Prenatal treatment

Introduction: the possibility to treat children in utero

Advances in the fields of paediatric cardiology and surgery mean the treatment of congenital heart defects has improved and grown remarkably in recent years. While newborns can receive important and often life-saving medication or surgery immediately after birth, some clinicians dare to go even further by attempting to treat babies affected by congenital heart disease while they are still in the uterus, that is, before they are even born.

The emergence of prenatal cardiac treatment might be a reason to hope for some of those cases with a relatively bad prognosis.

Impairments in the heart’s development

Some severe congenital cardiac malformations begin as relatively simple primary lesions. During pregnancy, while the foetus is growing and developing, these can cause complex secondary damage to sections of the heart, vessels or lungs, which can affect the postnatal prognosis and treatment options. So, for example, a severely narrowed or blocked valve can cause pathological changes to the blood flow and blood pressure conditions. As the heart is still developing, such impairments can delay its normal growth in the uterus and result in an underdeveloped ventricle and, at worst, heart failure. As the haemodynamics in the heart and the vessels of the foetus differ from those outside the uterus, severe problems frequently do not occur until birth. However, often by then the only remaining option is a univentricular palliative operation, as one of the two ventricles is already lost and a biventricular circulation cannot be preserved.

In the past 10 or so years, there has been a growing number of attempts to prevent such an unfavourable outcome through foetal cardiac surgery and intervention. In this context, very small endoscopes, cannula systems and refined imaging techniques have been developed. Thus, foetal diseases have become more and more accessible for treatment.

Aims of intrauterine treatment

The idea of foetal cardiac treatment is to correct the initial defect as soon as possible to minimise the resulting secondary damage and promote normal growth of the cardiovascular structures. One benefit to this approach is that the foetus can develop new heart muscle cells; thus, underdeveloped heart chambers can re-grow. The main aim of this kind of treatment is to avoid the single ventricle situation and to preserve a biventricular circulation after birth, as there is evidence that children with a univentricular circulation have considerable problems in the long term. Foetal cardiac treatment therefore increases the chances of successful postnatal surgery and outcome significantly.

The first successful attempt of a prenatal cardiac intervention was achieved in London in 1991, when Darryl Maxwell dilated an aortic valve.

Besides the described structural malformations there are rare cases with isolated congenital arrhythmias that do not respond to pharmacological therapy. These can lead to serious problems, to the point of heart failure. Therefore the implantation of a pacemaker is almost always necessary immediately after birth. There have been attempts to also treat these rhythm disorders in the uterus to delay the time of delivery until the foetus has developed sufficiently.

However, the experience is so far limited to a few reported cases, none of which have been successful. Accordingly, foetal pacing is still a controversial issue among experts.

Since, for now, this kind of treatment must be considered as purely experimental, it will not be discussed further in this article.

Who is it relevant for?

Appealing as this approach may sound, it must be emphasised that foetal cardiac treatment is not a universal remedy for preventing all complex congenital heart defects. Foetal cardiac interventions are still considered experimental. Furthermore, this kind of intervention only makes sense in a few congenital heart defects, and each case must be assessed individually by an expert. The experience with this kind of intervention is still scarce.

Generally, only those types of heart malformation that include severely narrowed or blocked valves or the absence of necessary openings between two chambers are considered suitable for foetal cardiac treatment. These are:

• defects associated with a critical stenosis or atresia of the aortic valve
• defects associated with a critical stenosis or atresia of the pulmonary valve in connection with an intact ventricular septum
• defects involving a restriction or closure of the septum between the two atria, associated with obstructive left heart anomalies (heart defects involving mitral or aortic atresia, therefore depending on the communication between the atria)

According to estimation by Helena Gardiner (2008), no more than approximately 60 cases of valvular stenosis might be considered suitable for a foetal intervention each year in the UK. Equally, only approximately 15 cases of transposition of the great arteries or hypoplastic left heart syndrome a year might benefit from this kind of treatment in the UK.

Kinds and techniques of foetal cardiac treatment

Minimally invasive interventions for structural malformations

Currently, the technique of choice for prenatal cardiac treatment is the percutaneous intervention, which is only minimally invasive, so stress for the foetus is reduced. Only in exceptional cases is a very small incision (laparotomy) made in the mother’s womb. The whole procedure is performed under ultrasound guidance. With both the mother and foetus anaesthetised, a cannula is inserted through the maternal womb directly to the foetal heart to perforate the narrowed/blocked valve or the restrictive/closed septum.

Current state of affairs

Foetal cardiac treatment is not available everywhere. It is not a part of routine care yet and must still be considered experimental and a high-risk procedure. There are no universally accepted guidelines and experience in this field is so far limited to a few centres worldwide that are still refining the technique. Not all foetal interventions have been successful and there is still a high perinatal and infant mortality rate. However, as reported by Pavlovic et al., the success rate of foetal cardiac treatment is steadily improving in single large-volume centres; generally, recent studies suggest a higher success and survival rate, according to Mathias Nelle et al. Currently, the clinic with the biggest programme is the Children’s Hospital in Boston, which to date has the largest series of in utero treatment of critical aortic stenosis.

Success of different interventions

For now, aortic valve stenosis is the malformation with the best outcome after foetal interventional treatment. Technical success (success of the procedure) is achieved in approximately 80% of cases, resulting in a new sub-group of neonate patients with specific problems, such as borderline ventricles, a thickening within the muscular lining of the heart chambers (endocardial fibroelastosis) or abnormalities of the mitral valve apparatus.

In contrast to that, success was so far only achieved in a few foetuses with pulmonary stenosis/atresia and intact ventricular septum. As was observed, the treatment of this lesion, even if technically successful, bears a high risk of a reccurring stenosis.

Similarly, only a few cases with intact or restrictive atrial septum associated with obstructive left heart anomalies have been treated prenatally so far, and the experience is limited to the group of the Children’s Hospital in Boston. In the latest series of treated foetuses, the survival rate after intervention was more than 50%. However, it is still unclear if this kind of treatment is successful long-term and has normal pulmonary vascular circumstances. At present, an improvement of the lung function is not achieved in most cases.

Risks and problems

Risks for mother and foetus

In foetal cardiac treatment both mother and foetus are put at risk. The foetus, especially, is a highly vulnerable organism that can react to the slightest irritation. Foetal cardiac interventions must be undertaken with the greatest care by a multidisciplinary team of experts, and the potential benefit has to be clarified and weighed against the involved risks.

According to published literature, the risk for the mother is relatively low. Complications are most often related to anaesthesia or to the need to have an emergency caesarean operation after the intervention because the foetus is not doing well. Moreover, prenatal treatment can lead to uterine contractions and preterm labour up to the point of premature delivery. Further potential complications include infections within the amniotic sac or the so-called maternal mirror-syndrome, where both mother and foetus suffer from water retention.

Compared to the maternal risk, the risk for the foetus is relatively high. Potential complications include:

• rupture of the amniotic sac (amniorrhexis)
• bleeding from the middle layer of the uterine wall or the placenta
•  injuries to the foetal heart including valves and electrical conducting system, as well as to the surrounding organs, for example, lungs, liver and associated secondary complications
• increase in fluid in the sac around the heart (pericardial effusion)
• arrhythmia/slow heart beat
• foetal death due to cerebral haemorrhage, tamponade or water retentions (hydrops)

In order to detect potential complications, it is of utmost importance to closely observe the foetus and its heart rate during and after the procedure.

Controversial aspects

A controversial aspect of prenatal treatment is its prior aim to preserve a biventricular circulation and thus avoid the necessity of palliative operations, such as the Norwood procedure. However, it has to be said that, like other kinds of treatment, this procedure has also improved over the years and can now result in perfectly good outcomes. Equally, overall medical progress is steadily leading to improved outcomes (which means less morbidity and mortality) and prognosis in single-ventricle patients. Accordingly, a good univentricular palliation can be superior to a bad biventricular repair. So, as Mladen Pavlovic et al. put it, “The perceived benefits of prenatal intervention compete with steadily improving postnatal treatment options, resulting in reduced morbidity and mortality even in the most significant lesions.” It is therefore important to focus on improving the quality of survival rather than just the survival in itself.

The problem remains to select those patients where foetal cardiac intervention can be expected to result in a biventricular physiology with a generally good outcome.

Question of timing and suitable candidates

It’s not yet possible to accurately predict the natural course of a foetal cardiac malformation in utero, so it is difficult to predict whether a specific malformation will inevitably progress to a univentricular circulation after birth. According to Helena Gardiner, a third of cases of severe aortic or pulmonary stenosis or atresia in the UK currently have a two-ventricle circulation after birth without prior foetal treatment. It therefore remains difficult to select candidates that are suitable for prenatal treatment.

Furthermore, as it is hardly possible to predict the further course of a malformation, it is often unclear whether a certain lesion should be treated immediately or if it is better to await further development. Apart from that, foetal interventions cannot be performed until a relatively advanced gestational age (approximately the 18th week of gestation), because the cardiovascular structures must be a certain size. In addition, malformations are usually detected quite late, when they are already fairly advanced (at around the 20th week of gestation). This may mean the secondary damage has already progressed too far to be treatable by the time it is detected.

To help solve these problems, differentiated criteria for patient selection have to be developed and implemented. According to Edgar Jaeggi and Gerald Tulzer, this just happened for the selection of patients with pulmonary stenosis/atresia and intact ventricular septum. It remains to be seen if this development can contribute to a better prognosis for these patients and to long-term success.

Future prospects

As this branch of foetal cardiac treatment is relatively new, long-term results are not yet available. Accordingly, it is difficult to assess the efficacy of this kind of treatment just yet. To confirm a positive prognostic influence of foetal cardiac interventions, further studies with more patients will have to be undertaken in the future. On this basis, the development of guidelines and universal standards will be possible.

For the time being, the most important factor is a careful assessment of each individual foetus’s anomaly and a careful patient selection. This is best achieved by a closely collaborating team of experts.

According to Hikoro Matsui and Helena Gardiner, those engaging in foetal therapy are optimistic and expect significant advances in case selection, technical procedures and equipment.