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Fetal Diagn Ther 2006;21:72–76 DOI: 10.1159/000089052 Received: July 13, 2004 Accepted after revision: December 14, 2004 Amiodarone in Treatment of Fetal Supraventricular Tachycardia A Case Report and Review of Literature Mandakini Pradhana Manishaa Renu Singha Aditya Kapoorb Departments of a Medical Genetics and b Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, U.P., India Key Words Fetal supraventricular tachycardia Amiodarone Hydrops fetalis Abstract We report a case of nonimmune hydrops fetalis detected at 32 weeks of gestation. Fetal heart rate was 300 beats per minute. Ultrasound and fetal Doppler echocardiography showed it to be due to supraventricular tachycardia (SVT). Following failed maternal therapy with digoxin alone, amiodarone with digoxin was used. Conversion to sinus rhythm and resolution of hydrops followed this treatment. Since there is no ideal treatment protocol for these cases at present, we reviewed reports of transplacental treatment of SVT. Copyright © 2006 S. Karger AG, Basel Introduction Nonimmune hydrops accounts for 80% of cases of hydrops fetalis. Cardiac causes are seen in more than 25% cases after 28 weeks’ gestation. Fetal tachyarrhythmia is associated with a significant perinatal morbidity and mortality when hydrops occurs. Although the natural his- © 2006 S. Karger AG, Basel 1015–3837/06/0211–0072$23.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com Accessible online at: www.karger.com/fdt tory remains poorly understood, it seems that half of the fetuses with supraventricular tachycardia (SVT) develop hydrops and of these the majority will develop clinical hydramnios. Perinatal mortality ranges from 40 to 90% in untreated hydrops. A number of drugs like digoxin, propranolol, flecainide, procainamide, verapamil, and amiodarone have been used with varying success in these cases. Here, we report a case of fetal SVT complicated with heart failure; transplacental therapy with amiodarone and digoxin could achieve a sinus rhythm after failure with digoxin alone. Case Report A 28-year-old G3 P2 was referred to our clinic for investigation and treatment of polyhydramnios, observed at 32 weeks of gestation. Her investigations for gestational diabetes (glucose tolerance test), intrauterine infection (antibody titers for toxoplasmosis, cytomegalovirus, rubella, parvovirus B19) were normal. The previous ultrasound done at 20 weeks did not show any abnormality. On ultrasonography, a single live fetus with ascites, pleural and pericardial effusion, and skin edema was seen. The fetal heart rate (FHR) was 300 beats per minute, with a 1:1 atrioventricular conduction. There was no structural cardiac defect. Amniotic fluid index was increased (30 cm) with increased placental thickness (9 cm). The diagnosis of heart failure secondary to SVT was made. Transplacental treatment with digoxin was initiated at the dose of Dr. Mandakini Pradhan Department of Medical Genetics Sanjay Gandhi Postgraduate Institute of Medical Sciences Rae Bareli Road, Lucknow, U.P (India) Tel. +91 522 2668700 2335, Fax +91 522 26680172, E-Mail [email protected] 0.25 mg 6 hourly for 24 h, then once daily. The maternal plasma digoxin levels measured before the subsequent dose was between 1.7 and 2 g/l. Though initially the tachycardia responded to digoxin with reversion to sinus rhythm after 48 h, the tachycardia recurred again within next 24 h. Subsequently, amiodarone at the dose of 1,000 mg/day for 2 days followed by 400 mg/day in two divided doses was added to the existing digoxin therapy of 0.25 mg/ day. FHR reverted to sinus rhythm after 24 h of starting amiodarone. Regular ultrasonography showed FHR in the normal range and there was gradual decrease in fetal ascites and pericardial and pleural effusion until it resolved completely by 35 weeks. The same treatment was continued up to 37 weeks; she delivered a baby girl weighing 2.7 kg by cesarean section in view of transverse lie. The baby had sinus rhythm with no evidence of pre-excitation or signs of cardiac failure at birth, and therefore did not require any treatment. Echocardiography and thyroid profile on 1st, 3rd, and 7th day were normal. The child is now 6 months of age and has not had any recurrence of tachyarrhythmia. Apart from amiodarone, flecainide is another widely used antiarrhythmic drug. Hence, we have analyzed all published data retrieved through PubMed to compare their effectiveness and side effects in treatment of fetal SVT. For the articles which were published in languages other than English, the abstract of the articles were used for analysis. Discussion Identification of the type of arrhythmia is essential before starting transplacental therapy. A tachycardia is defined as FHR in excess of 200 beats/min. SVT is diag- nosed if there is 1:1 atrioventricular conduction, and atrial flutter when the atrial rate is in excess of ventricular rate [1]. In particular, ventricular tachycardia must be excluded, as it contraindicates treatment with digoxin [2]. The earliest gestation at which the SVT has been diagnosed is at 13 weeks [3]. As it is difficult to predict which fetus with tachycardia will eventually develop hydrops, most centers initiate treatment as soon as the diagnosis of fetal tachycardia is established [4]. Most authorities recommend that the fetus should be in SVT more than 50% of the time to initiate treatment. The primary form of pharmacological intervention is maternal transplacental therapy. Other routes of treatment are intravascular and intramuscular treatment of fetus, which is mainly used in refractory cases. Digoxin is the most common drug used to treat fetal tachycardia [4]. Transplacental digoxin has been found to be effective in treating SVT complicated by fetal hydrops in a small percentage, but there has been no consensus regarding antiarrhythmic treatment if digoxin therapy fails. Sotalol was earlier thought to be drug of choice for fetal SVT because it is efficient in treating arrhythmia in infants [5]. However, there has been report of 4 sudden fetal deaths in 21 fetuses treated with sotalol, 3 of which occurred just after initiation of treatment. This suggested a proarrhythmic affect of this drug [4]. Verapamil is also not recommended as it has been associated Table 1. Outcome of transplacental treatment of SVT: literature review S. Authors no. 1 Belhassan et al. [12] Total no. of cases 1 Diagnosis 1st-line therapy Outcome 2nd-line therapy Outcome/side effects NM D failed A SR 2 Valhot et al. [13] 1 H D failed A SR 3 Owen et al. [6] 1 H D+V failed – Fetus died 4 Kofinas et al. [14] 1 H D failed F SR 14 H F SR IUD failed 5 Allan [8] 11 1 2 6 Amiel et al. [15] 2 H D+A+S SR 2 7 De Catte et al. [9] 1 H A SR 1 1 NH A SR 1 NH 22 D SR 12 H 13 D6 SR IUD SR Del NND 8 Chen et al. [16] 9 Frohn-Mulder et al. [17] 35 F7 Amiodarone in Treatment of Fetal Supraventricular Tachycardia 1 3 3 3* 1 D 2 SR 1 Hypothyroidism in fetus F Del V/P 4 6* 2 SR 4 NND 2 Fetal Diagn Ther 2006;21:72–76 73 Table 1 (continued) S. Authors no. Total no. of cases Diagnosis 1st-line therapy Outcome 10 Vanderhal et al. [18] 1 H F SR 11 Van Gelder et al. [19] 1 H D failed 1 2nd-line therapy Outcome/side effects – Conjugated hyperbilirubinemia in fetus F SR 12 Hajdu et al. [20] 1 H D failed A SR 13 Amano et al. [21] 1 H D failed F SR 14 Hamel et al. [22] 1 H F SR 1 15 Chang et al. [23] 1 H D SR 1 NH 63 D SR SVT – Alive IUD SR SVT 5 2 10 4 16 Simpson and Sharland [1] 110 39 24 V H 47 D6 D+V 14 SR IUD Alive SVT SR IUD SVT F 27 SR IUD NND 1 1 3 1 7 1 4* 15 4 2 17 Edwards et al. [24] 1 H* * F SR 1 18 Vautier et al. [11] 3 H F SR IUD 2 1 NH 28 D H9 D SR SVT SR 15 5* 2 19 Ebenroth et al. [25] 37 20 Krapp et al. [26] 20 H F+D SR 21 Jouannic et al [7] 25 H 25 D7 SVT Del SVT SVT SR SVT IUD TOP SR SVT TOP 5 1* 1 2 7 2 2 1 2 1* 1 1 D+S 2 F 12 A4 22 Nakata et al. [27] 23 Porat et al. [3] 24 Strasburger et al. [10] 1 H F SR 1 H D+F SR 15 H D Failed 14 F 3 SR 3 A (DFT) V 1 1 1 F 1 SR Neonatal death SR D+V D S+A D+V+A 3 1 1 1 SR 2 + NND 1 SR but NND SR IUD F 8 P P+V F 1 1 5 SR SVT SR SVT* F A 5 A 2 A 2 A 15 Alive 3 Neonatal death 1 1 1 7 1 P+A (3rd line) -SR 5 20 SR 5 TSH elevated in 2 cases SR 1 + IUD 1 SR 1 15 2 Fetal SVT treated at 13 weeks Transient hypothyroidism in 5 fetuses A = Amiodarone; D = digoxin; F = flecainide; V = verapamil; S = sotalol; P = propranolol; SR = sinus rhythm; H = hydropic fetus; NH = nonhydropic fetus; IUD = intrauterine death; NM = not mentioned in the abstract (article not in English language); TOP = termination of pregnancy; Del = delivery; NND = neonatal death; TSH = thyroid-stimulating hormone; DFT = direct fetal therapy. * Treated after delivery. ** Twin pregnancy, one fetus with SVT and hydrops. 74 Fetal Diagn Ther 2006;21:72–76 Pradhan/Manisha/Singh/Kapoor with neonatal death owing to its negative inotropic effects [6]. Flecainide is a potent class 1c antiarrhythmic drug that is available for treatment of atrial, junctional, and ventricular arrhythmias. It acts on fast sodium channel and slows conduction throughout the conduction system; its greatest effect is on bundle of His. Up to 30–40% of the fetuses do not respond to this therapy [1]. Amiodarone belongs to class III drugs and acts by prolonging action potential, thus lengthening the refractory period. Amiodarone is effective against a wide variety of atrial and ventricular arrhythmias [7]. It has been found to be safe in pediatric patients also. A review of all published experience with transplacental flecainide and amiodarone was done to evaluate which of the two is more effective in controlling SVT and at the same time has fewer side effects (table 1). Amiodarone as transplacental therapy used alone or in combination with digoxin and/or sotalol in 37 cases (nine studies) was successful in 33 (89.2%) of them. The side effect in the form of fetal hypothyroidism was seen in 8 cases; all of which were transient, were treated, and had no long-term sequel. Flecainide was used transplacentally in 108 cases (fifteen studies). It successfully controlled arrhythmia in 85 (78.7%) of them. There were 8 (7.4%) cases of sudden fetal death in four reports [1, 7, 8, 11]. Though there have been more studies done on flecainide than on amiodarone on transplacental fetal therapy, there have been reports about sudden intrauterine death with flecainide, which has limited its use. On the other hand, there has been no death reported while using amiodarone alone. The main side effect seen is fetal hypothyroidism, as it contains 37% iodine by weight; this fetal iodine overload may be responsible for fetal hypothyroidism [7]. The hypothyroidism that was observed in three reports (total 8 cases); 2 presented elevated thyroid stimulating hormone at day 3–4 and required thyroid hormone substitution therapy for 2–6 months with normal outcome [7], and in another case intra-amniotic instillation of L-thyroxine was done weekly for 3 weeks; thyroid levels on treatment normalized quickly and baby was normal at the time of birth [9]. In the remaining 5 cases the hypothyroidism was transient [10]. Amiodarone was successful in reverting SVT in patients who were not responding to flecainide treatment as well [7], but there were no reports showing tachycardia refractory to amiodarone being controlled by flecainide. Hence, we conclude that amiodarone is an attractive therapeutic modality for management of fetal SVT. References 1 Simpson JM, Sharland GK: Fetal tachycardias: management and outcome of 127 consecutive cases. Heart 1998;79:576–581. 2 Maxwell DJ, Crawford DC, Curry PVM, Tynan MJ, Lindsey DA: Obstetric importance, diagnosis, and management of fetal tachycardias. Br Med J 1998;297:107–110. 3 Porat S, Anteby EY, Hamani Y, Yagel S: Fetal supraventricular tachycardia diagnosed and treated at 13 weeks of gestation: a case report. Ultrasound Obstet Gynecol 2003; 21: 302– 305. 4 Oudijk MA, Ruskamp JM, Ambachsheer BE, Ververs TF, Stoutenbeek P, Visser GH, Meijboom EJ: Drug treatment of fetal tachycardias. Pediatr Drugs 2002;4:49–63. 5 Pfammatter J-P, Paul T: New antiarrhythmic drug in pediatric use: sotalol. Pediatr Cardiol 1997;18:28–34. 6 Owen J, Colvin EV, Davis RO: Fetal death after successful conversion of fetal supraventricular tachycardia with digoxin and verapamil. Am J Obstet Gynecol 1988;158:1169–1170. 7 Jouannic JM, Sophie D, Laurent F, Bidois JL, Villain E, Dumez Y, Dommergues M: Fetal supraventricular tachycardia: a role of amiodarone as second line therapy? 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