EDITORIAL COMMENTARY
Use of maternal flecainide concentration in management of fetal supraventricular tachycardia: A step in the right direction Bettina F. Cuneo, MD,* D. Woodrow Benson, MD, PhD† From the *Children’s Hospital Colorado, University of Colorado School of Medicine Denver, Colorado, and †Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin.
It has been a little more than 30 years since initial reports of successful transplacental treatment of fetal supraventricular tachycardia (SVT) first appeared.1 However, anyone who treats fetal SVT knows this is still a complicated and challenging endeavor, and the ultimate goal—delivery of a nonhydropic term infant in sinus rhythm—can be difficult to achieve. In this issue of HeartRhythm, Vigneswaran et al2 make a significant contribution to fetal SVT management in their study of the relationship between maternal serum flecainide concentrations and conversion of fetal SVT to sinus rhythm. SVT is a common abnormality of heart rhythm in fetuses, infants, and children, and in the past 60 years we have learned a great deal about the mechanisms of SVT or paroxysmal atrial tachycardia as it was also known. Based on electrocardiographic and electrophysiologic features of SVT mechanisms, it is now known that the term SVT is frequently a misnomer. For example, in SVT using an accessory atrioventricular (AV) connection, participation of both atria and ventricles is essential for the continuation of tachycardia. In contrast, in tachycardia thought to result from reentry within the AV node, the precise role of the atria and ventricles in maintaining tachycardia is unclear. Finally, there are types of SVT, for example, ectopic atrial tachycardia, that are supraventricular, as the atria are the principal site of the electrophysiologic disturbance. These types of SVT have been termed atrial or primary atrial tachycardias. Based on electrophysiologic and magnetocardiographic findings, the most common mechanism of fetal SVT is an AV reentrant tachycardia using an accessory AV connection, in which both the atrium and the ventricles participate.3,4 We know that accessory AV connections used in fetal SVT are developmental cardiac malformations, and we have learned that postnatal changes in the AV connection reduce susceptibility to SVT.5,6 This finding is relevant to the natural history of fetal SVT and can provide reassurance when counseling parents when their fetus appears to have medically refractory SVT. Address reprint requests and correspondence: Dr D. Woodrow Benson, Children’s Hospital of Wisconsin, Medical College of Wisconsin, 9000 W Wisconsin Avenue, MS550A, Milwaukee, WI 53226. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
Diagnosis of fetal SVT is primarily through its echo Doppler characteristics including atrial and ventricular rates and AV relationship (1:1 or 41:1). By using Doppler images, tachycardia cycle length can be divided into ventriculoatrial (VA) and AV intervals; the AV and VA intervals are useful for further characterizing fetal SVT into long and short VA tachycardias. The finer nuances of fetal SVT including initiating and terminating events can be gleaned from magnetocardiography, a technique used largely on a research basis.6 The ultimate goal of fetal SVT management—the delivery of a nonhydropic term infant in sinus rhythm—is challenging on many levels. First, most experience is from single centers and there have been no randomized controlled trials evaluating the efficacy of different antiarrhythmic medications in a large number of maternal/fetal patients. Consequently, management strategies tend to be somewhat provincial. Second, both the fetal patient and his normal mother are exposed to the antiarrhythmic medication and its side effects, including, but not limited to, the risk of proarrhythmia, nausea, fatigue, and dizziness. If one medication is not successful in converting the SVT, additional medications are often added, increasing the risk of side effects. Third, the mother can be effectively monitored during transplacental treatment with electrocardiograms and serum drug concentrations, but the effect of the treatment on the fetus is limited to changes in the heart rate, rhythm, and mechanical PR interval surmised by echocardiography. Finally, one of the most challenging aspects of fetal SVT “treatment” is the ongoing discussion between obstetrical care providers and perinatal cardiologists as to whether to deliver or continue in utero treatment of the fetus with SVT. The placenta provides a link between the circulations of the mother and fetus. It has been shown that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the fetus via passive diffusion, but some drugs are pumped across the placenta by various active transporters located. Transplacental drug transfer has been difficult to study because transfer characteristics differ across mammalian species in a drug-specific manner. The medications used most commonly to treat fetal SVT are digoxin, flecainide, and sotalol, alone or in combination. http://dx.doi.org/10.1016/j.hrthm.2014.08.017
Cuneo and Benson
Editorial Commentary
The choice of antiarrhythmic agent is usually guided by the mechanism of tachycardia, the fetal state, and the preference of the treating physician. For example, long VA SVT does not typically respond to digoxin, while digoxin can be effective in 40%–60% of short VA tachycardias. Furthermore, transplacental pharmacokinetics differ between antiarrhythmic medications and the fetal state, that is, the presence or absence of hydrops fetalis. Conversion to sinus rhythm is most urgent for the hydropic fetus with a poor biophysical profile score and may necessitate multiple medications or multiple routes of administration (transplacental plus direct fetal therapy). Although amiodarone is an effective antiarrhythmic medication in the fetus7 because of its potential side effects, it is mostly used if other antiarrhythmic medications alone or in combination have failed to convert fetal SVT.8 Flecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat a variety of tachycardias in patients of all ages. It has been available in Europe for more than 3 decades and in the United States for more than 2 decades. Despite some concerns about safety,9 early studies of the fetus by Dr Lindsay Allen showed efficacy for SVT.10 Antiarrhythmic properties of flecainide are due to dose-dependent depression of conduction throughout the myocardium and prolongation of refractory periods in the AV node, atria, and ventricles. Transplacental transfer is excellent, and previous studies have shown that maternal flecainide administration frequently results in rapid and sustained conversion to sinus rhythm in both hydropic and nonhydropic fetuses. When using flecainide to treat fetal SVT, the SVT mechanism is important. For example, because flecainide can increase the ventricular response to atrial flutter, it is contraindicated for that arrhythmia. In the initial experience of flecainide for treatment of fetal SVT, morality of both hydropic and nonhydropic fetuses (as high as 18%) was a major concern. However, over the past decade, reported morality has been limited to severely hydropic fetuses. In this issue of HeartRhythm, findings of Vigneswaran et al2 further support the safety and efficacy of flecainide for the treatment of fetal SVT. This new study clearly shows the
2055 utility of maternal serum flecainide concentration. In their study, SVT conversion was excellent, with no fetal mortality even with high doses (4300 mg/d) and high flecainide concentrations. Furthermore, in their study, failure of flecainide treatment to convert SVT was not related to maternal drug concentration. While these results are important for the treatment of fetal SVT, this is a single-center observational study. Fortunately for the field, the gauntlet has been thrown11 and a randomized multicenter trial, the Fetal Atrial Flutter and Supraventricular Tachycardia trial recently funded by the Canadian Institutes of Health Research, is underway. Until then, based on results to date, treatment of the fetus with sustained tachycardia is mandatory, and flecainide is safe and effective.
References 1. Harrigan JT, Kangos JJ, Sikka A, Spisso KR, Natarajan N, Rosenfeld D, Leiman S, Korn D. Successful treatment of fetal congestive heart failure secondary to tachycardia. N Engl J Med 1981;304:1527–1529. 2. Vigneswaran TV, Callaghan N, Andrews RE, Miller O, Rosenthal E, Sharland GK, Simpson JM. Correlation of maternal flecainide concentrations and therapeutic effect in fetal supraventricular tachycardia. Heart Rhythm 2014;11:2047–2053. 3. Ko JK, Strasburger JF, Benson DW. Supraventricular tachycardia mechanisms and their age distribution in pediatric patients. Am J Cardiol 1992;69:1028–1032. 4. Strasburger JF, Wakai RT. Fetal cardiac arrhythmia detection and in utero therapy. Nat Rev Cardiol 2010;7:277–290. 5. Benson DW, Dunnigan A, Benditt DG. Follow-up evaluation of infant paroxysmal atrial tachycardia: transesophageal study. Circulation 1987;75: 542–549. 6. Wakai RT, Strasburger JF, Li Z, Deal BJ, Gotteiner NL. Magnetocardiographic rhythm patterns at initiation and termination of fetal supraventricular tachycardia. Circulation 2003;107:307–312. 7. Strasburger JF, Cuneo BF, Michon MM, Gotteiner NL, Deal BJ, McGregor SN, Oudijk MA, Meijboom EJ, Feinkind L, Hussey M, Parilla BV. Amiodarone therapy for drug-refractory fetal tachycardia. Circulation 2004;109:375–379. 8. Jaeggi ET, Carvalho JS, De Groot E, Api O, Clur SB, Rammeloo L, McCrindle BW, Ryan G, Manlhiot C, Blom NA. Comparison of transplacental treatment of fetal supraventricular tachyarrhythmias with digoxin, flecainide, and sotalol: results of a nonrandomized multicenter study. Circulation 2011;124:1747–1754. 9. Fish FA, Gillette PG, Benson DW; The Pediatric Electrophysiology Group. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. J Am Coll Cardiol 1991;18:356–365. 10. Allan LD, Chita SK, Sharland GK, Maxwell D, Priestley K. Flecainide in the treatment of fetal tachycardias. Br Heart J 1991;65:46–48. 11. Saul JP, Cain NB. Can we do a prospective trial for fetal tachycardia? The barriers to clinical trials in small patient populations. Circulation 2011;124:1703–1705.
Use of maternal flecainide concentration in management of fetal supraventricular tachycardia: A step in the right direction Bettina F. Cuneo, MD,* D. Woodrow Benson, MD, PhD† From the *Children’s Hospital Colorado, University of Colorado School of Medicine Denver, Colorado, and †Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin.
It has been a little more than 30 years since initial reports of successful transplacental treatment of fetal supraventricular tachycardia (SVT) first appeared.1 However, anyone who treats fetal SVT knows this is still a complicated and challenging endeavor, and the ultimate goal—delivery of a nonhydropic term infant in sinus rhythm—can be difficult to achieve. In this issue of HeartRhythm, Vigneswaran et al2 make a significant contribution to fetal SVT management in their study of the relationship between maternal serum flecainide concentrations and conversion of fetal SVT to sinus rhythm. SVT is a common abnormality of heart rhythm in fetuses, infants, and children, and in the past 60 years we have learned a great deal about the mechanisms of SVT or paroxysmal atrial tachycardia as it was also known. Based on electrocardiographic and electrophysiologic features of SVT mechanisms, it is now known that the term SVT is frequently a misnomer. For example, in SVT using an accessory atrioventricular (AV) connection, participation of both atria and ventricles is essential for the continuation of tachycardia. In contrast, in tachycardia thought to result from reentry within the AV node, the precise role of the atria and ventricles in maintaining tachycardia is unclear. Finally, there are types of SVT, for example, ectopic atrial tachycardia, that are supraventricular, as the atria are the principal site of the electrophysiologic disturbance. These types of SVT have been termed atrial or primary atrial tachycardias. Based on electrophysiologic and magnetocardiographic findings, the most common mechanism of fetal SVT is an AV reentrant tachycardia using an accessory AV connection, in which both the atrium and the ventricles participate.3,4 We know that accessory AV connections used in fetal SVT are developmental cardiac malformations, and we have learned that postnatal changes in the AV connection reduce susceptibility to SVT.5,6 This finding is relevant to the natural history of fetal SVT and can provide reassurance when counseling parents when their fetus appears to have medically refractory SVT. Address reprint requests and correspondence: Dr D. Woodrow Benson, Children’s Hospital of Wisconsin, Medical College of Wisconsin, 9000 W Wisconsin Avenue, MS550A, Milwaukee, WI 53226. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
Diagnosis of fetal SVT is primarily through its echo Doppler characteristics including atrial and ventricular rates and AV relationship (1:1 or 41:1). By using Doppler images, tachycardia cycle length can be divided into ventriculoatrial (VA) and AV intervals; the AV and VA intervals are useful for further characterizing fetal SVT into long and short VA tachycardias. The finer nuances of fetal SVT including initiating and terminating events can be gleaned from magnetocardiography, a technique used largely on a research basis.6 The ultimate goal of fetal SVT management—the delivery of a nonhydropic term infant in sinus rhythm—is challenging on many levels. First, most experience is from single centers and there have been no randomized controlled trials evaluating the efficacy of different antiarrhythmic medications in a large number of maternal/fetal patients. Consequently, management strategies tend to be somewhat provincial. Second, both the fetal patient and his normal mother are exposed to the antiarrhythmic medication and its side effects, including, but not limited to, the risk of proarrhythmia, nausea, fatigue, and dizziness. If one medication is not successful in converting the SVT, additional medications are often added, increasing the risk of side effects. Third, the mother can be effectively monitored during transplacental treatment with electrocardiograms and serum drug concentrations, but the effect of the treatment on the fetus is limited to changes in the heart rate, rhythm, and mechanical PR interval surmised by echocardiography. Finally, one of the most challenging aspects of fetal SVT “treatment” is the ongoing discussion between obstetrical care providers and perinatal cardiologists as to whether to deliver or continue in utero treatment of the fetus with SVT. The placenta provides a link between the circulations of the mother and fetus. It has been shown that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the fetus via passive diffusion, but some drugs are pumped across the placenta by various active transporters located. Transplacental drug transfer has been difficult to study because transfer characteristics differ across mammalian species in a drug-specific manner. The medications used most commonly to treat fetal SVT are digoxin, flecainide, and sotalol, alone or in combination. http://dx.doi.org/10.1016/j.hrthm.2014.08.017
Cuneo and Benson
Editorial Commentary
The choice of antiarrhythmic agent is usually guided by the mechanism of tachycardia, the fetal state, and the preference of the treating physician. For example, long VA SVT does not typically respond to digoxin, while digoxin can be effective in 40%–60% of short VA tachycardias. Furthermore, transplacental pharmacokinetics differ between antiarrhythmic medications and the fetal state, that is, the presence or absence of hydrops fetalis. Conversion to sinus rhythm is most urgent for the hydropic fetus with a poor biophysical profile score and may necessitate multiple medications or multiple routes of administration (transplacental plus direct fetal therapy). Although amiodarone is an effective antiarrhythmic medication in the fetus7 because of its potential side effects, it is mostly used if other antiarrhythmic medications alone or in combination have failed to convert fetal SVT.8 Flecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat a variety of tachycardias in patients of all ages. It has been available in Europe for more than 3 decades and in the United States for more than 2 decades. Despite some concerns about safety,9 early studies of the fetus by Dr Lindsay Allen showed efficacy for SVT.10 Antiarrhythmic properties of flecainide are due to dose-dependent depression of conduction throughout the myocardium and prolongation of refractory periods in the AV node, atria, and ventricles. Transplacental transfer is excellent, and previous studies have shown that maternal flecainide administration frequently results in rapid and sustained conversion to sinus rhythm in both hydropic and nonhydropic fetuses. When using flecainide to treat fetal SVT, the SVT mechanism is important. For example, because flecainide can increase the ventricular response to atrial flutter, it is contraindicated for that arrhythmia. In the initial experience of flecainide for treatment of fetal SVT, morality of both hydropic and nonhydropic fetuses (as high as 18%) was a major concern. However, over the past decade, reported morality has been limited to severely hydropic fetuses. In this issue of HeartRhythm, findings of Vigneswaran et al2 further support the safety and efficacy of flecainide for the treatment of fetal SVT. This new study clearly shows the
2055 utility of maternal serum flecainide concentration. In their study, SVT conversion was excellent, with no fetal mortality even with high doses (4300 mg/d) and high flecainide concentrations. Furthermore, in their study, failure of flecainide treatment to convert SVT was not related to maternal drug concentration. While these results are important for the treatment of fetal SVT, this is a single-center observational study. Fortunately for the field, the gauntlet has been thrown11 and a randomized multicenter trial, the Fetal Atrial Flutter and Supraventricular Tachycardia trial recently funded by the Canadian Institutes of Health Research, is underway. Until then, based on results to date, treatment of the fetus with sustained tachycardia is mandatory, and flecainide is safe and effective.
References 1. Harrigan JT, Kangos JJ, Sikka A, Spisso KR, Natarajan N, Rosenfeld D, Leiman S, Korn D. Successful treatment of fetal congestive heart failure secondary to tachycardia. N Engl J Med 1981;304:1527–1529. 2. Vigneswaran TV, Callaghan N, Andrews RE, Miller O, Rosenthal E, Sharland GK, Simpson JM. Correlation of maternal flecainide concentrations and therapeutic effect in fetal supraventricular tachycardia. Heart Rhythm 2014;11:2047–2053. 3. Ko JK, Strasburger JF, Benson DW. Supraventricular tachycardia mechanisms and their age distribution in pediatric patients. Am J Cardiol 1992;69:1028–1032. 4. Strasburger JF, Wakai RT. Fetal cardiac arrhythmia detection and in utero therapy. Nat Rev Cardiol 2010;7:277–290. 5. Benson DW, Dunnigan A, Benditt DG. Follow-up evaluation of infant paroxysmal atrial tachycardia: transesophageal study. Circulation 1987;75: 542–549. 6. Wakai RT, Strasburger JF, Li Z, Deal BJ, Gotteiner NL. Magnetocardiographic rhythm patterns at initiation and termination of fetal supraventricular tachycardia. Circulation 2003;107:307–312. 7. Strasburger JF, Cuneo BF, Michon MM, Gotteiner NL, Deal BJ, McGregor SN, Oudijk MA, Meijboom EJ, Feinkind L, Hussey M, Parilla BV. Amiodarone therapy for drug-refractory fetal tachycardia. Circulation 2004;109:375–379. 8. Jaeggi ET, Carvalho JS, De Groot E, Api O, Clur SB, Rammeloo L, McCrindle BW, Ryan G, Manlhiot C, Blom NA. Comparison of transplacental treatment of fetal supraventricular tachyarrhythmias with digoxin, flecainide, and sotalol: results of a nonrandomized multicenter study. Circulation 2011;124:1747–1754. 9. Fish FA, Gillette PG, Benson DW; The Pediatric Electrophysiology Group. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. J Am Coll Cardiol 1991;18:356–365. 10. Allan LD, Chita SK, Sharland GK, Maxwell D, Priestley K. Flecainide in the treatment of fetal tachycardias. Br Heart J 1991;65:46–48. 11. Saul JP, Cain NB. Can we do a prospective trial for fetal tachycardia? The barriers to clinical trials in small patient populations. Circulation 2011;124:1703–1705.
