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| REVIEW ARTICLE |
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| Year : 2005 | Volume
: 6
| Issue : 1 | Page : 5-17 |
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Innovations in fetal cardiology: Medical and catheter intervention therapy
Mary T Donofrio
Children's National Heart Institute of the Children's National Medical Centre, Washington, DC, USA
| Date of Web Publication | 18-Jun-2010 |
Correspondence Address:
Mary T Donofrio
Director of Fetal Heart Program and Associate Director of Echocardiography Children's National Heart Institute of the Children's National Medical Centre, 111 Michigan Avenue NW, Washington, DC 20010
USA
 Source of Support: None, Conflict of Interest: None  | Check |
How to cite this article:
Donofrio MT. Innovations in fetal cardiology: Medical and catheter intervention therapy. Heart Views 2005;6:5-17 |
Recent technological advances in ultrasound imaging and fetal echocardiography have given us a window into understanding the natural history and progression of congenital heart disease in-utero. It has become evident that structural diseases evolve in-utero. In addition, physiologic derangements progress as well. Dysrhythmias and heart failure may lead to fetal distress and possible in-utero demise. Fetal intervention therapy either medical, catheter driven, or surgical is based on the fundamental principle that by intervening, the natural history of disease process will change favorably. In order for us to study and prove that this is true, we must first gain an understanding of the unaltered progression of heart disease in-utero. In addition, we must have measurable goals that we hope to achieve, whether it be to completely reverse the process of progression of valve disease to hypoplastic right or left heart syndrome, or to minimize myocardial and/or end-organ injury in the fetus with impaired myocardial performance.
First and foremost in the design of techniques used for fetal intervention is the principle that the risk to the mother must be minimized. For this reason, catheter based interventions have an appeal but they are certainly limited by difficulties in accessing the fetus through the maternal abdomen. The same difficulty holds true for medical therapy for which the mother is usually given the drug to be delivered to the fetus in hopes that an adequate amount will cross the placenta and reach the fetus. Since most of us believe that the well being of the mother takes priority, any intervention strategy must take into account this additional and most important patient.
 In-Utero Progression of Structural Heart Disease | |  |
Cardiac embryogenesis is completed by 7 weeks of gestation [1] . It is during this time that most structural cardiac defects develop. In recent years with improvement in ultrasound technology and image acquisition, investigators have shown by serial evaluation that many lesions continue to evolve beyond this initial period of cardiac development. It is theorized that flow alterations caused by the original structural defect may ultimately result in abnormal chamber and vessel growth. For example, aortic valve stenosis has been shown to result in hypoplasia of the left ventricle if it occurs early in gestation [2],[3],[4] [Figure 1]. Similarly, pulmonary stenosis in select fetuses leads to hypoplasia of the right ventricle [3] .
Initially, with severe stenosis of the semilunar valve in-utero, the ventricle hypertrophies in response to the increased afterload. If the obstruction persists, ventricular function ultimately become compromised, leading to reduced output and worsening diastolic function, that in the absence of atrioventricular valve regurgitation, results in redistribution of blood flow to the opposite ventricle. During this critical time period, the unaffected ventricle carries the combined cardiac output and the injured ventricle becomes hypoplastic.
For hypoplastic left heart syndrome, the timing of the onset of aortic stenosis has been shown to influence the degree of hypoplasia of the ventricle. [4] If obstruction occurs before 14 weeks, the ventricle is notably hypoplastic by 20 weeks. If the obstruction develops after 20 weeks often there is a left ventricular chamber present that is hypertrophied and scarred. Finally, if obstruction occurs late in gestation, the left ventricle may be normal in size.
Semilunar valve obstruction also may affect growth of the distal vessels. Diffuse arch hypoplasia has been shown to progress in-utero, especially in the presence of additional left heart obstruction [5] and branch pulmonary artery hypoplasia has been shown to occur in defects with right ventricular outflow obstruction [6] . Atrioventricular valve regurgitation is an important problem in the fetus. Valve regurgitation can be due to either a structural abnormality of the valve in diseases such as Ebstein's anomaly, or can be due to ventricular failure from increased afterload from primary semilunar valve disease. No matter what the etiology, atrioventricular valve regurgitation is not well tolerated by the fetus and may lead to fetal distress, hydrops fetalis and/or fetal demise [7] .
The foramen ovale is an important anatomic structure of the fetal heart. In the normal fetal circulation, patency of the foramen ovale allows blood from the placenta to bypass the pulmonary arteries by flowing across the atrial septum, into the left ventricle and antegrade into the aorta. Right atrial pressure is higher than left atrial pressure, and in-utero flow is right to left. At birth, with the onset of respiration, pulmonary blood flow and left atrial pressure increases, and the foramen ovale close [8] . There have been reports documenting foramen ovale closure in fetuses with normal hearts. In all cases but one, closure resulted in right heart dilation and hydrops fetalis [9],[10],[11] .
In the fetus with congenital heart disease the foramen ovale is equally and perhaps even more important to maintain fetal well being. In defects with obligate intra-atrial shunting such as hypoplastic right heart syndrome, closure of the foramen ovale results in an inability of the circulating blood to pass through the heart and maintain an adequate combined cardiac output to the fetus [12] .
In addition, in select congenital heart defects the foramen ovale may be at risk of premature closure from either a primary abnormality in atrial septal morphology [12],[13],[14] or from altered in-utero physiology from a structure defect that leads to increased left atrial pressure. Defects such as transposition of the great arteries with a restrictive ductus arteriosus and those with left heart obstruction (i.e. aortic stenosis, mitral stenosis, hypoplastic left heart syndrome) fall into this category [12],[15],[16],[17],[18] [Figure 2].With either structural or physiologic foramen ovale restriction or closure in-utero, severe prenatal and/or postnatal compromise may result [12] . The effect foramen ovale closure has on in-utero physiology and cardiovascular development, and on the postnatal presentation and outcome in fetuses with hypoplastic left heart syndrome has been reported. Even at the most experienced centers, the postnatal mortality of this subgroup of infants with hypoplastic left heart syndrome is approximately 80%, and is believed to be due at least in part to permanent injury to the pulmonary arteries and veins from significant left atrial hypertension in-utero [14],[17],[18] .
Structural congenital heart defects may therefore result from either primary or secondary developmental changes. In addition, fetal wellness is dependent in some cases on structural development. Given the likelihood of progression of specific disease in-utero, attempts to design successful intervention strategies may be very beneficial in the management of these fetuses so as to improve overall outcomes.
| Physiology of progression of heart disease in-utero | | |
The study of in-utero progression of heart disease must include both an evaluation of how alterations in cardiac flow affect structural and morphologic fetal development, as well as how the physiologic derangement caused by structural defects that lead to congestive heart failure affect the fetus as a whole. Certainly as described above, semilunar valve stenosis results in ventricular failure and permanent injury to the myocardium. In addition, however, diminished myocardial function and/or alterations in normal in-utero flow may also lead to alterations in normal fetal development and the process of myocardial organogenesis.
Normal cardiac chamber development has been studied using both animal and human models. Studies have shown that as normal development progresses, many changes occur in the structure and biochemical processes in the fetus. Structural changes include an increase in the number and size of the myocytes and an increase in the myofibril density. The transverse tubules and sarcoplasmic reticulum develop and there is substantial growth of the coronary arteries. Biochemically, there is an increase in myosin adenosine triphosphate activity, myofibrils sensitivity to calcium, and a decrease in the cardiac glycogen level [19],[20],[21] .
The fetal myocardium has different functional properties when compared to the adult myocardium. Animal studies have shown that the fetal left ventricle does have the ability to increase cardiac output, however the increase is limited since the heart is functioning at the upper end of the Starling pressure-volume curve making reserve limited [22],[23] . Interestingly, in one of these studies [23] , left ventricular preload was increased by banding the pulmonary artery and shifting foramen ovale flow to the left atrium. This preparation is similar to the congenital heart disease physiology of pulmonary stenosis and hypoplastic right heart syndrome. The consequences of a limited ability of the fetal left ventricle to improve combined cardiac output beyond a certain point is uncertain and needs to be investigated.
Animal studies that have evaluated how primary structural defects affect chamber development suggests that the etiology of ventricular hypoplasia maybe due to a combination of factors including both intrinsic myocardial disease as well as reduced flow through an otherwise normal chamber resulting from either inadequate inflow or obstructed outflow. If the fetal aorta is obstructed, the left ventricular cavity fails to grow and the right ventricular cavity is increased in size; however if the fetal pulmonary artery is obstructed there is more variability in the outcome. If obstruction occurs early, then the tricuspid valve and right ventricle are small. If obstruction occurs later in gestation, then the right ventricle is dilated and significant tricuspid regurgitation develops [24] . Intervention strategies, therefore, should be designed taking these factors into account. The relief of ventricular obstruction may not only benefit the fetus by reducing the risk of chamber underdevelopment, but also may improve forward cardiac output and overall combined functional reserve.
Fetal congestive heart failure may result from secondary causes such as high-output conditions including anemia, twin-twin interactions, and arteriovenous fistulous connections. Cardiac dysrhythmias either fast or slow, and primary pump failure from either myocarditis or cardiomyopathic processes may also lead to symptoms of heart failure [25],[26] . Tachydysrhythmias may develop at any gestational age and may or may not be associated with structural heart defects. The most common heart defects known to be associated with the tachydysrhythmias include structure diseases with atrial dilation (i.e. Ebstein's anomaly of the tricuspid valve), cardiac tumors, and primary myocardial disease.
The bradydysrythmias, in particular complete heart block, can occur at any gestational age and usually result from antibodies crossing the placenta in maternal lupus, or are associated with structural cardiac diseases with atrioventricular discordance. There has been much interest in studying the mechanisms of progressive atrioventricular nodal disease and myocardial injury that occurs in fetuses exposed to lupus antibodies. Investigators have shown that analysis of fetal echocardiographic Doppler waveforms of mitral inflow and aortic outflow can identify early atrioventricular nodal dysfunction and first-degree heart block in fetuses at risk [Figure 3]. In one study, first-degree heart block was present in 8 of 24 fetuses with anti-SSA/Ro 52-kd antibodies. One fetus had progression to complete heart block and 6 had spontaneous resolution of the first degree block prior to delivery. In a single fetus, resolution of second degree to first degree block was achieved with betamethasone therapy delivered to the mother [27] . Overall, what is known is that fetuses with heart block have an increased mortality with most deaths occurring in-utero or during infancy even if pacing is initiated [28],[29] . The cardiac evaluation of these fetuses to assess progression of disease has been difficult since the heart is dilated and the ventricular rate is low. It could be that the inability to effectively diagnose worsening cardiovascular status from a low heart rate is what leads to myocardial damage and poor outcome. We have designed a protocol to assess these fetuses using both the standard biophysical profile used by the obstetricians to assess fetal well being as well as the cardiovascular profile to assess cardiac function and the fetal circulation [30],[31] . Using this protocol, we have been able to follow the progression of disease and initiate an early delivery if there is evidence of worsening cardiac function as documented by the cardiovascular profile score. In 2 cases thus far we have avoided fetal compromise, and with epicardial pacing postnatally, cardiac function recovered [32] .
Fetal congestive heart failure with diminished combined cardiac output may therefore result from either primary or secondary causes. The detrimental effects include hydrops fetalis, fetal compromise, lack of fetal growth, and alterations in systemic blood flow. Given the poor prognosis for many fetuses who develop heart failure, any attempts to design successful intervention strategies would be very beneficial in their management.
Additional Considerations
We have only begun to understand the total effect structural and/or physiologic alterations from congenital heart disease have on fetal development. It may be that even though the fetus seems to be doing well by our current clinical measures, that in fact the hemodynamic alterations caused by the specific defect may be affecting normal growth and development.
We recently undertook a study to assess the cerebral circulation in fetuses with congenital heart disease [33] . We hypothesized that fetuses with congenital heart disease likely have circulatory abnormalities that compromise in-utero cerebral oxygen supply and delivery, that fetuses with decreased cerebral oxygen supply will have autoregulation of blood flow that enhances cerebral perfusion ("brain sparing"), and that the degree of cerebral autoregulation will be dependent on the specific cardiac defect and correlate with in-utero head circumferences. Fetuses with congenital heart disease were compared to normal fetuses. Data obtained included the cardiac diagnosis, fetal head circumference, weight, and gestational age, and cerebral and umbilical artery Doppler, which was used to calculate the cerebral-to-placental resistance ratio as a measure of cerebral autoregulation.
We found abnormal cerebral flow in 44% of fetuses with heart disease with the incidence being greatest in fetuses with hypoplastic left or right heart syndrome. Only one normal fetus had abnormal cerebral flow [Figure 4]. The relationship between cerebral autoregulation and gestational age, and among weight, head circumference, and cerebral autoregulation differed across normal and heart disease fetal groups. Fetuses close to term with heart disease and cerebral autoregulation had smaller head circumferences than normal fetuses. By these results, we concluded that "brain sparing" does occur in fetuses with congenital heart disease and fetuses with single ventricular physiology are most affected. Inadequate cerebral blood flow, despite autoregulation, may alter brain growth and development in fetuses with specific congenital heart defects.
Our study suggests that neurodevelopmental abnormalities found in babies with congenital heart disease may not be exclusively due to surgical sequelae, but rather inadequate fetal cerebral oxygen and/or substrate delivery, even in the presence of cerebral autoregulation. Prospective identification of fetuses at risk for cerebral abnormalities should prompt institution of early postnatal neurodevelopmental therapy to improve prognosis. In addition, fetal cardiac intervention protocols designed to promote normal in-utero chamber development and blood flow, should also include an analysis to determine if restoration of a more normal circulation improves fetal cerebral perfusion and postnatal neurologic outcome for these children.
| Fetal Intervention | | |
Medical Therapy
Treatment of fetal tachydysrhythmias can often be managed by medical therapy. The most common dysrhythmia is supraventricular tachycardia though atrioventricular nodal tachycardia and ventricular tachycardia have been documented to occur as well. Given that fetuses with refractory tachydysrhythmias develop cardiac failure, brain injury and fetal compromise, it is clear that normalization of the rhythm is indicated, and that aggressive management strategies are justified. In this era, it is standard of care to treat all supraventricular tachycardia in the presence of associated congestive heart failure [34],[35],[36] . The most common therapy is maternal transplacental administration of antiarrhythmic medications. Many agents have been utilized and have varying success rates. The difficulty arises in that to treat the fetus, the therapy needs to be delivered, many times in higher than normal doses, to the mother. The goal is to achieve adequate transplacental penetration such that a therapeutic level of drug reaches the fetus. In the hydropic fetus this may be difficult, and delivery of the medication via fetal umbilical venous puncture or intraperitoneal injection has been performed [37] .
Catheter Based Pacing
Catheter based pacing for complete heart block has been attempted. The first reported case was in 1986 in a fetus with severe hydrops fetalis. [38] Within hours after the procedure, the fetus died. A second case, reported in 1994 also resulted in fetal demise soon after the procedure [39] . At present this seems to be a technique without substantial clinical utility though as the technology advances, there may be a place for this fetal intervention to increase heart rate.
Catheter Balloon Dilation of Aortic Valve Stenosis
The first report of percutaneous fetal aortic valvuloplasty was in 1991. In this landmark study, 3 attempts were made in 2 fetuses with the cardiac diagnosis of aortic valve stenosis and left ventricular dysfunction. Access was achieved via percutaneous needle puncture using an 18G chorionic villus sampling needle. The needle was placed through the maternal abdomen using ultrasound guidance, into the uterus and through the left ventricular apex. In the first case, which was performed at 28 weeks, a 2.5mm coronary balloon was used. The aortic valve was not crossed after multiple attempts. Three episodes of bradycardia occurred that were reversed with isoprenaline. The fetus died within 24 hours of the procedure. Postmortem examination revealed bilateral pleural effusions but no pericardial effusion. The aortic valve appeared to have a ragged tear, apparently from the balloon procedure. The second case was done at 31 weeks and was aborted after the balloon ruptured in the ventricle and could not be withdrawn from the heart. A 3.5mm custom-made balloon was used. A second attempt at 33 weeks was successful as documented echocardiographically by improved forward aortic flow. The mother went into preterm labor one week later. After delivery, the baby underwent postnatal aortic balloon dilation but died at 4 weeks of age from persistent left ventricular dysfunction from endocardial fibroelastosis. Following this initial report, the same group of investigators reported the first successful fetal aortic balloon valvuloplasty in 1995 [41] . A fetus at 33 weeks with severe aortic stenosis and left ventricular failure underwent balloon valvuloplasty of the aortic valve using a similar technique of accessing the valve using an 18G needle through the maternal abdomen. In this case a 5mm specially designed balloon was used. The only complication was that the fetus suffered a bradycardic episode that was successfully treated with isoprenaline. Following the procedure, there was improved flow across the aortic valve, slightly improved left ventricular function, and some right to left shunting across the foramen ovale. One month after the procedure at 38 weeks gestation the baby was delivered. A postnatal valvuloplasty was performed and ultimately left ventricular function recovered.
In 2000, Kohl reported the results on "the world experience of percutaneous ultrasound guided balloon valvuloplasty in human fetuses with severe aortic valve disease" [42] . In this review which spanned a period between 1989 and 1997, there were data available for 12 fetuses from 6 centers. The gestational age at the time of intervention ranged between 27 and 33 (mean 29.2) weeks. Eight fetuses had aortic stenosis, 2 had aortic atresia, and 2 had aortic stenosis with associated pulmonary stenosis or atresia. All had poor left ventricular function. Technically successful valvuloplasties were reported in 7 fetuses, with only one long-term survivor (case described above [41] ). Of the 5 who did not have successful procedures, one underwent successful postnatal intervention and survived. Ten of 12 fetuses who underwent the procedure died. Four died within 24 hours of the procedure; 2 from bradycardia, one from bleeding, and one at valvotomy after an emergency delivery. The remaining 6 died in the neonatal period from left ventricular failure.
For all cases, access into the left ventricle was achieved by advancing a needle using ultrasound guidance through the maternal abdomen, across the uterus and into the left ventricular apex. In 10 of 12 an 18G needle was used and a 0.014 guidewire was delivered into the ventricle through the needle. In one case a 16G needle was used and the balloon catheter was inserted directly into the left ventricle. For all, coronary artery balloon catheters were used with lengths of 2.0cm and balloon diameters ranging between 3 and 4mm. In 6 of 9 cases in which sharp needles were used, the balloon was torn or cut off during the procedure. Technical failure was reported to be caused by an inability to line up the needle with the left ventricular apex, recurrent and/or persistent bradycardia, and/or an inability to cross the valve.
Hydrops fetalis was a significant risk factor for fetal demise. Early death from sustained bradycardia occurred in 3 of 5 fetuses. One fetus survived to delivery only because an emergency Cesarian section was performed but then died soon after. In one fetus with hydrops fetalis, after balloon dilation the hydrops resolved and the left ventricle seemed to recover. The baby died during postnatal valvotomy. There were no maternal deaths reported. The only morbidity was due to the need for emergency Cesarian sections in 2 women; one for sustained fetal bradycardia and the other for chorioamnionitis.
More recently, the group at Boston Children's Hospital has rejuvenated interest in fetal aortic balloon catheter valvuloplasty. [43] In 2000 they began to offer the procedure to mothers of fetuses with critical aortic stenosis at a gestational age less than 26 weeks. The reason that this gestational age was chosen was that review of the literature suggested that progression from aortic stenosis to hypoplastic left heart syndrome seems to occur mostly in the second to early third trimester. Selection criteria for intervention included the following: 1) fetal diagnosis of aortic stenosis; 2) presence of severe left ventricular dysfunction; 3) left ventricular length that was not < 2 standard deviations below the mean for gestational age at the time of diagnosis; 4) left to right flow at the atrial septum; 5) retrograde flow in the transverse arch. No family was refused intervention because of fetal distress.
General anesthesia was used for maternal sedation. Fetus were sedated and paralyzed with intramuscular injections of fentanyl, atropine, and vecuronium. The fetal heart was accessed using a 19G cannula and stylet needle under ultrasound guidance. The needle was placed through the maternal abdomen, across the uterus, and into the left ventricular apex. A 0.014 guidewire was then placed through the needle in an attempt to cross the aortic valve. A coronary balloon, originally chosen to be 10% smaller than the aortic valve diameter, was used for dilation.
The technique was modified after the initial experience to improve the technical success rate. First, the balloon size was increased to 120% of the aortic diameter. Second, the cannulas, guidewires, and balloon shafts were premeasured and marked so that their position in the fetal heart could be better documented. Third, fetal positioning became crucial to the procedure and no attempts were made to access the heart until positioning was ideal. Position criteria included: 1) left chest anterior; 2) no limbs between the uterus and the heart; 3) LV apex within 9cm from the abdominal wall; 4) left ventricular outflow tract parallel to the catheter course.
If positioning could not be obtained by external techniques an incision in the maternal abdomen with exposure of the uterus was made so that the fetus could be better positioned. [Figure 5] and [Figure 6]. From 2000-2004, 20 fetuses underwent intervention. In all, aortic obstruction was the primary lesion. Gestational age at diagnosis ranged between 17 and 26 weeks. There was an interval of one to 6 weeks between diagnosis and the procedure, and of note, several fetuses during the waiting period developed progressive left ventricular hypoplasia. The first 3 of 4 interventions were technically unsuccessful. Of the next 16 patients, 13 had technically successful procedures defined as the wire crossing the aortic valve. Of the 20 procedures, 10 were done percutaneously and 10 via a mini laparotomy. Seven of 20 died in-utero, and there was one family that opted to terminate the pregnancy after an unsuccessful dilation attempt. Of the 14 that had technically successful procedures, 2 died. One had hydrops fetalis prior to the procedure and died one day after the procedure, and one had a prolonged bradycardic episode during the procedure and died 3 days later. The one fetus who died after a technically unsuccessful procedure underwent a very long procedure with significant in-utero stress. One baby died after an early delivery from an incompetent cervix 3 weeks after an unsuccessful procedure. Of the eight survivors, 3 of 14 fetuses with successful dilations have had successful 2 ventricular repairs, 6 of 14 have gone on to have palliation for hypoplastic left heart syndrome, and 3 of 14 are still in-utero. Of the 6 technical failures, the 3 who survived have all gone on to have repair for hypoplastic left heart syndrome.
Fetal complications of the procedure included balloon rupture in 2, fetal bradycardia in 15, and pericardial effusions in 2. Of the 3 technical successes that currently have a 2 ventricular heart, one had postnatal aortic balloon valvuloplasty at 18 months of age for moderate stenosis. He was well at 2 years. The other 2 had significant left heart obstruction at birth including coarctation of the aorta and aortic stenosis. Both were treated in the neonatal period and survived [Figure 7]. Assessment of cardiac growth in those that underwent a successful procedure vs those that did not revealed improved growth of the mitral valve, the aortic valve and the ascending aorta in those that had a successful procedure. Analysis of the data did not reveal any clear predictors of success though subjective analysis suggested that the fetuses that were more likely to have a 2 ventricular repair had a larger preintervention left ventricle with unobstructed inflow and persistent relief of the aortic obstruction after the procedure. The only maternal complication included respiratory compromise requiring oxygen therapy and diuresis in one.
Catheter Balloon Dilation of Pulmonary Valve Stenosis/Atresia
Experience with fetal pulmonary valvuloplasty is not as extensive and there are only limited reports in the literature. In a report published in 2002 [44] , 2 fetuses with pulmonary atresia underwent pulmonary valvuloplasty. Both had imminent hydrops fetalis with symptoms of cardiomegaly, pericardial effusions, and abnormal umbilical venous Doppler. For one, there was also a restrictive atrial septum and for the other, severe tricuspid regurgitation was present. For the first case, the intervention was done at 28 weeks. General anesthesia was used in the mother. The second case was done at 30 weeks. Sedation and local anesthetic was used in this mother and the fetus was given intramuscular injections of pancuronium, fentanyl, and atropine. Both procedures were done using ultrasound guided percutaneous access with 16G needles. Coronary balloons, 4mm and 3.5mm respectively, were used for dilation. The right ventricle was entered by puncture of the maternal abdomen and uterus. Following the procedure both fetuses had immediate improvement in right ventricular function and subsequent resolution of hydrops. The first case was delivered at 38 weeks and the second at 35 weeks after restenosis was noted. In both prostaglandin was started and repeat pulmonary valvotomy performed. Systemic to pulmonary artery shunts were placed, however both have since been converted to 2 ventricle circulations.
| Catheter Relief of a Restricted or Closed Foramen Ovale | | |
The subgroup of infants born with hypoplastic left heart syndrome and a restrictive or closed atrial septum account for approximately 6% of cases [14] . These babies are born with profound cyanosis and many times die before any intervention can be undertaken. In addition, of those that survive to have their atrial septum opened, 83% have been reported to die within 6 months, presumably from abnormalities in the pulmonary vascular bed that have developed as a result of longstanding fetal left atrial hypertension [14] . Given this information, the group at Boston Children's Hospital has developed a protocol to investigate the possibility of opening the atrial septum in this high risk group of patients [45] . From 2002-2003, 7 procedures were performed to open the atrial septum in fetuses with hypoplastic left heart syndrome. In 4 cases the septum was intact, and in 3 it was restrictive. Prominent pulmonary vein reversal was documented in all 7. Two fetuses were hydropic.
The procedure was performed between 26 and 34 weeks gestation. In 5 cases general anesthesia was used and in 2, spinal anesthesia with intravenous sedation was used on the mother. Fetuses were sedated and paralyzed with intramuscular or intravenous injection of fentanyl and vecuronium.
Using ultrasound guidance, either an 18 or 19G cannula mounted on a metal obturator was percutaneously put through the maternal abdomen, into the uterus, and to the right atrial surface. The introducer was advanced through the right atrium and placed against the septum. The septum was then perforated with either the cannula itself or with a 22G needle placed through the introducer. A 0.014 wire was then placed across the septum into the left atrium so that a balloon angioplasty catheter could be positioned for dilation. The balloon was inflated 2 times to a diameter of 3mm. [Figure 8]. Technical success was achieved in 6 cases. The technical failure occurred in the mother given spinal anesthesia where uterine tone limited appropriate cannula placement. One fetus died within 4 hours of the procedure. Autopsy revealed a large right hemothorax and a small hemopericardium. This was the only fetus in which an 18G needle was used. Four of the 5 fetuses who survived and had a successful procedure had echocardiographic evidence of a new atrial septal communication measuring > 2mm. In the fifth fetus, the new atrial hole was tiny despite the technically successful procedure. In all, pulmonary vein flow remained abnormal. Of the 6 fetuses that survived, the one who had a technically unsuccessful procedure went on to have his atrial septum opened postnatally in the catheterization laboratory and subsequently underwent a Norwood operation. Three others, despite the successful fetal procedure, underwent postnatal opening of the atrial septum in the catheterization laboratory. One underwent a successful Norwood operation and then bi-directional Glenn at 6 months of age. The other 2 underwent Norwood operations but died after complicated postoperative courses. One of these infants had a CT of the chest that revealed macrocystic replacement of the left lung. One newborn went immediately to the operating room for opening of the atrial septum and also underwent an early Norwood operation. This infant survived the immediate postoperative period but died suddenly prior to hospital discharge. The final fetus was delivered at 34 weeks because of distress and hydrops fetalis. No intervention was undertaken and the baby died. The results of this study document the feasibility of percutaneous intervention for creation of an atrial septal opening in fetuses with hypoplastic left heart syndrome. Though the study does not demonstrate clinically utility for this procedure at present, it is clear that the technique is possible and can be performed at minimal risk to the mother and fetus.
Early Delivery
Though not highlighted in the literature, the fetal intervention of initiating an early delivery is always a possibility once a viable gestational age is reached. Currently by using fetal echocardiography with color and pulsed Doppler interrogation, cardiac anatomy as well as physiology can be evaluated in great detail. It may be that if a restrictive atrial septum or ductus arteriosus is detected, then the best option is early delivery. In addition, with the increased use of the cardiovascular profile score [32] , it may be determined that the early recognition of worsening cardiovascular status may warrant delivery. It behooves those of us taking care of fetuses with heart disease, both congenital and acquired, to strive to gain a better understanding of in-utero cardiovascular physiology and progression of disease processes so that we can make these very difficult decisions with the support of sound scientific information as well as clinical experience.
| Postprocedure Monitoring and Maternal Considerations | | |
Following any intervention, serial ultrasound should be performed to assess both maternal and fetal changes. These studies should be performed as part of a multidisciplinary team approach and should include input from obstetrical and perinatal colleagues. Since during these procedures 2 patients need to be considered, care must be taken such that the mother is followed closely for complications such as placental abruption, bleeding, amniotic leak, and/or chorioamnionitis. The fetus needs to be followed for signs of distress and/or hydrops fetalis. In addition, the progression of disease needs to be noted and delivery planning made depending on the results of subsequent clinical evaluations.
| Summary and Conclusions | | |
Current advances in technology and improvements in ultrasound imaging have given us the ability to diagnose fetal cardiac defects and abnormalities in cardiovascular physiology in fetuses very early in gestation. Because of this, the sub-subspecialty of fetal cardiology has emerged. It no longer is adequate to diagnose the defect, counsel the family, and then send them away until the time of delivery. We now need to treat the fetus as a separate and individual patient. We have learned over the past 10 years that cardiac defects progress in-utero and in most instances the progression is towards a more severe combination of structural defects. We have also learned that in some cases, the physiology of the heart changes and can lead to fetal compromise in-utero.
The era of fetal cardiac intervention is upon us. Certainly, the group in Boston has taught us that by using improved techniques and specially designed tools, accessing the fetus through the maternal abdomen is possible at minimal risk to the mother and to the fetus in most cases. What we have still to learn, however are answers to the questions: Should we do it, on whom, and when? In order to find these answers, we must continue to investigate and truly understand the natural and unnatural history of congenital and acquired heart disease in-utero. We need to learn which diseases progress and what markers to look for in our assessment of the fetus with heart disease. We need to know in which diseases the foramen ovale and ductus arteriosus are important and in which diseases they are more likely to constrict or close.
Finally, we need to understand how the heart and its normal or abnormal development affect the fetus as a whole. We need to learn how changes in flow, pressure, and oxygen and substrate content of blood affects brain, lung, and other organ development, and we need to learn if there are critical times in development of the heart and other organs when the fetus is most at risk. Only with this information, will intervention strategies be most effective. It may be that ballooning the aortic valve may be most effective if it is done at a time before there is permanent damage to the left ventricle. It is possible that the results thus far in infants who have undergone in-utero aortic valve dilation are less than ideal because by the time the left ventricle becomes dilated and echo bright, and flow reversal is present in the aortic arch, it is too late for salvage of the chamber.
It may be that the goal we should strive for is not solely to prevent the disease hypoplastic left heart syndrome but to reduce left atrial and left ventricular pressure and improve antegrade flow in the aorta, so that there is improved fetal brain development, lung development, and coronary perfusion. It may be that the goal of ballooning the pulmonary valve is not solely to prevent hypoplastic right heart syndrome but to reduce the risk of hydrops fetalis and perhaps minimize the development of right ventricular coronary sinusoids.
Certainly, the ability to open the atrial septum in defects in which there is an obligate atrial level shunt will be lifesaving and as this technique is perfected, it is most likely to have the greatest clinical impact on fetal and infant outcomes. Finally, we must keep in mind that medical treatment of the fetus through the mother and the decision of if and when to deliver early are interventions as well, and should not be taken lightly. We have entered a new era in medicine and the outlook for the future is promising. With continued advances in technology and the desire to completely understand these new patients of ours, we can only succeed in this endeavor.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
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