Prenatal Evaluation and Management - Neonatal Cardiology, 3rd Ed.

Neonatal Cardiology, 3rd Ed. Michael Artman

Chapter 4. Prenatal Evaluation and Management

■ INTRODUCTION

■ FETAL ECHOCARDIOGRAPHY

Indications

Limitations of Fetal Echocardiography

■ MAGNETIC RESONANCE IMAGING

■ FETAL ARRHYTHMIAS

Diagnosis and Classification Therapy

■ FETAL INTERVENTIONAL CATHETERIZATION

■ COUNSELING FAMILIES

■ SUGGESTED READINGS

■ INTRODUCTION

Evaluation of a fetus for structural or functional cardiovascular disease has become routine now that there is widespread use of fetal ultrasound in obstetrical practice. In addition, greater understanding of the genetic basis for congenital cardiovascular defects has prompted screening of patients who might not have been referred for evaluation in the past. It is important to understand the uses and limitations of fetal echocardiography to optimally utilize this technology and to provide appropriate counseling to parents. This chapter provides a limited overview of fetal cardiology as a foundation for understanding selected aspects of fetal cardiovascular disease. Comprehensive references on fetal cardiology and, in particular, fetal echocardiography are listed at the end of this chapter.

■ FETAL ECHOCARDIOGRAPHY

Fetal echocardiography is the primary method for diagnosing fetal cardiovascular disease and monitoring progression and management of the disease process. In centers with experienced fetal echocardiography programs, significant congenital cardiovascular defects can be accurately diagnosed in approximately 95% of cases. Additional information about the application of echocardiography to assess cardiac and vascular function in the fetus is presented in Chapter 3.

A complete fetal echocardiogram is similar in scope to a postnatal transthoracic echocardiogram. Cardiac and great vessel anatomy and relationships, cardiac function, blood flow patterns, and cardiac rhythm are all assessed. A wide range of cardiovascular diseases can be detected and defined in the fetus, including simple and complex cardiovascular structural malformations, cardiomyopathies, tumors, and arrhythmias. Newer techniques of three- and four-dimensional echocardiography are being applied in many centers, but at present, the role of these modalities in improving detection, management, and follow-up requires additional research.

If indicated (see below), the first fetal echocardiogram is generally performed around 18 to 22 weeks’ gestation using a standard transabdominal approach. In some centers, transvaginal fetal echocardiography is offered as early as 11 weeks’ gestation. However, controversy exists regarding the usefulness of early transvaginal ultrasound, and it is not widely used at present. Initial transabdominal studies typically provide excellent resolution of the cardiovascular structures and are sufficiently early in gestation to allow for comprehensive planning.

Indications

As discussed in Chapter 15, the incidence of congenital cardiovascular malformations in the United States is around 10 per 1000 live births. The incidence of structural cardiovascular malformations in all pregnancies is not known but it is certainly higher because severe structural or functional cardiovascular malformations may be lethal in the fetus and some mothers elect to terminate the pregnancy if an extracardiac malformation or chromosomal abnormality is detected. In these situations, the presence of a congenital cardiovascular malformation may go unrecognized.

Because a complete diagnostic fetal echocardiogram is time consuming and labor intensive, fetal echocardiography is not well suited for routine screening of all pregnant women. Therefore, it is important to develop a strategy for appropriate targeted referrals for fetal echocardiography. The indications for fetal cardiac evaluation have been outlined in an American Heart Association Scientific Statement in 2014 (see Suggested Readings). These indications are based primarily on maternal, familial, or fetal factors. They are categorized and listed in Table 4-1.

Maternal Factors

Congenital cardiovascular disease in the mother increases the risk of a structural cardiovascular malformation in the fetus. However, the incremental increase in risk varies depending on the type of maternal cardiovascular disease. For example, a mother with an atrioventricular septal defect has a 10% to 12% risk of having a fetus with some type of congenital cardiovascular malformation. In contrast, a mother with tetralogy of Fallot (not associated with a microdeletion of chromosome 22q11) has only about a 2% risk of having an infant with cardiovascular disease. Given the autosomal dominant pattern of inheritance of some forms of long QT syndrome (LQTS), a mother with confirmed LQTS will have a 50% chance of the fetus having LQTS. Despite considerable progress, the complex genetics and inheritance of congenital cardiovascular malformations remain incompletely understood (see also Chapter 15). In the past, the situation was even more unclear because many children with congenital cardiovascular disease did not survive to reproductive age and fetal echocardiography was not available. As more women with congenital cardiovascular malformations survive into adulthood and have children, the relationship between maternal congenital cardiovascular disease and the risk to offspring will become clearer.

TABLE 4-1. Indications for Fetal Echocardiography

Maternal factors

• Maternal congenital cardiovascular malformation

• Exposure to known cardiovascular teratogen (anticonvulsants, alcohol, rubella, etc.)

• Metabolic disorder (diabetes mellitus, phenylketonuria)

• Connective tissue disease

• Maternal anxiety*

• Advanced maternal age*

Familial factors

• Previous child or fetus with congenital cardiovascular malformation

• Paternal congenital cardiovascular malformation

• Family history of genetic syndrome (especially DiGeorge and related syndromes, Holt-Oram, Noonan, Marfan, Williams, long QT syndrome)

• Family history of malformation syndrome

• Family history of other birth defects

Fetal factors

• Suspected structural cardiovascular malformation on obstetrical ultrasound

• Extracardiac malformation

• Chromosomal abnormality

• Twin-to-twin transfusion syndrome

• Hydrops fetalis

• Arrhythmia

^• Increased nuchal translucency

*These are relative indications without proven utility.

In addition to congenital cardiovascular disease in the mother, other maternal factors, including viral infections, certain medical conditions, and diabetes mellitus, may predispose the fetus to be at risk for congenital cardiovascular disease (see Chapter 15). The presence of a connective tissue disorder in the mother is associated with fetal atrioventricular block and cardiomyopathy. Specific maternal antibodies, namely, anti-SSA/Ro and anti-SSB/ La, have been implicated in the development of fetal atrioventricular block and cardiomyopathy, but the precise cellular and molecular mechanisms are not entirely clear. Maternal connective tissue disease should prompt an evaluation for autoantibodies and fetal monitoring for the presence or development of atrioventricular block and cardiomyopathy. The corollary is that if an infant is born with congenital complete atrioventricular block, the mother should be evaluated for the presence of subclinical connective tissue disease. Over half of previously asymptomatic mothers are found to have laboratory evidence of connective tissue disease or later present with clinical findings. The most common disease found is Sjogren syndrome, followed by systemic lupus erythematosus.

Maternal anxiety and advanced maternal age are relative indications for fetal echocardiography. A normal fetal echocardiogram may be reassuring to a mother who, for whatever reason, is overly concerned about the possible presence of fetal cardiovascular disease. The value of fetal echocardiography in the setting of advanced maternal age (especially if amniocentesis is refused) has not been proven.

Familial Factors

The risk of recurrence of congenital cardiovascular malformations in subsequent siblings is related to the genetic basis of the particular defect or to other underlying maternal factors (see above). In general, the risk of recurrence is approximately two to five times greater than in the unaffected population. However, this figure may be much higher if there is underlying maternal disease that has already affected a previous fetus or if a known autosomal- dominant single-gene defect is present. In most cases of recurrent congenital cardiovascular malformations, the same defect recurs. However, even in the case of families with confirmed single-gene defects, the penetrance and phenotypic expression may be quite variable (Chapter 15). The presence of other forms of birth defects in previous children is also associated with a higher incidence of cardiovascular malformations.

Fetal Factors

Obstetrical ultrasound evaluation is routine and common. However, a routine obstetrical ultrasound evaluation does not constitute a complete fetal echocardiogram. A normal four-chamber screen (Figure 4-1) is essential for excluding many serious major structural congenital heart defects, but a number of malformations may be missed (see “Limitations of Fetal Echocardiography” below). It is estimated that the four-chamber view is abnormal in about 1 in 500 pregnancies and in about 60% of fetuses with major structural cardiovascular malformations. The value of a routine obstetrical ultrasound as a screen for fetal cardiovascular malformations is improved when a sweep to evaluate the right and left ventricular outflow tracts is included with the four-chamber screen. More recently, the so-called three- vessel-with-trachea view, which images the main pulmonary artery trunk, ascending aorta, and superior vena cava to assess for conotruncal abnormalities, is recommended.

FIGURE 4-1. Normal four-chamber view. Echocardiographic image obtained in a normal fetus at 26 weeks’ gestation. Abbreviations: LA, Left Atrium; LV, Left Ventricle; RA, Right Atrium; RV, Right Ventricle;

Detection of cardiovascular disease increases to 90% if all three views are recorded.

An abnormal four-chamber view or outflow tract screen should prompt referral for a complete fetal echocardiogram. In addition, detection of specific cardiovascular malformations or extracardiac malformations constitutes an indication for a complete fetal echocardiogram. Extracardiac anomalies that have a high association with cardiovascular malformations include omphalocele, diaphragmatic hernia, duodenal atresia, tracheo-esophageal fistula, cystic hygroma, and single umbilical artery. Many chromosomal abnormalities (eg, trisomy 21) are associated with congenital cardiovascular malformations. If the karyotype analysis from amniocentesis is abnormal, fetal echocardiography should be performed. Finally, nuchal translucency is being used with increasing frequency as a screen for congenital cardiovascular disease. By itself, increased nuchal translucency is of only moderate specificity, but when associated with tricuspid insufficiency or an abnormal flow pattern in the ductus venosus, the likelihood of congenital cardiovascular disease is high. In addition, the greater the nuchal translucency is, the more likely congenital cardiovascular disease is present. Currently, many perinatologists use a nuchal translucency greater than the 95th percentile as an indication for fetal echocardiography.

Twin pregnancies are characterized by an increased incidence of fetal complications, especially in monozygotic twins. Most monochorionic twins share blood supply through vascular anastomoses in the placenta.

In 10% to 20% of monozygous twin pregnancies, this shared blood supply is unequal and results in twin-to- twin transfusion syndrome. Severe twin-to-twin transfusion syndrome produces asymmetrical fetal growth and, if untreated, results in death of one or both fetuses in over 80% of cases, especially if this condition is noted before 28 weeks’ gestation. Cardiovascular compromise is common in the recipient twin. Fetal echocardiographic findings include ventricular hypertrophy and dilation, tricuspid regurgitation, and, less commonly, mitral regurgitation. The prevalence of pulmonary valve stenosis is fourfold greater in twin-to-twin transfusion syndrome than in twin pregnancies without evidence of twin-to- twin transfusion syndrome. It has been proposed that progressive right ventricular hypertrophy and severe tricuspid regurgitation result in decreased flow across the pulmonary valve with resulting acquired pulmonary stenosis (or atresia in severe cases). A variety of treatments have been used for twin-to-twin transfusion syndrome, including selective fetocide, serial amnioreduction, septostomy of the intertwin membrane, and endoscopic laser photocoagulation. Selective endoscopic laser photocoagulation of anastomotic vessels is currently the primary treatment in many centers and should be considered when twin-to-twin transfusion syndrome is diagnosed, regardless of the initial severity.

Hydrops fetalis is a serious fetal condition defined as abnormal fluid accumulation in two or more fetal compartments. Fluid may collect in the pleural, pericardial, and/or abdominal cavities. Excess fluid often collects in the skin as well. In some cases, there is placental edema and/or polyhydramnios. Fetal ultrasound is invaluable in diagnosing, assessing severity, and monitoring treatment of hydrops fetalis. Hydrops fetalis has many causes (Table 4-2), most of which are not related to primary cardiovascular abnormalities. The most common cause of hydrops fetalis is severe anemia, which can be due to a variety of conditions. In the past, if the fetus was not anemic, the etiology of hydrops fetalis was often undefined (idiopathic), but more recently, the list of conditions that can cause hydrops has expanded. With greater accuracy in diagnosis, it has become clear that a number of genetic abnormalities and inborn errors of metabolism (especially lysosomal storage diseases) can cause hydrops fetalis. A cause is now identified in approximately 75% cases of nonimmune hydrops fetalis.

A primary cardiovascular abnormality causes about 20% to 25% of cases of nonimmune hydrops fetalis. Most of those cases are secondary to tachy- or brady-arrhyth- mias, but structural cardiovascular defects can also cause hydrops fetalis. Figure 4-2 illustrates an example of echocardiographic findings in a fetus with hydrops and large pericardial and pleural effusions associated with complex cardiovascular structural abnormalities.

Decreased systemic perfusion leading to hydrops fetalis affects the fetus only when the pathophysiological process impacts both ventricles. A common example is sustained supraventricular tachycardia, which may present in utero with biventricular systolic dysfunction. The ability of the fetal heart to increase output in response to stress is very limited compared to that of the newborn heart. As discussed in Chapter 3, the fetal ventricles cannot readily increase end-diastolic volume or preload. This limitation in ability to increase preload, in the presence of an already low afterload and high contractile state, does not allow the fetal heart to increase its output during stress. Consequently, decompensation occurs in response to any process that causes dysfunction of both ventricles. Structural defects that may be associated with hydrops fetalis include heterotaxy syndromes (particularly with associated complete atrioventricular block), atrioventricular septal defects, and hypoplastic left heart syndromes. Isolated defects that cause hydrops often are associated with severe tricuspid or mitral regurgitation, which increase atrial filling pressures and lead to fluid accumulation.

Fetal echocardiography is also used to assess cardiovascular function in the fetus. Indicators of diastolic dysfunction in the fetus include umbilical venous pulsations, flow reversal in the ductus venosus, or abnormal single phase atrioventricular valve inflow. Systolic function can be assessed using left ventricular ejection fraction or shortening fraction, but given the load dependency of these measures, other methods to assess ventricular function are preferred. The myocardial performance index, or Tei index, is often use to evaluate cardiac function on the fetal echocardiogram. To obtain the Tei index, ejection time (semilunar valve open time) is subtracted from time in systole (time from atrioventricular valve closure to opening) to provide the sum of isovolumic contraction and relaxation times. This sum is then divided by the ejection time to give the Tei index. Values below 0.43 to 0.45 are considered normal.

The Cardiovascular Profile Score uses cardiac and extracardiac findings to evaluate overall fetal cardiovascular function. This scoring system has been shown to correlate with outcomes in fetuses with structural cardiovascular disease, twin-to-twin transfusion syndrome, arteriovenous malformations with high cardiac output, hydrops fetalis, and cardiomyopathy. Additional information regarding the use of ultrasound to assess fetal cardiac and vascular function is presented in Chapter 3.

TABLE 4-2. Causes of Hydrops Fetalis
Hematologic causes	Inborn errors of metabolism (partial listing)
• Isoimmunization (hemolytic disease; Rh most common)	^• Glycogen storage disease, type IV
• Other hemolytic disorders	^• Lysosomal storage diseases
^• Disorders of red cell production	^• Thyroid disorders
^• Fetal hemorrhage	Genetic syndromes (partial listing)
Cardiovascular causes	^• Achondrogenesis
• Nonstructural abnormalities	^• Arthrogyposis
^• Tachyarrhythmias	^• Prune-belly syndrome (Eagle-Barrett syndrome)
• Complete atrioventricular block	^• Noonan syndrome
• Myocarditis	^• Smith-Lemli-Opitz syndrome
• Cardiomyopathies	^• Tuberous sclerosis
^• Structural abnormalities	Chromosomal abnormalities (partial listing)
^• Hypoplastic left heart syndrome	• Trisomy syndromes (trisomy 13, 15, 18, or 21)
^• Arteriovenous malformation (including within the placenta)	^• Turner syndrome
	• Beckwith-Wiedemann syndrome
^• Highly vascularized tumors (most commonly hemangiomas)	Intrathoracic tumors or masses
^• Highly vascularized tumors (most commonly hemangiomas)	• Mediastinal teratoma
^• Heterotaxy syndromes	• Rhabdomyoma
^• Atrioventricular septal defects	^• Bronchopulmonary sequestration
^• Cardiac tumors	• Cystic adenomatoid malformation of the lung
^• Ebstein anomaly	• Diaphragmatic hernia
• Tetralogy of Fallot with absent pulmonary valve	Abdominal tumors or masses • Polycystic kidneys
Infectious causes	• Neuroblastoma
• Parvovirus (B19V)	• Hepatic tumor (hepatoblastoma or mesenchymal hamartoma)
• Toxoplasmosis	• Hepatic tumor (hepatoblastoma or mesenchymal hamartoma)
• Cytomegalovirus	Other conditions
^• Herpes simplex	• Placental abnormalities
^• Hepatitis B	• Cystic hygroma
^• Syphilis	• Intussusception
^• Lysteria monocytogenes	^• Teratoma

Echocardiography is also used to assess fetal cardiac rate and rhythm and is essential in monitoring fetal wellbeing and response to medical therapy for arrhythmias (see below).

Limitations of Fetal Echocardiography

Despite its enormous utility and overall accuracy, fetal echocardiography has limitations. The foramen ovale and ductus arteriosus are open in the normal fetus, and it is impossible to predict whether these communications will close postnatally. Thus, an atrial septal defect or persistent patent ductus arteriosus cannot be diagnosed in the fetus. It can be difficult to diagnose coarctation of the aorta in the fetus because the ductus arteriosus delivers the majority of blood flow to the lower body and placenta (Chapter 8 and Figure 8-1). The area of coarctation is typically just proximal to the insertion of the ductus arteriosus into the descending aorta, and it is normally narrow because of the limited flow that passes through this area (the aortic isthmus). The presence of a posterior shelf narrowing the area further and leading to a postnatal coarctation can be difficult to appreciate. Because the coarctation is often at the distal end of the isthmus on the posterior wall of the aorta, very near the insertion of the ductus arteriosus, the right ventricle may be ejecting against the obstruction.

FIGURE 4-2. Pericardial effusion. Echocardiographic image was obtained at 22 weeks’ gestation in a fetus with severe tricuspid regurgitation and markedly depressed systolic contractile function. Abbreviation: PE, pericardial effusion.

This leads to the finding of right ventricular dilation and hypertrophy in the fetus, a finding that should lead to the presumptive diagnosis of coarctation of the aorta if the pulmonary valve is normal. Finally, hypoplasia of the transverse aortic arch and abnormal blood flow patterns in the aortic isthmus by color Doppler can suggest coarctation in the fetus.

Small ventricular septal defects or mild stenosis of the atrioventricular or semilunar valves may be undetected during a fetal echocardiogram. Because of the small size and limited flow within the pulmonary veins, fetal echocardiography cannot completely exclude partial anomalous pulmonary venous connection or pulmonary vein stenosis. Some fetal abnormalities may be subtle or unapparent at the initial fetal echocardiogram at around 18 weeks’ gestation, but the severity may progress with gestation, leading to later diagnosis. Examples include right and left heart obstructive lesions, cardiomyopathies, atrioventricular valve regurgitation, and arrhythmias.

■ MAGNETIC RESONANCE IMAGING

Given the utility of magnetic resonance imaging of the cardiovascular system in infants and children, it is reasonable to consider this approach for delineating fetal cardiovascular anatomy and physiology. However, there are significant limitations to the application of this modality in the fetus. Fetal cardiovascular structures are small, the heart rate is rapid, and the fetus is prone to move during the course of an examination. These inherent problems are accentuated by the lack of an easy and reliable method for accurate gating of the images to the appropriate phases of the cardiac cycle to reduce motion artifact. The recently developed approach of applying metric-optimized gating in an iterative manner to improve image quality may be the most promising approach at present. Unfortunately, fetal movement continues to interfere with image acquisition and processing, limiting the utility and widespread application of magnetic resonance imaging for the fetal cardiovascular system.

■ FETAL ARRHYTHMIAS

Diagnosis and Classification

Fetal cardiac arrhythmias typically present as an abnormal fetal heart rate or irregular rhythm noted during a routine prenatal examination. Fetal arrhythmias are noted in approximately 2% of all pregnancies, but in the majority of cases (roughly 90%), the arrhythmia is transient and self-limited and does not require any intervention. A sustained fetal heart rate below 100 or above 180 beats per minute is abnormal and warrants further investigation. During fetal heart rate monitoring, a gradual increase or decrease in heart rate is suggestive of normal fetal heart rate acceleration, especially if the rate remains below 200 beats per minute.

Abrupt onset and termination of an accelerated heart rate is highly suggestive of fetal supraventricular tachycardia. Fetal supraventricular tachycardia is most commonly due to atrioventricular reentrant tachycardia and less commonly to atrial flutter. Atrial ectopic tachycardia and permanent junctional reciprocating tachycardia are unusual but must be considered in the differential diagnosis. Intrauterine ventricular tachycardia and atrial fibrillation are quite rare. Chapter 10 presents additional details about arrhythmia mechanisms and pathophysiology.

Fetal tachycardia is not always an abnormal cardiac rhythm. Fetal distress and chorioamnionitis are also associated with sinus tachycardia, although the rate is usually less than 200 beats per minute. Fetal tachycardia due to a primary arrhythmia may follow an unpredictable course. Many fetuses will tolerate brief periods of tachycardia quite well and do not need therapy. The major determinants of the impact of supraventricular tachycardia on the fetus are the duration and frequency of the episodes and the rate of the tachycardia. Frequent and/or sustained tachycardia carries a high risk of hydrops fetalis. Once a fetus with an arrhythmia becomes hydropic, the mortality is quite high, and intervention must not be delayed (see below).

FIGURE 4-3. Complete atrioventricular block. M-mode tracing obtained at 25 weeks’ gestation in a fetus with hetero- taxy syndrome. Atrial activity (detected by movement of the atrial wall) is unrelated to ventricular contractions. The atrial rate is approximately 140 beats per minute, and the ventricular rate is approximately 60 beats per minute. Abbreviations: A, atrial contraction; V, ventricular contraction.

Fetal bradycardia is defined as a heart rate less than 100 beats per minute. Figure 4-3 is an example of complete atrioventricular block with a slow ventricular rate in a fetus at 26 weeks’ gestation with heterotaxy syndrome and a two-chambered heart. Other causes of fetal bradycardia include frequent blocked premature atrial contractions and long QT syndrome. In general, premature atrial contractions are benign and resolve with time. In contrast, long QT syndrome and complete atrioventricular block are serious conditions that require careful monitoring and further investigation.

Premature atrial contractions are relatively common and usually follow a benign course. Only about 0.5% (or less) of fetuses with isolated premature atrial contractions will develop sustained supraventricular tachycardia. Thus, reassurance can be offered, although it is generally recommended that the fetal heart rate be monitored weekly for several weeks to exclude a sustained arrhythmia. If sustained elevations of fetal heart rate are noted, then referral for further evaluation is indicated.

Fetal heart rate monitoring and fetal echocardiography are commonly used to diagnose fetal arrhythmias, but these methods have limitations. Simple auscultation or Doppler assessment of the fetal heart rate is useful for diagnosing tachycardia, bradycardia, and irregular rhythms, but the electrophysiological mechanism is left undetermined. Fetal electrocardiography can often provide additional insight into the mechanism for the arrhythmia, but sometimes the diagnosis is obscure. Direct recording of the fetal electrocardiogram (ECG) noninvasively is difficult because of interference from the higher-amplitude signals from the mother. Fetal electrocardiography is most commonly applied during labor, when a scalp electrode can be placed.

More advanced recording techniques include electronic signal processing to isolate the fetal ECG and magnetocardiography. The fetal magnetocardiogram is a recording of the magnetic field that is generated by the electrical activity of the fetal heart. Fetal magnetocardiography is noninvasive and can provide high-quality signals that have been useful for diagnosing various types of fetal arrhythmias. The major limitation of this technique is that the fetal magnetic signal is very weak, requiring expensive and sophisticated magnetic field sensors and specially isolated rooms to house the equipment. This technique is available in a limited number of centers worldwide.

Therapy

General Principles

Drug therapy for the fetal arrhythmias represents an especially complex and challenging problem. This is a unique situation in which the patient being treated receives the drug via another individual who also metabolizes the drug prior to delivering it to the patient. Factors that complicate effective drug therapy for the fetus are outlined in Table 4-3.

Virtually all maternally ingested drugs cross the placenta to the fetus, primarily by passive diffusion. The rate and extent of transfer varies depending on the concentration gradient of free drug. Maternal, placental, and fetal factors interact to influence the relative distribution and free drug concentrations in the various compartments. The major determinants of placental transfer include extent of protein binding, relative degrees of lipid and water solubility, molecular mass of the drug, maternal drug clearance, and placental function (placental blood flow and metabolism). The physicochemical properties of a drug remain constant, but drug transfer may vary because of changes in maternal drug clearance or placental blood flow and metabolism.

■ TABLE 4-3. Difficulties Related to Providing Effective Fetal Drug Therapy

• Maternal drug metabolism and clearance are affected by pregnancy and change during gestation.

• Fetal drug distribution, metabolism, and excretion are variable and change during gestation.

• Fetal circulatory patterns and blood flow distribution are unique.

• Fetal monitoring and sampling are difficult.

Although additional complexity exists, the general principles governing drug responses in newborn infants also apply to the fetus. Fetal drug responses are determined by drug concentration at the receptor (pharmacokinetic principles) and drug receptor effector interactions, leading to biochemical and/or physiological effects (pharmacodynamic principles). However, pharmacokinetics and pharmacodynamics in the fetus are exceedingly difficult to study, especially in humans. Drug therapy in the human fetus is usually extrapolated from experiments in other species or from case reports, and it is problematic to use these studies to predict drug responses at various gestational ages in the human fetus. In addition to unique circulatory patterns, fetal drug distribution is affected by lower fetal protein binding, higher percentage of total body weight as water in the fetus, and age dependent changes in relative organ weights and metabolic capacity.

As in older children and adults, most drug metabolism in the fetus occurs in the liver. However, a unique property of the fetus is that the fetal adrenal gland participates in drug metabolism to a much greater degree than in infants and older children. Although fetal hepatic metabolic activity is relatively low and intrinsic drug clearance is generally reduced compared to infants and children, the more rapid maternal and placental clearance of most drugs diminishes the impact of impaired fetal drug clearance. Therefore, drug concentration at fetal receptor sites is determined largely by maternal and placental clearance rather than by fetal drug clearance.

Treatment of Fetal Arrhythmias

Management of fetal arrhythmias remains a therapeutic challenge and requires a combined approach with input from pediatric cardiologists, perinatologists, adult cardiologists, and neonatologists. There are basically three options when a fetal arrhythmia is detected: (1) no intervention except for heightened and frequent monitoring, (2) drug therapy, or (3) delivery and treatment (if necessary) of the neonate. The success of medical therapy for fetal arrhythmias is less in the presence of hydrops fetalis. Decisions must be made jointly to develop the most effective approach to therapy for each patient.

Supraventricular tachycardia Gestational age, duration and frequency of episodic supraventricular tachycardia, and the presence of hydrops fetalis or associated structural cardiovascular disease all influence the therapeutic approach. For example, a fetus presenting at 38 weeks’ gestation with sustained supraventricular tachycardia and mild hydrops fetalis should be delivered urgently and the arrhythmia managed after birth. Conversely, a fetus at 24 weeks’ gestation with supraventricular tachycardia and no evidence of hydrops fetalis should be monitored closely with consideration of drug therapy if there are sustained or prolonged episodes of tachycardia. If a fetus with supraventricular tachycardia and significant hydrops fetalis is thought to be at high risk for morbidity and mortality because of extreme prematurity, then aggressive intrauterine therapy is indicated in an effort to restore sinus rhythm and promote resolution of fetal hydrops. In this case, therapy can be continued until elective delivery later in gestation.

Intrauterine supraventricular tachycardia is currently the most common indication for fetal cardiovascular drug therapy. The mainstay of diagnosis and monitoring efficacy remains fetal echocardiography. Fetal electrocardiography is cumbersome, labor intensive, and limited to use at a handful of centers at present. A combination of two-dimensional, Doppler, and M-mode echocardiography can generally provide sufficient information to determine the fetal atrial and ventricular rates and insight into the mechanism of the tachyarrhythmia.

In general, most supraventricular tachycardias in newborn infants are relatively easy to control medically. In contrast, management of supraventricular tachycardia in the fetus is less likely to be successful because of the inability to maintain a sufficiently high drug concentration in the mother to provide an effective concentration in the fetus. At present, the drugs most commonly used are digoxin, sotalol, and flecainide (generally in that order of priority). Amiodarone is reserved for refractory cases because of unreliable placental transfer and the potential for thyroid toxicity in the fetus.

Maternal drug toxicity often limits use of antiarrhythmic agents for treating fetal supraventricular tachycardia.

Many of these drugs have toxic effects, including proarrhythmia. Maternal toxicity is common because high maternal doses are often necessary to ensure adequate transplacental passage of the drug to the fetus. It is helpful to involve adult cardiologists experienced in the use of these drugs to help follow the mother and to monitor for adverse maternal effects.

Direct drug administration to the fetus via the umbilical vein, intraperitoneal administration, or fetal intramuscular injection is possible and has the advantage of bypassing the maternal and placental components. Drugs that have been administered by these routes include adenosine, propafenone, digoxin, amiodarone, and flecainide. However, in most instances, the experience is limited, and specific details are lacking. Although some centers may advocate these approaches as the preferred method (especially for cases of hydrops fetalis), they are technically more demanding, may incur greater risk to the fetus, and are generally reserved for selected high-risk situations.

Bradycardia Fetal bradycardia is defined as a ventricular rate less than 100 beats per minute. Transient episodes of slowing of the heart rate that last less than a minute or two are common and benign, especially during the first and second trimesters. These brief episodes are attributed to sinus bradycardia and do not require any special intervention. Prolonged or persistent sinus bradycardia may be due to pathological conditions, such as fetal hypoxia, congenital sinus node dysfunction (rare), or long QT syndrome. Atrial bigeminy or trigeminy with blocked premature beats may result in a low average heart rate, but these conditions are generally benign and resolve spontaneously. It is important to differentiate blocked premature beats from second- or third-degree atrioventricular block.

Although rare (occurring in 1 in 15 000 to 22 000 live births), third-degree or complete atrioventricular block is irreversible and potentially life threatening. Complete atrioventricular block is associated with structural cardiovascular malformations in about 50% of fetuses. The most common structural malformation is heterotaxy syndrome with left atrial isomerism, occurring in nearly 70% of cases. The remainder of fetuses with complete atrioventricular block and structural cardiovascular disease usually have some form of discordant atrioventricular and ventriculoarterial connections (ie, l-transposition variants). Hypoplastic right heart syndrome, ventricular septal defect, and tetralogy of Fallot have also been associated with complete atrioventricular block, albeit infrequently.

Fetal diagnosis of left atrial isomerism should prompt careful evaluation and follow-up in anticipation of atrioventricular block, and, likewise, in utero diagnosis of complete atrioventricular block requires a thorough structural evaluation. Fetal complete atrioventricular block in the setting of heterotaxy syndrome has a poor prognosis, with combined fetal and neonatal survival rates of 20% or less. Direct pacing of the fetal heart has been reported in only a few isolated cases and is without long-term success. Additional technical improvements and new approaches are necessary for fetal cardiac pacing to become a reasonable option. Thus, treatment at present is limited to maternal administration of beta-sympathomimetic agents, such as salbutamol or terbutaline. These drugs have been shown to increase fetal heart rate by 10% to 20%, but it is not clear whether there is any beneficial impact on overall fetal mortality. However, if hydrops fetalis develops in this setting, it seems prudent to attempt drug therapy; if no benefit is seen, then delivery of the infant should be considered.

In fetuses without structural cardiovascular disease, complete atrioventricular block is attributed to transplacental passage of maternal IgG antibodies (anti-SSA/Ro or anti-SSB/La) in the setting of maternal connective tissue diseases, most commonly systemic lupus erythematosus or Sjogren syndrome. The incidence of congenital complete atrioventricular block in first pregnancies among mothers with connective tissue disorders is around 2% and increases to up to 18% for recurrent pregnancies. It is thought that the maternal antibodies promote inflammation of the developing conduction system and myocardium, resulting in atrioventricular block and myocardial dysfunction. However, the mere presence of anti-SSA/Ro or anti-SSB/La in the mother does not necessarily mean that the fetus will develop atrioventricular block. Indeed, the minority of pregnancies in this situation result in fetal atrioventricular block. Atrioventricular block generally occurs after 18 weeks’ gestation, peaks around 20 to 24 weeks, and almost always occurs before 30 to 32 weeks. In general, the prognosis for autoimmune-mediated complete atrioventricular block is better than in the setting of structural cardiovascular disease but still carries an overall fetal/neonatal mortality rate of approximately 25%.

Given the proposed pathogenesis of atrioventricular block (inflammation of the developing conduction system), it seems logical that the administration of antiinflammatory agents to the mother might prevent or ameliorate atrioventricular block in the fetus. It has been difficult to resolve this issue because this is a rare condition and considerable controversy exists regarding the efficacy of such agents administered to the mother. There have been a small number of case studies of maternal plasma exchange or administration of immunoglobulins or azathioprine, but the numbers are too small to allow meaningful conclusions.

Steroids are often administered to the mother, but considerable controversy persists. Results from studies of maternal steroid therapy reveal several consistent findings. First, fluorinated corticosteroids, such as dexamethasone or betamethasone, must be used since these are only minimally metabolized by the placenta (in contrast to prednisone, which is largely inactivated by placental metabolism and exhibits poor transfer to the fetus). Second, there now is a general consensus that complete atrioventricular block is irreversible and that steroid therapy is not effective in reversing this condition. Third, progression to complete atrioventricular block can be very rapid and occurs within 1 week after a normal fetal echocardiogram.

Controversy exists regarding the efficacy of steroids in preventing progression of first- or second-degree atrioventricular block to complete atrioventricular block. There is some evidence, based on a limited number of cases, that if prolongation of the PR interval (first-degree atrioventricular block) is detected in the fetus, then maternal steroid therapy decreases the likelihood of progression to complete atrioventricular block. Measurement of fetal PR interval by conventional Doppler techniques may not be sufficiently accurate. It is likely that large trials using fetal ECG recording or measuring spectral tissue Doppler-derived atrioventricular intervals will be necessary to resolve this issue. Given the potential adverse effects (both short and long term) of steroid therapy on the fetus, careful consideration of this therapy is necessary. The risk of therapy must be balanced against the high mortality and morbidity associated with congenital complete atrioventricular block. Given the existing information, if a prolonged PR interval is diagnosed in the fetus of a mother with anti-SSA/Ro or anti-SSB/La antibodies, it seems reasonable to initiate steroid therapy.

■ FETAL INTERVENTIONAL CATHETERIZATION

During the past few decades, widespread use of fetal echocardiography has provided increased understanding of the natural progression of various cardiovascular malformations detected in utero. It is clear that severe aortic stenosis can progress to hypoplastic left heart syndrome. As this condition carries relatively high postnatal morbidity and mortality, it is reasonable to consider fetal intervention in an effort to promote ventricular growth and preserve a biventricular circulation after birth. Similarly, an intact atrial septum or a severely restrictive foramen ovale complicating hypoplastic left heart syndrome is associated with poor fetal and neonatal outcomes because of compromised fetal circulation and injury to the developing pulmonary venous bed. This is another situation in which fetal intervention might be anticipated to improve long-term outcomes.

Fetal intervention for aortic valve stenosis or an obstructed atrial septum remains controversial and is limited to only a few centers worldwide. The risks to the fetus and the mother must be considered, especially if general anesthesia is administered to the mother, because the intervention has the potential for jeopardizing two lives. In addition, as the neonatal management of these conditions improves (both surgical and catheter-based interventions), there must be compelling evidence that fetal intervention is highly likely to be superior to conventional postnatal intervention alone. Unfortunately, there are no randomized controlled trials with which to judge the efficacy of fetal interventional catheterization. Furthermore, the ability to predict which fetus with aortic stenosis will progress to a functional univentricular circulation is imprecise. Dilation of the pulmonary valve in the fetus with pulmonary atresia/critical stenosis and intact ventricular septum has also been performed but much less frequently than dilation of a stenotic aortic valve.

The degree of success from these approaches is debatable and extends beyond simply achieving technical success (crossing the valve and inflating the balloon successfully). Success must be measured by favorable biventricular morphology and function, a normal or near normal pulmonary vascular bed, and, in the longer term, improved functional and neurodevelopmental outcomes. At present, this is an evolving field, and much remains to be learned regarding patient selection, timing of intervention, and long-term outcomes before firm recommendations can be made. An international registry has recently been created to document fetal interventions, and data have been published through June 2014. It is hoped that comprehensive documentation of technical and outcome data from a multicenter cohort will inform caretakers and families about the potential benefit of fetal therapy and the associated risks.

■ COUNSELING FAMILIES

It is important to provide clear and understandable communication of results diagnostic testing and information to the mother and family. Discussing a normal fetal echocardiogram is relatively easy and straightforward. Even so, it is important to provide an overview of the potential limitations of a “normal” fetal echocardiogram.

Much more difficult is the discussion that must follow the detection of significant structural or functional cardiovascular disease in the fetus. Unfortunately, relatively little attention and training are devoted to this important aspect of fetal cardiology. In many cases, the parents already suspect that there may be some problem with the fetus because they have been referred for advanced testing. It is best to discuss the results in an environment other than the examination room if possible. The overall objective is to provide accurate information about the diagnosis, pathophysiology, prognosis, and options that are available. Specific details are dependent on the precision and certainty of the diagnosis, the gestational age, anticipated prenatal and postnatal course, surgical outcomes (if surgery is an option), and the presence or absence of underlying extracardiac anomalies and/or known genetic syndromes. If the diagnosis is incomplete or uncertain, then a follow-up examination within a few days is imperative. A complete and accurate diagnosis is essential for proper counseling.

The pediatric cardiologist counseling the parents must have sufficient knowledge and experience to provide accurate up-to-date information regarding the long-term prognosis for the specific cardiovascular abnormality. Frequently, the family is overwhelmed at the time of initial diagnosis, and a follow-up session within a few days may be beneficial. It is not appropriate to withhold information or to use vague euphemisms in a misguided attempt to protect the family. In especially complex cases (eg, maternal disease or genetic syndromes), it is helpful to enlist the aid of perinatologists, surgeons, and genetic counselors, for example, to provide accurate information about the anticipated outcome and prognosis.

If the problem is severe and detected early enough, termination of the pregnancy may be considered. The role of those providing counseling should be to help the family make the decision that is best for them and then to support the family in their decision. Whichever route the parents choose will change the course of their lives, and it is imperative that their decision is based on current state-of-the-art information and that the family is as comfortable and confident as possible with their decision.