Sotalol as firstline treatment for fetal tachycardia and

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skin edema, pericardial effusion or pleural effusion. Fetal echocardiography was used to rule out structural heart disease. On two separate occasions, at least ...
Ultrasound Obstet Gynecol 2013; 42: 285–293 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12390

Sotalol as first-line treatment for fetal tachycardia and neonatal follow-up L. B. VAN DER HEIJDEN*, M. A. OUDIJK†, G. T. R. MANTEN†, H. TER HEIDE*, L. PISTORIUS† and M. W. FREUND* *Department of Pediatric Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands; †Department of Obstetrics, University Medical Centre Utrecht, Utrecht, The Netherlands

K E Y W O R D S: digoxin; fetal hydrops; fetal SVT; fetal tachycardia; flecainide, sotalol

ABSTRACT Objectives In fetal tachycardia, pharmacological therapy with digoxin, flecainide and sotalol has been reported to be effective. In a recent retrospective multicenter study, sotalol was considered to be less effective than the other drugs in treatment of fetal supraventricular tachycardia (SVT). The aim of this study was to re-evaluate the efficacy and safety of maternally administered sotalol in the treatment of fetal tachycardia. Methods This was a retrospective review of the records of 30 consecutive fetuses with tachycardia documented on M-mode echocardiography between January 2004 and December 2010 at Wilhelmina Children’s Hospital, a tertiary referral university hospital. Patients were subdivided into those diagnosed with supraventricular tachycardia and those with atrial flutter (AF) and presence of hydrops was noted. Other variables investigated included QTc interval measured on maternal electrocardiogram before and after initiation of antiarrhythmic therapy, fetal heart rhythm and heart rate pre- and postnatally, oral maternal drug therapy used, time to conversion to sinus rhythm (SR), percentage of fetuses converted following transplacental treatment, maternal adverse effects, presence or absence of tachycardia as noted on postnatal ECG, postnatal therapy or prophylaxis and neonatal outcome. Findings are discussed with reference to the literature. Results A total of 28 patients (18 with SVT, 10 with AF) were treated with sotalol as first-line therapy. Fetal hydrops was present in six patients (five with SVT, one with AF). All hydropic patients converted antenatally to SR (67% with sotalol as a single-drug therapy, 33% after addition of flecainide). Of the non-hydropic patients, 91% converted to SR (90% with sotalol only, 10% after addition of flecainide or digoxin). In 9% (with AF) rate control was achieved. There was no mortality. No serious

drug-related adverse events were observed. Postnatally, rhythm disturbances were detected in 10 patients, two of whom still had AF. In eight, SVT was observed within 3 weeks postnatally, and in five of these within 72 hours. Conclusions Sotalol can be recommended as the drug of first choice for treatment of fetal AF and has been shown to be an effective and safe first-line treatment option for SVT, at least in the absence of hydrops. Postnatal maintenance therapy after successful prenatal therapy is not necessarily indicated, as the risk of recurrence is low beyond 72 hours of age. Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.

INTRODUCTION Fetal arrhythmias, such as premature atrial beats, sinus tachycardia and fetal tachyarrhythmias, occur in fewer than 0.6% of all pregnancies. The incidence of clinically relevant fetal tachyarrhythmias is significantly lower and has not been described. Fetal tachyarrhythmias consist mainly of atrioventricular re-entrant tachycardia (supraventricular tachycardia (SVT)) and atrial flutter (AF)1 . Sustained tachycardias, in particular, are associated with fetal hydrops, neurological morbidity and intrauterine death2 – 9 . Several retrospective studies on prenatal diagnosis and management have been published, which describe the use of sotalol, digoxin and/or flecainide as single-drug or combination therapy10 – 16 . In a recently published retrospective multicenter study, Jaeggi et al. reported sotalol to be less effective in treatment of SVT than either digoxin or flecainide9 . Sotalol is a non-selective β-adrenoceptor antagonist which prolongs cardiac repolarization independent of its antiadrenergic action (class III antiarrhythmic properties)17 . Sotalol has proven to be safe and efficacious in the treatment of tachycardia in infants18,19 .

Correspondence to: Dr M.W. Freund, Department of Pediatric Cardiology, Wilhelmina Children’s Hospital, University Medical Centre (UMC), KG 01.319.0/P.O. Box 85090, 3508 AB, Utrecht, The Netherlands (e-mail: [email protected]) Accepted: 30 December 2012

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.

ORIGINAL PAPER

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Furthermore, sotalol is hemodynamically well-tolerated and confers a relatively low proarrhythmic risk20 . It passes the placental barrier rapidly and almost completely21,22 . With these properties, sotalol is considered to be a potent antiarrhythmic agent in the treatment of fetal tachycardia. Previous experience with sotalol in fetal tachycardia has been reported in earlier studies15,22,23 . The aim of this retrospective study is to re-evaluate the efficacy and safety of maternally administered sotalol as first-line treatment in patients with fetal SVT and AF by presenting our most recent experience with the use of sotalol in the treatment of fetal tachycardia and discussing this in conjunction with recently published data9,15 .

METHODS This study includes all fetuses diagnosed with tachycardia between January 2004 and December 2010 at Wilhelmina Children’s Hospital, a tertiary referral university hospital. Tachycardia was detected during routine prenatal visits, and patients were subsequently referred to our perinatal center. Patients were subdivided into two groups based on the mechanism of fetal tachycardia revealed on M-mode echocardiography; they were diagnosed with either SVT, defined as 1:1 atrioventricular conduction with a rate of >180 beats per minute (bpm) or AF with a regular atrial rate of > 300 bpm with fixed or variable atrioventricular block14 . Fetuses were considered to be hydropic if two or more of the following findings were present: ascites, skin edema, pericardial effusion or pleural effusion. Fetal echocardiography was used to rule out structural heart disease. On two separate occasions, at least two hours apart, evaluation of fetal heart rhythm for at least 60 min was performed. Treatment was initiated in cases of sustained tachycardia or when hydrops was present. A perinatologist, in consultation with a pediatric cardiologist, performed evaluation and treatment. During follow-up, an arrhythmia was classified as ‘converted’ when a sustained conversion to sinus rhythm (SR) on M-mode echocardiography was achieved. An arrhythmia was classified as ‘controlled’ when the heart rate was lower than 180 bpm without conversion to SR. Relapse was defined as recurrence of fetal tachycardia after conversion to SR. Fetuses with a relapse who eventually achieved permanent SR were counted as a treatment success after the final cardioversion. The project was reviewed by the Local Research Ethics Committee (University Medical Centre Utrecht, 2010). Written informed consent was obtained from all participants. The ultrasound systems used were Aplio (Toshiba, Tokyo, Japan) and Voluson 730 and Voluson E8 (GE Medical Systems, Kretztechnik, Tiefenbach, Austria).

Drug treatment The drugs used for transplacental treatment included sotalol, digoxin and flecainide. Sotalol was used in 28 patients as the initial mode of therapy. Digoxin or flecainide was added to the treatment for patients in

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.

whom adequate control could not be achieved with sotalol as a single-drug therapy. Prior to initiation of oral maternal drug therapy, patients were interviewed to reveal a possible history of arrhythmic events. All patients were hospitalized for at least 48 hours. A maternal electrocardiogram (ECG) was performed to evaluate pre-existing maternal arrhythmias. QTc intervals were measured on ECG before and 2 days after initiation of antiarrhythmic therapy. Sotalol was administered only when QTc intervals were less than 470 ms. In accordance with Goldenberg et al., QTc was defined as normal when intervals were < 450 ms, as borderline when they were between 450 and 470 ms, and as prolonged when they were > 470 ms in the adult female24 . Serum levels of sotalol were not routinely obtained. In all patients with a QTc interval of > 470 ms after initiation of treatment, a weekly ECG was performed. The sotalol dosage was not altered. The initial dosage of sotalol was 160–320 mg daily in two to three doses. The initial dosage depended on body weight of the mother and presence or absence of fetal hydrops. In cases in which maternal body weight was < 100 kg, an initial dose of 80 mg twice daily was used in non-hydropic fetuses, and 80 mg three times daily was used in hydropic fetuses. The initial dosage in patients > 100 kg was 80 mg three times daily in non-hydropic fetuses and 160 mg twice daily in hydropic fetuses. In one case presenting with AF with a ventricular heart rate of 145 bpm, a lower initial dose of 40 mg twice daily was used to achieve cardioversion. In cases of persistence of tachycardia, the dosage of sotalol was increased to a maximum of 480 mg daily. The dosage of digoxin was 0.375–1.000 mg daily in two to four doses. The initial dosage of flecainide was 100–150 mg twice daily. The maximum dosage of flecainide was 400 mg daily. On at least every weekly visit, participants were interviewed to reveal potential adverse effects of the drug therapy.

Postnatal evaluation Postnatal ECGs, 24–72-h ECG monitoring in the pediatric ward and echocardiography were performed in the neonates, including measurement of the left ventricular end-diastolic diameter (LVEDd; normal value, 20 ± 3.6 mm) and the shortening fraction (SF; normal value, ≥ 28%)25 . After discharge, all newborns were seen on a routine basis at the pediatric cardiology outpatient clinic at 1 week, 3 months and 12 months after birth. In cases in which follow-up examination was performed by a pediatrician elsewhere, this was done in consultation with a pediatric cardiologist at our center.

Statistical analysis Variables included in this study were: gestational age at confirmation of diagnosis, mechanism of tachycardia as noted on prenatal M-mode echocardiography, heart rate, presence or absence of hydrops, QTc interval measured on maternal ECG before and after initiation of antiarrhythmic therapy, oral maternal drug therapy

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Table 1 Summary of clinical data for patients initially treated with sotalol or flecainide for supraventricular tachycardia (SVT) or atrial flutter (AF)

Patient

Year

GA at diagnosis

Sotalol treatment 1 2004 27 + 3 2 2004 28 + 4 3 2004 36 + 1 4 2004 36 + 0 5 2004 27 + 5 6 2005 35 + 6 7 2005 35 + 4 8 2005 30 + 2 9 2006 32 + 0 10 2007 29 + 6 11 2007 34 + 2 12 2007 28 + 3 13 2007 31 + 5 14 2008 29 + 2 15 2008 34 + 4 16 2008 27 + 1 17 2008 24 + 4 18 2009 25 + 5 19 2009 34 + 6 20 2009 34 + 3 21 2009 36 + 5 22 2010 19 + 4 23 2010 32 +0 24 2010 37 + 0 25 2010 28 + 1 26 2010 34 + 3 27 2010 38 + 6 28 2010 36 + 5 Flecainide treatment 1 2004 31 + 1 2 2006 23 + 5

SVT/AF

Hydrops

In-utero anti-arrhythmic treatment

SVT SVT AF AF SVT AF AF AF AF AF AF SVT SVT SVT AF SVT SVT SVT SVT SVT SVT SVT SVT SVT SVT SVT SVT AF

No No No No Yes No No Yes No No No No No No No No No Yes No Yes Yes No No No Yes No No No

S+D S S+D S+D S S S S S S S S S S S S S S+F S S S S+F S S S+F S S S

SVT SVT

Yes Yes

F F

Postnatal rhythm diagnosis

Conversion time (days)

Relapse

Delivery mode

23 6 Rate control Rate control 6 7 3 35 2 9 1 1 2 9 5 6 19 9 4 2 1 75 3 1 14 1 1 2

No No No No No No Yes No No Yes No No No No No No Yes No No No No Yes No No No No No No

VD CS CS CS VD VD CS VD CS VD VD CS VD VD VD VD VD VD VD VD VD VD VD VD VD CS VD VD

40 + 6 41 + 2 40 + 5 38 + 1 40 + 4 39 + 0 41 + 3 39 + 1 40 + 0 39 + 6 40 +4 40 + 1 38 + 4 36 + 0 40 + 3 39 + 5 39 + 0 41 + 2 39 + 5 41 + 0 37 + 1 39 + 5 39 + 6 41 + 1 39 + 6 40 + 4 40 + 1 39 + 6

SR SVT† AF* AF* SR SR SR SVT† SR SR SR SR SR SR SR SR SVT‡ SR SR SVT† SVT† SR SR SR SVT† SVT‡ SVT‡ SR

5 6

No No

VD VD

40 + 0 39 + 3

SR SR

GA at birth

Rhythm disturbance occurred: *directly after birth, †within 72 hours postpartum or ‡2–3 weeks after birth. CS, Cesarean section; D, digoxin; F, flecainide; GA, gestational age; S, sotalol; SR, sinus rhythm; VD, vaginal delivery.

used and results, time to conversion, percentage of fetuses converted at day 5 and day 10 after initiation of transplacental treatment, maternal adverse effects, gestational age at birth, mode of delivery, Apgar score, presence or absence of tachycardia as noted on postnatal ECG, left ventricular function, postnatal therapy or prophylaxis and neonatal outcome. Kaplan−Meier survival statistics were performed using SPSS 15.0.1 for Windows (SPSS Inc., Chicago, IL, USA).

RESULTS A total of 30 referrals with fetal tachycardia were reviewed in this study (Table 1). Details on fetal diagnosis, fetal state and antenatal therapy are shown in Figure 1. Twenty-eight of the 30 referrals were initially treated with sotalol and included in this study. SVT was present in 18 of these 28 fetuses (64%). They had a mean heart rate of 253 ± 28 bpm, and mean gestational age at the time of presentation was 30.4 ± 5.0 weeks. In 14 of these patients (78%), cardioversion was achieved with sotalol as single-drug therapy (Figure 2a). In four fetuses, because

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adequate heart rate control could not be achieved with sotalol as single-drug therapy, digoxin (n = 1) or flecainide (n = 3) was added after 5–8 days and was successful, resulting in a success rate of 100% in transplacental therapy in fetuses with SVT. The median interval from initiation of therapy to cardioversion was 5 (range, 1–75) days in the SVT group. In 50% of the patients with SVT initially treated with sotalol, rhythm control was achieved on day 5, and in 78% it was achieved on day 10 (Figure 2b). AF was present in 10 of the 28 fetuses (36%). They had a mean atrial rate of 411 ± 45 bpm and a variable degree of atrioventricular block, which resulted in a mean ventricular heart rate of 205 ± 25 bpm. Mean gestational age at presentation was 34.1 ± 2.5 weeks. Cardioversion with sotalol as a single-drug therapy was achieved in eight of the 10 fetuses (80%, Figure 2a), with a median interval from initiation of therapy to cardioversion of 4 (range, 1–35) days. Cardioversion was achieved in five of the 10 fetuses (50%) at day 5 and in seven of the 10 fetuses at day 10 (70%). In the two remaining patients with AF, despite addition of digoxin after 3–8 days, cardioversion was not successful but rate control was achieved (Figure 2b).

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Fetal hydrops n=8 (SVT = 7, AF = 1)

Sotalol n=4 (SVT = 3, AF = 1)

Cardioversion n=4 (SVT = 3, AF = 1)

Sotalol and flecainide n=2 (SVT = 2)

Cardioversion n=2 (SVT = 2)

Flecainide n=2 (SVT = 2)

Cardioversion n=2 (SVT = 2)

Drug therapy n = 30 (SVT = 20, AF = 10)

No relapse n = 15 (SVT = 9, AF = 6)

No fetal hydrops n = 22 (SVT = 13, AF = 9)

Sotalol n = 18 (SVT = 11, AF = 7)

Cardioversion n = 18 (SVT = 11, AF = 7)

Relapse n=3 (SVT = 2, AF = 1)

Sotalol and flecainide n=1 (SVT = 1)

Cardioversion n=1 (SVT = 1)

Relapse n=1 (SVT = 1)

Sotalol and digoxin n=3 (SVT = 1, AF = 2)

Cardioversion n=1 (SVT = 1) Rate control n=2 (AF = 2)

Figure 1 Flowchart with details of fetal diagnosis and hydrops with treatment modalities and outcomes during the fetal period. AF, atrial flutter; SVT, supraventricular tachycardia.

80

80

80

60 40 + +

20 0

0

20

40 Days

60

Fetuses (%)

(c) 100

Fetuses (%)

(b) 100

Fetuses (%)

(a) 100

60 40 +

20

80

0

0

20

40 Days

60

+ +

60 40 20

80

0

0

20

40 Days

60

80

Figure 2 (a) Kaplan–Meier survival curves showing freedom from prenatal conversion of supraventricular tachycardia (SVT) and atrial flutter (AF) to sinus rhythm after treatment with sotalol as a single therapy, before starting additional therapy. (b) Overall freedom from prenatal conversion of SVT and AF over time; cardioversion at day 5 and 10 was achieved in 50% and 78% of fetuses with SVT and in 50% ; and 70% of fetuses with AF. (c) Freedom from changes in first-line treatment with sotalol of SVT and AF over time. SVT (n = 18), . AF (n = 10),

Changes in first-line therapy with sotalol over time were rare (6/28 patients; 21%) and comparable among the arrhythmia groups (Figure 2c).

Non-hydropic fetuses At presentation, 22 of the 28 fetuses showed no signs of fetal hydrops (79%, 13 with SVT and nine with

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.

AF). Mean ventricular heart rate at diagnosis was 231 ± 38 bpm, and mean gestational age was 32.0 ± 4.7 weeks. Treatment with sotalol as a single-drug therapy was initiated in all and was successful in 18 patients (Figure 3). In three patients (one with SVT, two with AF), digoxin was added after 3–8 days because adequate heart rate control could not be achieved with sotalol as a single-drug

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80

80

60

60

Fetuses (%)

(b) 100

Fetuses (%)

(a) 100

40

40

+

20

20

+

+

0

0

20

40 Days

60

80

0

0

20

40 Days

60

80

Figure 3 (a) Kaplan–Meier survival curves showing freedom from prenatal termination of atrial tachycardia in non-hydropic fetuses vs hydropic fetuses with sotalol as a single therapy. (b) Overall freedom from prenatal termination of atrial tachycardia in non-hydropic and hydropic patients. Cardioversion at 5 and 10 days was achieved in 55% and 77% of non-hydropic patients and in 33% and 67% of ; hydropic (n = 6), . hydropic patients. Non-hydropic (n = 22),

therapy. One of these patients, presenting at 27 + 3 weeks with SVT (250 bpm), converted to normal SR after 23 days with sotalol (480 mg daily) and digoxin (0.375 mg daily). In the other two patients, both presenting at 36 weeks with AF at 400–440 bpm with 2:1 atrioventricular block, SR was not achieved. Rate control with sotalol (160 mg twice daily) and digoxin (0.250 mg 2–4 times daily) was well-tolerated (115–145 bpm). In one non-hydropic patient presenting at 19 + 4 weeks with SVT (250 bpm), flecainide was added to the initial therapy with sotalol after 5 days (Figure 3). Cardioversion was achieved with sotalol (240 mg daily) and flecainide (300 mg daily) at 3 weeks after diagnosis. Several relapses occurred, but eventually sotalol (240 mg daily) and flecainide (400 mg daily) resulted in sustained SR. Because of maternal adverse effects (dizziness and fatigue), the dosage of sotalol was subsequently decreased gradually without recurrence of fetal tachycardia. Relapse occurred in three other non-hydropic fetuses. In one patient with AF (300 bpm) with a ventricular rate of 145 bpm, sotalol was initiated in a low dosage of 40 mg twice daily, and the patient converted to SR after 2 days. One relapse occurred, but SR was achieved with sotalol (80 mg twice daily). Another two patients, one presenting with SVT (210 bpm) and the other with AF (440 bpm, ventricular rate of 220 bpm), converted to SR with sotalol (80 mg twice daily), but a relapse occurred. Increase of sotalol to 240 mg and 320 mg daily, respectively, was successful in restoring SR. On day 5 of treatment, 12 of the 22 non-hydropic patients (55%) were converted to SR and on day 10, cardioversion was achieved in 77% (Figure 3). In the 20 non-hydropic cases in which conversion to SR was achieved, the median interval from treatment initiation to cardioversion was 3.5 (range, 1–75) days.

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.

Hydropic fetuses Six fetuses (21%) were hydropic at the time of presentation; five of these had SVT (28% of all SVT cases) and one had AF (10% of all AF cases). Mean gestational age was 30.5 ± 4.3 weeks and mean heart rate was 252 ± 20 bpm. Cardioversion with sotalol as a single-drug therapy was achieved in four of six patients (67%, Figure 3). In the other two patients, flecainide was added to the initial treatment with sotalol because adequate control could not be achieved. One patient presented at 25 + 5 weeks with SVT at 245 bpm and the other at 28 + 1 weeks with SVT at 225 bpm. In both patients flecainide (300 mg daily) was added 1 week after sotalol was initiated, and they converted to SR within 9–14 days from diagnosis. In conclusion, all six hydropic patients converted antenatally to SR. The interval between treatment initiation and cardioversion varied between 1 and 35 (median, 7.5) days. Rhythm control by day 5 and day 10 was achieved in 33% and 67% of patients, respectively. No relapses occurred (Figure 3). Signs of fetal hydrops disappeared in all cases, and the median interval between initiation of antiarrhythmic therapy and disappearance of signs of fetal hydrops was 10.5 (range, 1–26) days.

Maternal adverse effects during pregnancy Maternal adverse effects of sotalol therapy were encountered in 15 cases and consisted of dizziness (n = 11), fatigue (n = 4), nausea and vomiting (n = 3), headache (n = 3) and dyspnea (n = 1). In most cases, symptoms were minor. In two patients, one using sotalol as a singledrug therapy and the other using a combination of sotalol and flecainide (as outlined above), the reported adverse effects diminished with lowering of the sotalol dosage from 80 mg twice daily to 40 mg twice daily after SR was achieved. Drug changes were not required. There were no

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Patients n = 30 Antenatally Initially treated with flecainide n=2

Initially treated with sotalol n = 28

Sinus rhythm n = 26

Sinus rhythm n = 18

SVT within 3 days n=5

AF directly after birth n=2

Rhythm disturbance during postnatal follow-up n=8

Sinus rhythm n=2

AF after unsuccessful cardioversion n=1

Sinus rhythm after cardioversion n=1

Postnatally

SVT 2–3 weeks postnatally n=3

Figure 4 Flowchart showing postnatal outcomes for all cases (n = 30). AF, atrial flutter; SVT, supraventricular tachycardia.

serious side effects such as fainting, syncope or arrhythmia. Adverse effects occurred independent of drug dosage and gestational age and were not associated with addition of a second agent. In two cases, delivery was induced at term, partly because of maternal adverse effects. Both patients, respectively reporting dizziness and dizziness combined with nausea and vomiting, converted antenatally to SR with sotalol as a single therapy.

Maternal ECG The mean ± SD QTc interval before initiation of treatment was 425 ± 23 (range, 395–466) ms. After initiation of antiarrhythmic therapy, the mean ± SD QTc interval was 441 ± 25 (range, 402–497) ms; two patients had a QTc interval of > 470 ms (487 and 497 ms, respectively), the first using a combination of sotalol and flecainide, and the second using sotalol (80 mg twice daily) as a single-drug therapy. In nine patients, an increase of the QTc interval of more than 20 ms was detected (varying between 21 and 71 ms, mean 38 ms). These included the two patients with a QTc interval of > 470 ms after initiation of sotalol therapy. In all patients with a QTc interval of > 470 ms after initiation of treatment, an ECG was performed weekly. Furthermore, all patients were told not to use other medications with a QTc-prolonging effect.

Management and outcome after birth In the 28 patients initially treated with sotalol, the mean gestational age at birth was 39.8 ± 1.2 weeks. A Cesarean section was performed in seven women; in five cases for obstetric reasons, in one case because of the inability to objectify the fetal condition, and in one case because of suspected fetal distress. Postnatal follow-up varied in length between 19 and 102 (median, 50) months and was possible in all cases as there were no intrauterine deaths. Figure 4 describes the postnatal outcome.

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Directly after birth SR was confirmed in all but two patients (93%). Antiarrhythmic drug therapy was not administered to these 26 patients. In the two patients without SR directly after birth (7%), rate control was achieved antenatally and the postpartum ECG showed AF. Electrical cardioversion established normal SR in one of these patients, and a maintenance dose of sotalol was discontinued after 3 months. In the other patient, several attempts to convert electrically failed, and a maintenance therapy of digoxin and sotalol was initiated. The patient converted within a few days. Digoxin was discontinued 2 months after birth and sotalol 8 months after birth. No recurrent tachycardias were detected in either case. In eight of the 26 infants with SR directly after birth (31%), SVT was observed 5 hours to 3 weeks postnatally. In the remaining 18 patients (69%; 11 with fetal SVT, seven with fetal AF) no rhythm disturbances were detected after birth and there were no events during follow-up (median, 54 (range, 19–102) months). Five of the eight patients with recurrent atrial tachycardia showed SVT within 3 days after birth (63%). The antenatal rhythm diagnosis was concordant with the postnatal rhythm diagnosis in four of these patients (SVT) and discordant in one (with antenatal rhythm diagnosis of AF and postnatally diagnosis of SVT). One of these five children (antenatal diagnosis concordant with postnatal diagnosis) was diagnosed with atrioventricular re-entry tachycardia based on Wolff−Parkinson−White syndrome. This child had one relapse at the age of 3 months. A maintenance dose of sotalol therapy was stopped 15 months after birth without recurrence of tachycardia (follow-up at 31 months). Four patients received sotalol in a maintenance dose for 8–12 months, after which treatment was discontinued successfully without recurrent signs of tachycardia. Three of the eight patients developed atrial tachycardia 2–3 weeks after birth (37%). One was diagnosed with ectopic atrial tachycardia and at the time of writing is doing well on antiarrhythmic therapy with sotalol

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Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.

14 — — — 10 — — — — — — 95 — 100 — — — — 37 — — — — — — 26 — 2 — — — — 9 — — — — 55 — 70 43‡ 78 U — 66 — 55 — 80 — — 9 — 35 21‡ 18

AF SVT AF SVT

9 — 9 — 17 — 10 — 15‡§ 2 5 28 8‡ 7 17 — 1 3 5 — 1 — 24‡ 9 21 75 16 20 35 — 9 6 36 5 10 Lisowski et al. (2000) , MC Krapp et al. (2002)28 Oudijk et al. (2003)22 Uzun et al. (2012)16 , MC Jaeggi et al. (2011)9 , MC Shah et al. (2012)15 This study

AF SVT AF SVT AF

29

Study

If possible, cases of AF and SVT were differentiated. Success was defined as conversion to sinus rhythm. *These patients were initially treated with more than one transplacental drug. Patients who received additional therapy after failure of monotherapy are not presented here (no details in original article). †Overall success rate is presented here. ‡Numbers not separated into SVT and AF. §Of 20 fetuses not converted with digoxin as a single therapy. ¶14 fetuses after addition of flecainide, six fetuses after failure with verapamil as second-line therapy and subsequent substitution by flecainide. #21 patients received F + D directly from the beginning (no monotherapy tried). The six patients with failed digoxin monotherapy are presented in brackets. AF, atrial flutter; D, digoxin; F, flecainide; M, miscellaneous; MC, multicenter study; S, sotalol; SVT, supraventricular tachycardia; U, unknown.

— 95‡ 89† 93 (95)# U 62‡ 100† — 20‡¶ 2S+D 15(+6) F + D# U 12 S + D‡ 1 S + D, 3 S + F — 24‡ — 6 14 — —

U — — — 50 — —

— 17‡ — 0 78 — —

12 D + M* — 2S+D 6 F + D# — — 2S+D

67† — 78† 17# — — 80†

SVT AF SVT AF SVT SVT AF SVT

Success rate (%) n Success rate (%) n Hydropic fetuses (n) All fetuses (n)

Table 2 Overview of treatment for fetal tachycardia

In this single-center retrospective study in fetuses with atrial tachycardia, our treatment protocol with sotalol as first-line therapy showed a final success rate of nearly 100% and resulted in no mortality. In our study population, 64% had SVT and 36% had AF, which is a common distribution8,9 . Previous studies using several therapeutic strategies showed success rates between 60% and 95% in patients with SVT and data from 2000 onwards are summarized in Table 29,15,16,22,28,29 . In our SVT group, the overall efficacy of sotalol as a single-drug therapy was 78%, which is comparable to the conversion rate recently reported by Jaeggi et al. in 35 fetuses receiving sotalol9 . However, Shah et al. reported a lower conversion rate of 43%15 . After adding transplacental digoxin or flecainide, our overall success rate was 100%. This is higher than the conversion rate reported by Shah et al. using sotalol and transplacental digoxin15 . However, their group included a higher percentage of fetuses with hydrops. Jaeggi et al. recently reported a conversion rate of c. 80% in a group of 14 patients, with and without hydrops, receiving digoxin, and a high conversion rate of c. 95% in a group of 26 patients treated with flecainide9 .

Sotalol

DISCUSSION

Flecainide

Transplacental monotherapy

AF

n

Digoxin

Significant neurological morbidity was present after birth in one patient, presenting at 36 + 5 weeks with SVT at 280 bpm with fetal hydrops (ascites, skin edema, pericardial effusion). Antenatal treatment with sotalol achieved SR within 2 days. The infant was born at 37 + 1 weeks’ gestation with normal Apgar scores and blood gases after a spontaneous vaginal delivery. SVT occurred 5 hours after birth. Cardioversion with adenosine was successful and maintenance therapy with sotalol was initiated. During postnatal evaluation, magnetic resonance imaging depicted a large infarct of the left medial cerebral artery with hemorrhagic components due to venous thrombosis of the transverse sinus. Based on imaging, these abnormalities most likely originated from at least 6 weeks before delivery and may have resulted from low cardiac output. There was no fetal or postnatal mortality.

Success rate (%)

Morbidity and mortality

SVT

In 20 of the 28 patients with fetal tachycardia treated with sotalol as the initial mode of therapy, postnatal echocardiography data were available for retrospective study. Echocardiography showed minor tricuspid regurgitation in three and minor mitral regurgitation in two patients. The mean ± SD LVEDd was 21.7 ± 3.3 (range, 17.5–30.0) mm, the mean SF was 34.5 ± 6.4 (range 24.6–48.2) %.

AF

Postnatal echocardiography

n

After addition of second drug

(last follow-up at 46 weeks). In the other two patients, a maintenance dose of sotalol was discontinued after 12 months. No relapses occurred.

Success rate (%)

291

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292

Besides considering the overall conversion rate as a marker of success, time to conversion is an important variable in discriminating the efficacy of different drugs. Our success rates with sotalol in SVT of 50% at day 5 and 78% at day 10 compare favorably with the conversion rates of 38% at day 5 and 45% at day 10 with sotalol reported by Jaeggi et al.9 . Our results seem to be more in line with their conversion rates of 59% and 70% with flecainide9 . However, when interpreting these results, one must take into account the differences between both cohorts; in the study cohort of Jaeggi et al. hydrops was present in 43% of patients treated with sotalol and 38% of patients treated with flecainide, but only 27.8% of SVT patients in our sotalol study cohort had hydrops. In conclusion, sotalol is an effective and safe first-line treatment option for SVT, at least in the absence of hydrops. Furthermore, the combination of sotalol and flecainide has been shown to be successful and well-tolerated, which has been reported previously for fetal tachycardia in one fetus9 . In our AF group, sotalol as a single-drug therapy was successful in achieving SR in 80% of patients. This is superior to conversion rates after treatment with flecainide or transplacental digoxin, as supported by other studies (38–50%)8,9 . After addition of transplacental digoxin, adequate heart rate control was achieved in the remaining 20% of our patients. Our success rate is consistent with the high conversion rate of 80–100% after sotalol therapy reported in other papers15,23 . In this study, rhythm control at day 5 and day 10 was achieved in 50% and 70% of patients, respectively, after sotalol treatment. Although Jaeggi et al. reported this to be only 29% and < 40%, respectively, they also showed the best results after treatment with sotalol9 . In conclusion, confirming the results of other studies, sotalol must be considered as the first-choice treatment option in fetal AF. Treatment in both non-hydropic and hydropic patients was successful in all cases. This compares favorably with earlier reported conversion rates of 73–89% in the non-hydropic group and 30–80% in the hydropic group13,14,23,26,27,29,30 . The lowest success rate in hydropic patients of 19.5% is described for digoxin8 . Rhythm control using sotalol was achieved in 55% of non-hydropic patients but in only 33% of hydropic patients at day 5. Flecainide has been considered to be the more successful drug in treating hydropic fetuses9,13,15,16,27,28,31 . Considering our results in the light of other reports, and taking into account the low number of hydropic patients in our study, sotalol seems to be less favorable than flecainide as initial treatment in hydropic SVT9,15,27 . Major maternal side effects such as fainting, syncope or arrhythmia were not observed in this study, which is in line with earlier reports9,15,16,27 . However, minor side effects such as dizziness and fatigue, and to a lesser extent nausea, vomiting, a tendency to faint, headache and dyspnea were experienced but well-tolerated in c. 50% of patients. In a non-pregnant population using flecainide and sotalol, these minor side effects were described in up to 25% of patients20,32 . As women

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.

van der Heijden et al. in the third trimester of pregnancy are more prone to cardiovascular instability, one may expect a higher rate of adverse effects. Nevertheless, in literature addressing fetal tachycardia, incidences of minor side effects are low, if reported at all, assuming that minor side effects are probably under-reported9,11,13,15,16,27,31 . All fetuses, except for one, were delivered at term, indicating that sotalol is well-tolerated and effective. This is in contrast to the high prematurity rate observed by Simpson et al. (24%). However, they also reported a higher number of hydropic fetuses4 . Postnatal recurrence of tachycardia in those who converted antenatally to SR occurred in 31% of patients, 63% within 72 hours and 37% within 3 weeks after birth. This is in line with the observation of Moodley et al.33 . In infants who converted antenatally to SR and did not present with an SVT within the first 72 hours after birth, the risk of developing an SVT between 4 days and 1 month of age was 12%. Recurrence of SVT within the first year in those without SVT within the first month after birth was not observed33 . Postnatal maintenance therapy after successful prenatal therapy is therefore not necessarily indicated, as this therapy has side effects18,20 . Rather, postnatal inpatient monitoring for 72 hours, a year-long outpatient follow-up and instruction of parents is indicated. The occurrence of cerebral complications in one fetus confirms that fetuses with long-lasting SVT complicated by hydrops are at risk for of cerebral damage5,6,29,34 . There was no mortality in our study population. Nevertheless, when critically reviewing previously published data, mortality rates up to 15% and even 28% have been reported4,8,9,15,23 . This was mainly related to the presence of fetal hydrops, and was not strongly associated with the treatment given. Our overall management has been improved by implementing more frequent visits to the outpatient clinic and optimizing the dosage protocol as a result of our previous experiences23 . This is the most likely explanation for the absence of mortality in our study. Although this is the largest retrospective singleinstitution series, statements are still based on relatively small case numbers, in particular for hydropic fetuses. The sample size is too small to allow comparisons between covariables and other studies. Careful interpretation of the data is necessary. Furthermore, sotalol levels were not routinely monitored; treatment was based on body weight and presence or absence of fetal hydrops. The use of only one cut-off point (100 kg body weight) could have led to different sotalol serum levels among patients. This single-center experience shows that first-line sotalol therapy is highly successful in transplacental treatment of fetuses with sustained SVT or AF. Sotalol showed a superior efficacy in fetal AF and proved to be an effective and safe first-line treatment option for SVT, at least in the absence of hydrops. There was no mortality. Considering both the experience with treatment of fetal tachycardia at our institution and recently published literature, sotalol can be recommended as the drug of first choice in treatment of non-hydropic and hydropic fetal AF and non-hydropic fetal SVT. Flecainide must

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Sotalol in fetal tachycardia be considered as first-line treatment in hydropic patients with SVT and as a second-line treatment in cases of therapy-resistant SVT, when adequate control could not be achieved with sotalol as a single therapy. Postnatal maintenance therapy after successful prenatal therapy is not necessarily indicated, as the risk of recurrence is low beyond 72 hours of age. A 1-year pediatric cardiology follow-up, however, is mandatory. Existing treatment protocols for fetal tachycardia are mainly based on retrospective data and personal experience. An international multicenter randomized controlled trial would allow us to base treatment protocols on evidence without the limitations associated with retrospective research35 .

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