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:
- ▪
Atrioventricular reentrant tachycardia (AVRT), involving the atrioventricular node for antegrade conduction and a fast retrograde ventriculoatrial (VA) conducting accessory pathway
- ▪
Permanent junctional reciprocating tachycardia (PJRT), with reentry across a slow retrograde VA conducting accessory pathway
- ▪
Atrial ectopic tachycardia (AET) due to enhanced automaticity of atrial tissue
- ▪
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.
| 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 |
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.
Other Antiarrhythmic Agents.
Other antiarrhythmic agents such as verapamil, procainamide, and quinidine are not recommended for prenatal therapy because of the potential risks of severe side effects and/or insufficient antiarrhythmic action.
Treatment Results
Retrospective case series report inconsistent success rates for all antiarrhythmic medication in treating fetal SVA, which may be explained, among other things, by differences in the definition of a treatment success and in disease severity between patient cohorts. With this caveat in mind, in studies using oral digoxin as first-line agent, in utero cardioversion has been reported in 50% to 100% of fetuses with SVA without hydrops, but in 40% or less of fetuses with SVA and hydrops. Flecainide has resulted in sinus rhythm in 58% to 100% of SVA cases without hydrops and in 43% to 86% of those with hydrops. Sotalol monotherapy has been successful in 40% to 100% of SVA cases without hydrops and in 50% to 67% of those with hydrops. When used to treat drug-refractory SVT, transplacental amiodarone alone or in combination with digoxin was associated with a 71% rate of in utero cardioversion. Similar or higher cardioversion rates to amiodarone were obtained with combination treatment of digoxin plus flecainide, sotalol plus digoxin, and sotalol plus flecainide. Results of direct fetal drug therapy are largely unavailable.
Although these published data suggest similar treatment results with the currently used antiarrhythmic agents, drug-specific differences in their modes of action and pharmacokinetics likely predetermine the potential of a compound in terminating and, once this has been achieved, suppressing SVA recurrences. In the retrospective multicenter study by Jaeggi et al. comparing nonrandomized first-line treatment with one of three agents―digoxin, flecainide, or sotalol―the fetal response to antiarrhythmic therapy was significantly influenced by fetal hemodynamics, arrhythmia mechanism, and the choice of drug management. Slower cardioversion rates to a normal rhythm were found to be significantly associated with (1) a persistent tachycardia pattern (hazard ratio [HR], 3.1; P < .001) during the initial fetal echocardiogram when compared with intermittent arrhythmia; (2) fetal hydrops (HR, 1.8; P = .04) , presumably due to incomplete passage of maternally administered antiarrhythmic drugs across the placenta; (3) AF (HR, 2.0; P = .005) when compared with other forms of SVA; and (4) the choice of first-line therapy ( Fig. 9.1 ) . Sotalol was associated with higher rates of prenatal AF termination than digoxin (HR, 5.4; P = .05) or flecainide (HR, 7.4; P = .03). The median time to conversion of AF cases was almost 2 weeks with sotalol, whereas this was not achieved with digoxin or flecainide before delivery. Flecainide (HR, 2.1; P = .02) or digoxin (HR, 2.9; P = .01) were associated with a higher rate of conversion of fetal SVA other than AF to a normal rhythm compared with sotalol. The median time to cardioversion of AVRT, AET, and PJRT was 3 days with digoxin, 4 days with flecainide, but 12 days with sotalol. If the SVA persisted, tachycardia rates declined more with flecainide and digoxin. Finally, therapy initiation with digoxin, flecainide, or sotalol as monotherapy appeared safe unless fetal hydrops was present, which was associated with 21% perinatal mortality. This led to the study’s recommendation to consider drug combinations (e.g., flecainide plus digoxin for AVRT; sotalol plus digoxin for AF) as first-line treatment when rapid tachycardia control becomes a matter of urgency.
Ventricular Tachycardia
VT in the fetus is rare and reports are scarce. The echocardiographic diagnosis is based on a tachycardia with higher ventricular than the atrial rates and no relation between ventricular and atrial events (AV dissociation). If there is 1 : 1 retrograde AV nodal conduction, it is usually not possible to differentiate a regular VT from SVA by fetal echocardiography. Treatment and prognosis depend on the cause and pattern of the VT and the hemodynamic consequences. Accelerated idioventricular rhythm is a ventricular rhythm that is slightly faster than the sinus rate and is considered a benign form of VT. These rates are usually seen late in gestation and generally do not require treatment prenatally or postnatally. In the absence of a predisposing condition, idiopathic VT is a rare cause of tachyarrhythmia in the fetus. It is more commonly seen in young patients after birth and then usually has a benign course, although treatment may be required. Identifiable associations with VT include acute cardiac inflammation, cardiac tumors, and ion channelopathies. Anti-Ro antibody-mediated carditis should be suspected if runs of VT are observed in a fetus with a new diagnosis of congenital complete heart block (CHB). Transplacental maternal dexamethasone may then be used to ease the inflammation and to stop the tachycardia. The most common predisposing condition leading to fetal VT is LQTS. It is a likely cause if sinus bradycardia or second-degree heart block and a fast VT (torsade de pointes) coexist. With the arrival of fetal magnetocardiography, it has become possible to detect fetal QTc prolongation noninvasively. If fetal magnetocardiography is unavailable, the diagnosis of LQTS is confirmed by postnatal ECG and testing for LQTS known mutations.
Treatment
Perinatal data on treatment and outcome are limited and vary between conditions. For fetal VT greater than 200 beats/min, short-term maternal intravenous magnesium has been recommended as the first-line transplacental medication (see Table 9.1 ). Other treatment options to control a fetal VT may include intravenous maternal lidocaine as well as oral β-blocker and mexiletine. In the absence of LQTS, amiodarone, flecainide, or sotalol may also be useful.
Thyrotoxicosis
Fetal hyperthyroidism or thyrotoxicosis is another rare yet potentially life-threatening condition. It should always be considered in the differential diagnosis of a long-VA tachycardia of up to 200 beats/min, which includes AET and PJRT. It is most commonly observed in thyroid autoimmune disorders such Graves disease. The maternal diagnosis of Graves disease is suggested by physical signs―such as exophthalmos, an enlarged thyroid gland, and exaggerated reflexes―and is confirmed by finding markedly elevated levels of thyroid hormone. Transplacental passage of maternal thyroid-stimulating immunoglobulins (TSIs) leads to fetal thyroid gland stimulation and the clinical manifestations of this disorder, including fetal hydrops, restriction of growth, and goiter. Because fetal tachycardia and restricted growth may result from other pathologic processes, some have advocated sampling of umbilical blood to measure the levels of thyroid-stimulating antibodies, thyroid-stimulating hormone, and FT 4 for definitive diagnosis. If thyrotoxicosis goes unrecognized and untreated, the risk of fetal mortality and severe complications is high.
Treatment
The mainstay of prenatal treatment is inhibition of the excessive fetal synthesis of thyroid hormone by propylthiouracil (PTU) and slowing of the fetal heart rate by β-blockade.
Propylthiouracil.
PTU does not affect the release of thyroxin. The rapidity of response to PTU therefore depends on the amount of colloid stored in the thyroid gland. The drug is generally well tolerated, with side effects occurring in about 1% of treated adults. Adverse events are mainly related to the skin and include rash, itching, abnormal loss of hair, and dermal pigmentation. Agranulocytosis, nausea, vomiting, loss of taste, joint or muscle aches, numbness, and headache are other possible reactions. The agent crosses the placenta and may produce fetal hypothyroidism even if it is administered in relatively low doses. To limit this risk, treatment with PTU should be titrated to the lowest possible dose to maintain the maternal index for free thyroid in the high normal range. The fetal response can be monitored by serial measurement of the fetal heart rate and by direct measurement of T 4 and thyroid-stimulating hormone in the fetal cord blood. Ultrasonography may permit assessment of changes in the size of the thyroid gland. Infants born to mothers with Graves disease should be closely followed by a pediatrician to assess any thyroidal dysfunction. PTU was previously considered a safe medication for use during gestation. A recent Danish study revealed that 2% to 3% of children exposed to PTU early in gestation developed birth defects (neck cysts and urinary tract abnormalities) associated with this therapy.
Propranolol.
Propranolol or a similar maternal β-blocker may be used to slow fetal sinus tachycardia, thus reducing the risk of high-output cardiac failure. Propranolol is rapidly and completely absorbed, with levels peaking in the plasma from 1 to 3 hours after oral ingestion. The drug readily crosses the placenta. β-Blockade is contraindicated in the presence of severe maternal bradycardia, high-degree atrioventricular block, severe asthma, or bronchospasm, the Raynaud phenomenon, and other peripheral vasculopathies. Pharmacologic β-blockade is considered relatively safe for the fetus, although side effects have been reported in neonates following the use of propranolol in pregnancy, including restricted growth, hypoglycemia, bradycardia, and respiratory depression. Thus newborns of women consuming the drug close to delivery should be observed during the early days of life for symptoms of β-blockade.
Antiinflammatory Fetal Treatment
Antibody-mediated fetal heart disease in the setting of neonatal lupus erythematosus (NLE) is the main indication of the use of antiinflammatory medication during pregnancy.
Antibody-Mediated Fetal Heart Disease
The cardiac manifestations of NLE are strongly associated with the fetal exposure to a very high amount of maternal anti-Ro antibodies. The fetal risk of acquiring antibody-related heart disease increases from 5% for any mother carrying high Ro-antibody titers to up to 25% if a previous child had already been affected. The current understanding of the disease mechanism is that these maternal antibodies increasingly cross the placenta to the fetus in mid gestation, where they may interact with fetal Ro ribonucleoproteins and initiate cardiac inflammation in the susceptible fetus. Subsequent replacement of the inflamed cardiac tissue with fibrosis and calcification may then manifest as heart block, sinus node dysfunction, AV valve disease, endocardial fibroelastosis (EFE), and/or dilated cardiomyopathy.
Complete Heart Block
Congenital CHB, the most frequently observed cardiac NLE manifestation, predominantly develops at some time between 18 and 24 gestational weeks. The prenatal diagnosis of CHB is based on the echocardiographic demonstration of a complete failure of AV conduction, with atria and ventricles that beat independently at their own intrinsic pacemaker rates. Although the fetal atrial rate typically remains within the normal range between 130 and 150 beats/min, the ventricular rhythm is much slower, predominantly between 50 and 60 beats/min before birth ( ).
Other Manifestations of Neonatal Lupus Erythematosus
Many cardiologists have considered CHB an isolated disease of the AV conduction system, perhaps due to the difficulty of detecting the extent of the associated cardiac pathology accurately by ultrasound imaging. Yet it is now well established that acute and chronic diseases of the myocardium―including carditis, EFE, and dilated cardiomyopathy―are part of the clinical spectrum of cardiac NLE. Histologic findings of a more generalized process of inflammation and scarring are frequently present in other areas of the heart. The concept of more generalized inflammation has also been substantiated by the demonstration of immunoglobulin G, complement, and fibrin deposition on the fetal myocardium. Moreover, at least 20% of fetal CHB cases will display indirect echocardiographic findings suggestive of cardiac inflammation and damage, such as reduced ventricular contractility, valvar regurgitation, sinus bradycardia, pericardial effusion, and patchy echogenicity of myocardial tissues.
Treatment
The cardiac output of the fetus with CHB is negatively affected by the slowed ventricular rate, loss of the normal atrial contribution to ventricular filling, and, if present, concomitant myocardial inflammation and damage. Neonatal survival rates of predominantly untreated patient series with antibody-mediated CHB range from 66% to 86%. Risk factors associated with perinatal demise include an earlier gestational age at NLE diagnosis, fetal hydrops, carditis, EFE, and a ventricular rate less than 50 beats/min. Moreover, at least 5% to 10% of untreated fetuses with CHB and normal cardiac function at birth will develop late-onset CHF due to dilated cardiomyopathy in the early years of life. Biopsies obtained from these children predominantly revealed myocardial hypertrophy and interstitial fibrosis and, less commonly, myocyte degeneration. In a retrospective review of untreated patients with CHB, we found that in one-quarter of the more severely affected cases, symptoms associated with a poor outcome became apparent or developed only later in pregnancy. Carditis, hepatitis, and dilated cardiomyopathy were diagnosed only after birth in several cases that had been managed without antiinflammatory treatment. These factors have led to the routine use of dexamethasone at our center to limit or to prevent myocardial damage and EFE. Maternal injections of immune globulins (intravenous immunoglobulin [IVIG]) have become a useful adjunct to directly block maternal antibody expression on the fetal heart, in particular if there was evidence of myocardial inflammation, EFE, and/or incomplete heart block. The use of transplacental glucocorticoids for antibody-mediated fetal heart block remains controversial among specialists because the treatment will not reverse AV block that is already complete at the time of diagnosis because of the potential of adverse effects on the developing fetus, and because survival is often attained without prenatal intervention. Thus an alternative approach, advocated by others, could be to restrict transplacental treatment to the compromised fetus; but this may carry an increased risk of postnatal cardiomyopathy.
The following transplacental medication may be used to treat cardiac NLE.
Dexamethasone and Betamethasone.
Dexamethasone and betamethasone are potent synthetic glucocorticoids that are only minimally metabolized by the placenta and easily pass to the fetus, making these agents useful for direct fetal treatment. Dexamethasone is often preferred, as it can be given as a single oral dose per day. Unless the fetus is near term at the time of NLE diagnosis, we usually start dexamethasone at a dose of 8 mg/day for 2 weeks; this is then reduced to 4 mg/day to around 28 weeks and to 2 mg/day for the remainder of pregnancy. Maternal IVIG (1 g/kg every 3 weeks) is added if we detect EFE, incomplete heart block, or both. We would not offer prenatal treatment, but close observation for a late pregnancy referral after 32 weeks of gestation with isolated fetal CHB, ventricular rates greater than 50 beats/min, and no obvious evidence of EFE or heart failure as survival to birth without disease progression is expected.
Results.
The potential benefits of transplacental dexamethasone plus or minus IVIG include reduction of cardiac inflammation, reversal or stabilization of incomplete heart block, as well as improvement or resolution of AV valvar regurgitation, effusions, fetal hydrops, and/or EFE. There has also been improvement in outcome coinciding with the introduction of perinatal dexamethasone for CHB at our center. Current survival rates exceed 95% at 1 month and 90% at 10 years of life, which is significantly improved from our historical outcome data ( Fig. 9.2 ) and compared with predominantly untreated patient cohorts.
