Antenatal Therapy For Fetal Supraventricular Tachyarrhythmias

JOU R NA L OF T HE A M ER I C AN C OLL EG E OF C AR DI OL OG Y VOL. 74, NO.
7, 20
19
ª 2 0 1 9 B Y T H E A ME RIC A N C OL LEG E OF C ARD I OLO GY FOUN DA TI O
N PUBL ISH E D B Y E LS E V IER
Antenatal Therapy for

Fetal Supraventricular Tachyarrhythmias
Multicenter Trial
a b, c d
Takekazu Miyoshi, MD, Yasuki Maeno, MD, * Toshimitsu Hamasaki, PHD, Noboru Inamura, MD,
e f g h i
Satoshi Yasukochi, MD, Motoyoshi Kawataki, MD, Hitoshi Horigome, MD, Hitoshi Yoda, MD, Mio Taketazu, MD,
j k l m n
Masaki Nii, MD, Akiko Hagiwara, MD, Hitoshi Kato, MD, Wataru Shimizu, MD, Isao Shiraishi, MD,
n a a o p
Heima Sakaguchi, MD, Keiko Ueda, MD, Shinji Katsuragi, MD, Haruko Yamamoto, MD, Haruhiko Sago, MD,
q,
Tomoaki Ikeda, MD, * on behalf of the Japan Fetal Arrhythmia Group
ABSTRACT
BACKGROUND Standardized treatment of fetal tachyarrhythmia has not been established.
OBJECTIVES This study sought to evaluate the safety and efficacy of protocol-defined transplacental treatment for
fetal supraventricular tachycardia (SVT) and atrial flutter (AFL).
METHODS In this multicenter, single-arm trial, protocol-defined transplacental treatment using digoxin, sotalol, and
flecainide was performed for singleton pregnancies from 22 to <37 weeks of gestation with sustained fetal SVT or
AFL $180 beats/min. The primary endpoint was resolution of fetal tachyarrhythmia. Secondary endpoints were fetal
death, pre-term birth, and neonatal arrhythmia. Adverse events (AEs) were also assessed.
RESULTS A total of 50 patients were enrolled at 15 institutions in Japan from 2010 to 2017; short ventriculoatrial (VA)
SVT (n ¼ 17), long VA SVT (n ¼ 4), and AFL (n ¼ 29). One patient with AFL was excluded because of withdrawal of
consent. Fetal tachyarrhythmia resolved in 89.8% (44 of 49) of cases overall and in 75.0% (3 of 4) of cases of fetal
hydrops. Pre-term births occurred in 20.4% (10 of 49) of patients. Maternal AEs were observed in 78.0% (39 of 50) of
patients. Serious AEs occurred in 1 mother and 4 fetuses, thus resulting in discontinuation of protocol treatment in 4
patients. Two fetal deaths occurred, mainly caused by heart failure. Neonatal tachyarrhythmia was observed in 31.9%
(15 of 47) of neonates within 2 weeks after birth.
CONCLUSIONS Protocol-defined transplacental treatment for fetal SVT and AFL was effective and tolerable in
90% of patients. However, it should be kept in mind that serious AEs may take place in fetuses and that tachy-
arrhythmias may recur within the first 2 weeks after birth. (J Am Coll Cardiol 2019;74:874–85)
© 2019 by the American College of Cardiology Foundation.
From the aDepartment of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Suita, Japan; bDepartment
of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan; cDepartment of Data Science, National
Cerebral and Cardiovascular Center, Suita, Japan; dDepartment of Pediatric Cardiology, Osaka Women’s and Children’s Hospital,
e
Izumi, Japan; Department of Cardiology, Nagano Children’s Hospital, Azumino, Japan; fDepartment of Gynecology and
Obstetrics, Tohoku University Graduate School of Medicine, Sendai, Japan; gDepartment of Pediatrics, University of Tsukuba,
Tsukuba, Japan; hDepartment of Neonatology, Toho University Omori Medical Center, Tokyo, Japan; iDepartment of Pediatric
Cardiology, Saitama Medical University International Medical Center, Hidaka, Japan; jDepartment of Cardiology, Shizuoka Chil-
dren’s Hospital, Shizuoka, Japan; kDepartment of Internal Medicine, Kanagawa Children’s Medical Center, Yokohama, Japan;
Listen to this l m
Department of Pediatric Cardiology, National Center for Child Health and Development, Tokyo, Japan; Department of
manuscript’s audio
Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan; nDepartment of Pediatric Cardiology, National Cerebral and
summary by
o
Cardiovascular Center, Suita, Japan; Department of Advanced Medical Technology Development, National Cerebral and
Editor-in-Chief
Dr. Valentin Fuster on Cardiovascular Center, Suita, Japan; pCenter for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child
JACC.org. Health and Development, Tokyo, Japan; and the qDepartment of Obstetrics and Gynecology, Mie University, Tsu, Japan. *Drs.
Maeno and Ikeda contributed equally to this work. This work was supported by the Agency for Medical Research and Develop-
ment of the Ministry of Education, Culture, Sports, Science, and Technology of Japan (JP15lk0201001). The funding organization
had no role in the trial design; data collection, analysis, or interpretation; or manuscript preparation. All authors have reported
that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received January 18, 2019; revised manuscript received June 5, 2019, accepted June 10, 2019.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.06.024
J ACC VOL. 74 , NO. 7, 20 19 J A C C Miyoshi
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875 Miyoshi et al. 87
AUGUST 20, 2019:874–85 Transplacental Treatment for Fetal ATachyarrhythmias
UGUST 20, 2019:874–85
Transplacental Treatment for Fetal Tachyarrhythmias
F etal tachyarrhythmia develops in <0.1% of

pregnancies. The most common forms of fetal
tachyarrhythmia
tachycardia (SVT) and
include
atrial
supraventricular
flutter (AFL) (1).
P R OC EDUR ES . The
was described previously
study
(9).
criteria were as follows: 1) sustained fetal
tachyarrhythmia $180 beats/min,
design
Inclusion
with a
AB BRE V IATIO N S
AN D A C R O N YMS
AE = adverse event
AFL = atrial flutter

Although many cases are of minor clinical signifi- diagnosis of SVT or AFL (fetal tachyar-
AV = atrioventricular
cance, fast or long-lasting tachyarrhythmias often rhythmia is defined as sustained when
cause fetal heart failure and fetal hydrops (1,2). present $50% during a 40-min fetal heart AVRT = atrioventricular
re-entrant tachycardia
Without treatment, hydrops is found in 30% to 40% rate monitoring or a 30-min echocardiogra-
CI = confidence interval
of fetuses with SVT and in 7% to 43% of fetuses phy session); 2) 22 to <37 weeks of gestation;
EAT = ectopic atrial
with AFL (3,4). For fetuses with hydrops, elective 3) singleton pregnancy; and 4) patients’
tachycardia
pre-term delivery and other lifesaving interventions written consent to study participation.
SVT = supraventricular
are often attempted, but perinatal mortality is signif- Exclusion criteria were as follows: 1) the pa-
tachycardia
icantly higher than in fetuses without hydrops (3–5). tient had mental or psychiatric conditions
VA = ventriculoatrial
Available data suggest that the risk of fetal death that preclude safe study participation; 2) the
will be higher if tachyarrhythmia is left untreated in patient was anticipated to have contraindications to
fetal hydrops. the antiarrhythmic medications used in the study; 3)
SEE P AG E 8 86 serious, life-threatening malformations were diag-
nosed in the fetus; 4) the fetus was diagnosed with
Before designing this clinical trial, we conducted a multifocal atrial tachycardia or chaotic atrial tachy-
nationwide survey of fetal tachyarrhythmia in Japan cardia; and 5) the patient or fetus was not eligible, in
from 2004 to 2006 (6). A total of 82 fetuses were the investigator’s judgment, for this clinical study for
analyzed, of whom 41 received in utero treatment. other reasons.
Transplacental treatment was fairly effective in Fetal tachyarrhythmias were diagnosed using
90.2% (37 of 41) of cases and in 81.8% (9 of 11) of cases pulsed wave Doppler echocardiography and M-mode
with fetal hydrops. These findings were comparable recordings (9). Fetuses with multiple arrhythmias
to those of previous reports (2–4,7). Although several were classified according to the dominant mecha-
retrospective studies have supported the efficacy of nism. Fetal hydrops was characterized by the pres-
transplacental treatment for fetal SVT and AFL, the ence of subcutaneous edema in addition to at least 1
choice of first-line and second-line antiarrhythmic of the following findings: ascites, pleural effusion,
therapy remains controversial (8). Because most and pericardial effusion (10). All fetal ultrasound
studies are confounded by physician and institutional scans were reviewed by the Protocol Evaluation
preferences, there are few data supporting specific Committee.
treatment protocols. Recruiting centers were as follows: National Cere-
The primary goal of this study was to evaluate the bral and Cardiovascular Center, Kurume University
safety and efficacy of protocol-defined transplacental School of Medicine, Osaka Women’s and Children’s
treatment for fetal SVT and AFL. We conducted a Hospital, National Center for Child Health and
multicenter single-arm trial. Development, Kanagawa Children’s Medical Center,
University of Tsukuba, Toho University Omori Medi-
cal Center, Hokkaido University, Hyogo Prefectural
ME THODS Children’s Hospital, Nagano Children’s Hospital,
Shizuoka Children’s Hospital, Kobe City Medical
S T UDY D ES IGN AND P A RT I C I P ANTS. This study
Center General Hospital, Mie University, Okayama
was a multicenter, single-arm trial. The study Medical Center, and Osaka University, all in Japan.
protocol was approved by the Institutional Review
Board of the National Cerebral and Cardiovascular TRANS PLA C EN TAL T REATMEN T PROT O C O L .
Center of Japan in July 2010 (M20-045). Patient Proto- col-defined treatment with digoxin, sotalol,
enrollment began in October 2010. This study was or flecainide was continued until delivery (9).
conducted in accordance with the Helsinki Ineffective fetal therapy was defined as therapy
Declaration. Written informed consent was that did not resolve fetal tachyarrhythmia or when
obtained from the patients. This trial was fetal death was strongly suspected because of
registered in the University Hospital Medical progression of fetal hydrops. If the investigator
Information Network Clinical Trials Registry as judged that the pregnancy could not be
UMIN000004270. The Independent Safety Evalu- maintained to term, the woman was delivered of the
ation Committee was responsible for the overall fetus. When maternal or fetal adverse events (AEs)
safety of this trial. secondary to antiarrhythmic
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For fetuses with short ventriculoatrial (VA) SVT or

F I G U R E 1 Trial Profile
AFL without hydrops, digoxin was the first-line ther-
apy. Rapid initial saturation was performed with a
Screened 0.5- mg intravenous injection. Intravenous
(n = 88)
injections of
0.25 mg were administered at 8 and 16 h after the
Declined or ineligible (n = 38)* initial dose. If intravenous injections were not
feasible, oral digoxin (1.5 mg/day) was given in
3 divided doses. Subsequently, oral digoxin at
Registered
(n = 50) 0.75 mg/day was given in 3 divided doses, with
adjustment to maintain maternal serum concentra-
tions from 1.5 to 2.0 ng/ml. If fetal therapy was inef-
fective 3 days after establishing the target serum
Fetal treatment digoxin concentration, the investigator moved to the
second-line therapy. Sotalol at 160 mg/day in 3 divided
based on the protocol doses was added. If a regimen of 3 days of treatment at
(n = 50) 160 mg/day of sotalol was ineffective, the patient
then proceeded to 240 mg/day in 2 divided doses. If
Consent withdrawal (n = 1) 240 mg/day was ineffective after 3 days of treatment,
the patient proceeded to 320 mg/day in 2 divided
doses. If 320 mg/day was ineffective after 3 days of
Primary and secondary outcome at birth
treatment, the investigator moved to the third-line
(n = 49)
therapy. Flecainide was administered at 200 mg/day
in 2 divided doses in addition to digoxin. If 200
Fetal death (n = 2) mg/day was ineffective after 3 days of treatment, the
patient proceeded to 300 mg/day in 2 divided
Secondary outcome doses. If
at 1-month follow-up after birth 300 mg/day was ineffective after 3 days of treatment,
(n = 47) protocol-defined treatment was discontinued. If the
fetus had hydrops, fetal therapy started with the
second-line therapy.
Analysis
For fetuses with long VA SVT, sotalol and flecai-
Analysis for maternal outcome (n = 50) nide were used as first-line and second-line therapy,
respectively, regardless of the presence or absence of
excluded from analysis (n = 0)
fetal hydrops. The dosage and administration
Analysis for fetal outcome (n = 49) schedule were the same as those for fetuses with
excluded from analysis (n = 1) short VA SVT or AFL.
• consent withdrawal (n = 1)
ENDPO I NTS. The primary endpoint was
Analysis for neonatal outcome (n = 47)
resolution of fetal tachyarrhythmia, defined as
excluded from analysis (n = 2)
normal sinus rhythm or mean heart rate of <180
• fetal death (n = 2)
beats/min. Res- olution of fetal tachyarrhythmia was
judged by a 40- min fetal heart rate monitoring or
30-min echocardiography session. Secondary
*A total of 31 patients did not meet the inclusion criteria because of nonsustained fetal
endpoints were fetal death related to
tachyarrhythmia (n ¼ 16), ventricular tachycardia (n ¼ 5), $37 weeks of gestation
(n ¼ 5), twin pregnancy (n ¼ 1), and study participation refusal (n ¼ 4). Seven patients
tachyarrhythmia, pre-term birth, cesarean section
met the exclusion criteria for fetal life-threatening malformations: Ebstein’s anomaly performed as a result of fetal arrhythmia,
(n ¼ 4); hypoplastic left heart syndrome (n ¼ 2); and cardiac tumors with ventricular improvement in heart rate and less edema after
outflow obstruction (n ¼ 1). fetal therapy, prevalence of neonatal arrhythmia,
neonatal central nervous system disor- der, and
agents were observed, the investigator could reduce neonatal survival. Safety endpoints were maternal,
the dosage. Sotalol and flecainide were discontinued fetal, and neonatal AEs. All AEs were assessed by
if the corrected QT interval was >500 ms. After birth, the Independent Safety Evaluation Committee.
it was left up to each institution to decide whether to Because we focused on evaluating the safety of our
continue antiarrhythmic agents prophylactically. protocol-defined transplacental treatment, we
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assessed the maternal cardiac condition before and during this

treatment by using
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echocardiography as well as electrocardiography.

T AB L E 1 Baseline Characteristics
Maternal serum levels of the antiarrhythmic agents
and plasma brain natriuretic peptide levels were Total Short VA SVT Long VA SVT AFL
(N ¼ 49) (n ¼ 17) (n ¼ 4) (n ¼ 28)
also measured.
Maternal age, yrs 32 (21–40) 32 (21–39) 35 (31–38) 31.5 (24–40)
ST A T I ST I CA L A NA L Y SI S . Sample size was Primipara status 24 (48.0) 8 (47.1) 2 (50.0) 13 (46.4)
determined according to the precision-based Gestational age at 31 (24–36) 27 (24–35)* 32.5 (26–36) 32 (27–35)
method. A sample size of 50 produced a 2-sided diagnosis, weeks
Atrial rate, beats/min 430 245 230 450
Clopper-Pearson exact 95% confidence interval (CI)
(185–520) (185–280) (192–260) (410–520)†
with a width of Ventricular rate, beats/min 230 245 230 224.5
18.5 when the sample proportion was assumed to be (185–280) (185–280) (192–260) (205–260)
90%. More details were presented in the protocol Fetal hydrops at diagnosis 4 (8.0) 2 (11.8) 1 (25.0) 1 (3.6)
Fetal effusion or ascites at diagnosis 19 (38.0) 9 (52.9) 2 (50.0) 8 (28.6)
paper (9). All statistical analyses were performed ac-
Fetal abnormality‡ 6 (12.0) 2 (11.8) 2 (50.0) 2 (7.1)
cording to a pre-specified statistical analysis plan
Threatened pre-mature labor 10 (20.0) 3 (17.7) 1 (25.0) 6 (21.4)
finalized before database lock and release of data. All
analyses were performed using SAS for Windows Values are median (range) or n (%). *Significant difference when compared with fetuses with AFL and long VA
SVT (p < 0.05, the Steel-Dwass test). †Significant difference when compared with fetuses with short and long
software version 9.3 (SAS Institute, Cary, North Car-
VA SVT (p < 0.05, the Steel-Dwass test). ‡Beckwith-Wiedemann syndrome with umbilical hernia (AFL),
olina). According to the intention-to-treat principle, suspected Costello syndrome with hypoplastic lung (AFL), corrected transposition of the great arteries
(AFL), isolated ventricular septal defect (short VA SVT), tuberous sclerosis with cardiac tumors (long VA SVT),
the primary analysis group was defined as all regis- and heterotaxy syndrome with severe pulmonary valve stenosis and ventricular septal defect (long VA SVT).
tered pregnant mothers, fetuses, or neonates. AFL ¼ atrial flutter; SVT ¼ supraventricular tachycardia; VA ¼ ventriculoatrial.
Continuous data were presented as medians and

range. Categorical data were presented as frequencies
and percentages. For the primary endpoint, the Obstetrical complications were observed in 12 pa-
number and percentage of fetuses with resolution of tients (24.0%): threatened pre-term labor (n ¼ 10),
fetal tachyarrhythmia were calculated with a 2-sided placenta previa (n ¼ 1), and gestational diabetes
Clopper-Pearson exact 95% CI. The primary outcome mellitus (n ¼ 1). Median gestational age at diagnosis
was also analyzed on the basis of the per-protocol set was 31 weeks (range 24 to 36 weeks) (Table 1). Only 2
group to assess the robustness of conclusions from fetuses (4.0%) had ventricular rates between 180 and
the primary analysis group. The per-protocol set 200 beats/min: 1 with short VA SVT and another with
group excluded subjects with major protocol viola- long VA SVT. Fetal hydrops at diagnosis of fetal
tions or loss to follow-up. arrhythmia was observed in 4 fetuses (8.0%; 95% CI:
Secondary endpoints were analyzed similar to 2.2% to 19.2%). Six fetuses with morphological ab-
primary endpoints. The Steel-Dwass test was used to normalities (12.0%) were not excluded from this
compare continuous variables among 3 subtypes of study (Online Table 1). Beta-stimulants were used for
fetal tachyarrhythmia. A value of p < 0.05 was tocolysis in all 10 patients with threatened pre-term
considered significant in all analyses. For the safety labor but were discontinued before starting the pro-
analysis, the number of AEs and the number of sub- tocol treatment. Fetal hydrops was found in 2 of 10
jects with AEs were calculated according to causality. patients with threatened pre-term labor, and this was
RESULTS not statistically different from the incidence in pa-
tients without threatened pre-term labor (20.0% vs.
STUDY COHORT AND BASELINE CHARACTERISTICS. A 5.0%; difference of 15%; 95%CI: 20.8 to 49.6; Fisher
total of 50 patients were enrolled and treated at 15 exact test p ¼ 0.17).
institutions in Japan from October 2010 to January P R IMARY AND SE CO NDARY O UT COME S.
2017 (Figure 1). During the protocol treatment, 1 pa- Fetal tachyarrhythmia resolved in 44 of 49
tient with AFL was excluded because of withdrawal of patients overall (89.8%; 95% CI: 77.8% to 96.6%)
consent, thus leaving 49 patients available for anal- and in 3 of
ysis of primary and secondary outcomes. Safety 4 patients with fetal hydrops (75.0%). Two cases of
endpoints were assessed in all 50 patients. Except for fetal hydrops resolved in utero, and 1 fetus pro-
2 fetal deaths, 1-month follow-up was available for 47 gressed to hydrops, with hydrops present at de-
neonates. Maternal complications were observed in 7 livery in 3 neonates. Median gestational age at birth
patients (14.0%): type 2 diabetes mellitus, solitary was 38 weeks (range 29 to 40 weeks). Pre-term
kidney with mild renal dysfunction, patent ductus births occurred in 7 neonates (14.3%; 95% CI: 5.9%
arteriosus, history of depression or schizophrenia to 27.2%). A total of 22 patients (44.9%; 95% CI:
(n ¼ 1 each) and controlled hypothyroidism (n ¼ 2). 30.7% to 59.8%) underwent cesarean delivery, but
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treatment. Recurrence of tachyarrhythmia was

TA BL E 2 Primary and Secondary Outcomes
observed within 2 weeks after birth in all neonates
Total Short VA SVT Long VA SVT AFL
except 1 with SVT in the third week. Notably, 10 of
(N ¼ 49) (n ¼ 17) (n ¼ 4) (n ¼ 28)
15 had recurrence of tachyarrhythmia in the first
Final treatment agents
Digoxin 26 9 0 17
3 days. Intraventricular hemorrhage and periven-
Sotalol 4 0 4 0 tricular leukomalacia were detected in 1 (2.1%;
Digoxin and sotalol 15 6 0 9 95% CI: 0.1% to 11.3%) and 4 (8.5%; 95% CI: 2.4% to
Digoxin and flecainide 5 2 0 3 20.4%) neonates after birth, respectively. There
Resolution of fetal tachyarrhythmia 44 (89.8) 15 (88.2) 4 (100.0) 25 (89.3) were no neonatal deaths.
Recurrence in utero 14 (32.6) 7 (43.8) 1 (25.0) 6 (26.1)
The same analysis was repeatedly conducted for
Duration of treatment, weeks 6 (1–13) 11 (1–13)* 4 (1–12) 5.5 (1–9)
the primary endpoint on the per-protocol set. After
Maternal BNP levels before 13.7 14.0 13.0 13.3
treatment, pg/ml (2.0–294.2) (2.0–294.2) (8.7–22.6) (2.0–96.1) excluding 3 patients with life-threatening fetal mal-
Maximum maternal BNP levels 28.6 35.7 18.3 30.8 formations (tuberous sclerosis with cardiac tumors,
during treatment, pg/l (6.0–141.1) (11.9–118.0) (14.6–26.7) (6.5–141.1)
suspected Costello syndrome with hypoplastic lungs,
Delivery mode
and heterotaxy syndrome) that were confirmed as
Vaginal delivery 27 9 3 15
violations of the exclusion criteria at data review
Elective cesarean delivery 11 5 0 6
Urgent cesarean delivery 11 3 1 7
committee, resolution of fetal tachyarrhythmia was
Urgent cesarean delivery 3 1 0 2 observed in 43 of 46 patients (93.5%; 95% CI: 82.1% to
because of tachyarrhythmia 98.6%).
Gestational age at birth, weeks 37 (28–40) 37 (34–39) 37 (36–38) 37 (28–40)
On the basis of echocardiographic assessment, 49
Pre-term birth 10 (20.4) 3 (17.7) 1 (25.0) 6 (21.4)
patients were classified into 3 groups: short VA SVT
Birth weight, g 2,828 2,828 2,665 2,851
(1,828– (2,050– (2,506– (1,828– (n ¼ 17), long VA SVT (n ¼ 4), and AFL (n ¼ 28)
3,808) 3,808) 3,508) 3,518) (Table 1). Multiple arrhythmias were found in 4 fe-
SGA <10th percentile 3 (6.1) 2 (11.7) 0 (0.0) 1 (3.6) tuses; 3 fetuses with AFL had occasional short VA
Male 38 (77.6) 12 (70.6) 3 (75.0) 23 (82.1)
SVT, and 1 fetus with long VA SVT had occasional
Fetal hydrops at birth 3 (6.4) 0 (0.0) 1 (25.0) 2 (7.4)
AFL. Gestational age at diagnosis was lower in pa-
Neonatal tachyarrhythmia 15 (31.9) 8 (50.0) 2 (50.0) 5 (18.5)
tients with short VA SVT compared with other ar-
Antiarrhythmic medical 13 (27.7) 8 (50.0)* 2 (50.0) 3 (11.1)
therapy after birth rhythmias. Primary and secondary outcomes did not
Fetal death 2 (4.1) 1 (5.9) 0 (0.0) 1 (3.6) vary by type of fetal tachyarrhythmia (Table 2).
Neonatal death within 1 month 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Recurrence of neonatal tachyarrhythmia was more
Apgar score at 5 min 9 (0–10) 9 (0–10) 8.5 (6–9) 9 (5–10)
common in patients with SVT than AFL (50.0% vs.
Umbilical artery pH 7.31 7.32 7.31 7.30
(7.13–7.44) (7.22–7.37) (7.13–7.37) (7.21–7.44) 18.5%; p ¼ 0.03). In patients with short VA SVT and no
hydrops, the resolution rate was 46.7% (7 of 15) with
Values are n, n (%), or median (range). *Significant difference when compared with fetuses with AFL (p < digoxin alone, 71.4% (5 of 7) with digoxin plus sotalol,
0.05, the Steel-Dwass test).
BNP ¼ brain natriuretic peptide; SGA ¼ small for gestational age; other abbreviations as in Table 1.
and 100.0% (1 of 1) with digoxin in combination with
flecainide, thereby resulting in a total resolution rate
of 86.7% (Figure 2A). Five neonates had atrioventric-
ular (AV) re-entrant tachycardia (AVRT), 2 had ectopic
most of these operations were performed for atrial tachycardia (EAT), and 1 had ventricular
maternal or obstetrical indications such as previous tachycardia all found after birth. In all, 4 patients
cesarean delivery, arrest of labor, and infection; with long VA SVT, including 1 patient with fetal
only 3 (6.1%; 95% CI: 1.3% to 16.9%) cesarean sec- hydrops, fetal tachyarrhythmia resolved (Figure 2B).
tions were performed for fetal tachyarrhythmia. In 1 neonate each, AVRT and EAT were found after
Recurrence of tachyarrhythmia was observed in 15 birth. In patients with AFL without fetal hydrops, the
of 47 neonates (31.9%). Only 2 neonates continued resolution rate was 59.3% (16 of 27) with digoxin
to receive prophylactic digoxin after birth, and 1 did alone, 72.7% (8 of 11) with digoxin and sotalol, and
not have recurrence of tachyarrhythmia. Interest- 50.0% (1 of 2) with digoxin and flecainide, resulting in
ingly, 13 of 15 had had well-controlled tachyar- an overall resolution rate of 92.6% (Figure 2C). In 1
rhythmia before birth, but they still experienced neonate with AVRT, 1 with EAT, and 3 with AFL, the
recurrence postnatally. Except for 2 neonates with tachyarrhythmias were found after birth. The 2 neo-
AFL who converted to sinus rhythm with electrical nates with AVRT and EAT had occasional short VA
cardioversion, 13 neonates required antiarrhythmic SVT in utero.
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S A FET Y O U TCO M ES. Maternal, fetal, and Maternal serum digoxin concentrations after rapid
neonatal AEs related to the antiarrhythmic agents are initial saturation were not statistically different be-
shown in Table 3. Although maternal AEs related to tween oral administration and intravenous injection
transplacental treatment were observed in 39 (Online Table 2). Maternal and umbilical vein serum
patients (78.0%), there was only 1 serious event: concentrations of the antiarrhythmic agents at de-
Mobitz type II AV block was observed but resolved livery are shown in Table 4. Interestingly, 7 of 13 had
immediately after temporary discontinuation of higher serum sotalol levels of umbilical vein than
digoxin and sotalol. Nausea or vomiting, the most those of maternal vein.
common maternal adverse symptom, was
observed in 27 patients (54.0%). DISCUSSION
Electrocardiographic abnormalities were detected in
19 patients (38.0%). Elevated brain natriuretic The results of our study demonstrated that protocol-
peptide concentrations were found in 25 patients defined transplacental treatment for fetal SVT and
(50.0%). Despite a relatively high incidence of AFL was effective and tolerable in 90% of cases
maternal AEs, dose reduction allowed for contin- (Central Illustration). However, it should be kept in
uation of transplacental treatment. mind that serious AEs may take place in fetuses and
Fetal AEs related to transplacental treatment were that tachyarrhythmia may recur within 2 weeks after
observed in 12 fetuses (24.0%). Serious AEs resulting birth.
in discontinuation of the protocol-treatment occurred To the best of our knowledge, this is the first
in 4 fetuses. Fetal death occurred in 2 of 49 fetuses multicenter and largest prospective study of the
overall (4.1%; 95% CI: 0.5% to 14.0%). In 1 fetus heavy safety and efficacy of protocol-defined transplacental
for gestational age (>5.0 SD), AFL developed with treatment for fetal SVT and AFL. Dozens of studies
ascites, cardiac effusion, and polyhydramnios at showing the efficacy of fetal treatment have been
26 weeks of gestation. After digoxin and sotalol published, but they included stated limitations
combination therapy, the frequency and ventricular related to retrospective data collection and different
rate of fetal AFL decreased, but hydrops progressed, protocols across centers. Two previous prospective
resulting in fetal death at 27 weeks of gestation. Post- studies had limitations related to the single-center
mortem examination showed hypoplastic lungs, design with small sample size (<20 cases) (11,12). In
small ears, and flexion of the long finger in both this study, digoxin was selected as the first-line
hands, findings suggesting Costello syndrome. agent (9) because of its relatively safe profile, long
Another fetus of 34 weeks of gestation with a diag- history of use during pregnancy, and clinician
nosis of short VA SVT once achieved sinus rhythm familiarity with its use (13–15). Sotalol and flecainide
and resolved pleural effusion and ascites after were used as second-line and third-line agents,
digoxin and sotalol, but the tachyarrhythmia respectively, for cases with short VA SVT and AFL
recurred at 36 weeks of gestation. SVT was without fetal hydrops in this protocol (9). Compared
sustained even after increased dosage of sotalol to with the previous studies, our multicenter
240 mg/day, and the fetus developed pleural prospective study demonstrated suffi- cient safety
effusion and ascites. The fetus died at 37 weeks of and efficacy. Some studies recommended sotalol or
gestation during prepara- tions for cesarean section. flecainide as primary therapy for fetal SVT and AFL
These fetal deaths were mainly caused by (7,14–19). Two systematic reviews showed the
progression of fetal heart failure secondary to AFL superiority of flecainide as first-line treatment for
and SVT. In 1 fetus with AFL, 7:1 AV block was fetal SVT (20,21). However, both studies com-
observed after starting the combination of digoxin mented on the lack of prospective studies as a limita-
and sotalol. Because the ventricular rate decreased tion. Our protocol, which is based on the multicenter
to 50 beats/min for 5 min at 36 weeks of gestation, prospective study, can become baseline data for
cesarean section was performed, and the newborn further prospective trials to establish the safest and
was treated by electrical cardioversion. In another most effective treatment for fetal tachyarrhythmia.
fetus with AFL, 1:1 AV conduction at 275 Favorable efficacy of our protocol treatment was
beats/min was observed 5 days after starting the obtained with each type of fetal tachyarrhythmia. In
combination of digoxin and flecainide. The fetus this study, the measurement of AV and VA intervals
progressed to ascites and pleural effusion and was with Doppler echocardiography was used to classify
delivered by cesarean section at 32 weeks of gesta- tachyarrhythmias (12,22,23). Short VA SVT is the
tion. AFL resolved spontaneously just after birth. typical pattern in re-entry tachycardia. Fetuses with
Neonatal AEs related to transplacental treatment short VA SVT and no hydrops had a resolution rate of
were observed in 5 of 47 neonates (10.6%). Two of 47% with digoxin alone as the first-line drug and an
these AEs were serious.
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FIGURE 2 Outcomes by Type of Fetal Tachyarrhythmia
A
Short VA SVT (n = 17)
Non-hydrops Fetal hydrops
Digoxin &
Digoxin (n = 15)
Sotalol (n = 2)
Effective Ineffective Ineffective Effective
n=7 Digoxin & n=1 Digoxin & n=1

AVRT (2), VT (1) Sotalol (n = 7) EAT (1) Flecainide (n = 1)
Effective Ineffective Effective
n=5 Digoxin & n=1 n=1

AVRT (2) Flecainide (n = 1) Fetal death EAT (1)
Effective
n=1
AVRT (1)
B
Long VA SVT (n = 4)
Sotalol (n = 3) Sotalol (n = 1)
Effective Effective
n = 3 (Heterotaxy n = 1 (Cardiac
syndrome) tumors)
EAT (1) AVRT (1)
(A) In fetuses with short ventriculoatrial (VA) supraventricular tachycardia (SVT) and no hydrops, the resolution rate was 46.7% (7 of 15)
with digoxin alone, 71.4% (5 of 7) with digoxin plus sotalol, and 100.0% (1 of 1) with digoxin plus flecainide, resulting in an overall resolution
rate of 86.7%. Protocol treatment was discontinued in 1 patient because of fetal death. Five cases of atrioventricular re-entrant
tachycardia (AVRT), 2 of ectopic atrial tachycardia (EAT), and 1 of ventricular tachycardia (VT) were found after birth. (B) In all 4 fetuses
with long ventriculoatrial supraventricular tachycardia, including 1 fetus with hydrops, fetal tachyarrhythmia resolved. One case each of
atrioventricular re-entrant tachycardia and ectopic atrial tachycardia was observed after birth. (C) In atrial flutter (AFL) without fetal
hydrops, the resolution rate was 59.3% (16 of 27) with digoxin alone, 72.7% (8 of 11) with digoxin plus sotalol, and 50.0% (1 of 2) with
digoxin plus flecainide, resulting in an overall resolution rate of 92.6%. Protocol treatment was discontinued in 3 patients because of fetal
serious adverse event (SAE) and death. One case of atrioventricular re-entrant tachycardia, 1 of ectopic atrial tachycardia, and 3 of atrial
flutter were found after birth. Neonatal tachyarrhythmias are shown in the bottom of each box.
Continued on the next page

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FIGURE 2 Continued
C
AFL (n = 28)
Digoxin &
Digoxin (n = 27)
Sotalol (n = 1)
Effective Ineffective Ineffective
n=1
n = 16 Digoxin & Progression
AVRT (1), EAT (1) Sotalol (n = 11) of fetal hydrops
AFL (1)
Effective Ineffective
n=8 n=1
Digoxin &
Fetal death
Flecainide
AFL (2) (Suspected
(n = 2) Costello syndrome)
Effective Ineffective
n=1 n=1
Discontinuation
due to fetal SAE
overall resolution rate of 87%, comparable to that of a 93%. Also in this study, AFL accounted for 60% of
previous review article (3). Both cases of short VA SVT fetuses, a higher percentage than in previous reports
and fetal hydrops achieved resolution in utero. Long (25% to 30%) (1,3,6). A large multicenter retrospective
VA SVT is a rare tachyarrhythmia suggesting EAT or study showed that cardioversion at 5 and 10 days
atypical AVRT. Because digoxin was reported to be occurred in only 25% and 41% of fetuses with treated
ineffective in long VA SVT (24), in this study protocol, AFL, respectively (15). Sotalol was reported to effect
sotalol and flecainide were used as first-line and a higher proportion of fetal AFL termination
second-line therapy, respectively. All 4 cases with than
long VA SVT including 1 with fetal hydrops had res- digoxin or flecainide (15). A review article showed a
olution of fetal tachyarrhythmia. Therefore, our fetal AFL resolution rate of 45% with digoxin alone, a
findings indicate the effectiveness of protocol treat- finding suggesting that if AFL persists, postnatal
ment according to the waveforms assessed by conversion to sinus rhythm may be preferred over
Doppler echocardiography. Because no single agent is second-line transplacental treatment (3). However,
universally effective (12,15), it is important to give the our results showed a high resolution rate in fetuses
most efficient drug at the lowest effective dose to with AFL but no hydrops, thus suggesting that pre-
avoid the risk of maternal and fetal morbidity. We mature delivery should be limited to treatment-
believe that appropriate drug selection for each type refractory AFL with hydrops.
of tachyarrhythmia contributes to avoiding maternal Our prospective study demonstrated a relatively
and fetal AEs. high incidence of maternal AEs related to antiar-
In this study, fetuses with AFL and no hydrops rhythmic agents. Maternal AEs, including gastroin-
had a resolution rate of 59% with digoxin alone as testinal symptoms and electrocardiographic
first-line therapy and an overall resolution rate of abnormalities, were observed in 78% of patients;
however, most of these AEs were minor, and dose
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TA BL E 3 Continued
TA BL E 3 Maternal, Fetal, and Neonatal Treatment-Related AEs
and Serious AEs Patients Patients With
With AE Serious AE
Patients Patients With
With AE Serious AE Neonatal (n ¼ 47)
Maternal (n ¼ 50) Periventricular leukomalacia 1 (2.1) 0 (0.0)
Gastrointestinal Ileus 1 (2.1) 1 (2.1)¶
Nausea 20 0 (0.0) Bradycardia <100 beats/min 1 (2.1) 0 (0.0)

(40.0)* Clinical laboratory abnormalities
Vomiting 10 (20.0)* 0 (0.0) Hyperbilirubinemia 1 (2.1) 0 (0.0)
Stomach ache 1 (2.0) 0 (0.0) Erythrocytosis 1 (2.1) 0 (0.0)
Anorexia 1 (2.0) 0 (0.0) Hypoglycemia 1 (2.1) 1 (2.1)¶
Diarrhea 1 (2.0) 0 (0.0)
General Values are n (%). The causal relationship between AEs and antiarrhythmic agents
was determined by the Independent Safety Evaluation Committee. *Nausea or
Malaise 1 (2.0) 0 (0.0) vomiting were found in 27 patients (54.0%). During nausea or vomiting,
Limb pain 1 (2.0) 0 (0.0) median maternal digoxin levels were 1.96 ng/ml (range 0.94 to 3.77 ng/ml).
†Mobitz type II AV block during the administration of digoxin (0.75 mg/day;
Nervous system
2.10 ng/ml) plus sotalol (160 mg/day). ‡In 1 fetus with AFL, 3 days after starting
Headache 2 (4.0) 0 (0.0) sotalol (160 mg/ day) in combination with digoxin (0.75 mg/day; 1.30 ng/ml),
frequency and ventricular rate of fetal AFL decreased but hydrops
Head discomfort 1 (2.0) 0 (0.0)
progressed, resulting in fetal death at 27 weeks of gestation. In another fetus
Altered sensation of taste 1 (2.0) 0 (0.0) with short VA SVT, 2 days after increasing sotalol (240 mg/day) in
Drowsiness 1 (2.0) 0 (0.0) combination with digoxin (0.375 mg/day;
1.55 ng/ml), fetal death was detected during preparation for cesarean section at
Numbness 1 (2.0) 0 (0.0) 37 weeks of gestation. §In 1 fetus with AFL, fetal ventricular rate decreased to 50
Increased thirst 1 (2.0) 0 (0.0) beats/min for 5 min because of advanced AV block after starting the combination
therapy of digoxin (0.50 mg/day; 2.45 ng/ml) plus sotalol (160 mg/day). kIn 1
Obstetric
fetus with short VA SVT, paroxysmal atrial fibrillation was observed 4 days
Pre-term delivery 3 (6.0) 0 (0.0) after starting digoxin (0.75 mg/day; 0.90 ng/ml). In another fetus with AFL,
Threatened pre-mature labor 1 (2.0) 0 (0.0) 1:1 AV conduction at 275 beats/min was observed 5 days after starting the
third-line combination therapy of digoxin (0.375 mg/day; 1.68 ng/ml) plus
Polyhydramnios 1 (2.0) 0 (0.0) flecainide (200 mg/day; 425.8 ng/ml). ¶In 1 fetus with AFL, tachyarrhythmia
Electrocardiographic abnormalities was well controlled in utero by digoxin (0.25 mg/day; 1.36 ng/ml) and did
not recur; however, ileus was observed 2 weeks after birth. In another fetus
Sinus bradycardia <60 beats/min 17 (34.0) 0 (0.0)
with short VA SVT, tachyarrhythmia was well controlled in utero by sotalol
Second-degree AV block 9 (18.0) 1 (2.0)† (160 mg/day); however, ectopic atrial tachycardia and hypoglycemia (31 mg/ml)
were observed in the first day.
PR prolongation $200 ms 4 (8.0) 0 (0.0)
AE ¼ adverse event; AV ¼ atrioventricular; other abbreviations as in Table 1.
Pre-mature ventricular contractions 2 (4.0) 0 (0.0)
Nonspecific ST-T changes 1 (2.0) 0 (0.0)
QTc prolongation $450 ms 1 (2.0) 0 (0.0)
Clinical laboratory abnormalities flecainide, or 10% with sotalol, and visual distur-
Increased brain natriuretic peptide 25 (50.0) 0 (0.0) bances occurred in 14% with flecainide) (15). Our re-
levels
sults suggest that most previous retrospective studies
Liver dysfunction 1 (2.0) 0 (0.0)
underestimated the incidence of maternal AEs.
Impaired glycemic control 1 (2.0) 0 (0.0)
Combination therapy presents a greater risk of
Anemia 1 (2.0) 0 (0.0)
maternal and fetal AEs than monotherapy (8).
Fetal (n ¼ 50)
Fetal death 2 (4.0) 2 (4.0)‡
Although serious maternal AEs were rare, occurring at
Electrocardiographic abnormalities rates similar to those in reported series (15,25), we
Bradycardia <100 beats/min 6 (12.0) 1 (2.0)§
De novo arrhythmia 2 (4.0)k 1 (2.0)k
Pre-mature atrial contractions 1 (2.0) 0 (0.0) T AB L E 4 Maternal and Umbilical Vein Serum Concentrations of
General the Antiarrhythmic Agents at Delivery
Decreased fetal movement 1 (2.0) 0 (0.0)
Digoxin Sotalol Flecainide
Mild deceleration 3 (6.0) 0 (0.0)
(n ¼ 26) (n ¼ 13) (n ¼ 2)*
Continued in the next column
Maternal vein serum levels, 1.2 371.5 31.1/440.3
ng/ml (0.3–2.7) (18.3–2,000.7)
Umbilical vein serum levels, 0.6 440.0 15.7/305.1
reduction allowed for continued protocol treatment.
ng/ml (0–1.5) (60.4–1,263.8)
There are very few reports focusing on AEs related to Umbilical-to-maternal 53.5 107.1 50.5/69.3
transplacental antiarrhythmic treatment. Nausea, fa- vein ratio, % (0–100) (47.2–371.6)†
tigue, and loss of appetite are well-known maternal

Values are median (range) unless otherwise indicated. Analyses were performed in
AEs related to digoxin (8). Sinus bradycardia and AV cases with both maternal and umbilical vein blood available at delivery. Serum
block are common AEs with antiarrhythmic drugs (8). digoxin concentrations were measured by enzyme-multiplied immunoassay tech-
nique. Serum sotalol and flecainide concentrations were measured by high-
A previous report showed that one-third of mothers performance liquid chromatography. *Data in this column are the values in each
of the 2 cases. †7 of 13 had higher serum sotalol levels of umbilical vein than
had likely drug-related AEs (e.g., nausea and dizzi-
those of maternal vein.
ness occurred in 38% with digoxin, 20% with
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4 , al.
NO. 7, 2019
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C E N T R A L I L L U S TRA T I O N Results of the Transplacental Treatment Protocol for

Fetal Tachyarrhythmias
Sustained fetal supraventricular tachycardia (SVT) or

atrial flutter (AFL) ≥180 beats/min
Singleton with 22 to <37 weeks of gestation
(n = 49)
Short ventriculoatrial
(VA) SVT or AFL
(n = 45) Long VA SVT
(n = 4)
ydrops Fetal H
Non-h ydrops
First-Choice Therapy First-Choice Therapy First-Choice Therapy

Digoxin Digoxin & Sotalol Sotalol
54.8% (23/42) 33.3% (1/3) 100% (4/4)
Second-Choice Therapy Second-Choice Therapy

Digoxin & Sotalol Second-Choice Therapy
Digoxin & Flecainide
72.2% (13/18) Flecainide
100% (1/1)
Third-Choice Therapy
Digoxin & Flecainide
66.7% (2/3)
Antiarrhythmic Agents
Digoxin: Maternal serum concentrations from 1.5 to 2.0 ng/mL

Sotalol: Initial dose, 160 mg/day; Maximum dose, 320 mg/day
Flecainide: Initial dose, 200 mg/day; Maximum dose, 300
mg/day
Miyoshi, T. et al. J Am Coll Cardiol. 2019;74(7):874–85.
Antiarrhythmic agents were selected by types of fetal tachyarrhythmia and/or presence of fetal hydrops. In short ventriculoatrial supra-
ventricular tachycardia and atrial flutter without fetal hydrops, the resolution rate was 54.8% (23 of 42) with digoxin alone, 72.2% (13 of 18)
with digoxin plus sotalol, and 66.7% (2 of 3) with digoxin plus flecainide, resulting in an overall resolution rate of 90.5% (38 of 42). In short
ventriculoatrial supraventricular tachycardia and atrial flutter with fetal hydrops, the resolution rate was 33.3% (1 of 3) with digoxin plus
sotalol and 100% (1 of 1) with digoxin plus flecainide, resulting in an overall resolution rate of 66.7% (2 of 3). In all 4 fetuses with long
ventriculoatrial supraventricular tachycardia, including 1 fetus with hydrops, fetal tachyarrhythmia resolved by sotalol alone.
speculated about the need for serial drug concentra- mortality increased to 15% to 40%, compared with 0%
tion monitoring and maternal electrocardiography to to 4% in fetuses without hydrops (3–5,26–29). One
assess drug effects and toxicity, especially during fetal demise occurred 2 days after sotalol dose esca-
dose escalation. lation. A previous study investigated the timing of 4
Two fetal deaths occurred during combination fetal deaths (3 SVT and 1 AFL). Three deaths occurred
therapy with digoxin and sotalol. In fetuses with just days after the initiation of sotalol, and 1 death
hydrops and SVT or AFL, arrhythmia-related occurred after a dose increase (7). Several reports
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NO. 7, 2019
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showed fetal deaths within 3 days of transplacental the safety and efficacy of each agent separately.
flecainide treatment (28,29). It is difficult to draw However, the results of our first multicenter and
conclusions about a potential AE of sotalol and fle- largest prospective study could provide important
cainide in this group of fetuses at increased risk of baseline data as protocol-defined transplacental
prenatal demise. The occurrence of fetal death raises treatment for analyzing the effectiveness of future
the question whether these agents have a proar- protocols, at least for fetal short VA SVT and AFL
rhythmic effect because serum sotalol concentrations without fetal hydrops.
of umbilical vein can reach higher than those of
maternal vein (11). In this regard, fetal magneto- CO NCLUSIONS
cardiography has a potential role for detection of
repolarization abnormalities or conduction defects Our study demonstrated that protocol-defined trans-
that may lead to fetal sudden death. placental treatment for fetal SVT and AFL was effec-
tive and tolerable in 90% of cases. Maternal AEs were
ST UDY ST R E NGTHS. First of all, this was the observed in 78% of patients; however, most AEs were
first multicenter and largest prospective trial to minor, and dose reduction allowed for continued
confirm the safety and efficacy of protocol- protocol treatment. However, it should be kept in
defined transplacental treatment for fetal SVT and mind that serious AEs may take place in fetuses and
AFL. Further- more, our results showed a high that tachyarrhythmia may recur within 2 weeks after
resolution rate even in fetuses with AFL, a birth even if it is well controlled in utero. We believe
treatment-refractory type of fetal tachyarrhythmia. that our results will help optimize the design of
Second, our findings indicate the effectiveness of future randomized controlled trials to establish the
protocol treatment. Notably, all 4 patients with long safest and most effective treatment for fetal
VA SVT were effectively treated with sotalol alone tachyarrhythmia.
and with no mortality. Appropriate drug selection for ACKNOW LE DGMENTS The authors thank Dr.
each type of tachyarrhythmia is important not Makoto Nishibatake (chairperson), Dr. Masao
only to improve fetal and neonatal outcomes but Nakagawa, Dr. Ichiro Kawabata, and Dr. Naokata
also to avoid maternal and fetal AEs. Third, we Sumitomo for their contribution as members of the
prospectively confirmed accurate incidence of Independent Safety Evaluation Committee in this
maternal, fetal, and neonatal AEs related to study trial. The authors also thank Dr. Takeshi Kotake for
antiarrhythmic agents. Our results showed a rela- measuring serum sotalol and flecainide
tively high incidence of maternal AEs, thus suggest- concentrations.
ing underestimation in previous retrospective
studies. Notably, serious AEs resulting in discontin- ADDRESS F OR CORRESPO NDENCE: Dr.
uation of the protocol treatment were found in 4 fe- Yasuki Maeno, Department of Pediatrics and Child
tuses during combination therapy. This information Health, Kurume University School of Medicine, 67
will help obstetricians and pediatric cardiologists Asahi-machi, Kurume 830-0011, Japan. E-mail:
administering transplacental treatment for fetal SVT yasukim@med. kurume-u.ac.jp. Twitter: @YMaeno2.
and AFL.
PERSPECTIVES
ST UDY L IMITATIO NS. First, this was a single-arm
trial; however, this was the most completable pro-
spective study design in the limited number of the COMPETENCY IN PATIENT CARE AND PROCE-
cases in each year by referring the results of our DURAL SKILLS: Transplacental administration of
retrospective survey and historical control data from digoxin, sotalol, or flecainide in singleton pregnancies
the literature. Second, as a result of the limited from 22 to 37 weeks of gestation with sustained fetal
sample size, only 4 patients with fetal hydrops and SVT or AFL at ventricular rates $180 beats/min was
only 4 patients with long VA SVT were enrolled in this effective and tolerated in 90%. Maternal AEs were
study. We used a strict definition of fetal hydrops (10) frequent and usually mild, but they required treat-
because we intended to limit combination therapy in ment discontinuation in 8%, and fetal loss occurred in
truly severe cases in patients with fetal hydrops to 4%.
avoid AEs to mothers and fetuses. Hence, our study
did not have enough patients to make conclusions TRANSLATIONAL OUTLOOK: Further studies are
about combination therapy for the cases with fetal needed to establish the safest and most effective
hydrops and about the therapy for long VA SVT. antenatal treatment regimens for fetal supraventric-
Third, because we used a treatment protocol with ular tachyarrhythmias.
3 antiarrhythmic agents, it is difficult to analyze
V O L . 7 et
4 , al.
NO. 7, 2019
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AP P E N D I X For supplemental tables,
please see the online version of this paper.

Antenatal Therapy For Fetal Supraventricular Tachyarrhythmias

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JOU R NA L OF T HE A M ER I C AN C OLL EG E OF C AR DI OL OG Y VOL. 74, NO.

ª 2 0 1 9 B Y T H E A ME RIC A N C OL LEG E OF C ARD I OLO GY FOUN DA TI O

N PUBL ISH E D B Y E LS E V IER

Antenatal Therapy for

BACKGROUND Standardized treatment of fetal tachyarrhythmia has not been established.

F etal tachyarrhythmia develops in <0.1% of

AFL = atrial ﬂutter

For fetuses with short ventriculoatrial (VA) SVT or

assessed the maternal cardiac condition before and during this

echocardiography as well as electrocardiography.

Continuous data were presented as medians and

treatment. Recurrence of tachyarrhythmia was

FIGURE 2 Outcomes by Type of Fetal Tachyarrhythmia

n=7 Digoxin & n=1 Digoxin & n=1

Effective Ineffective Effective

n=5 Digoxin & n=1 n=1

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Maternal (n ¼ 50) Periventricular leukomalacia 1 (2.1) 0 (0.0)

Gastrointestinal Ileus 1 (2.1) 1 (2.1)¶

Nausea 20 0 (0.0) Bradycardia <100 beats/min 1 (2.1) 0 (0.0)

tigue, and loss of appetite are well-known maternal

C E N T R A L I L L U S TRA T I O N Results of the Transplacental Treatment Protocol for

Sustained fetal supraventricular tachycardia (SVT) or

First-Choice Therapy First-Choice Therapy First-Choice Therapy

Second-Choice Therapy Second-Choice Therapy

Digoxin: Maternal serum concentrations from 1.5 to 2.0 ng/mL

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