Introduction

Transposition of the great arteries (TGA) is the most common cyanotic congenital heart defect (CHD) presenting in the neonatal period, accounting for 5–9% of cardiac malformations . In TGA, the ventriculo-arterial connection is discordant, which means that the aorta arises from the morphological right ventricle, and the pulmonary artery arises from the morphological left ventricle ( Fig. 1 ). The pulmonary and systemic circulations are therefore in parallel rather than in series. As the deoxygenated blood is recirculated through the body (right ventricle–aorta connection) – whereas the oxygenated blood recirculates through the lungs (left ventricle–pulmonary artery connection) – at least two of the three possible communications between the pulmonary and systemic circulations are obligatory to support early survival: a patent ductus arteriosus, an atrial septal defect (always present during pregnancy) or a ventricular septal defect (VSD) (optional). Thus, TGA can be categorized based on the presence or absence of VSD. Usually, newborns with TGA with an intact ventricular septum (IVS) become cyanotic in the first days of life when the ductus arteriosus closes; among these, patients with reduced mixing opportunities (TGA-IVS with restrictive foramen ovale and/or closure of the ductus arteriosus) become symptomatic with extreme cyanosis early after birth. Leading inevitably to progressive hypoxia and acidosis, TGA is an almost always fatal when left untreated.

Schematic representation of transposition of the great arteries with an intact ventricular septum at birth. The aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle. Thus, aortic blood saturation is poor and newborns become cyanotic. At birth, two foetal communications exist concomitantly: the foramen ovale and the ductus arteriosus. Ao: aorta; DA: ductus arteriosus; FO: foramen ovale; LV: left ventricle; PA: pulmonary artery; RV: right ventricle.

The physiological and anatomical correction of TGA is the finest example of the successful evolution of the surgical treatment of CHD. Indeed, the advent of the arterial switch operation (ASO) allowed better postoperative survival and outcomes than atrial switch procedures . However, and even if data are scarce, preoperative mortality (describing a fatal adverse evolution during the time between birth and surgery) of newborns with TGA ranges from 3.6% to 10.3% . In comparison, in a retrospective study involving 19 European institutions, operative mortality was reported to be 6% . Since the widespread use of balloon atrial septostomy (BAS) and prostaglandin E1 (PGE1) therapy, no new major technique – with the exception of extracorporeal circulatory assistance, which is fortunately rarely used – has improved the postnatal condition of these newborns. Nevertheless, current non-invasive technologies allow us to closely monitor these patients and to identify those who will probably benefit from early surgery. Conversely, ASO can be delayed in certain circumstances. In this review of the literature, we discuss the different aspects of the preoperative management of newborns with TGA.

Foetal considerations

In the normal foetus, oxygen saturation of the umbilical venous blood, which is preferentially directed through the foramen ovale into the left atrium, is about 85% ( Fig. 2 ). Left ventricular blood, which is ejected into the ascending aorta, and consequently distributed to the brain, has a saturation of about 65%. In foetuses with TGA, pulmonary arterial blood saturation (ejected by the left ventricle) is very high. On the contrary, oxygen saturation of the blood delivered to the brain is about 45%. Thus, the brains of foetuses with TGA are exposed to a relative chronic hypoxia, which can explain a certain predisposition for neurological injuries after birth .

Schematic representation of foetal blood circulation in: A. A healthy foetus. Left ventricle ejects high saturated blood into the aorta. The brain receives a blood with a saturation of 65%; B. A foetus with transposition of the great arteries. Right ventricle ejects less oxygenated blood into the aorta. The brain is exposed to a blood with a saturation of 45%.

Notwithstanding the fact that in TGA and during foetal life, the pulmonary circulation receives blood with high oxygen saturation, which may act as a vasodilator, persistent pulmonary hypertension of the newborn (PPHN) is relatively frequent. The first hypothesis to explain this is that high saturation of pulmonary blood could reduce the development of pulmonary smooth muscle cells and make pulmonary vessels less reactive to vasoactive stimuli. Secondly, it could be explained by the high saturation of ductal blood, which can induce a prenatal ductal constriction leading to high pulmonary vascular resistance .

A restricted foramen ovale was reported in approximately 20% of foetuses with TGA . This restriction – not yet fully understood, but probably due to complex haemodynamic mechanisms affecting atrial filling patterns (pulmonary versus systemic venous returns), ductal arteriosus and/or ductus venous flows – may compromise early survival after birth.

Location of delivery

Despite the use of intravenous PGE1 therapy, early demise of neonates with TGA may occur in 4% and is related to inadequate interatrial communication . In fact, a patent ductus arteriosus allows essentially unidirectional flow either from the aorta to the pulmonary arteries or opposite, according to respective pressure levels. However, in TGA, systemic oxygenation requires mixing, that is to say reciprocal exchanges between the two compartments. Adequate mixing is provided either by a large defect such as atrial septal defect or by the coexistence of two communications. Although prenatal diagnosis of TGA was shown to be efficient in reducing early mortality – by decreasing the required time for BAS – and although several echocardiographic foetal signs were proposed to detect high-risk foetuses, an urgent BAS is mandatory in up to 12% of patients . Accordingly, some surgical centres developed a strategy of planned onsite deliveries to limit neonatal transport . If, obviously, centralization (requiring in utero transport) is advantageous, deficiency of prenatal detection, or large countries with few specialized centres, make this policy sometimes impossible to achieve. When performed by specialist transport teams, long-distance transport (by road or air) of a newborn with TGA can be done relatively safely . Indeed, in two Australian retrospective studies (totalling 234 patients), the reported mortality was 0.04% . BAS was performed before transport in 57% of patients and 54% received PGE1 infusion during transport. Few major complications were encountered and most newborns remain stable . In a cohort of 202 neonates who received PGE1 during transport, a strong predictor of complications was PGE1 dose, with a cutoff of 0.05 μg/kg/min . Thus, PGE1 should always be administrated with the lowest effective dose to avoid adverse effects such as hypotension or apnoea. Whereas elective intubation exposes infants to the risk of mechanical malfunction, it is sometimes preferable for them to be intubated before transport . Indeed, the space for potential resuscitation is frequently limited, especially on commercial aircraft . Anyway, as demonstrated in a recent study, children with a prenatal diagnosis had a lower prevalence of preoperative brain injury, probably because of a better neonatal haemodynamic state through early use of PGE1 . This last finding supports a policy of planned delivery in a tertiary centre with expertise in neonatal CHD management. This approach is also supported by the fact that morbidity is higher when admission occurs during the weekend .

Balloon atrial septostomy

When the foramen ovale is restrictive or even small, interatrial mixing is insufficient to allow adequate systemic oxygenation. BAS is thus needed to enlarge or create a bidirectional interatrial communication. This manoeuvre was first described in 1966 by Rashkind and consists of a disruption of the atrial septum via the passage of an inflated balloon-tipped catheter from the left to the right atrium through the foramen ovale ( Fig. 3 ) . This procedure may be performed either in an intensive care unit under echocardiographic guidance or in the cardiac catheterization laboratory under fluoroscopic guidance, according to the standard practices of the unit. Similarly, either the femoral vein or the umbilical vein can be used for the venous approach. Because systemic anticoagulation is rarely administered during the procedure, BAS has been suspected to induce brain injuries such as intraventricular haemorrhage, white matter injury and periventricular leukomalacia (PVL), by displacing pre-existing thrombi . This initial supposition was subsequently refuted by recent studies . Indeed, in a meta-analysis involving 10,108 neonates with TGA, no association was found between BAS and perioperative brain injuries . Furthermore, it was emphasized that neonates with TGA and restrictive atrial septal defect who require BAS had lower arterial oxygen saturations, lower Apgar scores and a greater incidence of metabolic acidosis . As Petit et al. showed that preoperative brain injuries were associated with hypoxaemia and delay to surgery rather than BAS, these findings may support a relationship between brain vulnerability, postnatal stresses and neurological complications . Consequently, the current trend is to limit BAS to newborns with restrictive foramen ovale, hypoxemia or clinical instability . Because mortality of the procedure can reach 3%, routine BAS is probably not now indicated, but it has to be considered at any time (or weighted against early surgery, see later) if there is any evidence of potential brain and/or somatic risk . Finally, when performed “out-of-hours”, BAS leads to more adverse outcomes; this observation advocates again for a planned delivery policy .

Balloon atrial septostomy. At birth, when the foramen ovale is restrictive, atrial mixing is inadequate, leading to profound hypoxia. Then, a balloon atrial septostomy is mandatory to enlarge the atrial communication. A. Schematic representation of the manoeuvre. A balloon-tipped catheter is introduced via the inferior vena cava into the right atrium. After passing through the foramen ovale, the balloon is inflated into the left atrium and then pulled across the septum to enlarge the opening. Finally, the balloon is rapidly deflated and the catheter is removed. B. Angiographic images showing the different steps of the manoeuvre.

Prostaglandin therapy

Intravenous PGE1, a potent vasodilator, is routinely used for reopening and maintaining the patency of the ductus arteriosus in neonates with TGA. Since its first use in the 1970s, this molecule has dramatically improved the management of neonates with ductal-dependent CHD . Although this therapy is lifesaving in these patients, it has several possible side-effects. Indeed, PGE1 can cause relevant peripheral vasodilation and subsequently hypotension. Because PGE1 is a proinflammatory molecule, fever, leucocytosis and tissue oedema are extremely frequent. Neurological side-effects can result in jitteriness, seizure-like activities and apnoea. Respiratory depression was reported in 12% of neonates, with a higher incidence of apnoea in low-birth-weight neonates (< 2.0 kg) . This PGE1-associated respiratory depression can be potentiated by the use of sedatives for procedures like BAS. As methylated xanthines such as aminophylline and caffeine citrate were proved to be efficient for reducing the incidence of apnoea, especially in neonates who receive concomitant sedation, these drugs are commonly used to prevent intubation for hypoventilation . Caffeine is usually administered intravenously with a loading dose of 20 mg/kg, followed by a 5 mg/kg/d maintenance doses . The mechanism of action of xanthines involves competing with adenosine receptors and thus inhibiting the action of adenosine (a sleep-promoting substance) on the central nervous system. Owing to the fact that the side-effects of PGE1 are dose-dependent, the lowest effective dose, which enables maintenance of ductal patency, must be defined for each patient to avoid complications. While in the published literature, PGE1 dose can reach 0.1 μg/kg/min, some authors advocate for a very low dose (0.005 μg/kg/min) . In practice, an effective dose of 0.02–0.03 μg/kg/min is generally administered . Prolonged PGE1 infusion should also be avoided because it is associated with longer preoperative mechanical ventilation and a longer duration of postoperative hospitalization . Long-term PGE1 treatment is also responsible for side-effects such as cortical hyperostosis, gastric-outlet obstruction and pseudo-Bartter syndrome . In addition, tissue oedema may make it harder for a neonate to be weaned postoperatively from the ventilator, as well as impairing wound healing. Thus, withdrawal of PGE1 treatment may always be attempted after BAS. Unfortunately, studies failed to identify predictors of successful withdrawal, and the proportion of infants in whom PGE1 is restarted is approximately 50% . Actually, no relationship was found between the size of the atrial septal defect and the ability to stop PGE1 treatment. As PGE1 was shown to relax pulmonary veins, the changes in pulmonary resistance caused by PGE1 may explain rebound hypoxaemia at discontinuation of the PGE1 infusion after BAS . Another issue of PGE1 therapy is the putative risk of necrotizing enterocolitis associated with enteral feeding. While the physiological and nutritional benefits of early enteral feeding in critical term and pre-term neonates have been well demonstrated, feeding apprehension may persist because of a theoretical risk of intestinal hypoperfusion due to a ductal steal phenomenon . In fact, a retrograde diastolic flow pattern in the descending aorta may potentially result in mesenteric ischaemia. This suspicion was sustained by the fact that in a retrospective study, an increased prevalence of necrotising enterocolitis was found in children with CHD . As a consequence, preoperative nutritional practices vary widely between centres . However, data from recent studies suggested that enteral feeding is well tolerated in ductus-dependent CHD . Consequently, strict avoidance of enteral feeds, in term and pre-term neonates with TGA regardless of PGE1 therapy, seems to be unnecessary in most cases. Moreover, the lack of initiation of enteral feeding before surgery was shown to be significantly correlated with prolonged postoperative course . Surprisingly, a minority of teams base their enteral feeding decisions on the ductal flow direction . In this situation, the use of non-invasive monitoring of oxygen delivery may help to accurately assess haemodynamics and to apply a personalized feeding strategy. Measurement or regional oxygen saturation (rSO ₂ ) may also indicate the need for fluid loading in this context of frequent capillary leak syndrome (tissue oedema) and its potential subsequent hypovolemia leading to hypotension. Somatic measurements of rSO ₂ may be done by targeting renal or mesenteric vascular beds .