Pulmonary atresia with intact ventricular septum

Pulmonary atresia with intact ventricular septum (PA-IVS) encompasses a group of cardiac anomalies that have in common a complete obstruction of the right ventricular (RV) outflow tract secondary to an absent pulmonary valve development, in the presence of an intact interventricular septum (1,2). In this condition there is a variable degree of RV development which will influence the prognosis, resulting in a broad spectrum of postnatal outcomes (3).

PA-IVS is an uncommon anomaly, accounting for 1-3% of congenital heart defects in postnatal life and up to 5% of prenatally detected heart disease (4-6). It has an incidence of 4-5/100,000 live births (5).

The exact morphogenesis of this disorder is unknown (7). However, it is thought that the abnormality in the pulmonary valve occurs after complete closure of the interventricular septum (around the sixth week of gestation) due to the presence of a correctly developed pulmonary trunk (8).  

The aetiology of this congenital heart disease is unknown. However, it has been associated with maternal rubella infection, possibly with an inflammatory origin of this distortion (9). Functional pulmonary atresia may also be present in the recipient twin of a monochorionic-diamniotic twin gestation with twin-to-twin transfusion syndrome. Pulmonary atresia in these cases originates from a structurally normal heart due to haemodynamic imbalance (10,11). This condition may resolve or persist and need to be treated after birth.

RV outflow tract obstruction can be classified into two types depending on the location of the obstruction (1,2,12): 

- In most cases (approximately 75-80%), the obstruction is in the pulmonary valve, with complete fusion of the valvular commissures associated with the presence of a thin membrane, further increasing the obstruction. This is called membranous or valvular obstruction. In this case, there is a well-developed infundibulum. It is considered a milder form.
- In the remaining 20-25% of cases, the obstruction is located in the RV outflow tract region with severe obstruction of the muscular infundibulum, termed subvalvular, muscular or infundibular. More severe forms are usually associated with small right ventricles and the presence of coronary anomalies, as well as a right ventricle-dependent coronary circulation. 

The RV will usually be hypoplastic with a thickened myocardial wall.  Less frequently, a normal-sized or even dilated RV is encountered, with a thin muscular wall. RV size will depend on the function of the tricuspid valve. Thus, two types of PA-IVS can be distinguished (2):

•    Type I: In approximately 75% of cases of PA-IVS, the tricuspid valve is competent. With RV outflow tract obstruction and a competent tricuspid valve or mild regurgitation, there is a significant increase in the intracavitary pressure, which impairs ventricular filling and consequently underdevelops the RV. Significant RV hypertrophy also obliterates the trabecular portion of the RV (4,13). Increased intraventricular pressure favours the formation of ventriculo-coronary connections, which connect the coronary arterial bed with the hypoplastic RV through the primitive coronary sinusoids (12). Other coronary abnormalities found include stenosis, absence of coronary orifices and anomalous coronary artery pathways. The presence of ventriculo-coronary connections is found in 17-36% of PA-IVS and RV-dependent coronary circulation in 8% of cases (6).

•    Type II: In 25% of cases of PA-IVS, the tricuspid valve is insufficient. The more severe the insufficiency, the more likely the tricuspid valve is dysplastic. There is an obstruction in the RV outflow tract, but because the tricuspid valve is insufficient, blood alternately enters and exits the RV, allowing it to develop. The RV can be normal-sized (6.5% of cases of PA-IVS) or dilated (13% of cases) (4). The pressure within the RV is lower than in type I; therefore, ventriculo-coronary connections do not develop. A 5-10% of cases may be associated with Ebstein's anomaly (12). When tricuspid regurgitation is massive, it can lead to fetal heart failure (14). 

Pulmonary perfusion will be ductus dependent, with a more significant impairment in neonates with a small ductus arteriosus. 

The most common clinical presentation is cyanosis, usually associated with mild tachypnea. Cyanosis results from the absence of blood flow through the pulmonary artery and the forced right-to-left shunt at the atrial level (12).  

The presence of coronary anomalies can lead to a right ventricle-dependent coronary circulation. Since part of the left ventricular myocardium is dependent on high-pressure blood from the RV, decompression of the RV outflow tract leads to a risk of ischaemia and infarction (12,15,16).

PA-IVS may be associated with other cardiac anomalies such as hypoplastic RV, ventriculo-coronary connections, aortic stenosis (secondary to bulging of the interventricular septum), atrial septal defect, Ebstein's anomaly or transposition of great vessels. Cases associated with heterotaxy have also been reported (1,2,6,12). 

Extracardiac anomalies can be associated in 10-14% of cases (2,4,6). In addition, this heart disease is not usually associated with chromosomal abnormalities, with a published association rate of 2.3-5% (4).

In the case of a previously affected child, the risk of recurrence is 1%; if two children are affected, the risk increases to 3% (17).  

Type I (competent tricuspid valve): 
Grayscale
- The four-chamber view shows a hypertrophic and hypokinetic RV with a variable degree of underdevelopment. Depending on the degree of RV hypoplasia, we can find a virtually absent, unipartite RV, with preservation of only the inflow portion and obliteration of the apical and infundibular portion, or,  a virtually normal, tripartite RV, in which none of the portions are completely obliterated. The tricuspid valve is usually small with a narrow valvular annulus, poor leaflet mobility, and severely limited opening. Progressive RV wall hypertrophy may lead to a displacement of the interventricular septum into the left ventricle. 
- The pulmonary artery is small or hypoplastic secondary to decreased blood flow through the pulmonary artery. The degree of underdevelopment is variable, and, in severe cases, it can be challenging to identify on grayscale imaging and can only be recognised by colour Doppler. The pulmonary valve is dysplastic, thickened and hyper-refringent. Occasionally some movement may be observed during the cardiac cycle but without the opening of the leaflets.

Colour and pulsed Doppler
- Colour Doppler demonstrates low RV filling during diastole. There is antegrade flow through the tricuspid valve, monophasic, of short duration, with mild tricuspid insufficiency. 
- At the pulmonary valve level, there is no blood flow through the pulmonary valve and reverse flow from the ductus arteriosus. 
- If there are ventriculo-coronary connections, they will be identified by colour Doppler. They are usually seen in the 5-chamber view: vessels with a path between the aortic root and the RV or its apex (vessels that cross the myocardium towards the RV cavity). These arterial connections present a turbulent bidirectional flow that is antegrade and of  low velocity from the RV to the coronary artery in systole and retrograde and high velocity from the coronary artery to the RV in diastole. Pulsed Doppler helps to confirm this bidirectional flow. 

Type II (incompetent tricuspid valve): 
Grayscale: 
- The four-chamber view shows a normal-sized or dilated RV. The tricuspid valve is usually dysplastic, with pansystolic and high-velocity tricuspid regurgitation reaching the atrial roof. This significant tricuspid regurgitation will cause dilatation of the right atrium. 
- The pulmonary artery has the same sonographic expression as in type I: reduced dimensions or hypoplastic. In addition, the pulmonary valve is dysplastic, thickened and hyper-refringent, with no opening of the leaflets during systole.

Colour and pulsed Doppler: 
- Pansystolic tricuspid insufficiency to the right atrium during systole is identified with colour Doppler. 
- At the pulmonary level, flow through the pulmonary valve is absent, with retrograde filling from the ductus arteriosus. 
- Reverse flow through the ductus venosus may be identified in severe cases. 
- No ventriculo-coronary connections are seen.

The differential diagnosis includes the following entities (1): 
- Pulmonary stenosis: this differs from pulmonary atresia in that there is antegrade flow across the pulmonary valve. Critical pulmonary stenosis may progress to pulmonary atresia.
- Pulmonary atresia with ventricular septal defect (VSD): this is a distinct entity from PA-IVS. Both have in common pulmonary atresia. However, there are differences between the two other than the presence of the VSD. In pulmonary atresia with VSD, the pulmonary artery is small or practically non-existent, ventriculo-coronary connections do not develop, and MAPCAs (major aorto-pulmonary collateral arteries) may be present.  
- Tricuspid atresia: there is no passage through the tricuspid valve.

Prenatal diagnosis of a PA-IVS involves a detailed fetal ultrasound to rule out the presence of other associated cardiac or extracardiac anomalies. 

Parents should be offered an invasive diagnostic testing to rule out associated chromosomal or genetic abnormalities, which are present in a small percentage of cases.

PA-IVS is suspected in the four-chamber view, the primary view performed in routine fetal morphological screening. In PA-IVS type I, a hypoplastic RV with low ventricular filling (assessed by colour Doppler) will be identified. In PA-IVS type II, the RV may be normal or dilated, with a usually dilated right atrium. Colour Doppler will reveal severe tricuspid regurgitation. The definitive diagnosis is made by visualising the small pulmonary artery without transvalvular flow and reverse flow through the ductus arteriosus. 

Sonographic abnormalities are already present in most cases in the first trimester, so it is also possible to make the diagnosis in the first trimester, although this is more difficult given the size of the heart.  

With such heterogeneous pathology, the prognosis of fetuses with PA-IVS will vary widely. The most important prognostic factors are the size of the tricuspid valve and RV, the function of the RV and the existence of ventriculo-coronary connections. 

These factors will determine the type of neonatal circulation and the type of neonatal repair: biventricular repair, hybrid or "1.5 ventricle" repair, or univentricular repair (6). 

There are a large number of markers and scores that have been used to predict the type of postnatal circulation. Most authors accept the following as prognostic markers: 
- Tricuspid valve z-score ≤-3: RV hypoplastic (18,19,20,21). 
- RV/LV length > 0.6-0.7: 0.6(22)-0.62(23)-0.64(24)-0.7(6): good right ventricular development.
- TV/MT valvular annulus <0.7 (20,22,23): RV hypoplastic.
- Tricuspid valve regurgitation > 2 m/s (6,): good RV function. 
- RV filling time/cardiac cycle time <31.5%(22)-36.5%(24) : diastolic RV dysfunction.
- Presence of ventriculo-coronary connections: increased risk of univentricular repair (6,22,23).

This disease has classically been considered of poor prognosis. Decades ago, an initial survival of 80% was reported, with a 10-15 year survival after surgical treatment of around 60% (25,26,27). More recent publications increase the survival at 10 years to be around 87% (28), or even higher (29). 

Biventricular circulation is generally considered to have a better prognosis than univentricular circulation, and there is a tendency to favour this pathway. However, occasionally this pathway can compromise functional class and exercise tolerance (2,30). Therefore, it is essential to individualise each case and select the best pathway for each patient, which is not always biventricular  repair (2,29). 

Low birth weight (5,25,29,31), presence of a unipartite hypoplastic RV (5,25,29), significant RV dilation (5,29) and muscular pulmonary atresia (31) are considered risk factors for mortality. The risk of death in patients with PA-IVS is highest in the first months of life (2).

Upon prenatal diagnosis of PA-IVS, parents should be counselled on fetal prognosis taking into account the type of PA-IVS, the degree of RV impairment (with the possibility of postnatal biventricular or univentricular circulation), associated cardiac or extracardiac anomalies and chromosomal abnormalities. 

Ultrasound follow-up every 3-4 weeks is recommended depending on the features of each case. PA-IVS type I presents a high risk of RV hypoplasia, and PA-IVS type II a high risk of transition to fetal hydrops.  

Intrauterine cardiac intervention in selected cases of PA-IVS may modify the natural history of this disease, improving the prognosis of these fetuses (2,19,20,20,22,24,32). In addition, several biventricular vs univentricular circulation prognostic scores should be used to select patients who are candidates for prenatal valvuloplasty (19,20,20,22,24). 

All patients with a prenatal diagnosis of PA-IVS should be born in a tertiary perinatal centre. 

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