Correlation of maternal flecainide concentrations and therapeutic effect in fetal supraventricular tachycardia Trisha V. Vigneswaran, MBBS, BSc(Hons), MRCPCH,* Nicky Callaghan, RGN, RSCN, BSc(Hons),* Rachel E. Andrews, MBBS, MA, MRCPCH,† Owen Miller, FRACP, FCSANZ, FRCPCH,* Eric Rosenthal, MD, FRCP, MRCPCH,* Gurleen K. Sharland, BSc, MD, FRCP,* John M. Simpson, MD, FRCP, FESC* From the *Department of Congenital Heart Disease, Evelina London Children’s Hospital, Guy’s and St. Thomas’ Hospitals, London, United Kingdom, and †Department of Cardiothoracic Transplantation, Great Ormond Street Hospital, London, United Kingdom. BACKGROUND Transplacental flecainide is an established therapy for fetal supraventricular tachycardia (SVT), but there is a paucity of data regarding the dose–response relationship. OBJECTIVE The purpose of this study was to investigate the relationship between maternal flecainide concentrations, arrhythmia control, and adverse fetal effects in fetal SVT. METHODS Fetuses with SVT treated with transplacental flecainide at our tertiary fetal cardiology unit between 1997 and 2012 were retrospectively studied. The maternal trough flecainide concentrations throughout treatment were collated, and clinical notes were reviewed to ascertain the response to therapy and fetal outcome. RESULTS Thirty-three fetuses were treated at a median (range) gestation of 28 weeks (20–38 weeks). Median fetal heart rate was 250/min (range 207–316/min). One patient was lost to follow-up, and this fetus was excluded from further analysis. In total, 25 of 32 fetuses (78%) converted to sinus rhythm. Median time to conversion to sinus rhythm was 3 days (range 2–12 days). Median flecainide concentration was 460 μg/L (range 250–866 μg/L) at conversion to sinus rhythm. Flecainide concentrations were not
Introduction Transplacental flecainide is an established treatment of fetal supraventricular tachycardia (SVT).1–6 However, there is a paucity of data regarding the dose–response relationship of flecainide for this indication. The pharmacodynamics are well described in healthy adults and adults with ventricular ectopics and tachycardias.7–9 The pharmacokinetics in pregnancy are less well described, particularly in the presence of fetal hydrops. In vitro experiments have shown a reduction of transplacental flecainide transfer when umbilical venous pressure is elevated.10 However, in hydropic human fetuses, Address reprint requests and correspondence: Dr. Trisha V. Vigneswaran, Department of Congenital Heart Disease, Evelina London Children’s Hospital, Westminster Bridge Rd, London SE1 7EH, United Kingdom. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
significantly different between responders and nonresponders (P ¼ .849). Twelve of 14 hydropic and 13 of 18 nonhydropic fetuses converted to sinus rhythm with similar flecainide concentrations (P ¼ .316). No fetus achieved cardioversion with a maternal serum flecainide concentration o250 μg/L. No fetus died while being treated with flecainide. CONCLUSION The clinical response to flecainide appears good, even in hydropic fetuses. Trough maternal flecainide concentrations, once therapeutic, do not predict cardioversion in the fetus with SVT. Flecainide therapy appears both safe and effective for the fetus when monitored appropriately. KEYWORDS Fetus; Arrhythmia; Supraventricular tachycardia; Flecainide ABBREVIATIONS AET ¼ atrial ectopic tachycardia; AV ¼ atrioventricular; ECG ¼ electrocardiogram; PJRT ¼ permanent junctional reciprocating tachycardia; SVT ¼ supraventricular tachycardia; VA ¼ ventriculoatrial (Heart Rhythm ]]]];]:]]]–]]]) rights reserved.
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2014 Heart Rhythm Society. All
transplacental flecainide has been shown to be effective in treating SVT and is more effective than digoxin.2 There have been concerns regarding the safety of flecainide in adult patients with impaired ventricular function11 and of toxic effects in newborn infants after treatment with transplacental flecainide.12–14 For the purposes of this study, fetuses with a ventricular rate 4200/min and equal atrial and ventricular rates were included. Previous data have shown that the majority of such cases presenting during fetal life are because of an orthodromic atrioventricular (AV) re-entrant tachycardia via an accessory pathway. Although atrial ectopic tachycardia (AET) and permanent junctional reciprocating tachycardia (PJRT) can produce similar findings, they are less common.15–17 AV nodal reentrant tachycardia is rare in fetal and neonatal populations.15 http://dx.doi.org/10.1016/j.hrthm.2014.07.031
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2 This study paper primarily examined the relationship between maternal serum flecainide concentrations and conversion of fetal SVT to sinus rhythm. A secondary aim was to assess the fetal safety profile of flecainide.
Methods Study population All fetuses with echocardiographically confirmed SVT with a 1:1 ratio of atrial:ventricular contraction treated with transplacental flecainide at our tertiary fetal cardiology center between January 1997 and December 2012 were retrospectively studied.
Classification of fetal tachycardias All fetal tachycardias were classified based on fetal echocardiogram findings alone. Fetal echocardiograms were performed using a number of different ultrasound systems, including the Agilent 7500 (Philips, Andover, MA) and the Toshiba Xario and Toshiba Aplio 500 models (Toshiba, Crawley, UK). Fetal SVT was defined as a ventricular rate 4200/min and a 1:1 ratio between atrial and ventricular contractions. This classification does not completely exclude ventricular tachycardia with 1:1 retrograde conduction, but such arrhythmias are exceedingly rare during fetal life.18 An algorithm outlining the diagnostic process is shown in Figure 1. Atrial and ventricular rates were calculated using the time interval between onset of consecutive atrial or ventricular contractions. Atrial flutter, chaotic atrial tachycardia, and atrial fibrillation all have an atrial rate 4300/min with degrees of AV block. In these 3 types of arrhythmia, the atrial rate is greater than the ventricular rate,4 and all such cases were excluded. Refinement of the SVT diagnosis was based on echocardiographic measurement of the time intervals between AV and ventriculoatrial (VA) contractions, using either M-mode echocardiography13,14,16 or spectral Doppler, simultaneously
Figure 1
interrogating the superior vena cava and aorta19 or a pulmonary vein and a branch pulmonary artery.20 The ratio of AV:VA intervals allows subdivision of fetal SVT into “short” and “long” VA tachycardias. In short VA tachycardia, the AV interval is longer than the VA interval; in long VA tachycardia, the VA interval is longer than the AV. Because the AV:VA ratio does not overlap between these groups, it is useful for subdividing the types of SVT and therefore directing appropriate treatment.16 In fetal life, a short VA tachycardia most commonly indicates AV re-entrant tachycardia but may rarely also represent AV nodal re-entrant tachycardia. A long VA tachycardia is associated with either PJRT or AET. Postnatally, PJRT and AET can be differentiated based on the surface electrocardiogram (ECG). However, they cannot be easily differentiated on fetal echocardiography even if the onset and offset are witnessed.21 Persistent SVT was defined as SVT present throughout the scanning period, which was 20 to 30 minutes. If a period of normal sinus rhythm was noted during echocardiography, the arrhythmia was defined as intermittent. Ideally, intermittent and persistent tachycardias would have been classified by long-term monitoring of the fetal heart rate; however, this was not judged practical because it would have involved either very prolonged periods of scanning or auscultation. Cardiotocography typically fails to reliably detect heart rates well above 200/min and so was not used. Intermittent SVT, which has been shown to have potential serious effects on the fetus, was also treated pharmacologically.22 Fetuses who remained in sinus rhythm at each clinical review after flecainide therapy were defined as permanent responders. Those who initially converted to sinus rhythm but then reverted to SVT were defined as nonsustained responders. Fetal hydrops was defined as abnormal fluid in at least 2 compartments (ascites, pleural effusions, pericardial effusions, or skin edema). All echocardiogram reports, which had been generated by the attending fetal cardiologist, were reviewed.
Algorithm for echocardiographic classification of fetal supraventricular tachycardia.
Vigneswaran et al
Flecainide and Fetal Supraventricular Tachycardia
Flecainide dosing During the study period, both flecainide and digoxin were used extensively to treat fetuses with SVT. First-line therapy for hydropic fetuses with SVT was transplacental flecainide. Nonhydropic fetuses were initially treated with transplacental digoxin (0.25 mg 3 times daily) or transplacental flecainide (100 mg 3 times daily). These were administered orally to the mother, based on the preference of the attending fetal cardiologist. If there was no response to digoxin, it was either replaced by flecainide or used concomitantly with flecainide. This decision and its timing were made on an individual patient basis by the attending fetal cardiologist. Patients who failed to respond to flecainide and had digoxin added to prenatal therapy were classified as a failure of flecainide therapy. Only serum flecainide concentrations before the addition of digoxin were included for the purposes of analysis in our study. Our analysis included patients who failed to respond to digoxin and in whom flecainide was added. Digoxin concentrations also were recorded. Flecainide was initiated at dose of 100 mg 3 times per day and altered depending on fetal response, serum flecainide concentrations, ECG findings and maternal side effects.
Drug monitoring Maternal serum trough flecainide concentrations were checked 2 to 7 days after initiation of therapy and at regular intervals throughout treatment. The laboratory-determined therapeutic range for flecainide was 200 to 700 μg/L. Trough flecainide concentrations were used for analysis and were obtained immediately before the morning or afternoon dose of flecainide was given, depending on clinic schedule. Peak flecainide concentrations were not measured. Liquid–liquid extraction was used to extract flecainide. Flecainide concentrations were measured using high performance liquid chromatography with fluorescence detection.23 Serum digoxin concentrations were measured at least 6 hours post-dose using a latex-enhanced immunoturbidimetric assay. The aim was a concentration within the laboratoryderived therapeutic range of 0.8 to 2.0 μg/L. The dose was tailored according to fetal response and maternal symptoms.
Maternal monitoring A history of palpitations and maternal heart disease was actively sought before commencement of flecainide. A twelve-lead ECG was recorded in all mothers before flecainide was started. In the initial years (1997–2002), patients were admitted for observation after commencement of therapy. In the subsequent years, patients were treated on an outpatient basis. At follow-up, a maternal ECG was recorded and any maternal side effects from flecainide and/or digoxin were elicited.
Follow-up Once flecainide was commenced, patients were reviewed within 1 week and, the timing of further follow-up was individually tailored depending on the fetal response.
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Initially, patients were reviewed weekly. Once rhythm control was established with therapeutic flecainide concentrations, less intensive review (every 2–4 weeks) was arranged. Fetal echocardiography was performed at each consultation. Adherence to flecainide was confirmed at consultation. Serum flecainide concentrations were not measured at every visit once conversion to sinus rhythm and/or resolution of hydrops was achieved, provided serum flecainide concentrations had been therapeutic and stable and there were no signs of toxicity on the maternal ECG. Once sinus rhythm had been achieved and sustained, the fetal heart rate was auscultated weekly by the local obstetric team to confirm sinus rhythm was maintained in addition to fetal cardiology clinic attendance.
Data collection Patients were identified from the fetal cardiology database (FileMaker Pro 8.0 version 1, FileMaker Inc, California). A retrospective review of medical case records was performed to collect information on gestation at presentation, fetal echocardiograms, therapies utilized, clinical course, complications and outcome.
Statistical analysis Discrete variables are presented as count or percentage. Data confirmed as not following gaussian distribution are given as median with range. Mann–Whitney U (two-tailed) test was used to look for significance between 2 nonparametric datasets and Kruskal-Wallis test for 3 or more nonparametric datasets. Two-tailed P values were calculated, and P o.05 was considered significant. Spearman r test was used to assess for nonparametric correlation. Analysis was performed using GraphPad Prism6 version 6.0c for Mac OS (GraphPad Software Inc, USA). The study was approved as an audit by Guy’s and St. Thomas’ NHS Trust. All of the data presened was collected for clinical reasons.
Results Thirty-three fetuses were treated with flecainide for persistent (n ¼ 23) or intermittent SVT (n ¼ 10). Four fetuses had previously failed therapy with transplacental digoxin. Median fetal heart rate was 250/min (range 207–316/min) with no significant difference in heart rate at presentation between hydropic and nonhydropic groups (medians 245, 250; P ¼ .121). Fourteen fetuses were hydropic at initiation. Four fetuses had long VA tachycardia and 29 had short VA tachycardia. One patient, who was born at term in sinus rhythm, did not attend prenatal follow-up and was excluded from further prenatal analysis, leaving 32 fetuses included in the study. Conversion to sinus rhythm occurred in 25 of 32 fetuses (78%), and the timing is shown in Figure 2. Median time to achieving sinus rhythm was 3 days (range 2–12 days). The proportion of successful conversions to sinus rhythm, which occurred within 6 days, was 84%. Sinus rhythm was
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converted and maintained sinus rhythm until birth. In these 5 fetuses, there was no significant difference in flecainide concentrations when the fetus was in SVT or in sinus rhythm (medians 440, 440; P ¼ .819). Three patients were started on digoxin after flecainide failed to convert the patients to sinus rhythm. Flecainide was replaced with digoxin in 1 case, and this fetus converted to sinus rhythm after 3 days of transplacental digoxin. Digoxin was added to flecainide therapy in 2 fetuses. One converted after 42 days of combined therapy, and the other was delivered after 3 days because of poor cardiac function. All fetuses treated with digoxin had a level within the laboratorydefined therapeutic range.
Flecainide dosing and concentration Figure 2
Cumulative time to initial conversion to sinus rhythm.
maintained until birth in 22 of 25 fetuses (Table 1). Three of the four fetuses with long VA tachycardia and 22 of the 28 fetuses with short VA tachycardia converted to sinus rhythm after flecainide therapy (Table 2). Ten fetuses had intermittent SVT at diagnosis. Eight of these fetuses maintained sinus rhythm after treatment. One initially cardioverted but then developed persistent SVT and hydrops, and 1 fetus remained in SVT. The fetus who remained in intermittent SVT did not develop hydrops. A maternal serum flecainide concentration was available for all patients. Median trough flecainide concentration at conversion to sinus rhythm was 460 μg/L (range 250–866 μg/L): 21 of 25 responders had a flecainide concentration within the therapeutic range and 4 were supratherapeutic (4700 μg/L). Median flecainide concentration achieved during therapy was 450 μg/L (range 210–840 μg/L) in the 7 fetuses who did not convert to sinus rhythm. There was no significant difference in flecainide concentrations achieved between responders and nonresponders (P ¼ .849). No fetus achieved sinus rhythm with a maternal flecainide concentration o250 μg/L. Five patients initially converted to sinus rhythm but later reverted to SVT while on flecainide with therapeutic concentrations; 2 of these fetuses subsequently Table 1
During the study period, daily doses of between 100 to 450 mg were used, depending on fetal response, maternal flecainide concentration, and maternal ECG changes. The maternal serum flecainide concentrations corresponding to the dosing regimen are shown in Figure 3.
Hydropic and nonhydropic fetuses Initial pharmacologic cardioversion occurred in 12 of 14 hydropic fetuses (86%) at a median of 3 days (range 2–12 days) and in 13 of 18 nonhydropic fetuses (72%) at a median of 6 days (range 2–9 days). There was no significant difference in heart rate in the hydropic and nonhydropic groups (medians 245, 250; P ¼ .467). There was no significant difference in flecainide concentrations between the hydropic and nonhydropic groups (medians: 462, 415; P ¼ .316). There was no significant difference in flecainide concentrations between hydropic/nonhydropic responders and nonresponders (P ¼ .551). Hydrops resolved before delivery in 11 of 12 fetuses who converted to sinus rhythm. One fetus developed hydrops during flecainide therapy. Flecainide was commenced after 3 weeks of unsuccessful digoxin therapy in a fetus who presented with intermittent SVT but developed sustained tachycardia. Three days after starting flecainide, the fetus developed ascites and subsequently a small pleural effusion.
Summary of findings
No. of fetuses Median gestation age (range) No. of hydropic fetuses (% of group) No. of cases of intermittent SVT (% of group) No. of cases of long ventriculoatrial tachycardia (% of group) Median flecainide concentration at initial conversion to sinus rhythm (range) Median flecainide concentration in SVT (range) Median time to conversion to sinus rhythm (range)
Permanent responders
Nonsustained responders
Nonresponders
Total no. of cases
22 28 (21–37) 11 (50) 8 (36) 2 (9) 460 (250–866)
3 33 (23–38) 1 (33) 1 (33) 1 (33) 441 (266–789)
7 31 (22–35) 2 (29) 1 (14) 1 (14) —
33 — 14 10 4 —
— 3 (2–12)
463 (380–690) 6 (2–6)
468 (223–840) —
— —
Permanent responders refers to fetuses who converted to sinus rhythm and maintained sinus rhythm until birth. Nonsustained responders refers to fetuses who converted to sinus rhythm with flecainide but later reverted back to supraventricular tachycardia (SVT). Nonresponders describes fetuses who never converted to sinus rhythm. There was no statistical significance between flecainide concentrations of responders/nonsustained responders and nonresponders (P ¼ .751).
Vigneswaran et al Table 2
Flecainide and Fetal Supraventricular Tachycardia
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Features of fetuses with short and long ventriculoatrial tachycardia
No. of cases Median gestation (range) No. of hydropic fetuses (% of group) Conversion to sinus rhythm (% of group) Median flecainide concentration at conversion to sinus rhythm (range) Median days to conversion to sinus rhythm (range) Permanent conversion to sinus rhythm (%)
Short ventriculoatrial tachycardia
Long ventriculoatrial tachycardia
28 28 (20–38) 14 (50) 22 (79) 450 (250–866)
4 29 (21–35) 1 (25) 3 (75) 490 (252–558)
The hydrops persisted despite conversion to sinus rhythm. The fetus reverted to SVT and for this reason was delivered at 31 weeks. Postnatally, the rhythm remained uncontrolled for 4 days until amiodarone was started. The neonate remained hydropic and was also found to be severely anemic, requiring multiple red cell transfusions.
Gestational age Fetuses were treated at median gestation of 28 weeks (range 20–38 weeks). There was no correlation between gestation at presentation and the time taken to achieve sinus rhythm (Spearman r ¼ –0.187, P ¼ .37). Median gestational age at presentation in the permanent responders, nonsustained responders, and nonresponders was 28, 33, and 32 weeks, respectively. There was no significant difference between these groups (P ¼ .897; Table 1).
Fetal outcome No fetal deaths occurred during treatment with flecainide. No fetus who responded to flecainide died. Two intrauterine deaths occurred after cessation of flecainide. In one hydropic fetus, flecainide therapy was stopped
3 (2–12) 20 (71)
4 (3–6) 2 (50)
Total no. of cases 32 15 25
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after 4 days, without fetal response, because of maternal symptoms of malaise, palpitations, and nausea with a flecainide concentration of 348 μg/L. Propafenone was commenced; however, the family decided to terminate the pregnancy. The second fetus had failed to respond to 14 days of flecainide therapy. Flecainide was stopped because of maternal QT prolongation (from 398 to 560 ms) in association with prolongation of the PR interval by 20% with an elevated flecainide concentration (814 μg/L) but in the absence of maternal symptoms. Three days after flecainide was stopped, sotalol was started and the fetus remained in SVT with hydrops 11 days into therapy. This fetus underwent direct therapy with an intracordal injection of amiodarone at 28 weeks. The fetus developed bradycardia during the procedure and subsequently died. In 3 of 8 fetuses who did not convert or maintain sinus rhythm, preterm delivery (between 31 and 36 weeks) was arranged because of the uncontrollable SVT.
Postnatal tachycardia characteristics Of the 31 live births, 26 had an ECG available for review; the remaining 5 were followed up at other centers. Over half
Figure 3 Flecainide dosing and corresponding maternal flecainide concentration, showing all maternal trough flecainide concentrations achieved with transplacental flecainide therapy. Shaded area represents our laboratory therapeutic range (200–700 μg/L). Horizontal lines indicate median flecainide concentrations.
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6 Table 3 Frequency of postnatal ECG findings according to fetal response Permanent responders Surviving fetuses No. of neonates with: Postnatal SVT Preexcitation No preexcitation PJRT AET
Nonsustained Nonresponders responders
22
3
5 (1)
9 2 14 0 1
2 1 1 1 0
4 (1) 1 3 (1) 1 0
Numbers in parentheses refer to the additional neonate who did not attend prenatal follow-up but was reviewed in our department in the postnatal period. AET ¼ atrial ectopic tachycardia; PJRT ¼ permanent junctional reciprocating tachycardia; SVT ¼ supraventricular tachycardia.
(16/26) had recurrence of tachycardia after birth (Table 3). Twenty-two of 27 cases with short VA tachycardia were seen at our center in the postnatal period. Four of 22 cases (18%) of short VA tachycardia had pre-excitation on resting ECG, and 12 of 22 (55%) had SVT after birth consistent with re-entrant tachycardia. All cases with long VA tachycardia had SVT in the first year of life with PJRT (n ¼ 2), AET (n ¼ 1) and undefined (n ¼ 1).
Discussion Flecainide has been used for the treatment of fetal tachycardias for more than 20 years despite the caution expressed related to potential proarrhythmic effects in adults after myocardial infarction.11 We have confirmed a good response of fetal SVT to transplacental flecainide therapy even in hydropic fetuses who have been regarded as a difficult group to control.2,3,5 Conversion to sinus rhythm, when achieved, occurred rapidly at a median interval of 3 days, which compares favorably to other drugs used to control fetal SVT.2,3,5 Our primary aim was to establish if there was a relationship between flecainide concentrations and fetal conversion to sinus rhythm. We were able to achieve a therapeutic concentration in all cases in this series. Below a serum flecainide concentration of 250 μg/L, we did not observe cardioversion. Within the therapeutic range (200–700 μg/L), our data did not confirm a close relationship between fetal response and trough flecainide concentration. There are a number of potential contributors to treatment failure after transplacental therapy. In certain cases there may be impaired placental transfer of flecainide. The mechanism of carriage of flecainide across the human placenta has not been studied in detail. Whether movement is via diffusion or active transport via the syncytiotrophoblastic carrier proteins is not definitively known. However, because flecainide is lipophilic with a low molecular weight, movement most likely occurs via passive diffusion across a non-hydropic placenta.24,25 Laboratory studies have shown that fetal flecainide transfer is impaired in fetal hydrops.10 Clinically, the reverse has been shown, with flecainide demonstrating superior bioavailability to other drugs, such as digoxin, in hydropic fetuses.2,4 Previous work in our department has
indicated distribution of flecainide from the mother’s blood across the placenta into the cord blood to be effective with concentrations of 80% in the umbilical cord blood,1 and other studies have shown placental transfer to be between 64% and 97%.3,26,27 In this series, we did not attempt to measure the fetal concentration of flecainide because this would have involved an invasive procedure in the fetus with its associated risks to the fetus.28 Therefore, we cannot determine whether treatment failure is related to lack of placental transfer in certain cases, and further research is needed to elucidate the pharmacokinetics of flecainide in pregnancy. The mechanism of fetal SVT may also play a role in the response to treatment. Four fetuses had a long VA tachycardia, which is a higher proportion than diagnosed in other series.5 This type of tachycardia usually is difficult to control, but the response to flecainide in our series was good, with 3 of 4 cases converting to sinus rhythm with flecainide therapy. A re-entrant tachycardia via an accessory pathway is the most likely mechanism for the short VA cases during fetal life,17,29 but the precise electrophysiologic properties of fetal SVT were not evaluated, only mechanical events using standard fetal echocardiography. Other techniques, notably magnetocardiography and tissue Doppler imaging, might have provided further information but are not in routine clinical use.30–33 The electrophysiologic properties of fetal conducting tissue may also affect the response to flecainide. Experimental studies have shown that neonatal canine Purkinje cells are less sensitive to the actions of flecainide compared to adult cells. They show less prolongation of the action potential duration and effective refractory period than do adult cells. Additionally, at faster heart rates, flecainide resulted in a greater reduction in the rate of depolarization of Purkinje fibers in adult compared to neonatal fibers.34 These data may be extrapolated to fetuses and indicate that fetuses of advanced gestation may respond better to flecainide. However, our data were not consistent with this, showing no impact of gestational age on response to flecainide therapy. Our finding that a flecainide concentration within the therapeutic range did not correlate with the response of the fetus is important in clinical practice. If a fetus treated with flecainide does not initially respond, then there may be justification to adjusting the maternal dose to achieve higher flecainide concentrations within the therapeutic range and allow further time for the fetus to respond. However, our data do not support a strong link between maternal trough flecainide concentrations and fetal clinical response. Our secondary aim was to assess the fetal safety profile of flecainide. There were no fetal deaths on flecainide in this series; however, 1 fetus developed hydrops during treatment. The most likely mechanism for the fetus becoming hydropic was a direct result of 3 weeks of uncontrolled tachycardia rather than a result of flecainide therapy. The maternal safety profile is the subject of further research.
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Flecainide and Fetal Supraventricular Tachycardia
Study limitations There are inherent limitations associated with an observational retrospective study. The timing of sampling was predose, but there may be some variability in the time from the previous flecainide dose. The concentrations measured were trough concentrations and not peak, so the relation of peak drug concentration to achieving sinus rhythm could not be assessed. Maternal compliance was ascertained as a routine, but we cannot exclude noncompliance with flecainide as a potential cause of treatment failure, although our measurement of flecainide concentrations does suggest that noncompliance was not a major problem. Assessment of tachycardias was made by echocardiographic means because of the relative inaccessibility of fetal ECG assessment and the lack of a magnetocardiographic facility for more detailed electrophysiologic information. However, the echocardiographic techniques we describe and use represent the reality of most clinical practice.
Conclusion Our results confirm a high degree of efficacy of flecainide in the treatment of fetal SVT, even in hydropic fetuses. Trough maternal flecainide concentrations did not appear to differentiate responders and refractory cases; thus, such concentrations do not seem to predict conversion to sinus rhythm in fetuses with SVT. We did not observe any fetal demise during flecainide therapy, suggesting that this drug is both safe and effective for fetuses when monitored appropriately.
References 1. Allan LD, Chitra SK, Sharland GK, Maxwell D, Priestley K. Flecainide in the treatment of fetal tachycardias. Br Heart J 1991;65:46–48. 2. Simpson JM, Sharland GK. Fetal tachycardia: management and outcome of 127 consecutive cases. Heart 1998;79:576–581. 3. Krapp M, Baschat A, Gembruch U, Geipel A, Germer U. Flecainide in the intrauterine treatment of fetal supraventricular Tachycardia. Ultrasound Obstet Gynecol 2002;19:158–164. 4. Krapp M, Kohl T, Simpson JM, Sharland G, Katalinic, Gembruch U. Review of diagnosis, treatment, and outcome of fetal atrial flutter compared with supraventricular tachycardia. Heart 2003;89:913–917. 5. Jaeggi ET, Carvalho JS, De Groot E. Comparison of transplacental treatment of fetal supraventricular tachyarrhythmias with digoxin, flecainide, and sotalol: results of a nonrandomized multicenter study. Circulation 2011;124:1747–1754. 6. Uzun O, Babaoglu K, Sinha A, Massias, Beattie B. Rapid control of foetal supraventricular tachycardia with digoxin and flecainide combination treatment. Cardiol Young 2012;22:372–380. 7. Muhiddin KA, Turner P, Blackett A. Effect of flecainide on cardiac output. (abstract) Clin Pharmacol Ther 1985;37:260. 8. Anderson JL, Stewart JR, Perry BA, Van Hamersveld DD, Johnson TA, Conard GJ, Chang SF, Kvam DC, Pitt B. Oral flecainide acetate for the treatment of ventricular arrhythmias. N Engl J Med 1981;305:473–477. 9. Woosley RL, Siddoway LA, Duff HJ, Roden DM. Flecainide dose-response relations in stable ventricular arrhythmias. Am J Cardiol 1984;53:59B–65B. 10. Schmolling J, Renke K, Richter O, Pfeiffer K, Schlebusch H, Höller T. Digoxin flecainide, and amiodarone transfer across the placenta and the effects of an elevated umbilical venous pressure on the transfer rate. Ther Drug Monit 2000;22:582–588.
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11. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–788. 12. Rasheed A, Simpson J, Rosenthal E. Neonatal ECG changes caused by supratherapeutic flecainide following treatment for fetal supraventricular tachycardia. Heart 2003;89:470. 13. Allan LD, Anderson RH, Sullivan ID, Campbell S, Holt DW, Tynan M. Evaluation of fetal arrhythmias by echocardiography. Br Heart J 1983;50: 240–245. 14. Kleinman CS, Donnerstein RL, Jaffe C, DeVore GR, Weinstein EM, Lynch DC, Talner NS, Berkowitz RL, Hobbins JC. Fetal echocardiography: a tool for evaluation of in utero cardiac arrhythmias and monitoring of in utero therapy: analysis of 71 patients. Am J Cardiol 1983;51:237–242. 15. Ko JK, Deal BJ, Strasburger JF, Benson DW. Supraventricular tachycardia mechanisms and their age distribution in pediatric patients. Am J Cardiol 1992;69:1026–1032. 16. Jaeggi E, Fouron JC, Fournier A, Van Doesburg N, Drblik SP, Proulx F. Ventriculo-atrial time interval measured on M mode echocardiography: a determining element in diagnosis, treatment, and prognosis of fetal supraventricular tachycardia. Heart 1998;79:582–587. 17. Wren C. Mechanisms of fetal tachycardia. Heart 1998;79:536–537. 18. Simpson JM, Maxwell D, Rosenthal E, Gill H. Fetal ventricular tachycardia secondary to long QT syndrome treated with maternal intravenous magnesium: case report and review of the literature. Ultrasound Obstet Gynecol 2009;34:475–480. 19. Fouron JC, Fournier A, Proulx F, Lamarche J, Bigras JL, Boutin C, Brassard M, Gamache S. Management of fetal tachyarrhythmia based on superior vena cava/ aorta Doppler flow recordings. Heart 2003;89:1211–1216. 20. Carvalho JS, Prefumo F, Ciardelli V, Sairam S, Bhide A, Shinebourne EA. Evaluation of fetal arrhythmias from simultaneous pulsed wave Doppler in pulmonary artery and vein. Heart 2007;93:1448–1453. 21. Hornberger LK, Sahn DJ. Rhythm abnormalities of the fetus. Heart 2007;93: 1294–1300. 22. Simpson JM, Milburn A, Yates RW, Maxwell DJ, Sharland GK. Outcome of intermittent tachyarrhythmias in the fetus. Pediatr Cardiol 1997;18:78–82. 23. Bhamra RK, Flanagan RJ, Holt DW. High performance liquid chromatographic method for the measurement of mexiletine and flecainide in blood plasma or serum. J Chromatogr 1984;11:439–444. 24. Finster M, Pedersen H. Placental transfer and fetal uptake of drugs. Br J Anaesth 1979;51(Suppl):25S–28S. 25. Dimas VV, Taylor MD, Cunnyngham CB, Overholt ED, Bourne DW, Stanely JR 3rd, Sheikh A, Wolf R, Valentine B, Ward KE. Transplacental pharmacokinetics of flecainide in the gravid baboon and fetus. Pediatr Cardiol 2005;26:815–820. 26. Wren C, Hunter S. Maternal administration of flecainide to terminate and suppress fetal tachycardia. BMJ 1989;296:249. 27. Bourget P, Pons JC, Delouis C, Fermont L, Frydman R. Flecainide distribution, transplacental passage, and accumulation in the amniotic fluid during the third trimester of pregnancy. (abstract) Ann Pharmacother. 1994;28:1031. 28. Maxwell DJ, Johnson P, Hurley P, Neales K, Allan L, Knott P. Fetal blood sampling and pregnancy loss in relation to indication. (abstract) Br J Obstet Gynaecol 1991;98:892. 29. Wren C. Cardiac arrhythmias in the fetus and newborn. Semin Fetal Neonatal Med 2006;11:182–190. 30. Campbell JQ, Best TH, Eswaran H, Lowery CL. Fetal and maternal magnetocardiography during flecainide therapy for supraventricular tachycardia. Obstet Gynaecol 2006;108:767–771. 31. Strasburger JF, Cheulkar B, Wakai RT. Magnetocardiography for fetal arrhythmias. Heart Rhythm 2008;5:1073–1076. 32. Rein AJJT, O’Donnell C, Geva T, Nir A, Perles Z, Hashimoto I, Li X-K, Sahn DJ. Use of tissue velocity imaging in the diagnosis of fetal cardiac arrhythmias. Circulation 2002;106:1827–1833. 33. D’Alto M, Russo MG, Paladini D, Di Salvo G, Romeo E, Ricci C, Felicetti M, Tartaglione A, Cardaropoli D, Pacileo G, Sarubbi B, Calabro R. The challenge of fetal dysrhythmias: electrocardiographic diagnosis and clinical management. J Cardiovasc Med (Hagerstown) 2008;9:153–160. 34. Yabek SM, Kato R, Ikeda N, Singh BN. Effects of flecainide on the cellular electrophysiology of neonatal and adult cardiac fibers. (abstract) Am Heart J 1987;113:70.
Introduction Transplacental flecainide is an established treatment of fetal supraventricular tachycardia (SVT).1–6 However, there is a paucity of data regarding the dose–response relationship of flecainide for this indication. The pharmacodynamics are well described in healthy adults and adults with ventricular ectopics and tachycardias.7–9 The pharmacokinetics in pregnancy are less well described, particularly in the presence of fetal hydrops. In vitro experiments have shown a reduction of transplacental flecainide transfer when umbilical venous pressure is elevated.10 However, in hydropic human fetuses, Address reprint requests and correspondence: Dr. Trisha V. Vigneswaran, Department of Congenital Heart Disease, Evelina London Children’s Hospital, Westminster Bridge Rd, London SE1 7EH, United Kingdom. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
significantly different between responders and nonresponders (P ¼ .849). Twelve of 14 hydropic and 13 of 18 nonhydropic fetuses converted to sinus rhythm with similar flecainide concentrations (P ¼ .316). No fetus achieved cardioversion with a maternal serum flecainide concentration o250 μg/L. No fetus died while being treated with flecainide. CONCLUSION The clinical response to flecainide appears good, even in hydropic fetuses. Trough maternal flecainide concentrations, once therapeutic, do not predict cardioversion in the fetus with SVT. Flecainide therapy appears both safe and effective for the fetus when monitored appropriately. KEYWORDS Fetus; Arrhythmia; Supraventricular tachycardia; Flecainide ABBREVIATIONS AET ¼ atrial ectopic tachycardia; AV ¼ atrioventricular; ECG ¼ electrocardiogram; PJRT ¼ permanent junctional reciprocating tachycardia; SVT ¼ supraventricular tachycardia; VA ¼ ventriculoatrial (Heart Rhythm ]]]];]:]]]–]]]) rights reserved.
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2014 Heart Rhythm Society. All
transplacental flecainide has been shown to be effective in treating SVT and is more effective than digoxin.2 There have been concerns regarding the safety of flecainide in adult patients with impaired ventricular function11 and of toxic effects in newborn infants after treatment with transplacental flecainide.12–14 For the purposes of this study, fetuses with a ventricular rate 4200/min and equal atrial and ventricular rates were included. Previous data have shown that the majority of such cases presenting during fetal life are because of an orthodromic atrioventricular (AV) re-entrant tachycardia via an accessory pathway. Although atrial ectopic tachycardia (AET) and permanent junctional reciprocating tachycardia (PJRT) can produce similar findings, they are less common.15–17 AV nodal reentrant tachycardia is rare in fetal and neonatal populations.15 http://dx.doi.org/10.1016/j.hrthm.2014.07.031
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2 This study paper primarily examined the relationship between maternal serum flecainide concentrations and conversion of fetal SVT to sinus rhythm. A secondary aim was to assess the fetal safety profile of flecainide.
Methods Study population All fetuses with echocardiographically confirmed SVT with a 1:1 ratio of atrial:ventricular contraction treated with transplacental flecainide at our tertiary fetal cardiology center between January 1997 and December 2012 were retrospectively studied.
Classification of fetal tachycardias All fetal tachycardias were classified based on fetal echocardiogram findings alone. Fetal echocardiograms were performed using a number of different ultrasound systems, including the Agilent 7500 (Philips, Andover, MA) and the Toshiba Xario and Toshiba Aplio 500 models (Toshiba, Crawley, UK). Fetal SVT was defined as a ventricular rate 4200/min and a 1:1 ratio between atrial and ventricular contractions. This classification does not completely exclude ventricular tachycardia with 1:1 retrograde conduction, but such arrhythmias are exceedingly rare during fetal life.18 An algorithm outlining the diagnostic process is shown in Figure 1. Atrial and ventricular rates were calculated using the time interval between onset of consecutive atrial or ventricular contractions. Atrial flutter, chaotic atrial tachycardia, and atrial fibrillation all have an atrial rate 4300/min with degrees of AV block. In these 3 types of arrhythmia, the atrial rate is greater than the ventricular rate,4 and all such cases were excluded. Refinement of the SVT diagnosis was based on echocardiographic measurement of the time intervals between AV and ventriculoatrial (VA) contractions, using either M-mode echocardiography13,14,16 or spectral Doppler, simultaneously
Figure 1
interrogating the superior vena cava and aorta19 or a pulmonary vein and a branch pulmonary artery.20 The ratio of AV:VA intervals allows subdivision of fetal SVT into “short” and “long” VA tachycardias. In short VA tachycardia, the AV interval is longer than the VA interval; in long VA tachycardia, the VA interval is longer than the AV. Because the AV:VA ratio does not overlap between these groups, it is useful for subdividing the types of SVT and therefore directing appropriate treatment.16 In fetal life, a short VA tachycardia most commonly indicates AV re-entrant tachycardia but may rarely also represent AV nodal re-entrant tachycardia. A long VA tachycardia is associated with either PJRT or AET. Postnatally, PJRT and AET can be differentiated based on the surface electrocardiogram (ECG). However, they cannot be easily differentiated on fetal echocardiography even if the onset and offset are witnessed.21 Persistent SVT was defined as SVT present throughout the scanning period, which was 20 to 30 minutes. If a period of normal sinus rhythm was noted during echocardiography, the arrhythmia was defined as intermittent. Ideally, intermittent and persistent tachycardias would have been classified by long-term monitoring of the fetal heart rate; however, this was not judged practical because it would have involved either very prolonged periods of scanning or auscultation. Cardiotocography typically fails to reliably detect heart rates well above 200/min and so was not used. Intermittent SVT, which has been shown to have potential serious effects on the fetus, was also treated pharmacologically.22 Fetuses who remained in sinus rhythm at each clinical review after flecainide therapy were defined as permanent responders. Those who initially converted to sinus rhythm but then reverted to SVT were defined as nonsustained responders. Fetal hydrops was defined as abnormal fluid in at least 2 compartments (ascites, pleural effusions, pericardial effusions, or skin edema). All echocardiogram reports, which had been generated by the attending fetal cardiologist, were reviewed.
Algorithm for echocardiographic classification of fetal supraventricular tachycardia.
Vigneswaran et al
Flecainide and Fetal Supraventricular Tachycardia
Flecainide dosing During the study period, both flecainide and digoxin were used extensively to treat fetuses with SVT. First-line therapy for hydropic fetuses with SVT was transplacental flecainide. Nonhydropic fetuses were initially treated with transplacental digoxin (0.25 mg 3 times daily) or transplacental flecainide (100 mg 3 times daily). These were administered orally to the mother, based on the preference of the attending fetal cardiologist. If there was no response to digoxin, it was either replaced by flecainide or used concomitantly with flecainide. This decision and its timing were made on an individual patient basis by the attending fetal cardiologist. Patients who failed to respond to flecainide and had digoxin added to prenatal therapy were classified as a failure of flecainide therapy. Only serum flecainide concentrations before the addition of digoxin were included for the purposes of analysis in our study. Our analysis included patients who failed to respond to digoxin and in whom flecainide was added. Digoxin concentrations also were recorded. Flecainide was initiated at dose of 100 mg 3 times per day and altered depending on fetal response, serum flecainide concentrations, ECG findings and maternal side effects.
Drug monitoring Maternal serum trough flecainide concentrations were checked 2 to 7 days after initiation of therapy and at regular intervals throughout treatment. The laboratory-determined therapeutic range for flecainide was 200 to 700 μg/L. Trough flecainide concentrations were used for analysis and were obtained immediately before the morning or afternoon dose of flecainide was given, depending on clinic schedule. Peak flecainide concentrations were not measured. Liquid–liquid extraction was used to extract flecainide. Flecainide concentrations were measured using high performance liquid chromatography with fluorescence detection.23 Serum digoxin concentrations were measured at least 6 hours post-dose using a latex-enhanced immunoturbidimetric assay. The aim was a concentration within the laboratoryderived therapeutic range of 0.8 to 2.0 μg/L. The dose was tailored according to fetal response and maternal symptoms.
Maternal monitoring A history of palpitations and maternal heart disease was actively sought before commencement of flecainide. A twelve-lead ECG was recorded in all mothers before flecainide was started. In the initial years (1997–2002), patients were admitted for observation after commencement of therapy. In the subsequent years, patients were treated on an outpatient basis. At follow-up, a maternal ECG was recorded and any maternal side effects from flecainide and/or digoxin were elicited.
Follow-up Once flecainide was commenced, patients were reviewed within 1 week and, the timing of further follow-up was individually tailored depending on the fetal response.
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Initially, patients were reviewed weekly. Once rhythm control was established with therapeutic flecainide concentrations, less intensive review (every 2–4 weeks) was arranged. Fetal echocardiography was performed at each consultation. Adherence to flecainide was confirmed at consultation. Serum flecainide concentrations were not measured at every visit once conversion to sinus rhythm and/or resolution of hydrops was achieved, provided serum flecainide concentrations had been therapeutic and stable and there were no signs of toxicity on the maternal ECG. Once sinus rhythm had been achieved and sustained, the fetal heart rate was auscultated weekly by the local obstetric team to confirm sinus rhythm was maintained in addition to fetal cardiology clinic attendance.
Data collection Patients were identified from the fetal cardiology database (FileMaker Pro 8.0 version 1, FileMaker Inc, California). A retrospective review of medical case records was performed to collect information on gestation at presentation, fetal echocardiograms, therapies utilized, clinical course, complications and outcome.
Statistical analysis Discrete variables are presented as count or percentage. Data confirmed as not following gaussian distribution are given as median with range. Mann–Whitney U (two-tailed) test was used to look for significance between 2 nonparametric datasets and Kruskal-Wallis test for 3 or more nonparametric datasets. Two-tailed P values were calculated, and P o.05 was considered significant. Spearman r test was used to assess for nonparametric correlation. Analysis was performed using GraphPad Prism6 version 6.0c for Mac OS (GraphPad Software Inc, USA). The study was approved as an audit by Guy’s and St. Thomas’ NHS Trust. All of the data presened was collected for clinical reasons.
Results Thirty-three fetuses were treated with flecainide for persistent (n ¼ 23) or intermittent SVT (n ¼ 10). Four fetuses had previously failed therapy with transplacental digoxin. Median fetal heart rate was 250/min (range 207–316/min) with no significant difference in heart rate at presentation between hydropic and nonhydropic groups (medians 245, 250; P ¼ .121). Fourteen fetuses were hydropic at initiation. Four fetuses had long VA tachycardia and 29 had short VA tachycardia. One patient, who was born at term in sinus rhythm, did not attend prenatal follow-up and was excluded from further prenatal analysis, leaving 32 fetuses included in the study. Conversion to sinus rhythm occurred in 25 of 32 fetuses (78%), and the timing is shown in Figure 2. Median time to achieving sinus rhythm was 3 days (range 2–12 days). The proportion of successful conversions to sinus rhythm, which occurred within 6 days, was 84%. Sinus rhythm was
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converted and maintained sinus rhythm until birth. In these 5 fetuses, there was no significant difference in flecainide concentrations when the fetus was in SVT or in sinus rhythm (medians 440, 440; P ¼ .819). Three patients were started on digoxin after flecainide failed to convert the patients to sinus rhythm. Flecainide was replaced with digoxin in 1 case, and this fetus converted to sinus rhythm after 3 days of transplacental digoxin. Digoxin was added to flecainide therapy in 2 fetuses. One converted after 42 days of combined therapy, and the other was delivered after 3 days because of poor cardiac function. All fetuses treated with digoxin had a level within the laboratorydefined therapeutic range.
Flecainide dosing and concentration Figure 2
Cumulative time to initial conversion to sinus rhythm.
maintained until birth in 22 of 25 fetuses (Table 1). Three of the four fetuses with long VA tachycardia and 22 of the 28 fetuses with short VA tachycardia converted to sinus rhythm after flecainide therapy (Table 2). Ten fetuses had intermittent SVT at diagnosis. Eight of these fetuses maintained sinus rhythm after treatment. One initially cardioverted but then developed persistent SVT and hydrops, and 1 fetus remained in SVT. The fetus who remained in intermittent SVT did not develop hydrops. A maternal serum flecainide concentration was available for all patients. Median trough flecainide concentration at conversion to sinus rhythm was 460 μg/L (range 250–866 μg/L): 21 of 25 responders had a flecainide concentration within the therapeutic range and 4 were supratherapeutic (4700 μg/L). Median flecainide concentration achieved during therapy was 450 μg/L (range 210–840 μg/L) in the 7 fetuses who did not convert to sinus rhythm. There was no significant difference in flecainide concentrations achieved between responders and nonresponders (P ¼ .849). No fetus achieved sinus rhythm with a maternal flecainide concentration o250 μg/L. Five patients initially converted to sinus rhythm but later reverted to SVT while on flecainide with therapeutic concentrations; 2 of these fetuses subsequently Table 1
During the study period, daily doses of between 100 to 450 mg were used, depending on fetal response, maternal flecainide concentration, and maternal ECG changes. The maternal serum flecainide concentrations corresponding to the dosing regimen are shown in Figure 3.
Hydropic and nonhydropic fetuses Initial pharmacologic cardioversion occurred in 12 of 14 hydropic fetuses (86%) at a median of 3 days (range 2–12 days) and in 13 of 18 nonhydropic fetuses (72%) at a median of 6 days (range 2–9 days). There was no significant difference in heart rate in the hydropic and nonhydropic groups (medians 245, 250; P ¼ .467). There was no significant difference in flecainide concentrations between the hydropic and nonhydropic groups (medians: 462, 415; P ¼ .316). There was no significant difference in flecainide concentrations between hydropic/nonhydropic responders and nonresponders (P ¼ .551). Hydrops resolved before delivery in 11 of 12 fetuses who converted to sinus rhythm. One fetus developed hydrops during flecainide therapy. Flecainide was commenced after 3 weeks of unsuccessful digoxin therapy in a fetus who presented with intermittent SVT but developed sustained tachycardia. Three days after starting flecainide, the fetus developed ascites and subsequently a small pleural effusion.
Summary of findings
No. of fetuses Median gestation age (range) No. of hydropic fetuses (% of group) No. of cases of intermittent SVT (% of group) No. of cases of long ventriculoatrial tachycardia (% of group) Median flecainide concentration at initial conversion to sinus rhythm (range) Median flecainide concentration in SVT (range) Median time to conversion to sinus rhythm (range)
Permanent responders
Nonsustained responders
Nonresponders
Total no. of cases
22 28 (21–37) 11 (50) 8 (36) 2 (9) 460 (250–866)
3 33 (23–38) 1 (33) 1 (33) 1 (33) 441 (266–789)
7 31 (22–35) 2 (29) 1 (14) 1 (14) —
33 — 14 10 4 —
— 3 (2–12)
463 (380–690) 6 (2–6)
468 (223–840) —
— —
Permanent responders refers to fetuses who converted to sinus rhythm and maintained sinus rhythm until birth. Nonsustained responders refers to fetuses who converted to sinus rhythm with flecainide but later reverted back to supraventricular tachycardia (SVT). Nonresponders describes fetuses who never converted to sinus rhythm. There was no statistical significance between flecainide concentrations of responders/nonsustained responders and nonresponders (P ¼ .751).
Vigneswaran et al Table 2
Flecainide and Fetal Supraventricular Tachycardia
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Features of fetuses with short and long ventriculoatrial tachycardia
No. of cases Median gestation (range) No. of hydropic fetuses (% of group) Conversion to sinus rhythm (% of group) Median flecainide concentration at conversion to sinus rhythm (range) Median days to conversion to sinus rhythm (range) Permanent conversion to sinus rhythm (%)
Short ventriculoatrial tachycardia
Long ventriculoatrial tachycardia
28 28 (20–38) 14 (50) 22 (79) 450 (250–866)
4 29 (21–35) 1 (25) 3 (75) 490 (252–558)
The hydrops persisted despite conversion to sinus rhythm. The fetus reverted to SVT and for this reason was delivered at 31 weeks. Postnatally, the rhythm remained uncontrolled for 4 days until amiodarone was started. The neonate remained hydropic and was also found to be severely anemic, requiring multiple red cell transfusions.
Gestational age Fetuses were treated at median gestation of 28 weeks (range 20–38 weeks). There was no correlation between gestation at presentation and the time taken to achieve sinus rhythm (Spearman r ¼ –0.187, P ¼ .37). Median gestational age at presentation in the permanent responders, nonsustained responders, and nonresponders was 28, 33, and 32 weeks, respectively. There was no significant difference between these groups (P ¼ .897; Table 1).
Fetal outcome No fetal deaths occurred during treatment with flecainide. No fetus who responded to flecainide died. Two intrauterine deaths occurred after cessation of flecainide. In one hydropic fetus, flecainide therapy was stopped
3 (2–12) 20 (71)
4 (3–6) 2 (50)
Total no. of cases 32 15 25
22
after 4 days, without fetal response, because of maternal symptoms of malaise, palpitations, and nausea with a flecainide concentration of 348 μg/L. Propafenone was commenced; however, the family decided to terminate the pregnancy. The second fetus had failed to respond to 14 days of flecainide therapy. Flecainide was stopped because of maternal QT prolongation (from 398 to 560 ms) in association with prolongation of the PR interval by 20% with an elevated flecainide concentration (814 μg/L) but in the absence of maternal symptoms. Three days after flecainide was stopped, sotalol was started and the fetus remained in SVT with hydrops 11 days into therapy. This fetus underwent direct therapy with an intracordal injection of amiodarone at 28 weeks. The fetus developed bradycardia during the procedure and subsequently died. In 3 of 8 fetuses who did not convert or maintain sinus rhythm, preterm delivery (between 31 and 36 weeks) was arranged because of the uncontrollable SVT.
Postnatal tachycardia characteristics Of the 31 live births, 26 had an ECG available for review; the remaining 5 were followed up at other centers. Over half
Figure 3 Flecainide dosing and corresponding maternal flecainide concentration, showing all maternal trough flecainide concentrations achieved with transplacental flecainide therapy. Shaded area represents our laboratory therapeutic range (200–700 μg/L). Horizontal lines indicate median flecainide concentrations.
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6 Table 3 Frequency of postnatal ECG findings according to fetal response Permanent responders Surviving fetuses No. of neonates with: Postnatal SVT Preexcitation No preexcitation PJRT AET
Nonsustained Nonresponders responders
22
3
5 (1)
9 2 14 0 1
2 1 1 1 0
4 (1) 1 3 (1) 1 0
Numbers in parentheses refer to the additional neonate who did not attend prenatal follow-up but was reviewed in our department in the postnatal period. AET ¼ atrial ectopic tachycardia; PJRT ¼ permanent junctional reciprocating tachycardia; SVT ¼ supraventricular tachycardia.
(16/26) had recurrence of tachycardia after birth (Table 3). Twenty-two of 27 cases with short VA tachycardia were seen at our center in the postnatal period. Four of 22 cases (18%) of short VA tachycardia had pre-excitation on resting ECG, and 12 of 22 (55%) had SVT after birth consistent with re-entrant tachycardia. All cases with long VA tachycardia had SVT in the first year of life with PJRT (n ¼ 2), AET (n ¼ 1) and undefined (n ¼ 1).
Discussion Flecainide has been used for the treatment of fetal tachycardias for more than 20 years despite the caution expressed related to potential proarrhythmic effects in adults after myocardial infarction.11 We have confirmed a good response of fetal SVT to transplacental flecainide therapy even in hydropic fetuses who have been regarded as a difficult group to control.2,3,5 Conversion to sinus rhythm, when achieved, occurred rapidly at a median interval of 3 days, which compares favorably to other drugs used to control fetal SVT.2,3,5 Our primary aim was to establish if there was a relationship between flecainide concentrations and fetal conversion to sinus rhythm. We were able to achieve a therapeutic concentration in all cases in this series. Below a serum flecainide concentration of 250 μg/L, we did not observe cardioversion. Within the therapeutic range (200–700 μg/L), our data did not confirm a close relationship between fetal response and trough flecainide concentration. There are a number of potential contributors to treatment failure after transplacental therapy. In certain cases there may be impaired placental transfer of flecainide. The mechanism of carriage of flecainide across the human placenta has not been studied in detail. Whether movement is via diffusion or active transport via the syncytiotrophoblastic carrier proteins is not definitively known. However, because flecainide is lipophilic with a low molecular weight, movement most likely occurs via passive diffusion across a non-hydropic placenta.24,25 Laboratory studies have shown that fetal flecainide transfer is impaired in fetal hydrops.10 Clinically, the reverse has been shown, with flecainide demonstrating superior bioavailability to other drugs, such as digoxin, in hydropic fetuses.2,4 Previous work in our department has
indicated distribution of flecainide from the mother’s blood across the placenta into the cord blood to be effective with concentrations of 80% in the umbilical cord blood,1 and other studies have shown placental transfer to be between 64% and 97%.3,26,27 In this series, we did not attempt to measure the fetal concentration of flecainide because this would have involved an invasive procedure in the fetus with its associated risks to the fetus.28 Therefore, we cannot determine whether treatment failure is related to lack of placental transfer in certain cases, and further research is needed to elucidate the pharmacokinetics of flecainide in pregnancy. The mechanism of fetal SVT may also play a role in the response to treatment. Four fetuses had a long VA tachycardia, which is a higher proportion than diagnosed in other series.5 This type of tachycardia usually is difficult to control, but the response to flecainide in our series was good, with 3 of 4 cases converting to sinus rhythm with flecainide therapy. A re-entrant tachycardia via an accessory pathway is the most likely mechanism for the short VA cases during fetal life,17,29 but the precise electrophysiologic properties of fetal SVT were not evaluated, only mechanical events using standard fetal echocardiography. Other techniques, notably magnetocardiography and tissue Doppler imaging, might have provided further information but are not in routine clinical use.30–33 The electrophysiologic properties of fetal conducting tissue may also affect the response to flecainide. Experimental studies have shown that neonatal canine Purkinje cells are less sensitive to the actions of flecainide compared to adult cells. They show less prolongation of the action potential duration and effective refractory period than do adult cells. Additionally, at faster heart rates, flecainide resulted in a greater reduction in the rate of depolarization of Purkinje fibers in adult compared to neonatal fibers.34 These data may be extrapolated to fetuses and indicate that fetuses of advanced gestation may respond better to flecainide. However, our data were not consistent with this, showing no impact of gestational age on response to flecainide therapy. Our finding that a flecainide concentration within the therapeutic range did not correlate with the response of the fetus is important in clinical practice. If a fetus treated with flecainide does not initially respond, then there may be justification to adjusting the maternal dose to achieve higher flecainide concentrations within the therapeutic range and allow further time for the fetus to respond. However, our data do not support a strong link between maternal trough flecainide concentrations and fetal clinical response. Our secondary aim was to assess the fetal safety profile of flecainide. There were no fetal deaths on flecainide in this series; however, 1 fetus developed hydrops during treatment. The most likely mechanism for the fetus becoming hydropic was a direct result of 3 weeks of uncontrolled tachycardia rather than a result of flecainide therapy. The maternal safety profile is the subject of further research.
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Flecainide and Fetal Supraventricular Tachycardia
Study limitations There are inherent limitations associated with an observational retrospective study. The timing of sampling was predose, but there may be some variability in the time from the previous flecainide dose. The concentrations measured were trough concentrations and not peak, so the relation of peak drug concentration to achieving sinus rhythm could not be assessed. Maternal compliance was ascertained as a routine, but we cannot exclude noncompliance with flecainide as a potential cause of treatment failure, although our measurement of flecainide concentrations does suggest that noncompliance was not a major problem. Assessment of tachycardias was made by echocardiographic means because of the relative inaccessibility of fetal ECG assessment and the lack of a magnetocardiographic facility for more detailed electrophysiologic information. However, the echocardiographic techniques we describe and use represent the reality of most clinical practice.
Conclusion Our results confirm a high degree of efficacy of flecainide in the treatment of fetal SVT, even in hydropic fetuses. Trough maternal flecainide concentrations did not appear to differentiate responders and refractory cases; thus, such concentrations do not seem to predict conversion to sinus rhythm in fetuses with SVT. We did not observe any fetal demise during flecainide therapy, suggesting that this drug is both safe and effective for fetuses when monitored appropriately.
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