Fetal cardiac interventions: worth it?

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Fetal cardiac interventions: worth it? J M Simpson Prenatal diagnosis of congenital heart disease is now firmly established. Large series have confirmed diagnostic accuracy for a wide range of cardiac lesions.1 Diagnosis of some types of congenital heart disease during fetal life provides a potential opportunity for intervention before birth. The rationale for prenatal cardiac intervention for congenital heart defects is compelling. Some congenital heart lesions, particularly those characterised by left or right heart obstruction, are now recognised to be ‘‘progressive’’ with increased severity later in gestation.2 3 If intervention can be undertaken early enough during fetal life then the deterioration which would otherwise have occurred later in gestation should be averted, translating into a better outcome for affected babies. Prenatal intervention for structural cardiac defects has been undertaken with technical success for a number of different cardiac lesions, including critical aortic stenosis,4–8 hypoplastic left heart syndrome with an intact or severely restrictive atrial septum9 and pulmonary atresia with intact ventricular septum.10 11 Such interventions are now feasible with high rates of technical success at an early stage in pregnancy. It would be expected that if the rationale for prenatal intervention is correct, then technical success would be mirrored by a dramatic improvement in outcome. For any intervention being undertaken during fetal life, the potential adverse effects of disturbing the intrauterine environment, should be outweighed by improved fetal cardiac development and postnatal outcome. Procedural complications, precipitation of preterm delivery,12 intrauterine death and maternal complications are therefore crucial in evaluating the overall benefit of such interventions to judge whether prenatal intervention is ‘‘worth it’’. It should also be emphasised that prenatal intervention is only being considered for a small minority of the whole population of fetuses diagnosed with congenital heart disease. At the Evelina Children’s Hospital, 855 fetuses were Correspondence to: Dr J M Simpson, Fetal and Paediatric Cardiology, Evelina Children’s Hospital, London SE1 7EH, UK; [email protected] Heart October 2009 Vol 95 No 20

diagnosed with congenital heart defects between January 2005 and April 2009. Of these, 14 had critical aortic stenosis (1.6%), 16 had pulmonary atresia with intact ventricular septum (1.9%) and 13 (1.5%) had pulmonary valve stenosis of a severe degree. Thus, for at least 95% of fetuses diagnosed with congenital heart defects prenatally, intrauterine therapeutic intervention will not be a consideration.

CRITICAL AORTIC STENOSIS The progression of critical aortic stenosis during fetal life with subnormal growth of left heart structures with advancing gestational age has been described.2 13 These series have demonstrated that severe obstruction of the aortic valve is associated with reduced left ventricular function in the majority of cases and that growth of the mitral valve, left ventricle and aorta is subnormal in most affected fetuses. Furthermore, deterioration of left heart growth occurs relatively early in gestation. In the late 1980s, there was no surgical treatment available to treat hypoplastic left heart postnatally in the United Kingdom and the justification for prenatal intervention was to prevent development of hypoplastic left heart syndrome which would be untreatable. The first series of intrauterine balloon aortic valvuloplasty was reported from our centre in 1991.6 That series described attempts at balloon aortic valvuloplasty in two fetuses, with one technical success. Both fetuses died, one within a day of the procedure and the other postnatally. There were some technical problems relating to the equipment which was used. The balloon catheters used at that time were difficult to withdraw into the sharp-tipped hollow needles which had been used to gain access to the fetal heart, leading to shearing of the balloon catheters so that retention of fragments of the catheter occurred. Currently, needles used to gain access to the fetal heart have a stillette which can be removed so that balloon catheters can be withdrawn more easily. The balloon catheters themselves are now low profile coronary balloon catheters which assists in their withdrawal into the needle. Long-term survival, with a

biventricular repair, of one child who had undergone fetal intervention5 was later described from the initial series. That child had had a dilated left ventricle, late in gestation when the intervention was undertaken.2 In 2000, Thomas Kohl et al reported the combined experience of all prenatal cardiac interventions for aortic valve stenosis which had been undertaken world wide.7 Although not designed as trial, the cases described could be divided in to those where there was technical success (n = 7) and those where there was technical failure (n = 5). Of those who underwent technically ‘‘successful’’ intervention, four died within 24 h of the procedure and there is one long-term survivor who has appeared in two previous series.2 5 Of the five who did not have technical success, there was one survivor who had a biventricular circulation postnatally. These data demonstrated that procedural risk is significant and prediction of fetuses who will be unsuitable for biventricular repair postnatally is not always accurate. Since the data of Kohl et al was published, the group at the Children’s Hospital in Boston has reported the largest experience of prenatal intervention.4 This group reported the outcome of 20 attempted fetal aortic valvuloplasties, which were technically successful in 14. Of those, only three have achieved a biventricular repair, a success rate of 15% based on intention to treat. Eleven fetuses required intracardiac adrenaline during the procedure because of severe fetal bradycardia and four fetuses (20%) died in utero or at a pre-viable gestational age. Half of the mothers in this series underwent a laparotomy to achieve direct access to the uterus with the aim of achieving a higher rate of technical success and better wire and balloon positions. Thus, even if technically successful, only a minority of fetuses achieve a biventricular repair, despite evidence of better growth of the aortic valve, mitral valve and left ventricle compared with fetuses in whom intervention could not be accomplished for technical reasons.4 More recent data also suggest that during the mid-trimester anatomical features alone cannot distinguish fetuses who will progress to hypoplastic left heart syndrome from those who will maintain growth sufficiently to permit a biventricular circulation.14 One of the key aims of prenatal intervention has been to increase the proportion of fetuses who achieve a ‘‘biventricular repair’’. Relatively little information has been published on the 1653

Viewpoint haemodynamic and functional status of those who have achieved a biventricular repair. Critical aortic stenosis typically affects not only the aortic valve but is also associated with hypoplasia and stenosis of the mitral valve, mitral valve regurgitation and endocardial fibroelastosis of the left ventricle. Burch et al15 have reported on a group of infants with critical aortic stenosis with severe pulmonary hypertension due to restrictive left ventricular physiology. In this group, aggressive attempts to pursue a biventricular circulation led to a clinical situation where a single-ventricle repair was no longer an option, and the functional result was inferior to a singleventricle repair. These data confirm that achievement of a ‘‘biventricular’’ circulation is not always a better outcome than a single-ventricle repair. Few of the published series on the results of prenatal intervention for critical aortic stenosis give information on the type and number of postnatal operations, functional status or pulmonary hypertension. It is evident from published reports that new strategies for resection of endocardial fibroelastosis and early mitral valve surgery are having to be developed to deal with such complications so that there is no question that this remains a problem, even after fetal intervention.16 This would seem to reflect the selection criteria which have been used to select cases for prenatal intervention which did not exclude fetuses on the basis of either endocardial fibroelastosis or mitral stenosis.4 It is also highly likely that if there has a been a prenatal intervention, units may pursue biventricular repair more vigorously than if this had not been undertaken.

PRENATAL INTERVENTION ON THE ATRIAL SEPTUM Prenatal intervention on the atrial septum has been advocated for fetuses with hypoplastic left heart syndrome with an intact or highly restrictive atrial septum.9 The rationale for this has been first, to improve the clinical status of infants in the early neonatal period and reduce the incidence of severe hypoxia and acidosis which might otherwise ensue. Second, relief of left atrial hypertension may reduce the pulmonary vascular complications in this group who are known to have a guarded outcome during early childhood.17 The rationale for such interventions is not therefore in dispute. The technique involves introduction of a catheter over a sharp metal obturator into the right atrium. The catheter is advanced to the atrial septum where either the 1654

obturator itself or a Chiba needle has been used to perforate the atrial septum. Having entered the left atrium, the needle is withdrawn and a balloon catheter is advanced across the atrial septum to dilate the interatrial communication.9 Reports of prenatal intervention on the atrial septum indicate that the septal communications which are created are small and may reseal with advancing gestational age. Interventions published to date have been undertaken relatively late in gestation at 26–34 weeks’ gestational age.9 There are no data to suggest an early mortality benefit of such interventions, indeed five of the six fetuses with technically successful septal intervention died either prenatally (n = 1) or postnatally (n = 4).9 The single fetus with an unsuccessful prenatal intervention survived a Norwood surgery after birth. Reports of the early postnatal management of patients who underwent prenatal septoplasty demonstrated that the majority (six of nine) still required decompression of the left atrium after birth, and no difference in hospital mortality was noted between patients who had prenatal intervention and those who did not.18

PRENATAL INTERVENTION ON THE PULMONARY VALVE A case for prenatal intervention on the pulmonary valve can be made in a similar way to that for the aortic valve. Progression of right heart hypoplasia can be documented during fetal life3 19 and a significant proportion will not achieve a biventricular repair. A United Kingdom population-based study of pulmonary atresia with intact ventricular septum reported that 29% of the initial cohort achieved a biventricular circulation and 11% had a single-ventricle repair. Prenatal intervention has been undertaken on the pulmonary valve but in relatively few cases.20 In two of the cases initially reported, this procedure was undertaken because of impending hydrops10 with haemodynamic benefit, although these fetuses would have had a predicted biventricular repair based on the predictive scoring system recently published from the same centre.11 The same group, in their more recent paper, have included data on a further case of pulmonary atresia with intact ventricular septum, in whom intervention was complicated by preterm delivery and neonatal death.11 Currently, far fewer fetuses with critical pulmonary valve stenosis or pulmonary atresia with intact ventricular septum have undergone fetal intervention than with critical aortic stenosis. This might in

part be related to those conditions being viewed as less severe than critical aortic stenosis and, in part, owing to the morphology of those conditions. For example, right ventricular to coronary communications (with the potential for right ventricle-dependent coronary circulation) are more common in fetuses with smaller tricuspid valve annulus and pulmonary arteries.21 However, if intrauterine perforation of the pulmonary valve can be matched by echocardiographic improvement in the size of right heart structures, then the low resistance nature of the pulmonary circulation might prove relatively forgiving if there is residual tricuspid regurgitation or persisting abnormalities of right ventricular systolic or diastolic function. This contrasts with the profound effects of residual lesions affecting systemic arterial haemodynamics in fetuses who have undergone balloon dilatation of the aortic valve.

CONCLUSIONS Despite a positive impact on echocardiographic parameters, only a small minority of infants with critical aortic stenosis who underwent prenatal intervention prenatally have achieved a biventricular repair. For those who have achieved a biventricular repair it will be important in future publications for data to be presented which include functional status, information on pulmonary artery pressures and residual lesions. A recent description of a requirement for surgical resection of endocardial fibroelastosis confirm that left ventricular haemodynamics remain far from ideal. Similarly, prenatal intervention on the atrial septum has not yet been matched by a significant improvement in mortality. The focus in recent publications, reexamining the natural history of cardiac defects which may be suitable for intervention,3 11 14 may permit more accurate targeting of interventions. For example, mitral valve disease or endocardial fibroelastosis were not judged contraindications to prenatal intervention, but these are important factors in determining the feasibility and quality of biventricular repair. Postnatally, better surgical approaches for mitral valve abnormalities and endocardial fibroelastosis16 may yet permit improved outcome for infants with left heart abnormalities commonly associated with critical aortic stenosis. Thus, in the best case, prenatal intervention on the aortic valve should be considered only part of a process of overhaul of left heart structures, which will need to continue postnatally, rather than prenatal Heart October 2009 Vol 95 No 20

Viewpoint intervention being a single definitive intervention. Evolving hybrid approaches22 23 may also mean that infants with left heart disease may be managed without the use of cardiopulmonary bypass and this potentially leaves options open for either single-ventricle or biventricular repair for a longer period of time than is currently feasible. Even with ‘‘state of the art’’ surgery and intervention, it will remain crucial to identify, as early as possible, those infants who will be better served by a single-ventricle repair rather than a poor quality biventricular repair which may close off other therapeutic options.15 In answer to the question posed in the title, given the data available, it is certainly not the case that fetal intervention is always worth it. This is plain in the small proportion of fetuses who reach the desired end points and the risk of the procedure. Conversely, given the reports of growth of cardiac structures after intervention it is also difficult to argue that it is never worth pursuing fetal intervention. For critical aortic stenosis, which has been studied most closely, the best candidates are probably those fetuses who have evidence of severe aortic valve obstruction, but who have competent mitral valves and absence of, or only mild, endocardial fibroelastosis. Although this would reduce the number of potential candidates for fetal intervention still further, it would target those in whom aortic valve stenosis is the ‘‘rate-limiting’’ lesion rather than those in whom the constellation of left heart abnormalities is far more complex and in whom stenosis of the aortic valve is only a part.

Heart October 2009 Vol 95 No 20

Competing interests: None declared. Provenance and peer review: Commissioned; not externally peer reviewed.

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Accepted 22 April 2009 Published Online First 13 May 2009 Heart 2009;95:1653–1655. doi:10.1136/hrt.2008.160739

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