Jurnal pediatric

J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 4 , N O . 7 , 20 1 9
ª 2 0 19 B Y T H E A M ERI C AN C OLLEGE OF CA RD IOLOGY F O U N D A T I O N
P U BL I S H E D B Y E L S E V I E R
Antenatal Therapy for
Fetal Supraventricular Tachyarrhythmias
Multicenter Trial
Takekazu Miyoshi, MD,
a
Yasuki Maeno, MD,
b,
* Toshimitsu Hamasaki, PHD,
c
Noboru Inamura, MD,
d
Satoshi Yasukochi, MD,e
Motoyoshi Kawataki, MD,f
Hitoshi Horigome, MD,g
Hitoshi Yoda, MD,h
Mio Taketa zu, MD,i
Masaki Nii, MD,
j
Akiko Hagiwara, MD,
k
Hitoshi Kato, MD,
l
Wataru Shimizu, MD,
m
Isao Shiraishi, MD,
n
Heima Sakaguchi, MD,
n
Keiko Ueda, MD,
a
Shinji Katsuragi, MD,
a
Haruko Yamamoto, MD,
o
Haruhiko Sago, MD,
p
Tomoaki Ikeda, MD,
q,
* 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-de fined 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 transplac ental treatme nt for fetal SVT and AFL was effe ctive 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.
Listen to this manuscript’ s
audio summary by
Editor-in- Chief
Dr. Valentin Fuster on
JACC.or g.
From the a
Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center, Suita, Japan; b
Department
of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan; c
Department of Data Science, National
Cerebral and Cardiovascular Center, Suita, Japan; d
Department of Pediatric Cardiology, Osaka Women’s and Children’s Hospital,
Izumi, Japan; e
Department of Cardiology, Nagano Children’s Hospital, Azumino, Japan; f
Department of Gynecology and
Obstetrics, Tohoku University Graduate School of Medicine, Sendai, Japan; g
Department of Pediatrics, University of Tsukuba,
Tsukuba, Japan; h
Department of Neonatology, Toho University Omori Medical Center, Tokyo, Japan; i
Department of Pediatric
Cardiology, Saitama Medical University International Medical Center, Hidaka, Japan; j
Department of Cardiology, Shizuoka Chil-
dren’s Hospital, Shizuoka, Japan; k
Department of Internal Medicine, Kanagawa Children’s Medical Center, Yokohama, Japan;
l
Department of Pediatric Cardiology, National Center for Child Health and Development, Tokyo, Japan; m
Department of
Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan; n
Department of Pediatric Cardiology, National Cerebral and
Cardiovascular Center, Suita, Japan; o
Department of Advanced Medical Technology Development, National Cerebral and
Cardiovascular Center, Suita, Japan; p
Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child
Health and Development, Tokyo, Japan; and the q
Department of Obstetrics and Gynecology, Mie University, Tsu, Japan. *Drs.
Maeno and Ikeda contributed equally to this work. This work was supporte d 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 AC C V O L . 7 4 , N O. 7 , 2 0 19 Miyoshi et al.
Transplacenta l Treatment for Fetal Tachyarrhythmias
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Fetal tachyarrhythmia develops in <0.1% of
pregnancies. The most common forms of fetal
tachya rr hy thm ia include suprave ntric ula r
tachycardia (SVT) and atrial flutter (AFL) (1).
Although many cases are of minor clinical signifi-
cance, fast or long-lasting tachyarrhythmias often
cause fetal heart failure and fetal hydrops (1,2).
Without treatment, hydrops is found in 30% to 40%
of fetuses with SVT and in 7% to 43% of fetuses
with AFL (3,4). For fetuses with hydrops, elective
pre-term delivery and other lifesaving interventions
are often attempted, but perinatal mortality is signif-
icantly highe r than in fetuse s without hydrops (3–5).
Availa ble data sugge st that the risk of fetal death
P R O C E D U RE S. The study design was
described previously (9). Inclusion criteria
were as follows: 1) sustained fetal
tachyarrhythmia $180 beats/min, with a
diagnosis of SVT or AFL (fetal tachyar-
rhythmia is defined as sustained when
present $50% during a 40-min fetal heart
rate monitoring or a 30-min echocardiogra-
phy sessio n); 2) 22 to <37 weeks of gestation;
3) singleton pregnancy; and 4) patients’
written consent to study participation.
Exclusion criteria were as follows: 1) the pa-
tient had mental or psychiatric conditions
that prec lud e safe study partic ipa tio n; 2) the
A B B R E V I A T I O N S
A N D A C R O N Y M S
AE = adverse event
AFL = atrial flutter
AV = atriovent ricu lar
AVRT = atriovent ricular
re-entran t tachycardia
CI = confidence interval
EAT = ectopic atrial
tachycard ia
SVT = supravent ricu l ar
tachycard ia
VA = ventriculoatrial
will be higher if tachyarrhythmia is left untreated in
fetal hydrop s.
S EE P AGE 8 8 6
Before designing this clinical trial, we conducted a
nationwide survey of fetal tachyarrhythmia in Japan
from 2004 to 2006 (6). A total of 82 fetuses were
analyzed, of whom 41 received in utero treatment.
Transpla c e ntal treatme nt was fairly effe c tiv e in
90.2% (37 of 41) of cases and in 81.8% (9 of 11) of cases
with fetal hydrops. These findings were comparable
to those of previous reports (2–4,7). Although several
retrospective studies have supported the efficacy of
transplacental treatment for fetal SVT and AFL, the
choice of first-line and second-line antiarrhythmic
therapy remains controversial (8). Because most
studies are confounded by physician and institutional
preferences, there are few data supporting specific
treatment protoc ols.
The primary goal of this study was to evaluate the
safety and efficacy of protocol-defined transplacental
treatment for fetal SVT and AFL. We conducted a
multic e nte r single -a r m trial.
MET HODS
S T U DY D E S IG N A N D P A RT ICIP A N TS. This study was
a multicenter, single-arm trial. The study protocol
was approved by the Institutional Review Board of
the National Cerebral and Cardiovascular Center of
Japan in July 2010 (M20-045). Patient enrollment
began in October 2010. This study was conducted in
accordance with the Helsinki Declaration. Written
informed consent was obtained from the patients.
This trial was registered in the University Hospital
Medical Information Network Clinical Trials Registry
as UMIN000004270. The Independent Safety Evalu-
ation Committee was responsible for the overall
safe ty of this trial.
patient was anticipated to have contraindications to
the antiarrhythmic medications used in the study; 3)
serious, life-threatening malformations were diag-
nosed in the fetus; 4) the fetus was diagnosed with
multifocal atrial tachycardia or chaotic atrial tachy-
cardia; and 5) the patient or fetus was not eligible, in
the investigator’s judgment, for this clinical study for
other reasons.
Fetal tachyarrhythmias were diagnosed using
pulsed wave Doppler echocardiography and M-mode
recordings (9). Fetuses with multiple arrhythmias
were classified according to the dominant mecha-
nism. Fetal hydrops was characterized by the pres-
ence of subcutaneous edema in addition to at least 1
of the following findings: ascites, pleural effusion,
and pericardial effusion (10). All fetal ultrasound
scans were reviewed by the Protocol Evaluation
Committee.
Recruiting centers were as follows: National Cere-
bral and Cardiovascular Center, Kurume University
School of Medicine, Osaka Women’s and Children’s
Hospital, National Center for Child Health and
Development, Kanagawa Children’s Medical Center,
University of Tsukuba, Toho University Omori Medi-
cal Center, Hokkaido University, Hyogo Prefectural
Children’s Hospital, Nagano Children’s Hospital,
Shizuoka Children’s Hospital, Kobe City Medical
Center General Hospital, Mie University, Okayama
Medical Center, and Osaka Univer sity, all in Japan.
TRA N S P L A CE N TA L TRE A TME N T P ROTO CO L . Proto-
col-defined treatment with digoxin, sotalol, or fle-
cainide was continued until delivery (9). Ineffective
fetal therapy was defined as therapy that did not
resolve fetal tachyarrhythmia or when fetal death was
strongly suspected because of progression of fetal
hydrops. If the investigator judged that the preg-
nancy could not be maintained to term, the woman
was delivered of the fetus. When maternal or fetal
adverse events (AEs) secondary to antiarrhythmic

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Analysis for maternal outcome (n = 50)
excluded from analysis (n = 0)
Analysis for fetal outcome (n = 49)
• consent withdrawal (n = 1)
Analysis for neonatal outcome (n = 47)
• fetal death (n = 2)
F IGUR E 1 Trial Profile
Screened
(n = 88)
Registered
(n = 50)
Fetal treatment
Declined or ineligible (n = 38)*
For fetuses with short ventriculoatrial (VA) SVT or
AFL without hydrops, digoxin was the first-line ther-
apy. Rapid initial saturation was performed with a 0.5-
mg intrav en ous injection. Intra ve no us injections of
0.25 mg were administered at 8 and 16 h after the
initial dose. If intravenous injections were not
feasible, oral digoxin (1.5 mg/day) was given in
3 divided doses. Subse que ntly, oral digoxin at
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
digoxin conc e ntra tion, the investiga tor move d to the
second-line therapy. Sotalol at 160 mg/day in 3 divided
based on the protocol
(n = 50)
Consent withdrawal (n = 1)
doses was adde d. If a regim e n of 3 days of treatment at
160 mg/da y of sotalol was ineffe ctive, the patient
then proc e e de d to 240 mg/da y in 2 divided doses. If
240 mg/da y was ineff e ctive afte r 3 days of treatment,
the patie nt proc ee d e d to 320 mg/da y in 2 divided
doses. If 320 mg/da y was ineff e ctive after 3 days of
Primary and secondary outcome at birth
(n = 49)
Fetal death (n = 2)
Secondary outcome
at 1-month follow-up after birth
(n = 47)
Analysis
*A total of 31 patients did not meet the inclusion criteria because of nonsusta ine d fetal
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
met the exclusion criteria for fetal life-threate ning malformations: Ebstein’s anomaly
(n ¼ 4); hypoplastic left heart syndrome (n ¼ 2); and cardiac tumors with ventricular
outflow obstruction (n ¼ 1).
agents were observed, the investigator could reduce
the dosage. Sotalol and flecainide were discontinued
if the corrected QT interval was >500 ms. After birth,
it was left up to each institution to decide whether to
contin ue antia rr hyth m ic agents prophyla ctica lly.
treatment, the investigator moved to the third-line
therapy. Flecainide was administered at 200 mg/day
in 2 divided doses in addition to digoxin. If 200 mg/day
was ineffective after 3 days of treatment, the patient
proce e de d to 300 mg/da y in 2 divided doses. If
300 mg/day was ineffective after 3 days of treatment,
protocol-defined treatment was discontinued. If the
fetus had hydrops, fetal therapy started with the
second -lin e therapy.
For fetuses with long VA SVT, sotalol and flecai-
nide were used as first-line and second-line therapy,
respectively, regardless of the presence or absence of
fetal hydrops. The dosage and administration
schedule were the same as those for fetuses with
short VA SVT or AFL.
E N D P O I N TS. The primary endpoint was resolution
of fetal tachyarrhythmia, defined as normal sinus
rhythm or mean heart rate of <180 beats/min. Res-
olution of fetal tachyarrhythmia was judged by a 40-
min fetal heart rate monitoring or 30-min echocar-
diography session. Secondary endpoints were fetal
death related to tachyarrhythmia, pre-term birth,
cesarean section performed as a result of fetal
arrhythmia, improvement in heart rate and less
edema after fetal therapy, prevalence of neonatal
arrhythmia, neonatal central nervous system disor-
der, and neonatal survival. Safety endpoints were
maternal, fetal, and neonatal AEs. All AEs were
assessed by the Independent Safety Evaluation
Committee. Because we focused on evaluating the
safety of our protocol-defined transplacental treat-
ment, we assessed the maternal cardiac condition
before and during this treatment by using

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echocardiography as well as electrocardiography.
Maternal serum levels of the antiarrhythmic agents
and plasma brain natriuretic peptide levels were
also measured.
ST A T I ST I CA L A N A L YSIS. Sample size was deter-
mined according to the precision-based method. A
sample size of 50 produced a 2-sided Clopper-Pearson
exact 95% confid en c e interval (CI) with a width of
18.5 when the sample propo rtion was assum e d to be
90%. More details were presented in the protocol
paper (9). All statistical analyses were performed ac-
cording to a pre-specified statistical analysis plan
finalized before database lock and release of data. All
analyses were performed using SAS for Windows
software version 9.3 (SAS Institute, Cary, North Car-
olina). According to the intention-to-treat principle,
the primary analysis group was defined as all regis-
tered pregnant mothers, fetuses, or neonates.
Continuous data were presented as medians and
range. Categorical data were presented as frequencies
and percentages. For the primary endpoint, the
number and percentage of fetuses with resolution of
fetal tachyarrhythmia were calculated with a 2-sided
Clopper-Pearson exact 95% CI. The primary outcome
was also analyzed on the basis of the per-protocol set
group to assess the robustness of conclusions from
the primary analysis group. The per-protocol set
group excluded subjects with major protocol viola-
tions or loss to follow -u p.
Secondary endpoints were analyzed similar to
primary endpoints. The Steel-Dwass test was used to
compare continuous variables among 3 subtypes of
fetal tachyarrhythmia. A value of p < 0.05 was
considered significant in all analyses. For the safety
analysis, the number of AEs and the number of sub-
jects with AEs were calcu late d acco rdin g to causality.
RESULT S
STUDY COHORT AND BASELINE CHARACTERISTICS. A
total of 50 patients were enrolled and treated at 15
institutions in Japan from Octob er 2010 to January
2017 (Figure 1). During the protocol treatment, 1 pa-
tient with AFL was excluded because of withdrawal of
consent, thus leaving 49 patients available for anal-
ysis of primary and secondary outcomes. Safety
endpo ints were assesse d in all 50 patients. Exce pt for
2 fetal deaths, 1-month follow-up was available for 47
neonates. Maternal complications were observed in 7
patients (14.0%): type 2 diabetes mellitus, solitary
kidney with mild renal dysfunction, patent ductus
arteriosus, history of depression or schizophrenia
(n ¼ 1 each) and controlle d hypothy roidis m (n ¼ 2).
TAB LE 1 Baseline Charac ter i sti cs
Total Short VA SVT Long VA SVT AFL
(N ¼ 49) (n ¼ 17) (n ¼ 4) (n ¼ 28)
Maternal age, yrs 32 (21–40) 32 (21–39) 35 (31–38) 31.5 (24–40)
Primipara status 24 (48.0) 8 (47.1) 2 (50.0) 13 (46.4)
Gestational age at 31 (24–36) 27 (24–35)* 32.5 (26–36) 32 (27–35)
diagnosis, weeks
Atrial rate, beats/min 430 245 230 450
(185–520) (185–280) (192–260) (410–520)†
Ventricular rate, beats/min 230 245 230 224.5
(185–280) (185–280) (192–260) (205–260)
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)
Fetal abnormality ‡ 6 (12.0) 2 (11.8) 2 (50.0) 2 (7.1)
Threatened pre-mature labor 10 (20.0) 3 (17.7) 1 (25.0) 6 (21.4)
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 VA
SVT (p < 0.05, the Steel-Dwass test). ‡Beckwith-Wiedemann syndrome with umbilical hernia (AFL), 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), and heterotaxy
syndrome with severe pulmonary valve stenosis and ventricular septal defect (long VA SVT).
AFL ¼ atrial flutter; SVT ¼ supraventricular tachycardia; VA ¼ ventriculoatrial.
Obstetrical complications were observed in 12 pa-
tients (24.0%): threatened pre-term labor (n ¼ 10),
placenta previa (n ¼ 1), and gestational diabetes
mellitus (n ¼ 1). Median gestational age at diagnosis
was 31 weeks (range 24 to 36 weeks) (Table 1). Only 2
fetuse s (4.0% ) had ventric ula r rates betwee n 180 and
200 beats/min: 1 with short VA SVT and another with
long VA SVT. Fetal hydrops at diagnosis of fetal
arrhyth mia was observe d in 4 fetuse s (8.0% ; 95% CI:
2.2% to 19.2%). Six fetuses with morphological ab-
normalities (12.0%) were not excluded from this
study (Online Table 1). Beta-stimulants were used for
tocolysis in all 10 patients with threatened pre-term
labor but were discontinued before starting the pro-
tocol treatment. Fetal hydrops was found in 2 of 10
patients with threatened pre-term labor, and this was
not statistically different from the incidence in pa-
tients without threa ten e d pre-te r m labor (20.0% vs.
5.0%; difference of 15%; 95%CI: 20.8 to 49.6; Fisher
exact test p ¼ 0.17).
P RIMA RY A N D SE CO N DA RY O U TCO ME S. Fetal
tachyarrhythmia resolved in 44 of 49 patients
overall (89.8%; 95% CI: 77.8% to 96.6%) and in 3 of
4 patients with fetal hydrops (75.0%). Two cases of
fetal hydrops resolved in utero, and 1 fetus pro-
gressed to hydrops, with hydrops present at de-
livery in 3 neonates. Median gestational age at birth
was 38 weeks (range 29 to 40 weeks). Pre-term
births occurred in 7 neonates (14.3%; 95% CI: 5.9%
to 27.2%). A total of 22 patients (44.9%; 95% CI:
30.7% to 59.8%) underwent cesarean delivery, but

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TAB LE 2 Primary and Secondary Outcomes
Total Short VA SVT Long VA SVT AFL
(N ¼ 49) (n ¼ 17) (n ¼ 4) (n ¼ 28)
Final treatment agents
Digoxin 26 9 0 17
Sotalol 4 0 4 0
Digoxin and sotalol 15 6 0 9
Digoxin and flecainide 5 2 0 3
Resolution of fetal tachyarrhythmia 44 (89.8) 15 (88.2) 4 (100.0) 25 (89.3)
Recurrence in utero 14 (32.6) 7 (43.8) 1 (25.0) 6 (26.1)
Duration of treatment, weeks 6 (1–13) 11 (1–13)* 4 (1–12) 5.5 (1–9)
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)
Maximum maternal BNP levels 28.6 35.7 18.3 30.8
during treatment, pg/l (6.0–141.1) (11.9–118.0) (14.6–26.7) (6.5–141 .1 )
Delivery mode
Vaginal delivery 27 9 3 15
Elective cesarean delivery 11 5 0 6
Urgent cesarean delivery 11 3 1 7
Urgent cesarean delivery 3 1 0 2
because of tachyarrhythmia
Gestational age at birth, weeks 37 (28–40) 37 (34–39) 37 (36–38) 37 (28–40)
Pre-term birth 10 (20.4) 3 (17.7) 1 (25.0) 6 (21.4)
Birth weight, g 2,828 2,828 2,665 2,851
(1,828– (2,050– (2,506– (1,828–
3,808) 3,808) 3,508) 3,518)
SGA <10th percentile 3 (6.1) 2 (11.7) 0 (0.0) 1 (3.6)
Male 38 (77.6) 12 (70.6) 3 (75.0) 23 (82.1)
Fetal hydrops at birth 3 (6.4) 0 (0.0) 1 (25.0) 2 (7.4)
Neonatal tachyarrhythmia 15 (31.9) 8 (50.0) 2 (50.0) 5 (18.5)
Antiarrhythmic medical 13 (27.7) 8 (50.0)* 2 (50.0) 3 (11.1)
therapy after birth
Fetal death 2 (4.1) 1 (5.9) 0 (0.0) 1 (3.6)
Neonatal death within 1 month 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Apgar score at 5 min 9 (0–10) 9 (0–10) 8.5 (6–9) 9 (5–10)
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)
Values are n, n (%), or median (range). *Significant difference when compared with fetuses with AFL (p < 0.05,
the Steel-Dwass test).
BNP ¼ brain natriuretic peptide; SGA ¼ small for gestational age; other abbreviations as in Table 1.
most of these operations were performed for
maternal or obstetrical indications such as previous
cesarean delivery, arrest of labor, and infection;
only 3 (6.1%; 95% CI: 1.3% to 16.9%) cesarean sec-
tions were performed for fetal tachyarrhythmia.
Recurrence of tachyarrhythmia was observed in 15
of 47 neonates (31.9%). Only 2 neonates continued
to receive prophylactic digoxin after birth, and 1 did
not have recurrence of tachyarrhythmia. Interest-
ingly, 13 of 15 had had well-controlled tachyar-
rhythmia before birth, but they still experienced
recurrence postnatally. Except for 2 neonates with
AFL who converted to sinus rhythm with electrical
cardiove r sion, 13 neonate s require d antiarrhythmic
treatment. Recurrence of tachyarrhythmia was
observed within 2 weeks after birth in all neonates
exce pt 1 with SVT in the third week. Notably, 10 of
15 had recu rr e nc e of tachya rr hy thm ia in the first
3 days. Intraventricular hemorrhage and periven-
tricula r leuko ma la cia were detecte d in 1 (2.1%;
95% CI: 0.1% to 11.3%) and 4 (8.5% ; 95% CI: 2.4% to
20.4%) neonates after birth, respectively. There
were no neonatal deaths.
The same analysis was repeatedly conducted for
the primary endpoint on the per-protocol set. After
excluding 3 patients with life-threatening fetal mal-
formations (tuberous sclerosis with cardiac tumors,
suspected Costello syndrome with hypoplastic lungs,
and heterotaxy syndrome) that were confirmed as
violations of the exclusion criteria at data review
committee, resolution of fetal tachyarrhythmia was
obser ve d in 43 of 46 patien ts (93.5%; 95% CI: 82.1% to
98.6%).
On the basis of echocardiographic assessment, 49
patients were classified into 3 groups: short VA SVT
(n ¼ 17), long VA SVT (n ¼ 4), and AFL (n ¼ 28)
(Table 1). Multiple arrhythmias were found in 4 fe-
tuses; 3 fetuses with AFL had occasional short VA
SVT, and 1 fetus with long VA SVT had occasional
AFL. Gestational age at diagnosis was lower in pa-
tients with short VA SVT compared with other ar-
rhythmias. Primary and secondary outcomes did not
vary by type of fetal tachyarrhythmia (Table 2).
Recurrence of neonatal tachyarrhythmia was more
comm on in patien ts with SVT than AFL (50.0% vs.
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
digoxin alone, 71.4% (5 of 7) with digoxin plus sotalol,
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
atrial tachycardia (EAT), and 1 had ventricular
tachycardia all found after birth. In all, 4 patients
with long VA SVT, including 1 patient with fetal
hydrops, fetal tachyarrhythmia resolved (Figure 2B).
In 1 neonate each, AVRT and EAT were found after
birth. In patients with AFL without fetal hydrops, the
resolution rate was 59.3% (16 of 27) with digoxin
alone, 72.7% (8 of 11) with digoxin and sotalo l, and
50.0% (1 of 2) with digoxin and flecainide, resulting in
an overall resolution rate of 92.6% (Figure 2C). In 1
neonate with AVRT, 1 with EAT, and 3 with AFL, the
tachyarrhythmias were found after birth. The 2 neo-
nates with AVRT and EAT had occasional short VA
SVT in utero.

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S A FE T Y O U TCO M E S. Maternal, fetal, and neonatal
AEs related to the antiarrhythmic agents are shown in
Table 3. Although maternal AEs related to trans-
placental treatment were observed in 39 patients
(78.0%), there was only 1 serious event: Mobitz type II
AV block was observed but resolved immediately af-
ter temporary discontinuation of digoxin and sotalol.
Nausea or vomiting, the most common maternal
adverse symptom, was observed in 27 patients
(54.0%). Electrocardiographic abnormalities were
detected in 19 patients (38.0%). Elevated brain
natriuretic peptide concentrations were found in 25
patients (50.0%). Despite a relatively high incidence
of maternal AEs, dose reduction allowed for contin-
uatio n of transp lac e ntal treatment.
Fetal AEs related to transplacental treatment were
observed in 12 fetuses (24.0%). Serious AEs resulting
in discontinuation of the protocol-treatment occurred
in 4 fetuses. Fetal death occurred in 2 of 49 fetuses
overall (4.1%; 95% CI: 0.5% to 14.0%). In 1 fetus heavy
for gestational age (>5.0 SD), AFL developed with
ascite s, cardia c effusion, and polyhyd ra mnio s at
26 weeks of gestation. After digoxin and sotalol
combination therapy, the frequency and ventricular
rate of fetal AFL decreased, but hydrops progressed,
resulting in fetal death at 27 weeks of gestation. Post-
mortem examination showed hypoplastic lungs,
small ears, and flexion of the long finger in both
hands, findings suggesting Costello syndrome.
Another fetus of 34 weeks of gestation with a diag-
nosis of short VA SVT once achieved sinus rhythm
and resolved pleural effusion and ascites after
digoxin and sotalol, but the tachyarrhythmia recurred
at 36 weeks of gestation. SVT was sustained even
after increased dosage of sotalol to 240 mg/day, and
the fetus developed pleural effusion and ascites. The
fetus died at 37 weeks of gestation during prepara-
tions for cesarean section. These fetal deaths were
mainly caused by progression of fetal heart failure
secondary to AFL and SVT. In 1 fetus with AFL, 7:1 AV
block was observed after starting the combination of
digoxin and sotalol. Because the ventricular rate
decreased to 50 beats/min for 5 min at 36 weeks of
gestation, cesarean section was performed, and the
newborn was treated by electrical cardioversion. In
another fetus with AFL, 1:1 AV conduction at 275
beats/min was observed 5 days after starting the
combination of digoxin and flecainide. The fetus
progressed to ascites and pleural effusion and was
delivered by cesarean section at 32 weeks of gesta-
tion. AFL resolve d sponta ne ou sly just afte r birth.
Neonatal AEs related to transplacental treatment
were observed in 5 of 47 neonates (10.6%). Two of
these AEs were serio us.
Maternal serum digoxin concentrations after rapid
initial saturation were not statistically different be-
tween oral administration and intravenous injection
(Online Table 2). Maternal and umbilical vein serum
concentrations of the antiarrhythmic agents at de-
livery are shown in Table 4. Interestingly, 7 of 13 had
higher serum sotalol levels of umbilical vein than
those of matern al vein.
DISCUSSION
The results of our study demonstrated that protocol-
defined transplacental treatment for fetal SVT and
AFL was effective and tolerable in 90% of cases
(Central Illustration). However, it should be kept in
mind that serious AEs may take place in fetuses and
that tachyarrhythmia may recur within 2 weeks after
birth.
To the best of our knowledge, this is the first
multicenter and largest prospective study of the safety
and efficacy of protocol-defined transplacental treat-
ment for fetal SVT and AFL. Dozens of studies showing
the efficacy of fetal treatment have been published,
but they included stated limitations related to retro-
spective data collection and different protocols across
centers. Two previous prospective studies had limi-
tations related to the single-center design with small
sample size (<20 cases) (11,12). In this study, digoxin
was selected as the first-line agent (9) because of its
relatively safe profile, long history of use during
pregnancy, and clinician familiarity with its use (13–
15). Sotalol and flecainide were used as second-line and
third-line agents, respectively, for cases with short
VA SVT and AFL without fetal hydrops in this
protocol (9). Compared with the previous studies, our
multicenter prospective study demonstrated suffi-
cient safety and efficacy. Some studies recommended
sotalol or flecainide as primary therapy for fetal SVT
and AFL (7,14–19). Two systematic reviews showed
the superiority of flecainide as first-line treatment
for fetal SVT (20,21). However, both studies com-
mented on the lack of prospective studies as a limita-
tion. Our protocol, which is based on the multicenter
prospective study, can become baseline data for
further prospective trials to establish the safest and
most effe ctive treatm e nt for fetal tachy a rrh yth mia.
Favorable efficacy of our protocol treatment was
obtained with each type of fetal tachyarrhythmia. In
this study, the measurement of AV and VA intervals
with Doppler echocardiography was used to classify
tachyarrhythmias (12,22,23). Short VA SVT is the
typical pattern in re-entry tachycardia. Fetuses with
short VA SVT and no hydr op s had a resolutio n rate of
47% with digoxin alone as the first-line drug and an

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F IGUR E 2 Outcomes by Type of Fetal Tachyarrhy thm ia
A
Short VA SVT (n = 17)
Non-hydrops Fetal hydrops
Digoxin (n = 15)
Digoxin &
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
AVRT (2)
Digoxin &
Flecainide (n = 1)
n = 1
Fetal death
n = 1
EAT (1)
Effective
n = 1
AVRT (1)
B
Long VA SVT (n = 4)
Non-hydrops
Sotalol (n = 3)
Fetal hydrops
Sotalol (n = 1)
Effective Effective
n = 3 (Heterotaxy
syndrome)
EAT (1)
n = 1 (Cardiac
tumors)
AVRT (1)
(A) In fetuses with short ventriculoa tr ia l (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 discontinue d in 1 patient because of fetal death. Five cases of atrioventr ic ular 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
ventriculoatr ial supraventricular tachycardia, including 1 fetus with hydrops, fetal tachyarrhythmia resolved. One case each of atrioven-
tricular 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 atrioventr icular re-entrant tachycardia, 1 of ectopic atrial tachycardia, and 3 of atrial flutter were found
after birth. Neonatal tachyarrhythmia s are shown in the bottom of each box.
Continued on the next page

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F IGUR E 2 Continue d
C
AFL (n = 28)
Non-hydrops Fetal hydrops
Digoxin (n = 27)
Digoxin &
Sotalol (n = 1)
Effective Ineffective Ineffective
n = 16
AVRT (1), EAT (1)
Effective
Digoxin &
Sotalol (n = 11)
Ineffective
n = 1
Progression
of fetal hydrops
AFL (1)
n = 8 Digoxin &
Flecainide
n = 1
Fetal death
AFL (2) (n = 2)
(Suspected
Costello syndrome)
Effective Ineffective
n = 1 n = 1
Discontinuation
due to fetal SAE
overall resolution rate of 87%, comparable to that of a
previous review article (3). Both cases of short VA SVT
and fetal hydrops achieved resolution in utero. Long
VA SVT is a rare tachyarrhythmia suggesting EAT or
atypical AVRT. Because digoxin was reported to be
ineffective in long VA SVT (24), in this study protocol,
sotalol and flecainide were used as first-line and
second-line therapy, respectively. All 4 cases with
long VA SVT including 1 with fetal hydrops had res-
olution of fetal tachyarrhythmia. Therefore, our
findings indicate the effectiveness of protocol treat-
ment according to the waveforms assessed by
Doppler echocardiography. Because no single agent is
universally effective (12,15), it is important to give the
most efficient drug at the lowest effective dose to
avoid the risk of maternal and fetal morbidity. We
believe that appropriate drug selection for each type
of tachyarrhythmia contributes to avoiding maternal
and fetal AEs.
In this study, fetuses with AFL and no hydrops
had a resolution rate of 59% with digoxin alone as
first-line therap y and an overa ll resolutio n rate of
93%. Also in this study, AFL accounted for 60% of
fetuses, a higher percentage than in previous reports
(25% to 30%) (1,3,6). A large multicenter retrospective
study showed that cardioversion at 5 and 10 days
occurred in only 25% and 41% of fetuses with treated
AFL, respectively (15). Sotalol was reported to effect a
highe r propo rtion of fetal AFL termina tion than
digoxin or fleca inide (15). A revie w article showed a
fetal AFL resolution rate of 45% with digoxin alone, a
findin g sugge stin g that if AFL persists, postnatal
conve rsio n to sinus rhyth m may be prefe r re d over
secon d-lin e trans pla ce nta l treatm e nt (3). However,
our results showe d a high resolution rate in fetuses
with AFL but no hydro p s, thus sugge sting that pre-
mature delive ry should be limite d to treatment-
refr ac tory AFL with hydrops.
Our prospective study demonstrated a relatively
high incidence of maternal AEs related to antiar-
rhythmic agents. Maternal AEs, including gastroin-
testinal symptoms and electrocardiographic
abnormalities, were observed in 78% of patients;
however, most of these AEs were minor, and dose

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TAB LE 3 Materna l, Fetal, and Neonatal Treatment- Re la ted AEs
and Serious AEs
Patients Patients With
With AE Serious AE
Maternal (n ¼ 50)
Gastrointestinal
Nausea 20 0 (0.0)
(40.0)*
Vomiting 10 (20.0)* 0 (0.0)
Stomach ache 1 (2.0) 0 (0.0)
Anorexia 1 (2.0) 0 (0.0)
Diarrhea 1 (2.0) 0 (0.0)
General
Malaise 1 (2.0) 0 (0.0)
Limb pain 1 (2.0) 0 (0.0)
Nervous system
Headache 2 (4.0) 0 (0.0)
Head discomfort 1 (2.0) 0 (0.0)
Altered sensation of taste 1 (2.0) 0 (0.0)
Drowsiness 1 (2.0) 0 (0.0)
Numbness 1 (2.0) 0 (0.0)
Increased thirst 1 (2.0) 0 (0.0)
Obstetric
Pre-term delivery 3 (6.0) 0 (0.0)
Threatened pre-mature labor 1 (2.0) 0 (0.0)
Polyhydramnios 1 (2.0) 0 (0.0)
Electrocardiographic abnormalities
Sinus bradycardia <60 beats/min 17 (34.0) 0 (0.0)
Second-degree AV block 9 (18.0) 1 (2.0)†
PR prolongation $200 ms 4 (8.0) 0 (0.0)
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
Increased brain natriuretic peptide 25 (50.0) 0 (0.0)
levels
Liver dysfunction 1 (2.0) 0 (0.0)
Impaired glycemic control 1 (2.0) 0 (0.0)
Anemia 1 (2.0) 0 (0.0)
Fetal (n ¼ 50)
Fetal death 2 (4.0) 2 (4.0)‡
Electrocardiographic abnormalities
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)
General
Decreased fetal movement 1 (2.0) 0 (0.0)
Mild deceleration 3 (6.0) 0 (0.0)
TAB LE 4 Mater na l and Umbilical Vein Serum Concentra t ions of
the Antiarr hy thm ic Agents at Delive ry
Digoxin Sotalol Flecainide
(n ¼ 26) (n ¼ 13) (n ¼ 2)*
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
ng/ml (0–1.5) (60.4–1,263.8)
Umbilical-to-mater nal 53.5 107.1 50.5/69.3
vein ratio, % (0–100) (47.2–371.6)†
Values are median (range) unless otherwise indicated. Analyses were performed in
cases with both maternal and umbilical vein blood available at delivery. Serum
digoxin concentrations were measured by enzyme-multiplied immunoassay tech-
nique. Serum sotalol and flecainide concentrations were measured by high-
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 those
of maternal vein.
TAB LE 3 Continued
Patients Patient s With
With AE Serious AE
Neonatal (n ¼ 47)
Periventricular leukomalacia 1 (2.1) 0 (0.0)
Ileus 1 (2.1) 1 (2.1)¶
Bradycardia <100 beats/min 1 (2.1) 0 (0.0)
Clinical laboratory abnormalities
Hyperbilirubinemia 1 (2.1) 0 (0.0)
Erythrocytosis 1 (2.1) 0 (0.0)
Hypoglycemia 1 (2.1) 1 (2.1)¶
Values are n (%). The causal relationship between AEs and antiarrhythmic agents
was determined by the Independent Safety Evaluation Committee. *Nausea or
vomiting were found in 27 patients (54.0%). During nausea or vomiting, median
maternal digoxin levels were 1.96 ng/ml (range 0.94 to 3.77 ng/ml). †Mobitztype
II AV block during the administration of digoxin (0.75 mg/day; 2.10 ng/ml) plus
sotalol (160 mg/day). ‡In 1 fetus with AFL, 3 days after starting sotalol (160 mg/
day) in combination with digoxin (0.75 mg/day; 1.30 ng/ml), frequency and ven-
tricular rate of fetal AFL decreased but hydrops progressed, resulting in fetal
death at 27 weeks of gestation. In another fetus with short VA SVT, 2 days after
increasing sotalol (240 mg/day) in combination with digoxin (0.375 mg/day;
1.55 ng/ml), fetal death was detected during preparation for cesarean section at
37 weeks of gestation. §In 1 fetus with AFL, fetal ventricular rate decreased to 50
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
fetus with short VA SVT, paroxysmal atrial fibrillation was observed 4 days after
starting digoxin (0.75 mg/day; 0.90 ng/ml). In another fetus with AFL, 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 flecainide
(200 mg/day; 425.8 ng/ml). ¶In 1 fetus with AFL, tachyarrhythmia 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 with short VA
SVT, tachyarrhythmia was well controlled in utero by sotalol (160 mg/day);
however, ectopic atrial tachycardia and hypoglycemia (31 mg/ml) were observed in
the first day.
AE ¼ adverse event; AV ¼ atrioventricular; other abbreviations as in Table 1.
flecainide, or 10% with sotalol, and visual distur-
bances occurred in 14% with flecainide) (15). Our re-
sults suggest that most previous retrospective studies
underestimated the incidence of maternal AEs.
Combination therapy presents a greater risk of
maternal and fetal AEs than monotherapy (8).
Although serious maternal AEs were rare, occurrin g at
rates similar to those in reporte d serie s (15,25), we
Continued in the next column
reduction allowed for continued protocol treatment.
There are very few reports focusing on AEs related to
transplacental antiarrhythmic treatment. Nausea, fa-
tigue, and loss of appetite are well-known maternal
AEs related to digoxin (8). Sinus bradycardia and AV
block are common AEs with antiarrhythmic drugs (8).
A previous report showed that one-third of mothers
had likely drug-related AEs (e.g., nausea and dizzi-
ness occurred in 38% with digoxin, 20% with

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Short ventriculoatrial
(VA) SVT or AFL
(n = 45)
ydrops Fetal H
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
CENT RAL IL LUS T RAT I O N Result s of the Transplacental Treat ment 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)
Long VA SVT
(n = 4)
Non-h ydrops
First-Choice Therapy
Digoxin
54.8% (23/42)
Digoxin & Sotalol
33.3% (1/3)
Sotalol
100% (4/4)
Second-Choice Therapy
Digoxin & Sotalol
72.2% (13/18)
Digoxin & Flecainide
100% (1/1)
Flecainide
Third-Choice Therapy
Digoxin & Flecainide
66.7% (2/3)
Antiarrhythmic Agents
Miyoshi, T. et al. J Am Coll Cardiol. 2019;74(7):874–85.
Antiarrhythmic agents were selected by types of fetal tachyarrhythm ia and/or presence of fetal hydrops. In short ventriculoatr ia l 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
ventriculoatr ia l 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
ventriculoatr ial supraventricular tachycardia, including 1 fetus with hydrops, fetal tachyarrhythmia resolved by sotalol alone.
speculated about the need for serial drug concentra-
tion monitoring and maternal electrocardiography to
assess drug effects and toxicity, especially during
dose escalation.
Two fetal deaths occurred during combination
therapy with digoxin and sotalol. In fetuses with
hydrop s and SVT or AFL, arrhythmia-related
mortality increased to 15% to 40%, compared with 0%
to 4% in fetuses without hydrops (3–5,26–29). One
fetal demise occurred 2 days after sotalol dose esca-
lation. A previous study investigated the timing of 4
fetal deaths (3 SVT and 1 AFL). Three deaths occurred
just days after the initiation of sotalol, and 1 death
occurred after a dose increase (7). Several reports

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showed fetal deaths within 3 days of transplacental
flecainide treatment (28,29). It is difficult to draw
conclusions about a potential AE of sotalol and fle-
cainide in this group of fetuses at increased risk of
prenatal demise. The occurrence of fetal death raises
the question whether these agents have a proar-
rhythmic effect because serum sotalol concentrations
of umbilical vein can reach higher than those of
maternal vein (11). In this regard, fetal magneto-
cardiography has a potential role for detection of
repolarization abnormalities or conduction defects
that may lead to fetal sudde n death.
ST U DY ST R E N G TH S. First of all, this was the first
multicenter and largest prospective trial to confirm
the safety and efficacy of protocol-defined trans-
placental treatment for fetal SVT and AFL. Further-
more, our results showed a high resolution rate even
in fetuses with AFL, a treatment-refractory type of
fetal tachyarrhythmia. Second, our findings indicate
the effectiveness of protocol treatment. Notably, all 4
patients with long VA SVT were effectively treated
with sotalol alone and with no mortality. Appropriate
drug selection for each type of tachyarrhythmia is
important not only to improve fetal and neonatal
outcomes but also to avoid maternal and fetal AEs.
Third, we prospectively confirmed accurate incidence
of maternal, fetal, and neonatal AEs related to study
antiarrhythmic agents. Our results showed a rela-
tively high incidence of maternal AEs, thus suggest-
ing underestimation in previous retrospective
studies. Notably, serious AEs resulting in discontin-
uation of the protocol treatment were found in 4 fe-
tuses during combination therapy. This information
will help obstetricians and pediatric cardiologists
administering transplacental treatment for fetal SVT
and AFL.
ST U DY L IMITA TIO N S. First, this was a single-arm
trial; however, this was the most completable pro-
spective study design in the limited number of the
cases in each year by referring the results of our
retrospective survey and historical control data from
the literature. Second, as a result of the limited
sample size, only 4 patients with fetal hydrops and
only 4 patients with long VA SVT were enrolled in this
study. We used a strict definition of fetal hydrops (10)
because we intended to limit combination therapy in
truly severe cases in patients with fetal hydrops to
avoid AEs to mothers and fetuses. Hence, our study
did not have enough patients to make conclusions
about combination therapy for the cases with fetal
hydrops and about the therapy for long VA SVT.
Third, beca use we used a treatm e nt protoc ol with
3 antiar rh ythm ic agents, it is diffic ult to analyze
the safety and efficacy of each agent separately.
However, the results of our first multicenter and
largest prospective study could provide important
baseline data as protocol-defined transplacental
treatment for analyzing the effectiveness of future
protocols, at least for fetal short VA SVT and AFL
witho ut fetal hydrop s.
CO NCLUSIONS
Our study demonstrated that protocol-defined trans-
placental treatment for fetal SVT and AFL was effec-
tive and tolerable in 90% of cases. Maternal AEs were
observed in 78% of patients; however, most AEs were
minor, and dose reduction allowed for continued
protocol treatment. However, it should be kept in
mind that serious AEs may take place in fetuses and
that tachyarrhythmia may recur within 2 weeks after
birth even if it is well controlled in utero. We believe
that our results will help optimize the design of
future randomized controlled trials to establish the
safest and most effective treatment for fetal
tachy a rrh yth mia.
A CK N OW L E D G ME N TS The authors thank Dr. Makoto
Nishibatake (chairperson), Dr. Masao Nakagawa, Dr.
Ichiro Kawabata, and Dr. Naokata Sumitomo for their
contribution as members of the Independent Safety
Evaluation Committee in this trial. The authors also
thank Dr. Takeshi Kotake for measuring serum sotalol
and fleca inid e concentrations.
A D D RE SS F O R CO RRE SP O N D E N CE : Dr. Yasuki
Maeno, Department of Pediatrics and Child Health,
Kurume University School of Medicine, 67 Asahi-machi,
Kurume 830-0011, Japan. E-mail: yasukim@med.
kurume-u. a c.jp. Twitter: @YMaeno2.
PERSPECTIVES
COMPETENCY IN PATIENT CARE AND PROCE-
DURAL SKILLS: Transplacental administration of
digoxin, sotalol, or flecainide in singleton pregnancies
from 22 to 37 weeks of gestation with sustained fetal
SVT or AFL at ventricular rates $180 beats/min was
effective and tolerated in 90%. Maternal AEs were
frequent and usually mild, but they required treat-
ment discontinuation in 8%, and fetal loss occurred in
4%.
TRANSLATIONAL OUTLOOK: Further studies are
needed to establish the safest and most effective
antenatal treatment regimens for fetal supraventric-
ular tachyarrhythmias.

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KE Y WO RD S a dve r se eve nt, atri al flutter ,
fetal e c hoca r diogr a phy , fetal
ta c hy a r r hy thm ia , suprave ntricular
tachycardi a, tra nspla ce nta l treatme nt
A P P E N D I X For supplemental tables, please
see the online version of this paper.

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