Prenatal diagnosis of hypoplastic left heart syndrome with PAPVC and FO restriction and pulmonary hypertension – coexisting factors suggesting poor prognosis due to pulmonary hypertension with histopathological confirmation

Introduction​

Hypoplastic left heart syndrome (HLHS) is one of the most common, prenatally diagnosed congenital heart diseases (CHD) [1-3]. In this CHD, the right ventricle serves as the main pump supplying blood to both pulmonary and systemic circulation, while the left ventricle has almost no haemodynamic function.
The outcome of patients with HLHS has improved over the years because of prenatal diagnosis, perinatal care, transfer in utero, early intra-venous Prostin administration, surgical techniques, and perioperative care. Neonatal HLHS is usually referred for planned cardiac surgery, but despite the development of neonatal cardiac surgery, some coexisting additional factors make the outcome poor [4-5]. Our retrospective analysis of the presented case has suggested paying attention to pulmonary hypertension as a new coexisting factor and prediction of poor prognosis.

Case report

A 29‐year‐old woman (gravida 2 para 2) was referred to our tertiary centre (Prenatal Cardiology, Obstetrical Department, Paediatric Cardiac Surgery Department in the same hospital) for fetal echocardiography examination at 27 weeks of gestation due to suspicion of hypoplastic left heart syndrome (detected at 20 weeks of gestation). She did not provide an ultrasound examination from the first trimester of pregnancy. At an initial echocardiographic examination in our centre, left heart syndrome with mitral and aortic valve atresia was confirmed. There was also fibroelastosis of the left ventricle. In pulmonary venous flow there was high velocity with reversal flow (Figure 1), but with low risk of restriction foramen ovale (FO) (velocity time integral – VTI f/r = 8). Next examination was at 32 weeks, without significant progression.
At 33 weeks, in addition to previous findings, partial anomalous pulmonary venous return was diagnosed. The left pulmonary veins formed a common collector, which went behind the left atrium intracardially, because the left atrium was not completely filled with blood despite power angio Doppler with low flow velocity, so it was an indirect sign not published before (Figure 2). An oxygen test was performed during the study, without pulmonary vein reaction.
At 35 weeks the velocity of blood flow in the foramen ovale was around 120 cm/s and VTI f/r = 5, so high risk of restrictive foramen ovale was diagnosed (Figure 3).
The last fetal echo examination was at 36 weeks with the following final conclusions: HLHS + mitral and aortic valve atresia, fibroelastosis, partial anomalous pulmonary venous return with reversal flow in pulmonary veins, restrictive foramen ovale (in the 36th week VTI f/r = 3) (Table 1), and dilatation of the pulmonary trunk (Figure 4).
At 38 weeks, a female newborn was born by elective caesarean section with birth weight 3200 g and Apgar score 9/9. Neonatal echocardiographic examination confirmed the prenatal diagnosis: partial anomalous pulmonary venous return (intracardially) with preserved communication and leak in IAS. Despite IV Prostin infusion, several hours later there was peripheral and central cyanosis with saturation around 60-80%.
On the 7th day of postnatal life the Norwood operation was performed. Part of the Norwood procedure is an excision of interatrial septum II, normally creating large communication between left and right atrium. In this patient there was an intracardiac type of partial anomalous pulmonary vein return. After surgical removal of IAS II, additional relief of pulmonary vein inflow was not needed.
Postoperative examination revealed neoAo regurgitation (72 cm/s), narrow pulmonary branches, good inflow systolic function in RV, but impaired outflow contractility. Due to hypotension, scanty diuresis on infusion of catecholamines, pericardial effusion, and poor general condition, the newborn was qualified for ECMO procedure. Despite initial improvement, on the 17th day her death was announced. Based on an autopsy and histopathology findings, concentric thickening of smaller and larger intrapulmonary vessels were revealed as features of pulmonary hypertension (Figure 5).

Discussion

Despite the development of reconstructive surgery in the early 1980s, a considerable number of infants with HLHS remain at high risk of mortality (Table 2) [6-8]. One of the most critical risk factors includes restrictive FO with secondary left atrial (LA) hypertension [9-12]. Restrictive FO causes obstructed blood flow from the left to the right atrium, and blood pressure in the left atrium increases, leading to passive lung congestion and haemodynamic instability. In newborns with a highly restrictive FO or intact atrial septum, even if the surgical procedure is performed immediately after delivery, the prognosis is worse (mortality 50%) than in newborns with unobstructed inter-atrial communication (mortality 23%) [7, 8]. One of the methods for assessing restricted FO is the evaluation of the ratio of the forward blood flow to the reversal flow (VTI f/r) in the pulmonary veins, using the spectral Doppler [13]. The greater the narrowing of the FO, the greater the reversal of blood flow. The ultrasound criterion of non-restricted FO is a VTI f/r ratio > 5 [14]. A forward to reversal VTI ratio of less than 5 and greater than 3 is associated with moderate FO restriction, whereas a VTI f/r of less than 3 is present in severe FO restriction and intact atrial septum cases [15-17].
Also, a maternal hyperoxygenation (MHO) test may be also useful in fetuses with HLHS. Żalińska et al., in their latest review, described the potential benefits of performing MHO during pregnancy [18]. Because of oxygen delivery to the fetus, pulmonary blood flow increases, and increased venous return to the left heart is caused by an increased pulmonary blood flow after MHO with substantial improvement in the left ventricular filling, which causes more blood pumping to the aorta and stimulates its growth. This phenomenon may play a significant role in fetuses with HLHS, because of the small left ventricle and narrowing aorta. Other publications also concluded that MHO in fetuses with HLHS could be useful in predicting emergent atrial septoplasty after birth [19-22].
In the present case, foramen ovale restriction was seen but relatively late – from the 35th week of gestation, so it was not considered as long lasting or predictive of poor neonatal condition just after birth [13]. The Norwood operation was planned and performed on the 7th day of postnatal life (in our centre the mean day for the Norwood procedure in 2020-2021 was on the 9-10th day). This surgical method is defined as the creation of an aortopulmonary connection and neoaortic arch construction resulting univentricular physiology and the creation of a source of pulmonary blood flow with a calibrated systemic-to-pulmonary artery shunt (connection of right ventricle to pulmonary artery) [23-25].
Jadczak et al. concluded that earlier development and longer presence of FO restriction in HLHS is associated with higher short-term mortality, regardless of the degree of restriction [13]. In this case, despite late diagnosis of FO restriction, early, planned operation, the newborn still had symptoms of cardio-pulmonary failure.
An important additional poor prognostic factor was dilated pulmonary trunk seen prenatally, suggesting abnormal lung development, which correlated with pulmonary hypertension [26].
The next important prenatal finding in the presented case was partial anomalous pulmonary venous connections (PAPVC). This prenatal anomaly is rarely described in the literature [27, 28]. Total anomalous pulmonary venous connections (TAPVC) and PAPVC represent rare anomalies, accounting for 1-3% of all cardiac malformations detected after birth, and supracardiac or infracardiac anomalous pulmonary venous connections are much better described than intracardiac [29].
In the presented case, PAPVC was first detected in the 3rd trimester, at 33 weeks of gestation, because only part of the left atrium was fulfilled by Doppler slow colour blood flow. It was assumed that this was due to abnormal connection of veins and was confirmed after birth during neonatal echocardiography as intracardial PAVC. This observation, as partial filling of left atrium by fetal blood in the case of PAVC, is reported for the first time. As far as we are concerned, it was not observed before.
Total and partial anomalous venous connection comprises a wide spectrum of congenital cardiovascular malformations in which one or more pulmonary veins returns to the right atrium or systemic venous circulation instead of draining directly into the left atrium [29]. Góra et al. [30] published 3 cases with HLHS + TAPVC and concluded that these complex heart defects, despite echocardiographic supervision and deliveries in the main obstetric centre, caused quick haemodynamic deterioration and the demise of newborns even before surgery. But histopathology of neonatal lungs was not possible in every case.
What is known, in fetuses with HLHS, severe restriction of FO, and premature closure of the atrial septum leads to left atrial hypertension and remodeling of the pulmonary vasculature, which can severely worsen the prognosis. In our case, in combination with restrictive FO, partial abnormal flow of pulmonary veins with abnormal flow contributed to the increase in features of pulmonary hypertension, which led to the most serious consequences. We were wondering – due to numerous unfavourable prognostic factors in the presented case (including PAPVC + restrictive FO + dilated main pulmonary artery) – whether earlier surgical intervention would be a better choice, perhaps in the first 24 hours of life.
Jayakumar et al. [27] described a rare situation in which the 2 right-sided and 2 left-sided pulmonary veins each formed a confluence and drained into the left atrium. It was similar to our case in which veins formed a common collector. The newborn developed progressive pulmonary venous congestion and severe acidosis. Because of dismal clinical outcomes in view of her comorbidities, including prematurity, severe IUGR, and obstructed pulmonary veins with recognized pulmonary vascular disease, surgical intervention was not performed in that case.
In the Washington centre, in fetuses with prenatal restriction of FO, the Rashkind procedure was performed in the first minute after birth in the delivery room [31]. The survival rate of the HLHS group with a highly restrictive FO or intact atrial septum, after the Rashkind procedure and the first stage of cardiac surgery, was 33-48%. In the Boston centre, in-utero surgical treatment was performed, and the 6-month survival rate of patients treated in utero was significantly greater than for those in whom FO balloon septostomy was only performed after birth (69% vs. 38%, respectively) [32]. These two observations make us think that early intervention in the most difficult cases of HLHS may be a chance for these newborns to prolong their survival, and prenatal echocardiography and early diagnosis is a clue to further management.
In the presented case, on the first neonatal echo, restriction of the foramen ovale was not seen, and despite complex HLHS the neonatal condition was stable, and there were no clinical symptoms of pulmonary hypertension.

Conclusions

Partial anomaly pulmonary venous return, wide main pulmonary artery, and restrictive foramen ovale were unfavourable risk factors in our case of HLHS, and despite relatively early surgical intervention, there was a poor outcome with autopsy-histopathology findings of pulmonary hypertension.

Conflict of interest

The authors declare no conflict of interest.

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