Pharmacologic Intervention in the Fetus

Introduction

With the arrival of echocardiography and magnetic resonance imaging (MRI), providing the means of noninvasively detecting and monitoring anomalies occurring during pregnancy, the fetus has increasingly become the target of prenatal treatment. Nonetheless, pregnancy is a unique situation, as treatment of the fetus cannot be approached independently from the concomitant treatment of the mother, especially when a medication is used for indications other than those listed in the drug monograph. This includes the off-label administration of pharmaceutical agents via the maternal circulation or directly into the fetus to treat tachyarrhythmias, cardiac inflammation, and/or congestive heart failure (CHF) and to promote lung maturation. Other interventions, such as the supplementary maternal inhalation of oxygen, may be useful to promote the growth of underdeveloped left heart structures and improve oxygen delivery to the fetal brain―for example, in cases of congenital heart disease (CHD) or with intrauterine growth restriction (IUGR) due to placental failure. This chapter discusses the rationale and outcomes of fetal pharmacotherapy for selected cardiovascular indications, with the caveat that controlled studies on drug efficacy and drug safety as well as universally accepted recommendations to guide prenatal treatment are largely unavailable.

Antiarrhythmic Fetal Treatment

Arrhythmias may present as an irregularity of the fetal cardiac rhythm; as an irregular, abnormally slow or fast heart rate; or as a combination. In most cases such anomalies present as brief episodes of little clinical relevance, and no treatment is required. This includes irregularities of the cardiac rhythm caused by premature atrial contractions. Of more concern are enduring episodes of a cardiac rate that is too fast (greater than 180 beats/min). Prenatal causes typically include different forms of supraventricular and atrial tachyarrhythmias (SVAs), with ventricular tachycardia (VT) and junctional ectopic tachycardia (JET) as rare causes. A persistently fast rate may be well tolerated; at the severe end of the spectrum, however, it may lead to low cardiac output, fetal hydrops, and death. Arrhythmia-induced fetal hydrops (defined by more than one of these symptoms: abdominal, pleural, or pericardial effusion or skin edema) is the single most important predictor of perinatal death. Hence, if a disturbance of cardiac rhythm is suspected, it is important to determine its impact on the fetal circulation and to decide on the urgency and choice of perinatal care. Detailed fetal ultrasonic examination provides essential information on the level of fetal activity as an indicator of well-being, cardiac function, fetal hydrops, and on anomalies that may underlie an arrhythmia, such as cardiac tumors or structural heart disease. Most arrhythmias can be reliably distinguished from one another by a stepwise analysis of the rate, rhythm, and chronology of atrial and ventricular systolic events as depicted by M-mode and Doppler ultrasound tracings. The correct interpretation of these findings will not only reduce the risk of unnecessary pharmacologic treatment or premature delivery of fetuses with more benign findings but also facilitate the choice of care of those with a major disorder of rhythm.

The cardiac rhythm disturbances described in the following text might benefit from transplacental antiarrhythmic treatment.

Atrial and Supraventricular Tachyarrhythmias

SVA, the most frequent cause of a fetal tachycardia, can be produced by four main mechanisms in this population, namely:

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Atrioventricular reentrant tachycardia (AVRT), involving the atrioventricular node for antegrade conduction and a fast retrograde ventriculoatrial (VA) conducting accessory pathway
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Permanent junctional reciprocating tachycardia (PJRT), with reentry across a slow retrograde VA conducting accessory pathway
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Atrial ectopic tachycardia (AET) due to enhanced automaticity of atrial tissue
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Atrial flutter (AF) due to a circular macroreentrant pathway contained within the atrial wall

AVRT and AF account for 90% of referrals with fetal tachyarrhythmias.

The different SVA mechanisms can be distinguished by fetal echocardiography on the basis of the arrhythmic pattern and the relationship of atrial and ventricular systolic events. AVRT typically presents as a short VA tachycardia ( ), as the atrial electromechanical activation via the fast retrogradely conducting accessory pathway follows shortly after the ventricles, with average heart rates of about 250 (range, 180 to 300) beats/min. Typical AVRT patterns are either a persistent, regular tachycardia or an episodic condition with an abrupt arrhythmia onset and termination, which is also known as paroxysmal supraventricular tachycardia (PSVT). In long VA tachycardia ( ), which is often slower (median, 210 beats/min; range, 170 to 240 beats/min) and better tolerated but more difficult to control than AVRT, the atrial contraction closely precedes the ventricular contraction. This pattern of activation is seen during AET and PJRT but also characterizes sinus tachycardia. In AF ( ), the median atrial rate is about 440 (300 to 600) beats/min, which is sufficiently fast that only every second or third flutter wave is conducted through the atrioventricular node, producing ventricular rates between 150 and 250 beats/min.

Perinatal Management

Three management options can be considered if fetal SVA is detected. The first is not to attempt treatment. The second option is to institute intrauterine antiarrhythmic therapy, and the third is to deliver the fetus and opt for neonatal care. The decision of care should be based on the gestational age at presentation; arrhythmia characteristics including the mechanism, rate, and duration of the tachycardia; presence and degree of fetal compromise; maternal health; and the possible risks and benefits of the fetal therapy versus those of an earlier delivery by cesarean section.

AVRT and AF complicated by fetal hydrops is associated with a perinatal mortality of 20% or higher, even with active treatment. In the absence of hydrops, this risk ranges from 0% to 4%. Antiarrhythmic drugs exhibit a variety of cardiac actions that can be used either to terminate a SVA and, once achieved, to maintain a normal rhythm or to slow the tachycardia to a more normal rate if the SVA persists. Once the tachycardia is controlled, fetal hydrops typically resolves within a few days to several weeks.

As a general rule, the likelihood of fetal heart failure increases if AVRT―rather than AF, AET, or PJRT―is the arrhythmia mechanism and the tachycardia is fast, incessant, and detected at a younger gestational age. Unless the fetus is near term, the recently published American Heart Association (AHA) guidelines recommend pharmacologic treatment to terminate or slow the tachycardia for (1) incessant SVA (present in >50% of observation time) with or without hydrops and for (2) intermittent SVA (in <50% of time) in the presence of cardiac dysfunction or hydrops. Serial observation without pharmacologic therapy is recommended for fetuses with a well-tolerated intermittent SVA or with an incessant SVT less than 200 beats/min, as fetal hydrops will only rarely develop under such circumstances. Nonetheless, Simpson et al., reporting the outcomes of intermittent fetal tachyarrhythmias over a 12-year period at their center, found that even an intermittent tachycardia pattern may have deleterious hemodynamic effects on the fetus. Of 28 fetuses who had an intermittent SVA, 14 were hydropic, which was associated with one intrauterine death, two neonatal deaths, and one infant death. The arrhythmia recurred postnatally in 11 of 23 (48%) fetuses. Maternal antiarrhythmic therapy may also be indicated for intermittent fetal tachyarrhythmias. Another reason to treat SVA before birth is that permanent conversion to a normal rhythm will enable a vaginal delivery by allowing the interpretation of the fetal heart rate for signs of distress during labor. With this rationale in mind, our center is offering the option of transplacental antiarrhythmic treatment to most mothers with a fetal SVA unless the tachycardia is only brief and/or detected near term. For fetuses with brief SVA (<10% of the time), close monitoring for signs of progression is the preferred management option, as the SVA will often resolve spontaneously. For incessant fetal SVA that is detected only at or near term, delivery usually by cesarean section with postnatal conversion to sinus rhythm is the usual choice. Most prenatally treated newborns with AVRT, AET, or PJRT will receive antiarrhythmic drug therapy during the first year of life, whereas AF is expected not to recur after conversion at birth.

Pharmacotherapy

Transplacental fetal treatment for SVA was first attempted with digoxin and procainamide, respectively, almost 40 years ago. Today treatment is predominantly initiated either with digoxin, flecainide, or sotalol, whereas combinations of antiarrhythmic agents and/or amiodarone are mainly reserved for therapy-resistant and/or poorly tolerated tachycardia. Direct fetal drug treatment with amiodarone, digoxin, or both is used to treat life-threatening conditions. Because of the potential risk of hazardous proarrhythmia, each antiarrhythmic treatment other than digoxin should probably be started in an inpatient setting to allow serial monitoring of the maternal electrocardiogram (ECG) as well as the fetal effects. To exclude unsafe maternal conditions, such as long-QT syndrome (LQTS) for class III agents or ventricular preexcitation for digoxin, the pregnant mother should undergo a detailed medical assessment including a 12-lead ECG, testing of her serum electrolytes, and perhaps an echocardiogram to confirm normal cardiac findings prior to the administration of any medication. Thyroid function should be checked if fetal hyperthyroidism is suspected or if treatment with amiodarone is considered. A clear understanding of the drug dosages, pharmacokinetics, and actions is essential if the tachycardia is to be treated efficiently and safely. The risk of adverse drug reactions may be further reduced by restricting treatment whenever possible to a single agent and by avoiding excessive dosages, toxic concentrations, or potentially hazardous combinations if additional pharmacologic treatment is required.

Table 9.1 lists clinical usage information of the main antiarrhythmic agents to treat fetal SVA; these are discussed in turn.

Table 9.1

Prenatally Used Cardiovascular Drugs: Treatment Indications, Drug Dosages, and Possible Adverse Effects

Drug	Main Fetal Indications	Usual Dosages	Therapeutic Concentrations	F/M Ratio	Maternal Effects, Risks, and Symptoms	Fetal/Newborn Risks
Digoxin	SVT, AF, CHF	LD: 0.5 mg q12h over 2 days MD: 0.375–0.75 mg/day	1–2.0 ng/mL 1.3–2.6 nmol/L	0.8–1 ↓ in hydrops	Dose-dependent effects and narrow therapeutic range: nausea, dizziness, anorexia, disturbed vision, fatigue, sinus bradycardia, first degree block	Not reported
Flecainide	SVT, AF, VT	200–400 mg/day in 2–3 doses	<1 µg/mL	0.7–0.9	QRS prolongation, proarrhythmia, negative inotropy, blurred vision, nausea, paresthesia, headache	Proarrhythmia, negative inotropy
Sotalol	AF, SVT, VT	160–480 mg/day in 2–3 doses	Not measured	0.7–2.9	Dose-dependent effects: bradycardia, fatigue, hypotension, headache, nausea, dizziness, proarrhythmia	Proarrhythmia, bradycardia
Amiodarone	SVT, VT	LD: 1.6–2.4 g/day for 2–7 days MD: 0.2–0.4 g/day Direct: 2.5–5 mg/kg fetal weight IV slowly over 10 min	1–2.5 µg/mL	0.1–0.3 ↓ in hydrops	Dose-dependent effects: QT-prolongation, bradycardia, thrombocytopenia, rash Not expected with short-term use: lung fibrosis, thyroid dysfunction, hepatitis; corneal microdeposits, neuropathy, myopathy	Proarrhythmia, bradycardia, transient thyroid dysfunction, growth restriction, bradycardia
Lidocaine	VT	LD: 1–1.5 mg/kg IV followed by infusion of 1–4 mg/min	1.5–5 µg/mL toxic >9 µg/mL	0.5–0.7	Drowsiness, numbness, minor adverse neural reactions	Central nervous system depression at high serum levels
Propranolol	Thyrotoxicosis	60–120 mg in 2–3 doses	Not measured	0.9–1.3	Bradycardia, AV block, fatigue, hypotension, bronchospasm, cold extremities	Growth restriction, bradycardia, hypoglycemia, respiratory depression
Propylthiouracil	Thyrotoxicosis	50–200 mg/day	Not measured	1.9	Agranulocytosis, nausea, vomiting, loss of taste, skin rash, itching, drowsiness, dizziness, headache	Risk of hypothyroidism and goiter
Dexamethasone	Cardiac NLE	8 mg/day for 2 weeks, then 4 mg/day to 30 weeks and 2 mg/day to birth After birth: taper mother off steroids Newborn (if carditis or EFE), prednisone 2 mg/kg/day for 2 weeks followed by 1 mg/kg/day for 4 weeks IVIG 1 dose at birth	Not measured	0.3	Adrenal gland suppression, weight gain, fluid retention, hypertension, mood changes, insomnia, irritability, psychosis, striae, diabetes, impaired wound healing, increased susceptibility to infections	Oligohydramnios, growth restriction, impaired wound healing
β-Agonists	CHB <50 beats/min	Salbutamol 30–40 mg/day in 3–4 doses Terbutaline: 10–30 mg/day in 4–6 doses	Not measured	0.5	Palpitations, tremor, sweating, dyspnea, hyperglycemia, chest pain, nausea, nervousness, dizziness, arrhythmias	Neonatal hypoglycemia
Immunoglobulin	EFE; incomplete AV block	1 g/kg IV q 2–3 wk (maximal dose: 70 g/dose) Neonatal: single dose of 1 g/kg IV and prednisone for 6–8 weeks	Not measured	Variable	Headache, chest pain, fever, chills, nausea, malaise, anaphylaxis, aseptic meningitis	Not reported

AF, Atrial flutter; AV, atrioventricular; CHB, complete heart block; CHF, congestive heart failure; EFE, endocardial fibroelastosis; F/M ratio, ratio of fetal to maternal serum concentrations; IV, intravenous; IVIG, intravenous immunoglobulin; LD, loading dose; MD, maintenance dose; NLE, neonatal lupus erythematosus; SVT, supraventricular tachycardia; VT, ventricular tachycardia.

Digoxin

Digoxin's actions include parasympathetic slowing of the sinus node, prolongation of AV nodal refractoriness, and enhanced myocardial contractility. Maternal digoxin intake leads to characteristic ST- and T-segment changes on the ECG. In the absence of hydrops, digoxin is well absorbed and transferred to the fetus, reaching fetal serum concentrations that are close to those in maternal serum within 3 to 5 days. Fetal myocardial digoxin levels are often higher than serum concentrations because of enhanced uptake of drug by cardiac tissue. There are numerous known drug interactions, including those with amiodarone and flecainide, both of which increase the level of digoxin. No serious digoxin-related adverse events have been reported in healthy women, but nausea, anorexia, headache, visual disturbances, and dizziness are among the more common patient complaints. Digoxin is contraindicated in any mother with ventricular preexcitation (Wolff-Parkinson-White syndrome), hypertrophic cardiomyopathy, or high-degree AV block.

Flecainide

Flecainide inhibits slow Na ⁺ channels (class I) and β-receptors (class II), which prolongs the conduction and refractoriness of all cardiac tissues, including the AV node and accessory pathways. The Na ⁺ channel–blocking effect is use dependent, which means that the effect increases as the heart rate increases. Flecainide prolongs the duration of PR, QRS, and QT intervals. The agent is well absorbed and transferred to the fetus to reach therapeutic levels within 3 days. To minimize the risk of proarrhythmia, the avoidance of excessive QRS prolongation is recommended as well as keeping the maternal flecainide serum concentrations, if measured, below 1 µg/mL. There are numerous interactions with other agents, including amiodarone, which is also metabolized by cytochrome p450. Flecainide increases serum digoxin levels by approximately 20%. Maternal complaints include blurred vision, nausea, constipation, dizziness, and headache. Serious maternal events have not been reported, but there is one case of unexplained demise in utero more than 2 decades ago of a nonhydropic fetus. Flecainide is not to be used in mothers with congestive heart failure, ventricular arrhythmias, or major CHD.

Sotalol

Sotalol is both a K ⁺ channel blocker (class III) and a β-blocker (class II), with β-blockade as the main effect at doses less than 160 mg/day. The combined effects prolong the duration of action potentials and tissue refractoriness throughout the heart and decrease the heart rate. Sotalol prolongs the maternal PR and QT duration but does not affect QRS intervals. The agent is well absorbed, reaching peak plasma concentrations within 2 to 4 hours of oral administration, and is well transferred across the placenta to reach a fetal steady state similar to the maternal drug level. Sotalol is usually well tolerated by mother and fetus. Symptoms related to β-blockade may include arterial hypotension, bradycardia, worsening of asthma or obstructive lung disease, fatigue, depression, and insomnia. There is one report of an unexplained fetal death in the absence of fetal hydrops.

Amiodarone

Amiodarone is a pregnancy class D agent, which means that there is definite evidence of fetal risk with its use. This agent therefore should not be used in non–life-threatening situations or if safer alternatives are available. The duration of therapy with amiodarone should also be minimized, with discontinuation once the arrhythmia is controlled and hydrops has resolved. The compound has multiple actions, including blockage of K ⁺ channels (class III), Na ⁺ channels (class I), Ca ²⁺ channels (class IV), and β-receptors (class II). Electrophysiologic effects include prolongation of the refractoriness of cardiac tissues and, at fast heart rates, slowing of conduction through the His-Purkinje system and ventricular myocardium. Amiodarone has no negative effect on cardiac contractility. The drug has unusual pharmacokinetics, with absorption of the drug given orally ranging from one- to two-thirds and plasma peak concentrations reached within 3 to 7 hours of ingestion. Amiodarone is metabolized in the liver to desethylamiodarone, which also has antiarrhythmic properties. Both are lipophilic and preferentially accumulate in fat, liver, lung, skin, and myocardium. Drug excretion is slow and occurs via shedding of epithelial cells of the skin and gastrointestinal tract. Consequently, amiodarone's effects may persist for weeks following cessation of the drug. Amiodarone and desethylamiodrone cross the placenta only incompletely, which explains the need for high amiodarone doses to treat fetal SVA. Interference with the pharmacokinetics of other drugs is common, including with digoxin and flecainide. Amiodarone has numerous possible side effects that are typically reversible with dose reduction or cessation of treatment. Thyroid dysfunction affects almost 10% of chronically treated patients. The most serious complication in adults is pulmonary toxicity, which can rarely occur early after treatment initiation. Amiodarone should be immediately discontinued if the mother develops pulmonary inflammatory changes. A nonproductive cough and dyspnea are the main symptoms of affected individuals at presentation. Pleuritic pain, weight loss, fever, and malaise can also occur. As with other class III agents, there is a risk of torsade de pointes, which can be minimized by avoiding excessive QTc prolongation. Adverse fetal effects attributed to the use of amiodarone include transient congenital thyroid dysfunction, growth retardation, and mild neurodevelopmental abnormalities.

Direct Fetal Treatment

Direct fetal treatment should be considered if other less invasive treatment measures have failed or if immediate treatment is required to terminate or slow down a life-threatening SVA. In the presence of fetal hydrops, the transplacental transfer of most antiarrhythmic medication is hampered and therapeutic levels of drugs may not be reached even with high maternal doses. To overcome this problem, repeated intravenous, intramuscular, and intraperitoneal fetal injections of amiodarone and/or digoxin, in addition to transplacental maternal medication, have been successfully used to deal with treatment-refractory fetal AVRT, although fetal deaths with the use of this strategy have occurred. Amiodarone seems to be predestined for direct use, both because of its efficiency and long half-life, thus limiting the number of invasive fetal procedures required to maintain therapeutic levels. Direct intravenous adenosine may instantly terminate AVRT, but because of its short duration of action, it should be administered in combination with a longer-acting antiarrhythmic agent.

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