With cross sectional echocardiography providing the means non-invasively to detect and monitor the evolution of anomalies occurring during pregnancy, the fetus has increasingly become the object of intended treatment. This includes the administration of pharmaceutical agents via the maternal circulation or directly into the fetus to control fetal cardiac arrhythmias, to improve congestive heart failure, to treat inflammation and infections and to prevent pulmonary immaturity. Moreover, the increasing ability to use ultrasonic and fetoscopic guidance directly to intervene on the fetus with progressive cardiovascular pathology promises to magnify the advantage offered by prenatal detection of congenital cardiac disease. We will discuss the principles, risks, and contemporary results of intra-uterine fetal treatment for specific cardiac arrhythmias, along with anomalies, which, in the absence of universally accepted guidelines for management, remains a contentious topic among experts.
FETAL ARRHYTHMIAS
Fetal arrhythmia may present as an irregularity of the cardiac rhythm, as an abnormally slow or fast heart rate, or as a combination of irregular rhythm and abnormal heart rate. In most cases, such anomalies as encountered during fetal life present as brief episodes of little clinical relevance. No treatment is usually required. This includes irregularities of the cardiac rhythm caused by blocked and conducted premature atrial contractions. Of more concern are sustained episodes of a cardiac rate that is too fast, greater than 180 beats per minute, or one that is too slow, less than 100 beats per minute. The most common causes for such problems are supraventricular tachycardia, atrial flutter, and severe bradyarrhythmias associated with complete heart block. While a persistently fast or slow rate may be well-tolerated, at the more severe end of the spectrum, it may result in low cardiac output, cerebral damage, fetal hydrops, and death. The finding of arrhythmia-related fetal hydrops is the single most important predictor of adverse fetal outcome. On the other hand, a symptomatic fetal tachyarrhythmia or bradyarrhythmia may respond to, or improve on, pharmacological treatment. Hence, if a disturbance of rhythm is suspected, it is important to determine the likely arrhythmic mechanism, to clarify the impact on the fetal circulation, and to conclude on the urgency and choice of care. Detailed fetal ultrasonic examination provides essential information on the level of fetal activity as an indicator of well-being, on the size and function of the fetal heart, and the distribution and extent of accumulation of fluid in the fetal pleural, pericardial, and abdominal spaces and the skin. Detailed fetal echocardiography is helpful to detect cardiac tumours, Ebstein’s malformation of the tricuspid valve, left isomerism, and congenitally-corrected transposition, all of which may be associated with abnormally fast or slow heart rates. Key to the proper management is a clear understanding of the underlying pattern and mechanism of the arrhythmia. Stepwise analysis of the rate, rhythm, and chronology of atrial and ventricular mechanical events by means of echocardiographic techniques allows the distinction between the different anomalies ( Table 12-1 ). The correct diagnosis will reduce the risk of unnecessary pharmacological treatment, or premature delivery of fetuses with more benign findings, and facilitate the care of those with a major disorder of rhythm. We will discuss in detail those cardiac disorders that might take advantage of transplacental treatment, specifically fetal tachyarrhythmia, fetal thyrotoxicosis, and immune-mediated isolated atrioventricular block and endocardial fibroelastosis.
| Arrhythmia | A Rate | A-A Interval | AV Relation | V Rate | V-V Interval | V-A Interval | Relevance +Outcome | |
|---|---|---|---|---|---|---|---|---|
| Irregular rhythm | Isolated PAC, conducted | Normal | Irregular | 1:1 | Normal | Irregular | Variable | Minor, transient |
| Isolated PAC, blocked | Normal | Irregular | >1:1 | Normal | Irregular | Minor, transient | ||
| Bradycardia | Sinus | 75–90 | Regular | 1:1 | 75–90 | Regular | Long VA | Depends on cause |
| Atrial bigeminy, blocked | Normal | Regular irregular | 2:1 | 65–90 | Regular | Minor, transient | ||
| 2:1 AV block | Normal | Regular | 2:1 | 60–75 | Regular | Major, may progress | ||
| Third-degree AVB | Slow–normal | Regular | Dissociated | 35–80 | Regular | Dissociated | Major, irreversible | |
| Tachycardia | Sinus | 160–200 | Regular | 1:1 | 160–200 | Regular | Long VA | Depends on cause |
| AV reentry | 190–280 | Regular | 1:1 | 190–280 | Regular | Short VA | Major, treatable | |
| Atrial flutter | 300–500 | Regular | Mainly 2:1 | 150–250 | Mainly regular | Major, treatable | ||
| AET, PJRT | 180–230 | Regular | 1:1 | 180–230 | Regular | Long VA | Major, treatable | |
| Ventricular (+VA block) | Normal | Regular | <1:1 | 160–260 | Regular–irregular | Dissociated | Major, treatable |
FETAL TACHYARRHYTHMIA
Mechanisms
A persistent or intermittent fast fetal heart rate is usually the consequence of supraventricular tachycardia, atrial flutter, or sinus tachycardia, with atrial fibrillation, ventricular tachycardia, and junctional ectopic tachycardia as more unusual causes. 1,2 Supraventricular tachycardia itself can be produced by three different mechanisms, namely atrioventricular re-entrant tachycardia, typically involving the atrioventricular node for antegrade conduction and a fast retrograde ventriculo-atrial conducting accessory pathway, permanent junctional reciprocating tachycardia related to retrograde conduction through the slow pathway of the atrioventricular node, and atrial ectopic tachycardia due to enhanced atrial focal automaticity. These can be distinguished echocardiographically on the basis of the arrhythmic pattern and the ventriculo-atrial time relationships. 3 The most common form underscoring fetal tachycardia, atrioventricular re-entry, presents electro-mechanically as a short ventriculo-atrial arrhythmia, the atrium being activated shortly after the ventricles via the fast retrogradely conducting accessory pathway. Re-entry within the atrioventricular node, another potential mechanism of a short ventriculo-atrial tachycardia, is probably rare in the fetus. Therapeutic intervention to terminate atrioventricular or atrioventricular nodal re-entrant tachycardia is aimed at interrupting the balance in timing between the electrical pathways required to sustain the re-entrant circuit.
In long ventriculo-atrial supraventricular tachycardia, which is considerably less common but often more difficult to control when compared to atrioventricular re-entry, the atrial contraction closely precedes the ventricular contraction. This pattern of activation is seen during atrial ectopic tachycardia and permanent junctional reciprocating tachycardia, but also characterises sinus tachycardia. Treatment of atrial ectopic tachycardia aims at the suppression of the ectopic generation of impulses. A variety of treatable conditions occurring during pregnancy may be responsible for sustained sinus tachycardia, including fetal distress, anaemia, infections, maternal β-stimulation, and fetal thyrotoxicosis. The importance of sinus tachycardia is in recognising and treating the underlying cause.
Atrial flutter is sustained by a circular macro–re-entrant pathway that is completely contained within the atrial wall. The atrioventricular node is not part of the re-entry circuit, but serves to transmit the atrial flutter waves to the ventricles. The atrial rate typically exceeds 300 beats per minute, which is sufficiently fast that only every second or third atrial re-entrant wave is conducted through the atrioventricular node, producing ventricular rates of between 150 and 250 beats per minute. Management of atrial flutter aims to terminate the atrial re-entrant circuit, or to delay atrioventricular nodal conduction to achieve a more physiologic fetal heart rate, with improved cardiac filling and output.
Reasons for Fetal Care
There is extensive experience in the management of fetal supraventricular tachycardia and atrial flutter, while data on fetal ventricular tachycardia and junctional ectopic tachycardia is limited to a handful of case reports. Irrespective of the arrhythmic mechanism, three options can be considered if a fetal tachyarrhythmia is detected. The first is not to attempt treatment. The second option is to institute intra-uterine pharmacological therapy, while the third option is to deliver the fetus and opt for neonatal care. The choice should be based on the condition of the fetus; the characteristics of the arrhythmia in terms of duration, heart rate, and mechanism; the gestational age; the condition of the mother; and the willingness of the mother to undergo treatment. The benefits and risks of the different options must be discussed with both the parents.
In the non-hydropic fetus with a new diagnosis of an intermittent, or even persistent, tachyarrhythmia after 35 weeks of gestation, observation without anti-arrhythmic pharmacologic therapy may be a safe approach, because hydrops will rarely develop, presumably due to improved intrinsic myocardial properties of the fetal heart during late gestation. On the other hand, pharmacological control of the arrhythmia will facilitate vaginal delivery by allowing the interpretation of the tracings showing the fetal heart rate during labour. If close monitoring without treatment is not feasible, delivery by caesarian section and postnatal conversion to sinus rhythm is the usual choice.
Prior to 35 weeks of gestation, the risks associated with premature delivery probably outweigh the potential hazards of pharmacological treatment to the mother and the fetus. Treatment with drugs aims prenatally to control the disturbance of rhythm in order to prevent or treat fetal cardiac failure. Irrespective of the mechanism of tachycardia and the underlying fetal heart rate, the likelihood of heart failure increases if the tachycardia is incessant and if the fetus has a lower gestational age at diagnosis. 4 It is well established, nonetheless, that an intermittent arrhythmia pattern may also result in fetal hydrops and death. 5 As a consequence, intra-uterine treatment with drugs is offered to the majority of fetuses encountered with intermittent and incessant tachyarrhythmia, even in the absence of fetal compromise. Still, for those cases presenting with only brief and occasional runs of tachycardia in the absence of haemodynamic impairment, abstention from pharmacological treatment and close monitoring for signs of progression may be a valid option, as the arrhythmia often resolves spontaneously.
While antiarrhythmic drugs are usually well-tolerated, some of the most commonly used agents, such as digoxin and flecainide, have narrow margins between levels in the serum that are therapeutic, and those that may be associated with toxicity. In addition, virtually all antiarrhythmic agents have proarrhythmic potentials to provoke new, or to exacerbate existing, arrhythmias. These risks must be factored into a common-sense analysis of risk versus benefit. To our knowledge, no serious maternal complications owing to transplacental or direct fetal anti-arrhythmic pharmacological therapy have been reported thus far in the medical literature. The rate of mortality of treated non-hydropic fetuses with supraventricular tachycardia or atrial flutter ranges between 0% and 5%, whereas up to one-fifth of hydropic fetuses will have a fatal outcome. Comprehensive data on the outcome of untreated fetal tachyarrhythmia is not available.
Treatment
There is no single medication that can safely and effectively convert all fetal tachyarrhythmias to a normal rhythm. In the absence of such a magic bullet, schemes for management are frequently based on personal preferences and experiences, and thus may significantly differ among institutions. In Table 12-2 , we illustrate the pharmacokinetics and risks of agents that are commonly used to treat fetal tachyarrhythmias, while in Table 12-3 we list the published experience with first and second lines of drugs used for treatment, discussing these features later in the text.
| Drug | Fetal Indications | Dosage and Therapeutic Concentrations | F:M Ratio | Maternal Effects | Fetal and Neonatal Effects |
|---|---|---|---|---|---|
| Digoxin | SVT, AF |
|
| Narrow therapeutic range; Nausea, anorexia, disturbed vision, fatigue, sinus bradycardia, AV block, VT | Contraindicated in WPW syndrome (not known prenatally) |
| Flecainide | SVT, AF |
| 0.7–0.9 | Proarrhythmia, blurred vision, nausea, paresthesia, headache, negative inotropy | Proarrhythmia, negative inotropy |
| Sotalol | SVT, AF, VT | Oral 80 mg q 12h–160 mg q 8h | 0.7–2.9 | Proarrhythmia, bradycardia, fatigue, hypotension, dizziness | Proarrhythmia, bradycardia |
| Amiodarone | SVT, VT |
|
| Proarrhythmia, bradycardia, lung fibrosis, thyroid dysfunction, hepatitis, photosensitivity; corneal micro-deposits, neuropathy, myopathy | Proarrhythmia, transient thyroid dysfunction, growth restriction |
| Propranolol | Thyrotoxicosis | Oral 60–120 mg q 6–8h | 0.9–1.3 | Bradycardia, AV block, fatigue, hypotension, worsening of diabetes, bronchospasm, cold extremities | Growth restriction, bradycardia, respiratory depression, hypoglycemia |
| Propylthiouracil | Thyrotoxicosis |
| 1.9 | Agranulocytosis, nausea, vomiting, loss of taste, skin rash, itching, drowsiness, dizziness, headache | Risk of hypothyroidism; goiter |
| Dexamethasone | Immune-mediated AV block; EFE |
| 0.3 | Adrenal gland suppression, weight gain, fluid retention, hypertension, mood changes, insomnia, irritability, striae, hair growth, diabetes, impaired wound-healing, susceptibility to infections | Oligohydramnios, growth restriction, impaired wound-healing, (?) delayed brain development |
| β-agonists | Immune-mediated AV block |
| 0.5 | Palpitation, tremor, diaphoresis, dyspnea, hyperglycemia, chest pain, nausea, nervousness, dizziness, arrhythmias | Neonatal hypoglycemia |
| Immune-globulin | Immune-mediated AV block; EFE |
| ↑ with age | Headache, chest pain, fever, chills, nausea, malaise, anaphylaxis (rare), aseptic meningitis | Not reported |
| Authors | Case Numbers | Age | Hydrops | Medication | Choice | 1 Drug | ≥2 Drugs | Rhythm Control | Fetal Outcome | Maternal Events |
|---|---|---|---|---|---|---|---|---|---|---|
| Kleinman et al 9 |
|
|
|
|
|
|
|
| 1 FD (H) | 1: AV-block after verapamil |
| Van Engelen et al 10 | 34 SVT, 16 AF | n/m |
|
|
|
|
|
| 1 FD; 1 NND (2H) | |
| Frohn-Mulder et al 11 | 36 SVT; 14 AF | 16–41 |
|
|
|
|
| 3 FD; 2 NND (5H) | ||
| Simpson and Sharland 12 | 105 SVT; 22 AF | 21–36 |
|
|
|
|
|
|
| |
| Jaeggi et al 3 |
|
|
|
|
|
|
|
| 1 FD (H)# | |
| Ebenroth et al 13 | 34 SVT; 6 AF | n/a | Yes: 5 |
|
| 37 | 13 |
| ||
| Krapp et al 24 | 24 SVT | 26–36 | Yes: 15 |
|
| 24 |
|
| ||
| Fouron et al 15 | 5 short VA SVT |
|
|
| 4 | 1 |
| |||
| 6 AF | 27–36 |
|
|
| 4 | 2 |
| 1 NND | ||
| Jaeggi et al 16 | 15 AF | 27–38 | Yes: 0 |
| First | 11 | 2 |
| ||
| Allan et al 18 | 12 SVT; 2 AF | 23–36 | Yes: 9 | Flecainide | First | 14 | 12/14 (86) | 1 FD† | 2: vision anomaly + dizziness | |
| Van Engelen et al 10 | 34 SVT, 16 AF | n/a |
|
|
|
| 3 |
| ||
| Frohn-Mulder et al 11 | 36 SVT; 14 AF | 16–41 | Yes: 7 | Flecainide | First | 7 | 3/7 (43) | 1 ND (H) | ||
| Simpson and Sharland 12 | 105 SVT; 22 AF | 21–36 | Yes: 27 |
|
| 27 |
|
|
| |
| Joannic et al 14 | 22 SVT; 4 AF | 19–37 | Yes: 26 | Flecainide | First | 12 | 7/12 (58) | 1 FD; 1 TOP; 1 NND (3H) | ||
| Oudijk et al 17 | 10 SVT | 21–37 | Yes: 5 |
|
| 10 | 3 |
| 3 FD (2H) |
|
| 10 AF | Yes: 3 |
|
| 10 | 4 |
| 1 FD (H) | |||
| Oudijk et al 27 |
| n/m |
|
|
|
|
|
|
| No |
| Fouron et al 15 | 5 long VA SVT |
| Yes: 2 |
|
| 1 | 3 |
| No | |
| Sonesson et al 29 | 14 SVT | 24–35 | Yes: 8 |
| Second | 14 | 10/14 (71) | 2 FD (2H)# | No | |
| Strasburger et al 31 | 15 SVT; 9 AF 1 VT; 1 JET | Yes: 24 |
|
| 1 | 25 |
| 5 transient thyroid dysfunction |
| |
| Joannic et al 14 | 22 SVT; 4 AF | 19–37 | Yes: 26 |
|
| 4 | 9 |
|
|
Because of the risk of hazardous complications, each antiarrhythmic treatment other than digoxin should probably be started in an inpatient setting to allow serial monitoring of the maternal electrocardiogram and the fetal cardiac rhythm. To exclude unsafe maternal conditions, such as long-QT syndrome for class III agents, or ventricular pre-excitation for digoxin, the pregnant mother should undergo a detailed medical examination, a 12-lead electrocardiogram, and testing of the electrolytes in the maternal serum prior to administration of any medication. Thyroid function should be checked if fetal hyperthyroidism is suspected, or if treatment with amiodarone is considered. The risk of dangerous side-effects 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 pharmacological treatment is required.
Choice of Drug
A clear understanding of the pharmacokinetics, actions, and indications of the handful of clinically relevant pharmaceuticals is essential if the tachycardia is to be treated efficiently and safely.
Digoxin
Digoxin is the preferred choice for fetal atrioventricular re-entrant tachycardia and atrial flutter in the absence of fetal hydrops. The drug has two main effects. First, it induces vagal slowing of the sinus node and atrioventricular nodal conduction, and second, it enhances myocardial contractility. The positive inotropic effect is the result of an inhibition of the sodium-potassium adenosine triphosphatase pump, which leads to an increase in the level of sodium ions in the myocytes, triggering a rise in the intracellular level of calcium ions by the exchange of sodium and calcium ions.
Dosing and Pharmacokinetics
Oral or intravenous maternal digoxin loading is recommended for more urgent fetal indications. A standard oral loading dose of digoxin is 0.5 mg given twice daily for 2 days, followed by a maintenance dose of from 0.25 to 0.75 mg daily, aiming at achieving maternal concentrations at the upper therapeutic range, namely 2 to 2.5 ng/mL. When no loading dose is given, steady-state concentrations are achieved after 5 to 7 days on maintenance therapy. Approximately four-fifths of the tablet form is absorbed from the gastrointestinal tract, and one quarter of the drug is bound to plasma proteins. Elimination occurs via the kidneys, and adjustment of dosage is required in the setting of maternal renal failure. Digoxin readily crosses the placenta, reaching similar concentrations in the fetal and maternal serums. The transplacental passage of the drug is hampered in the setting of fetal hydrops, and adequate levels are usually not obtained in the fetal serum. 6
Interactions
There are numerous known interactions, including those with amiodarone and flecainide, both of which increase the levels of digoxin.
Adverse Effects and Precautions
Use of digoxin is contraindicated in the settings of Wolff-Parkinson-White syndrome, higher-degree atrioventricular block, and hypertrophic obstructive cardiomyopathy. The incidence of undesired symptoms correlates with the concentration of the drug achieved in the plasma. In the elderly adult treated with digoxin for cardiac conditions, adverse effects include loss of appetite, nausea, vomiting, diarrhoea, blurred vision, confusion, drowsiness, dizziness, nightmares, agitation, and depression. Uncommon symptoms are acute psychosis, delirium, amnesia, atrial or ventricular tachycardia, and atrioventricular block. No major adverse events have been reported during pregnancy.
Treatment of the Fetus
Successful transplacental treatment of fetal supraventricular tachycardia with digoxin was first reported in 1980. 7,8 The first larger case series reporting efficacy in reversing fetal supraventricular tachycardia to a normal rhythm was published 5 years later, 9 conversion to a normal rhythm being achieved in seven-tenths of cases with digoxin given either alone to the mother, or in combination with another antiarrhythmic drug. Similar results were obtained by others, 3,10–14 albeit that the rate of success declined to one-tenth if there was fetal hydrops. 10 Apart from fetal hydrops, digoxin administered transplacentally is less effective for atrial ectopic tachycardia and permanent junctional reciprocating tachycardia, while it is most efficient in atrioventricular re-entrant tachycardia. 3,15 The drug slows atrioventricular conduction and the rate of tachycardia in fetuses with atrial flutter, but is less likely to restore a normal cardiac rhythm when compared to sotalol alone, or to the combination of digoxin and sotalol. 16,17 Digoxin, therefore, is a safe and reasonably efficient first line of transplacental therapy for atrioventricular re-entrant tachycardia, the most common cause of persistent fetal tachycardia. In the presence of hydrops, atrial flutter, atrial ectopic, and permanent junctional reciprocating tachycardia, class 1c or class III agents either alone, or combined with digoxin, are more effective therapeutic choices.
Flecainide
Flecainide is the most extensively used class Ic agent for treatment of fetal supraventricular tachycardia. The drug blocks slow sodium channels, causing prolongation of the cardiac action potential. The electrophysiological effect is slowing of the electrical conduction in the His-Purkinje system and ventricular myocardium, along with reduction in ventricular contractility. The blocking effect on the cardiac sodium channels increases as the heart rate increases. This means that flecainide is potentially most useful to break an abnormal rhythm associated with a rapid heart rate.
Dosing and Pharmacokinetics
To treat a fetal arrhythmia, the standard oral dosage of flecainide is 300 mg/day, given in three doses. The drug is well-absorbed, and peak levels are obtained within 2 to 4 hours. A small amount of the drug is bio-transformed in the liver to nearly inactive metabolites. Flecainide is primarily excreted in the urine. The drug crosses the placenta readily, even in the presence of fetal hydrops. 18,19 Therapeutic levels in the mother are reached within 3 days of commencing treatment.
Interactions
There are numerous interactions with other agents. Amiodarone, for example, may increase the levels of flecainide by inhibiting cytochrome 450, which is used to metabolise flecainide. Flecainide increases the concentration of digoxin by about one-fifth.
Adverse Effects and Precautions
Flecainide depresses cardiac performance, particularly in patients with compromised myocardial function. The chance of proarrhythmia increases in the presence of major structural cardiac disease, ventricular dysfunction, ventricular arrhythmias, and hypokalemia. 20,21 Thus, flecainide should be avoided in individuals with any of these conditions. Flecainide can safely be used in predominantly healthy mothers carrying fetuses with supraventricular tachycardia. 22 Adverse events such as blurred vision, dizziness, headache, nausea, paresthesia, fatigue, tremor, and nervousness were uncommon in a placebo-controlled trial. 23 No major maternal side-effects are reported. 12–14,24
Trans-placental Treatment
When used as the drug of choice, flecainide controlled supraventricular tachycardia and atrial flutter in two-thirds of cases. 10–12,14,18 This improved to almost four-fifths if a second antiarrhythmic drug was added. 14 No maternal adverse effects were observed, but one-quarter of fetuses died either during fetal life or as neonates. Severe fetal bradycardia causing death was observed in one fetus with only mild ascites shortly after commencing treatment with flecainide. 14 Control in excess of nine-tenths of cases was observed when flecainide and digoxin were used in combination. 13,24 When given at therapeutic doses, therefore, flecainide provides safe and effective treatment for fetal supraventricular tachycardia. When flecainide was the preferred choice to treat hydropic fetuses, however, around one-sixth of fetuses died in the perinatal period.
Sotalol
Sotalol is used to treat both fetal supraventricular tachycardia and atrial flutter. No data exist on its use in fetal ventricular tachycardia. The actions of sotalol include those of both class II agents, providing non-selective β-blockade, and class III effects, with prolongation of the duration of the cardiac action potential. The drug inhibits inward potassium channels, progressively prolonging refractoriness of the working myocardial and conduction tissues at slower heart rates. 25 Clinically, this may mean that the prolongation of the action potential is more effective at preventing the initiation of a tachycardia than in terminating one once established. Sotalol exhibits a positive inotropic effect, particularly at a slower heart rate. 26 The β-blocking potency of sotalol is up to half of that of propranolol when compared milligram per milligram. Beta-blockade decreases the heart rate, and delays atrioventricular nodal conduction.
Dosing and Pharmacokinetics
To treat the fetus, the typical starting dose given to the mother is 160 mg per day, given in two doses. If there is fetal hydrops, we would commence with 320 mg per day, either alone or in combination with digoxin. If there is no conversion to a normal rhythm within several days of administration, we would increase the dose further to a maximal daily level of 480 mg, given in three doses. The drug is completely absorbed and peak concentration in the plasma is reached within 2 to 4 hours of oral administration. The compound is secreted in the urine, and it may be necessary to regulate the dose in mothers with renal failure. Placental transfer is excellent, and the drug does not accumulate in the fetus. 27
Adverse Effects
The most feared adverse effect is torsade de pointes, which may present with a range of clinical symptoms from palpitations to syncope to sudden death. The incidence of ventricular proarrhythmia in adults with supraventricular tachycardia is less than 2%. Probably the most effective way to prevent maternal proarrhythmia is by avoiding excessive prolongation of the QTc interval. 25 The prevalence of maternal electrocardiographic changes is unknown, but no significant prolongation of the neonatal QTc interval has been found after administration of up to 480 mg per day to the mother for treatment of fetal supraventricular tachycardia. 27 Adverse effects related to the β-blocking properties include arterial hypotension, bradycardia, worsening of asthma or obstructive lung disease, depression, fatigue, insomnia, and impaired sexual function. Its safety was assessed in a randomised, double-blind trial in adults, 28 with one-twentieth of patients discontinuing the drug because of side-effects related to β-blockade.
Treatment of the Fetus
When used as a first line agent, the drug controlled supraventricular tachycardia and atrial flutter in two-thirds of fetuses. 15,17,27 Higher rates of conversion to a normal rhythm were observed when sotalol was started jointly with digoxin when the arrhythmia was diagnosed, or eventually used as a combination to treat resistant supraventricular tachycardia. 3,17,19,29 Transient maternal side-effects, such as nausea, dizziness, and fatigue, were reported in one-tenth of mothers. 17 Conflicting data exist on the role in the fetus, even from the same investigators. 17,27 When used as a first line agent, however, the drug was shown to convert over nine-tenths of fetuses with supraventricular tachycardia or atrial flutter to a normal rhythm. Sotalol, therefore, is an efficient and safe drug with which to treat fetal supraventricular tachycardia and atrial flutter when there are no maternal contraindications to its actions. The overall rate of perinatal death in fetuses treated with transplacental sotalol was 18%.
Amiodarone
Amiodarone has mainly been used to treat drug-resistant fetal tachyarrhythmias associated with cardiovascular compromise. There is considerable data documenting its efficacy and reasonable safety in children and adults with supraventricular and ventricular tachycardias. The drug, which acts by blocking the potassium channels, lengthens the duration of the action potential and cardiac refractoriness at all heart rates. It also acts to produce β-blockade, to block the L-type calcium channels, and to slow His-Purkinje and myocardial conduction at rapid heart rates. It does not affect ventricular contractility.
Dosing and Pharmacokinetics
To achieve therapeutic fetal concentrations, oral loading doses of from 1600 to 2400 mg per day are given to the mother for from 2 to 7 days, followed by maintenance doses of 200 to 400 mg per day. 14,30,31 The drug has unusual pharmacokinetics, with absorption of the drug given orally ranging from one-third to two-thirds, and peak concentrations in the plasma being reached within 3 to 7 hours of ingestion. Amiodarone is metabolised in the liver to its major metabolite, desethylamiodarone, which also has antiarrhythmic properties. Because of their lipophilicity, the compounds accumulate in many tissues, including fat, liver, lung, skin, and myocardium. Excretion is predominantly via shedding of epithelial cells of the skin and gastrointestinal tract. The half-life for elimination is between 3 and 10 days for the first 50% of the drug, and is then slower due to slowed release from tissue stores. As a consequence, clinically important levels may persist for several months following cessation of administration. Amiodarone and desethylamiodarone incompletely cross the placenta to the fetus, with only one-sixth reaching the fetus for amiodarone, albeit a somewhat higher ratio existing for desethylamiodarone. 32 Transplacental transfer is reduced still further in hydropic fetuses. 33
Interactions
Amiodarone interferes with the pharmacokinetics of a large variety of drugs, such as digoxin, class Ic agents, tricyclic antidepressants, and general anaesthetics. Doses of most other drugs need to be reduced in individuals taking amiodarone.
Adverse Effects
Amiodarone has numerous side-effects. The most serious reaction is interstitial lung disease, which occurs in up to one-tenth of adults receiving doses of amiodarone greater than 400 mg per day over prolonged periods of time. Pulmonary fibrosis has also been documented during therapy at low doses and short duration. Clinical findings suggesting pulmonary toxicity include coughing, dyspnea, fever, chest pain, high sedimentation rates, and bilateral lung infiltrates. If diagnosed at an early stage, the disease may be reversible. Due to the high iodine content, and the structural similarity of amiodarone to thyroxine, thyroid dysfunction is common, being found in almost one-tenth of chronically treated individuals. Asymptomatic, reversible corneal microdeposits are almost universally present if the drug is taken for at least 6 months. Hepatitis may also occur. As a precaution, periodic ophthalmic, hepatic and thyroid function tests are recommended for patients receiving amiodarone. There is a low risk of torsade de pointes, which can be minimised by keeping the QTc interval in a near-normal range. Adverse fetal effects attributable to amiodarone include congenital hypo- and hyper-thyroidism, retardation of growth, bradycardia, and prolongation of the QTc interval.
Treatment of the Fetus
Transplacental amiodarone has been shown to restore sinus rhythm in two-thirds of hydropic fetuses with drug-refractory tachyarrhythmias. 14,31 Of the treated fetuses, one-twentieth died, and side-effects serious enough to withdraw the drug occurred in one woman, who suffered photosensitivity dermatitis and thrombocytopenia. Transient biochemical signs of thyroid dysfunction were seen in one-fifth of both fetuses and mothers. Other maternal side-effects were mild sinus bradycardia and transient incomplete atrioventricular block during loading with the drug. Because of the maternal and fetal risks, therefore, amiodarone should be reserved for drug-refractory fetal tachyarrhythmias in hydropic fetuses with ventricular dysfunction.
Direct Fetal Treatment
Direct fetal treatment is reserved for the rare, severely hydropic fetus with a drug-refractory tachyarrhythmia. As mentioned previously, the transplacental transfer of some antiarrhythmic agents is significantly hampered in the presence of fetal hydrops, and thus therapeutic levels of drugs may not be reached even with toxic maternal doses. To overcome this problem, repeated intravenous, intramuscular and intraperitoneal fetal injections of amiodarone, digoxin and adenosine, in addition to the conventional therapy, has been successfully performed to resolve multi-drug refractory fetal tachyarrhythmia complicated by fetal hydrops. 33–38 Direct intravenous adenosine may instantly terminate re-entrant supraventricular tachycardia, but because of its short duration of action, direct treatment should be combined with a longer acting antiarrhythmic agent. Amiodarone seems to be predestined for the direct use, both because of its efficiency and long-half life, limiting the number of invasive fetal procedures that are required to maintain therapeutic levels.
Other Antiarrhythmic Agents
Other antiarrhythmic agents, such as verapamil, procainamide, and quinidine are no longer used for prenatal therapy, because of substantial side-effects in both mother and fetus, and/or insufficient antiarrhythmic actions. By contrast, maternal intravenous infusion of magnesium and lidocaine, a blocker of the sodium channel that shortens the duration of the QT interval, has been used to suppress fetal torsades de pointes associated with congenital long QT syndrome diagnosed prenatally by fetal magnetocardiography. 39
Summarising the published results, digoxin remains a drug of choice in the treatment of fetal atrioventricular re-entrant tachycardia in the absence of fetal hydrops, although some centers nowadays favour more potent and equally safe medication. In terms of converting atrial flutter to sinus rhythm, sotalol appears to be more effective than digoxin. In the setting of fetal hydrops, a class Ic or class III drug, either alone or in combination with digoxin, is the preferred treatment for supraventricular tachycardia, with the most favourable outcomes reported for amiodarone. The primary use of amiodarone, an antiarrhythmic agent with no negative inotropy, should be considered if the fetal myocardial contractility is severely hampered. Control of the rate of tachycardia, or conversion to sinus rhythm, is achieved in the majority of cases within a few days of transplacental treatment with a single drug, or with combinations of therapeutic agents. Once the arrhythmia is under control, the antiarrhythmic treatment is usually maintained to birth, with weekly monitoring of the fetal heart rate to detect arrhythmic recurrence. If supraventricular tachycardia recurs spontaneously after birth, or is easily inducible, for example by transoesophageal electrophysiological study, the antiarrhythmic treatment, usually with a β-blocker, will be continued for at least 6 to 12 months. In up to one-fifth of infants, the supraventricular tachycardia will persist beyond 1 year of age. In contrast, postnatal recurrence of atrial flutter is uncommon, and antiarrhythmic long-term prophylaxis is usually not required. 16,40
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