proportion of patients needing these services into adulthood. These issues may limit their educational achievements, employability, insurability, and quality of life.[54]

Pregnancy Complications

Women who had correction of TOF are expected to have similar outcomes as the general obstetric population. Pregnancy complications are related to the degree of pulmonary hypertension, the severity of pulmonary regurgitation, and the magnitude of right and left ventricular dysfunction. Maternal cardiovascular events can include arrhythmias requiring treatment (eg, atrial flutter or fibrillation, ventricular tachycardia, cardiac failure during the third trimester, and pulmonary embolism). Offspring complications have been described, such as small for gestational age, prematurity, intrauterine demise, and increased incidence of CHD such as atrial septal defect, TOF, and atrioventricular septal defect.[55] 

Patients with moderate RV hypertension and those who had a palliative shunt are at an increased risk for cardiac events during pregnancy and miscarriage. Pregnancy in the setting of unrepaired TOF carries the risk of progressive RV dilatation and congestive heart failure, atrial and ventricular arrhythmias, postpartum hemorrhage, and progressive aortic root dilatation. Maternal causes of death in this patient population include pulmonary hemorrhage, thromboembolism, and brain abscess. Obstetric complications include prematurity, low birth weight, and increased risk of miscarriage.[56]

Mortality in Unrepaired Tetralogy of Fallot

The most frequent causes of mortality in patients with no surgical intervention include hypoxic spells (68%), cerebrovascular accidents (17%), and brain abscesses (13%). Within the first year of life, 25% of infants with severe RVOTO die if left untreated, 40% by 3 years of age, 70% by 10 years of age, and 95% by 40 years of age.[57][58]

Deterrence and Patient Education

Due to advances in surgical correction, TOF is not an uncommon diagnosis among the adult congenital heart disease population. As these patients age, they may require reoperation or transcatheter pulmonary valve replacement, arrhythmia treatment, and lifestyle modification to prevent cardiovascular disease secondary to dyslipidemia and diabetes.[15][59][52]

Most patients ' exercise capacity, measured as peak oxygen uptake and heart rate, is limited after TOF repair. However, patients can participate in all forms of physical activity with individualized guidelines. However, restriction from competitive sports is recommended for TOF patients with severe ventricular dysfunction (ie, EF <40%), severe outflow tract obstruction, or recurrent atrial or ventricular arrhythmias, with the possible exception of low-intensity activities.[20][60]

Pregnancy is generally well tolerated in women with TOF with good underlying hemodynamics. However, in women with important RVOT obstruction, severe pulmonary and or tricuspid regurgitation, as well as right and left ventricular dysfunction, the increased volume load during pregnancy can precipitate RV failure and arrhythmias.[61] There is also a higher incidence of cesarean section, miscarriage, preterm births (14%), and small gestational-age newborns (10%). Therefore, these patients are usually regarded as low to moderate risk. In addition, the chances of producing a fetus with a congenital heart defect are higher than among the general population.[62][63][62]

Enhancing Healthcare Team Outcomes

The diagnosis and management of TOF require an interprofessional team, including pediatric cardiologist specialists (ie, imaging, interventionist, and electrophysiologist), neonatologists, intensivists, pediatric cardiac surgeons, respiratory therapists, nurses, geneticists, nutritionists, physical and occupational therapists, psychologists or family therapists.[54]

In general, patients with TOF require several surgeries. Pulmonary valve replacement via surgical or transcatheter approach will eventually be necessary during early adulthood. These patients require lifelong subacute bacterial endocarditis prophylaxis.[64] Most patients will also require services to help with their neurodevelopmental disabilities, which are being increasingly recognized in patients with CHD. Should a woman with TOF reach childbearing age and decide to become pregnant, a professional team including obstetricians, high-risk perinatologists, adult congenital cardiologists, adult congenital interventionists, and electrophysiologists, as well as pediatric cardiac surgeons, will be required to assist throughout the pregnancy, peripartum and postpartum period.[65]