Journal of

Clinical Medicine

Review
Treatment of Fetal Arrhythmias
Alina Veduta 1 , Anca Maria Panaitescu 1,2, *, Anca Marina Ciobanu 1,2 , Diana Neculcea 1 ,
Mihaela Roxana Popescu 3 , Gheorghe Peltecu 1,2 and Paolo Cavoretto 4

1 Obstetrics and Gynecology Department, Filantropia Clinical Hospital, 11171 Bucharest, Romania;
[email protected] (A.V.); [email protected] (A.M.C.);
[email protected] (D.N.); [email protected] (G.P.)
2 Obstetrics and Gynecology Department, Carol Davila University of Medicine and Pharmacy,
020021 Bucharest, Romania
3 Cardiology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
[email protected]
4 Obstetrics and Gynecology Department, IRCCS San Raffaele Hospital, 20132 Milan, Italy;
[email protected]
* Correspondence: [email protected]; Tel.: +40-2318-8930

Abstract: Fetal arrhythmias are mostly benign and transient. However, some of them are associated
with structural defects or can cause heart failure, fetal hydrops, and can lead to intrauterine death.
The analysis of fetal heart rhythm is based on ultrasound (M-mode and Doppler echocardiography).
Irregular rhythm due to atrial ectopic beats is the most common type of fetal arrhythmia and is
generally benign. Tachyarrhythmias are diagnosed when the fetal heart rate is persistently above
180 beats per minute (bpm). The most common fetal tachyarrhythmias are paroxysmal supraven-
tricular tachycardia and atrial flutter. Most fetal tachycardias can be terminated or controlled by
transplacental or direct administration of anti-arrhythmic drugs. Fetal bradycardia is diagnosed





 when the fetal heart rate is slower than 110 bpm. Persistent bradycardia outside labor or in the
Citation: Veduta, A.; Panaitescu,
absence of placental pathology is mostly due to atrioventricular (AV) block. Approximately half of
A.M.; Ciobanu, A.M.; Neculcea, D.; fetal heart blocks are in cases with structural heart defects, and AV block in cases with structurally
Popescu, M.R.; Peltecu, G.; Cavoretto, normal heart is often caused by maternal anti-Ro/SSA antibodies. The efficacy of prenatal treatment
P. Treatment of Fetal Arrhythmias. J. for fetal AV block is limited. Our review aims to provide a practical guide for the diagnosis and
Clin. Med. 2021, 10, 2510. https:// management of common fetal arrythmias, from the joint perspective of the fetal medicine specialist
doi.org/10.3390/jcm10112510 and the cardiologist.

Academic Editor: Michael G. Ross Keywords: fetal arrhythmia; fetal ultrasound; tachyarrhythmia; bradyarrhythmia

Received: 24 April 2021

Accepted: 1 June 2021
Published: 6 June 2021
1. Introduction
Fetal arrhythmias are detected in 1–2% of pregnancies. Most fetal arrhythmias are
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
benign and transient; however, in some cases, the irregularity of the fetal heart rhythm can
published maps and institutional affil-
indicate a serious condition—either of fetal or maternal origin. Persistent fetal arrhythmia
iations. can cause low cardiac output, heart failure, hydrops, and fetal demise [1–4].
There are three main categories of fetal arrhythmias: (1) an irregular rhythm with
a normal fetal heart rate (FHR), as a consequence to premature beats or to conduction
anomalies; (2) tachyarrhythmias (defined as FHR > 180 beats per minute-bpm), and (3)
bradyarrhythmias (defined as FHR < 110 bpm) [1–5]. Some of the specific terminology
Copyright: © 2021 by the authors.
used in the article is explained in Appendix A (Table A1).
Licensee MDPI, Basel, Switzerland.
This article is an open access article
Premature beats (extrasystoles or ectopic beats) can be atrial, ventricular, or rarely
distributed under the terms and
junctional in origin [5].
conditions of the Creative Commons Premature atrial complexes (PACs; also referred to as premature atrial beats, atrial
Attribution (CC BY) license (https:// ectopic beats, or atrial extrasystoles) are caused by early activation of the atrial myocardium
creativecommons.org/licenses/by/ because of an impulse generated by an ectopic focus within the atrial myocardium rather
4.0/). than the sinus node. The interval between the last sinus beat and the ectopic beat is

J. Clin. Med. 2021, 10, 2510. https://doi.org/10.3390/jcm10112510 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2021, 10, 2510 2 of 22

shorter than the interval between two normal sinus beats. PACs are triggered from the
atrial myocardium in a variety of situations and are almost ubiquitous in the general
population [3,6,7].
Premature ventricular complexes (PVCs; also referred to as premature ventricular
beats, premature ventricular depolarizations, or ventricular extrasystoles) are triggered
from the ventricular myocardium. PVCs are not uncommon and appear in patients without
structural heart disease and in those with cardiac disease, independent of severity [3,6,7].
The established range of fetal heart rate is 110–160 bpm. FHR is gestational age
dependent, it normally gets slower as the pregnancy advances [8].
Tachyarrhythmias are diagnosed when the fetal heart rate is persistently above
180 bpm and are subdivided into: (1) sinus tachycardia (ST); (2) atrial tachycardia (atrial
flutter and atrial ectopic tachycardia); (3) conduction system tachycardia (atrioventricular
re-entry tachycardia (AVRT), junctional tachycardia (JT), and atrioventricular nodal re-entry
tachycardia (AVNRT); and (4) ventricular tachycardia (VT) [3,6]. This classification can
be simplified by dividing tachyarrhythmias into sinus tachycardia (ST), supraventricular
tachycardia (SVT), and ventricular tachycardia (VT, rare in fetuses) [3,6,7,9–11]. Among
fetal SVTs, long ventriculoatrial (VA) interval tachycardia is less frequent than short VA
interval tachycardia [12]. The most common fetal tachycardias are paroxysmal supraven-
tricular tachycardia (SVT) either with 1:1 atrioventricular (AV) conduction or atrial flutter
(AF) with variable (mostly 2:1) AV conduction [6,7,9–13].
Fetal bradycardia means that the ventricular rate is persistently slower than 110 bpm.
This happens frequently in fetal growth restriction, oligohydramnios, or during labor
and it is physiological up to a certain extent and duration. However, when the heart
rate decreases below 80 bpm for more than 10 min in labor, the risk of neonatal acidemia
increases rapidly and significantly [14]. Persistent bradycardia outside labor or in the
absence of placental pathology is mainly due to atrioventricular block (AV block) [2,12].
Approximately fifty percent of fetal bradyarrhythmia cases are associated with structural
heart defects, and the remaining cases that have normal cardiac structure are often caused
by maternal anti-Ro/SSA antibodies [2,12–15]. The efficacy of treatment for fetuses with
AV block is limited compared with that of treatment for fetal tachycardias, particularly
when associated with structural defects [12,15].
In utero treatment is necessary when there is significant sustained arrhythmia, and
delivery is not an option. Fetal hydrops or foreseeable progression to hydrops is an
indication for the treatment of arrhythmias. For most instances, treatment is represented
by transplacental medication. The treatment of fetal arrhythmia is a classic example
of pharmacological intervention in maternal–fetal medicine. There have been only rare
attempts to surgically manage intractable severe fetal arrhythmia [9]. A percutaneously
injectable, rechargeable fetal pacemaker was recently produced and successfully tested in
an animal model [16].
The aim of this paper is to provide a practical guide to the obstetricians for the
diagnosis and management of common fetal arrhythmias.

2. The Use of Ultrasound to Assess Fetal Heart Rhythm

Unlike the postnatal setting, where analysis of the heart rhythm is done by electro-
cardiogram (ECG), the analysis of fetal heart rhythm is based on ultrasound [4]. Despite
obvious limitations due to the difficult analysis of the fetal myocardial electric signal, a de-
tailed analysis of fetal arrhythmia is possible using M-mode and Doppler echocardiography
to assess mechanical processes [1,4,12–20]. In the presence of a suspected or ascertained
arrhythmia, the important features to be evaluated are: (1) FHR; (2) rhythm regularity;
(3) the relation and time intervals of the atrial and ventricular contractions [13].
M-mode echocardiography gives a linear representation of adjacent cardiac structures’
motion as a function of time. To obtain a useful M-mode recording, a 2D relevant image of
the fetal heart is needed; then, the M-mode sampling line is placed at the targeted location
on that image. In case of arrhythmia, the M-mode cursor is usually placed across an atrium
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3 of 23

J. Clin. Med. 2021, 10, 2510 3 of 22

image of the fetal heart is needed; then, the M-mode sampling line is placed at the targeted
location on that image. In case of arrhythmia, the M-mode cursor is usually placed across
and a ventricle,
an atrium and aso that theso
ventricle, relationship of atrial toof
that the relationship ventricular contractions
atrial to ventricular is recorded
contractions is
(Figure
recorded 1).(Figure
While1).
this method
While has veryhas
this method good
verytemporal resolution,
good temporal the onset
resolution, the and
onsetpeak
and
of atrial
peak or ventricular
of atrial contraction
or ventricular are not
contraction arewell defined
not well on the
defined on M-mode, which
the M-mode, limits
which its
limits
use in the
its use measurement
in the measurement of the AV time
of the intervals
AV time [4]. Furthermore,
intervals the application
[4]. Furthermore, of the
the application of
M-mode
the M-mode is limited in non-ideal
is limited fetalfetal
in non-ideal positions withwith
positions significant shadowing
significant shadowingof the
of cardiac
the car-
structures [13,18].
diac structures [13,18].

Figure 1.
Figure 1. M-mode, linear representation of adjacent cardiac structures motion as a function of time.
A 2D
A 2D relevant
relevant image
image of
of the
the fetal
fetal heart
heart isis first
first obtained;
obtained; then,
then, the
the M-mode
M-mode cursor
cursor is
is placed
placed at
at the
the
targeted location on that image. In case of arrhythmia, the M-mode cursor is usually
targeted location on that image. In case of arrhythmia, the M-mode cursor is usually placed across placed across
an atrium and a ventricle, so that the relationship of atrial to ventricular contractions is recorded.
an atrium and a ventricle, so that the relationship of atrial to ventricular contractions is recorded.
Arrows indicate ventricular (V) and atrial (A) contractions.
Arrows indicate ventricular (V) and atrial (A) contractions.

Pulsed Doppler
Pulsed Doppler echography
echography is is the
the method
method most most used
used by by fetal
fetal medicine
medicine specialists
specialists to to
assess the AV time intervals, on fetal echocardiography [13–20].
assess the AV time intervals, on fetal echocardiography [13–20]. For simultaneous recording For simultaneous record-
ingleft
of of ventricular
left ventricular
inflow inflow and outflow
and outflow waveforms,
waveforms, a widea cursor
wide cursor
(3–4 mm) (3–4ismm)
placedis on
placed
the
on the mitral and aortic valves, in the 5-chambers view of
mitral and aortic valves, in the 5-chambers view of the heart. Spectral Doppler waveforms the heart. Spectral Doppler
waveforms
for both thefor bothand
mitral the the
mitral andvalves
aortic the aortic valves are
are recorded recorded
during a fullduring
cardiac a full cardiac
cycle. The
cycle. The trace speed should be increased up to 4–5 cm/s
trace speed should be increased up to 4–5 cm/s to have a good representation of each to have a good representation
of each waveform.
waveform. During aDuring
normal a cardiac
normal cycle,
cardiacthe cycle, theoffilling
filling of the ventricles
the ventricles during gen-
during generalized
eralized (E
diastole diastole
wave),(E thewave),
activethe active
filling filling of during
of ventricles ventricles during
atrial systoleatrial systoleand
(A wave), (A wave),
blood
and blood
ejection intoejection
the aorta into the aorta
during during systole
ventricular ventricular
will besystole will (Figure
recorded be recorded2). The(Figure
A wave 2).
The A wave to
corresponds corresponds
the P waveto ofthe
the PECG.
waveThe of AV
the interval,
ECG. Thewhich AV interval,
is the time which is theatrial
between time
between
and atrial and
ventricular ventricular
contraction, cancontraction,
be measured can be measured
from the onset of fromthethe onsetto
A wave ofthe
theonset
A wave of
to the onset of the aortic flow (V wave). The AV interval represents
the aortic flow (V wave). The AV interval represents a mechanical analog to the electrical a mechanical analog
to the
PR electrical
interval of thePRECG;interval of thedescribed
it is often ECG; it isbyoften fetaldescribed by fetal medicine
medicine specialists specialists
as the mechanical
as the
PR mechanical
interval (Figure PR interval
2). The (FigurePR
mechanical 2).interval
The mechanical
is normally PRabout
interval
0.12 is normally about
s (gestational age,
0.12and
sex, s (gestational age, sex, andwith
heart rate dependent), hearttherate dependent),
upper with the of
limit of normality upper
0.14 s,limit of normality
or 0.15 s in later
of 0.14 s, or
gestation 0.15 s in later gestation [9,12,13,18–20].
[9,12,13,18–20].
Other
Other rarely used usedsampling
samplingsites sitesforforthethe simultaneous
simultaneous recording
recording of atrial
of the the atrial and
and ven-
ventricular waveforms are: the superior vena cava and aortic artery, by rotating 90 ◦ from
tricular waveforms are: the superior vena cava and aortic artery, by rotating 90° from the
the 4-chamber view [12,19]; the pulmonary venous and pulmonary arterial Doppler on the
4-chamber view [20].
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 4 of 23

J. Clin. Med. 2021, 10, 2510 4-chamber view [12,19]; the pulmonary venous and pulmonary arterial Doppler on 4the 4-
of 22
chamber view [20].

Figure 2.
Figure 2. The mechanical PR interval measured with a wide cursor on the mitral and aortic valves.
A—the active filling
A—the active filling of
of the
the ventricles
ventricles during
during atrial
atrial systole,
systole, Ao—aortic
Ao—aortic flow,
flow,E—the
E—thepassive
passivefilling
fillingof
of
the atria during generalized diastole, Mi—mitral
the atria during generalized diastole, Mi—mitral flow. flow.

3.
3. Irregular Rhythm with Normal HR
Irregular
Irregularrhythms
rhythmsdue duetotoectopic
ectopicbeats
beatsareare
thethe
most common
most common typetype
of fetal arrhythmias,
of fetal arrhyth-
most often seen in the third trimester. Premature atrial complexes (PACs)
mias, most often seen in the third trimester. Premature atrial complexes (PACs) are are extra beats in
extra
which the ectopic focus originates in the atria, and premature ventricle complexes
beats in which the ectopic focus originates in the atria, and premature ventricle complexes (PVCs)
are thoseare
(PVCs) that originate
those in the ventricles.
that originate In utero,In
in the ventricles. the prevalence
utero, of PAC toofPVC
the prevalence PACistoabout
PVC
10:1; PACs are difficult to differentiate from PVCs. Premature ventricular
is about 10:1; PACs are difficult to differentiate from PVCs. Premature ventricular beats arebeats
not
preceded by atrial contractions. PACs may be followed by a ventricular
are not preceded by atrial contractions. PACs may be followed by a ventricular contrac- contraction when
conducted to the ventricles,
tion when conducted to the or not, in cases
ventricles, of blocked
or not, in cases PACs [1]. Ectopic
of blocked beats
PACs [1]. are clearly
Ectopic beats
seen on fetal and umbilical artery Doppler waveforms (Figure 3). Nonetheless,
are clearly seen on fetal and umbilical artery Doppler waveforms (Figure 3). Nonetheless, tracing
of the cardiac
tracing flow waves
of the cardiac is preferable
flow waves whenever
is preferable possible,
whenever as umbilical
possible, artery
as umbilical Doppler
artery Dop-
waveforms are less informative on the origin of the ectopic
pler waveforms are less informative on the origin of the ectopic beats. beats.
Isolated ectopic beats are generally benign, regardless of the chamber of origin. Fetal
ectopy is associated with congenital cardiac defects in only 1% of cases, and fetal echocar-
diography is not always recommended. In general, antiarrhythmic therapy is not needed
for isolated PACs or PVCs. In most cases, these arrhythmias resolve spontaneously before
delivery [1]. However, ectopic beats can cause arrhythmia if there is a substrate for reentry
tachycardia [11]. Of note, due to immaturity, aberrant conduction pathways are more often
found in the fetal myocardium than in the adult myocardium [21].
Irregular rhythms due to conduction abnormalities (second degree heart block) are
more concerning and diagnosis should be followed by immediate referral to a fetal cardiologist.
The distinction between blocked ectopic beats and conduction anomalies can be diffi-
cult to make. If the atrial rate is faster than the capacity of the AV node to conduct impulses,
some of the impulses are blocked. Atrial tachycardia with functional atrioventricular block
often produces a lower than normal ventricular rate (about 70 bpm), which is difficult to
differentiate from the second-degree AV block. Bigeminal blocked PACs (blocked atrial
bigeminy—BAB) is a particular form of atrial tachycardia with atrioventricular block.
 J. Clin. Med. 2021, 10, x FOR PEER REVIEW 5 of 23
J. Clin. Med. 2021, 10, 2510 5 of 22

Figure 3.
Figure 3. Atrial
Atrial ectopic
ectopic beats
beats (indicated
(indicated by
by arrows)
arrows) on
on the
theumbilical
umbilicalartery
arteryDoppler
Dopplerwaveform.
waveform.

Isolatedthe
Rarely, ectopic beatsrhythm
irregular are generally benign,heart
with normal regardless
rate can of the chamber
be caused byofjunctional
origin. Fetal
or
ventricular escape beats
ectopy is associated withcaused by sinus
congenital node
cardiac dysfunction
defects in only[11].1% of cases, and fetal echocar-
diography is not always recommended. In general, antiarrhythmic therapy is not needed
4.
forTachyarrhythmias
isolated PACs or PVCs. In most cases, these arrhythmias resolve spontaneously before
Fetal[1].
delivery tachycardia is defined
However, ectopic beatsascan
a heart
causerate (HR) faster
arrhythmia thanis 180
if there bpm. Itfor
a substrate is reentry
called
sustained
tachycardia if [11].
the arrhythmia
Of note, dueistopresent for more
immaturity, thanconduction
aberrant 50% of thepathways
examination time of-
are more or
intermittent
ten found inwhen periods
the fetal of normal
myocardium HRin
than andtheperiods of tachycardia
adult myocardium alternate [1,3].
[21].
Descriptors of atrial
Irregular rhythms due tachyarrhythmia, such as “sporadic,”
to conduction abnormalities (second “frequently
degree heartrecurrent,”
block) are
“non-sustained
more concerning incessant,” and soshould
and diagnosis on, help
becharacterize
followed bythe arrhythmia,
immediate but may
referral be confus-
to a fetal cardi-
ing. These
ologist. terms describe the frequency and persistence of the arrhythmia, which constitute
a continuum of clinical
The distinction presentations.
between blocked Usually, the terms
ectopic beats ‘intermittent’
and conduction as opposed
anomalies cantobe‘sus-
dif-
tained’ refer to the frequency of the arrhythmia, while the terms ‘paroxysmal’/‘sporadic’
ficult to make. If the atrial rate is faster than the capacity of the AV node to conduct im-
as opposed
pulses, someto ‘persistent’/‘incessant’/‘permanent’
of the impulses are blocked. Atrialrefer to the persistence
tachycardia of the arrhythmia
with functional [1].
atrioventric-
ular Pathologically increased
block often produces fetal than
a lower heartnormal
rate can be encountered
ventricular in the
rate (about 70setting
bpm), of sinusis
which
tachycardia, supraventricular
difficult to differentiate fromtachyarrhythmia,
the second-degree and AVventricular tachycardiablocked
block. Bigeminal [1,6–11].PACs
(blocked atrial bigeminy—BAB) is a particular form of atrial tachycardia with atrioven-
4.1. Sinus Tachycardia
tricular block.
Sinus
Rarely,tachycardia
the irregularis characterized by a fetal
rhythm with normal HR rate
heart > 180can
bpmbe (often
caused<by 200junctional
bpm) with or
normal AV conduction (1:1) [3]. Frequent causes of
ventricular escape beats caused by sinus node dysfunction [11].sinus tachycardia are: maternal thy-
rotoxicosis, maternal medication (β-agonists), fetal anemia or hypoxia, and infections
(chorioamnionitis,
4. Tachyarrhythmias fetal cytomegalovirus infection). No specific antiarrhythmic therapy is
indicated, but the underlying cause has to be addressed.
Fetal tachycardia is defined as a heart rate (HR) faster than 180 bpm. It is called sus-
tained
4.2. if the arrhythmia
Supraventricular is present for more than 50% of the examination time or intermit-
Tachyarrhythmia
tent when periods of normal HR and periods of tachycardia alternate [1,3].
Supraventricular tachyarrhythmia (SVT) is defined by a non-sinus mechanism of the
Descriptors
accelerated heart of atrial
rate (fetaltachyarrhythmia,
HR > 180 bpm);such this as “sporadic,”
large group of“frequently
tachycardicrecurrent,”
disorders
“non-sustained incessant,” and so on, help characterize the arrhythmia, but
includes any non-sinus rapid rhythm that arises from structures above the bundle branches. may be con-
fusing. These terms
Supraventricular describe the frequency
tachyarrhythmias and persistence
include atrial of thefibrillation
flutter and atrial arrhythmia,[3].which
Basedcon-
on
stitute a continuum of clinical presentations. Usually,
the AV conduction type and time, SVTs are divided into two types: the terms ‘intermittent’ as opposed
to ‘sustained’ refer to the frequency of the arrhythmia, while the terms ‘paroxysmal’/‘spo-
radic’ as opposed to ‘persistent’/‘incessant’/‘permanent’ refer to the persistence of the ar-
rhythmia [1].
J. Clin. Med. 2021, 10, 2510 6 of 22

- Short ‘ventriculoatrial’ tachycardia; it usually involves re-entry mechanisms including

atrioventricular re-entry (AVRT) using a bypass tract or atrioventricular nodal re-entry
(AVNRT) [2];
- Long ‘ventriculoatrial’ tachycardia—atrial ectopic tachycardia or permanent junctional
reciprocating tachycardia (PJRT) [3,12].
The most common fetal tachycardia is re-entry SVT, namely orthodromic atrioventricu-
lar re-entry tachycardia (AVRT) (Figure 4a,b) [1–7]. Of note, the incidence of different forms
of SVT is age dependent. Atrioventricular nodal re-entry tachycardia (AVNRT) is very rare
in fetuses; in children, its relative prevalence increases with age [21]. AVRT is a paroxysmal
tachycardia (PSVT) and it accounts for about two-thirds of fetal tachyarrhythmias [1,10].
This type of tachycardia usually develops between 24 and 32 weeks of gestation [10]. The
mechanism is initiated by an ectopic beat [10,11].
Atrial flutter (AF) is the second most common fetal tachycardia (up to 30% of cases) [9,22,23].
It is defined by high atrial rates (300–500 bpm) and slower ventricular response in the
setting of variable atrioventricular conduction (Figure 5a,b) [2]. Usually, AF is diagnosed
later in gestation [1,3,20]. AF can be associated with myocarditis, anti-Ro (SSA) antibod-
ies, and structural heart disease; fetuses with AF develop hydrops in about 15% of the
cases [1,22–24]. Postnatal data shows that up to 20% of individuals with AF also have other
types of SVT [25,26].
The treatment of SVT consists of antiarrhythmic medication; the substances used to
treat fetal SVT are digoxin, flecainide, sotalol, and, more rarely, amiodarone. Correcting
abnormal maternal electrolytes levels and vitamin D deficiency can help the conversion of
tachycardia and maintain the sinus rhythm of the fetus [10].
Three options are available when tachyarrhythmias are diagnosed in a fetus: delivery,
in utero monitoring, or in utero treatment [1,3,9,27].
The decision to treat fetal SVT depends on several factors such as the mechanism
and persistence of tachycardia, gestational age, and associated congenital heart disease
(CHD) [1,25]. Practically, the probability of progression to hydrops is the most important
factor to consider when deciding the management of prenatally diagnosed arrhythmia.
Although it is difficult to predict if a fetus will develop hydrops and when it will occur, sev-
eral parameters are useful in assessing the risk of progression to hydrops. Early gestational
age, high ventricular rates, and incessant tachycardia are factors determining hydrops
progression [1,28].
Delivery is a valid option for fetuses at term and near term. Postnatal treatment of
tachyarrhythmia is usually effective. There is little reason to pursue transplacental drug
therapy for the term fetus with tachyarrhythmia but no hydrops. Some authors advocate
that hydrops in a near-term fetus is a clear indication for emergent delivery [3]. Nonetheless,
consideration should be given to the fact that in utero conversion of arrhythmia often allows
for hydrops remission. Therefore, a short trial of an effective agent (flecainide or sotalol
rather than digoxin) may be considered rather than delivery, for the hydropic fetus at
term. If the attempt to slow the FHR is ineffective, delivery in 48 to 72 h is indicated.
Hydrops that does not respond to treatment represents an indication for delivery, for term
as well as for premature fetuses. Any type of fetal hydrops can cause the rare maternal
mirror syndrome. Severe mirror syndrome or severe preeclampsia indicates delivery at
any gestational age.
Tachyarrhythmia is sometimes well tolerated, particularly the intermittent type which
manifest near term with moderate ventricular rates (up to 220 bpm). In cases with low
risk of progression to hydrops, close monitoring without transplacental therapy can be
considered [1,3]. In-hospital monitoring of the fetus for the initial 12/24 h to evaluate
fetal well-being and frequency of the arrhythmia is recommended. Once spontaneously
intermittent tachyarrhythmia has been documented in a fetus without structural heart
disease, outpatient monitoring by repeated ultrasound once or twice a week is possible [3].
Hydrops and neurologic sequelae have rarely been reported in case of intermittent fetal
tachycardia [3,23,27–30].
 J. Clin. Med. 2021, 10, x FOR PEER REVIEW 7 of 23
J. Clin. Med. 2021, 10, 2510 7 of 22

(a)

(b)
Figure 4. Fetal
Figure supraventricular
4. Fetal tachycardia:
supraventricular (a) Pulsed
tachycardia: Doppler
(a) Pulsed analysis;
Doppler (b) M-mode
analysis; analysis.
(b) M-mode analysis.

Atrial flutter
In utero therapy is the(AF) is the secondmanagement
recommended most commonfor fetal tachycardia
fetuses (up to 30%
with hydrops of cases)
or at
[9,22,23]. It is defined by high atrial rates (300–500 bpm) and slower
high risk of developing hydrops (sustained tachycardia with ventricular rates more than ventricular response
220 bpm). in thegoal
The setting of variable
of therapy is notatrioventricular conduction
necessarily to stop the SVT,(Figure
but to 5a,b)
slow [2]. Usually, AF is di-
the ventricular
rate enough to achieve a good cardiac output. As a rule, the motivation for inanti-Ro
agnosed later in gestation [1,3,20]. AF can be associated with myocarditis, utero (SSA)
treatment increases with prematurity. In very preterm fetuses (less than 32 weeks of15% of
antibodies, and structural heart disease; fetuses with AF develop hydrops in about
gestation),the cases [1,22–24].
combination Postnatal data
pharmacological shows in
therapy that up tothan
higher 20% usual
of individuals
doses or with
directAF also have
fetal
other types of SVT [25,26].
treatment with amiodarone, adenosine, or digoxin should be considered instead of delivery
if the initial course of transplacental therapy fails. As mentioned before, there is also good
reason for a short trial of an effective agent, in cases of hydropic fetuses at or near term.
 J. Clin. Med. 2021, 10, x FOR PEER REVIEW 8
J. Clin. Med. 2021, 10, 2510 8 of 22

(a)

(b)
FigureFigure
5. Fetal5.atrial
Fetalflutter: (a) Pulsed
atrial flutter: Doppler
(a) Pulsed analysis—ventricular
Doppler rate; (b)rate;
analysis—ventricular M-mode analysis—atrial
(b) M-mode rate.
analysis—
atrial rate.
The treatment of SVT consists of antiarrhythmic medication; the substances use
treat fetal SVT are digoxin, flecainide, sotalol, and, more rarely, amiodarone. Correc
J. Clin. Med. 2021, 10, 2510 9 of 22

The practice of fetal medicine centers varies widely in respect to the drug chosen as
initial treatment for fetal SVT. All of the following drugs: digoxin, flecainide, sotalol, and
amiodarone have been used as first-line transplacental therapy in SVT [1,9,10,12,13,31–48].
The effectiveness of transplacental treatment is dependent on pharmacokinetics, its capacity
to cross the placenta, and fetal bioavailability [1,5]. Importantly, in fetuses with hydrops, the
transplacental passage of digoxin is slow. The mechanism of tachycardia is also important
for the choice of treatment; it seems that for fetal PSVT with long VA interval, digoxin is
rarely effective [12].
For a longtime, digoxin has been used as first line therapy for fetal SVT, but none of
the recent studies and meta-analyses supports this idea [31–45]. Nonetheless, digoxin has
some practical advantages if treatment is considered for moderate fetal disease [1,3]. In
resource rich settings especially, there is expertise to initiate digoxin without continuous
cardiac monitoring and serum digoxin levels are considered easy to monitor. In contrast,
continuous inpatient cardiac monitoring is the standard practice for medical cardiover-
sion with flecainide or sotalol. Therefore, continuous inpatient maternal monitoring is
considered good practice for initiation of transplacental therapy with flecainide or sotalol.
If fewer resources are available, treatment with the β-blocker sotalol can actually be easier
to monitor [39].
According to systematic data, both flecainide and sotalol are more effective than
digoxin in converting fetal SVT, and even more so in hydropic fetuses. A study from
2016 showed the superiority of flecainide over digoxin, especially in cases of long VA
tachyarrhythmia [41]. An important study by Jaeggi et al. showed that flecainide was
the most efficient first-line medication for fetal SVT, overall [42]. Two relatively recent
meta-analyses showed that flecainide and sotalol achieve better results than digoxin in
treating fetal SVT. A meta-analysis of ten studies concluded that flecainide has a higher rate
of SVT termination than digoxin and both flecainide and sotalol are better than digoxin
in fetuses with hydrops and tachyarrhythmia [43]. In a meta-analysis of 21 studies on
the transplacental treatment of fetal tachycardia, both flecainide and sotalol were more
effective than digoxin for conversion of any fetal tachycardia to sinus rhythm, and the
difference was greatest in hydropic fetuses [44]. The experience of a large center with
very good results in fetal SVT treatment shows that drug change or multidrug therapy
were necessary in 68% of cases where digoxin was used as first-line therapy [45]. In the
particular setting of atrial flutter, treatment with flecainide or sotalol aims to terminate the
arrhythmia, while treatment with digoxin aims to slow the ventricular rate. Studies suggest
that sotalol might be the drug of choice to terminate or control fetal AF [42]. However,
we have to take into account that available data regarding fetal AF treatment is not from
randomized trials but rather from case series. In all instances, personal experience is an
important factor in the management of fetal SVTs and patients would be best served by
the input of a complex team of specialists in fetal medicine, obstetrics, neonatology, and
pediatric and adult cardiology.
The loading dose for digoxin is 1–2 mg, divided over 24 h, followed by the measure-
ment of the digoxin serum level. The target serum level for digoxin in general cardiology
is 1 to 2 ng/mL; for the transplacental treatment of fetuses, a maternal serum level in the
higher range, around 2 ng/mL, seems advisable. Maintenance doses usually need to be
higher in pregnant versus in nonpregnant women, ranging from 0.5 to 0.75 mg daily given
in three daily doses, because of increases in blood volume and in the renal clearance. The
maintenance dose is determined by titrating to the fetal response, over several days.
The usual initial dose for flecainide is 250 mg per day, orally in three doses (100, 50,
100 mg). It can be increased to 300 mg daily if needed, under strict continuous mater-
nal surveillance.
The usual initial dose for sotalol is 240 mg per day, orally in three equal doses. It can
be increased if needed, under strict continuous maternal surveillance.
J. Clin. Med. 2021, 10, 2510 10 of 22

An amiodarone loading of 12 to 13 g over a week has been reported to achieve conver-

sion to sinus rhythm, after a mean interval of six days. Amiodarone is very rarely used as
first-line therapy, as it has a long half-life and can cause neonatal hypothyroidism [47,48].
There is little data to document the duration of transplacental therapy, until cardiover-
sion. Available data shows that medical cardioversion of fetal SVT is achieved within 48 h,
in at least 50% of cases, irrespectively of the drug used [46]. The data on the actual mean
time to cardioversion is sparse and sometimes contradictory. One study reported that the
median time to conversion of SVT was 3 days with digoxin, 4 days with flecainide, and
12 days with sotalol [42]. Another study reported a median of one day for cardioversion
with sotalol [39]. As amiodarone crosses the placenta slowly, it takes a relatively long time
of amiodarone treatment to achieve the therapy goal. The time to conversion is significantly
longer in AF cases and in fetuses with hydrops [42]. The practical issue related to this
subject is how long to continue a treatment regimen if no improvement (conversion to sinus
rhythm or reduction of the ventricular rate) is seen. In general, the more unstable the fetus
is, the more likely one is to quickly (after 72 h) abandon a treatment that seems inefficient.
If the first-line therapy is inefficient, another drug can be used or added to the first-
line drug. Combination therapy usually consists of digoxin and one of the other drugs.
Flecainide increases digoxin serum levels, thus digoxin dose adjustment is needed when
adding flecainide to digoxin. Direct fetal administration (intramuscular digoxin or intra-
venous amiodarone by cordocentesis) is rarely considered, as most SVTs are eventually
controlled with transplacental medication.
Successful treatment (control of the SVT) is defined by either conversion to sinus
rhythm or reduction of the ventricular rate by more than 15% [41].
Once the arrhythmia is controlled, outpatient monitoring is possible, and medication
can be given in two rather than three daily doses. Attempts to taper the medication after a
long time of sinus rhythm or before delivery are sometimes made; this is justified in the
case of sotalol, which can have significant neonatal adverse effects.
If the conversion to sinus rhythm is achieved, there are no specific recommendations
for the delivery and the child can be evaluated after birth by the pediatric cardiologist, on an
outpatient basis. If sustained tachycardia is present during delivery, experienced support
personnel from neonatal intensive care and cardiology should be available at the time
of birth. Therefore, in utero transfer to a comprehensive center is always recommended,
under the circumstances.
There is increasing awareness of the potential risks of proarrhythmia to both the
mother and the fetus [49]. Before treatment initiation, assessment of the mother by a
cardiologist is warranted. Initiation of the treatment is usually done in hospital, sometimes
with continuous cardiac monitoring for 48 h. After initiation, monitoring consists in daily
electrocardiograms. Daily electrocardiograms are obtained to look for PR prolongation
(suggests digoxin toxicity), QT prolongation (suggests flecainide or sotalol toxicity), or
QRS prolongation (suggests flecainide or sotalol toxicity) [49].
Development of preeclampsia with maternal renal impairment is, in most instances, an
indication to stop the administration of any renally-cleared proarrhythmogenic substances.

4.3. Ventricular Tachycardia

Ventricular tachycardia (VT) is very rare in fetuses. It has been documented in as-
sociation with myocarditis, cardiac tumors, ventricular aneurysms, long QT syndrome,
and unstable atrioventricular block [1,10,50–52]. There is complete dissociation of atrial
and ventricular contraction, and the atrial rate is slower than the ventricular rate. Ex-
pectant management is an option for stable fetuses. First-line therapy of VT consists of
maternal intravenous magnesium sulphate [9,53]. Transplacental treatment with lido-
caine, dexamethasone, beta-blockers (propranolol), flecainide, and amiodarone has been
described [10,54]. One recent paper reported that, in the absence of tumors or cardiomyopa-
thy, beta blockers (excluding sotalol) should be the first-line therapy for fetal ventricular
tachycardia [55].
J. Clin. Med. 2021, 10, 2510 11 of 22

Other substances, such as verapamil (no longer prescribed for infants) or procainamide,
have been sometimes used to treat fetal tachyarrhythmias.
The usual doses and regimens as well as the adverse reactions of some of the agents
used to treat fetal tachyarrhythmia are presented in Table 1 [54].

Table 1. Agents used to treat fetal tachyarrhythmia [54].

Condition and Drug Dose Adverse Reactions

Supraventricular tachycardia (including atrial flutter)
LD 1–2 mg per 24 h PO in
Nausea, severe sinus bradycardia
3 divided doses MD
Digoxin or atrioventricular block,
375 (500)–750 µg daily POin three
maternal and fetal proarrhythmia
equal daily doses
Nausea, dizziness, fatigue,
bundle branch block, QT
160–480 mg daily in three equal prolongation, QRS prolongation,
Sotalol
doses PO maternal and/or fetal
proarrhythmia, neonatal
hypoglycemia
Visual and central nervous
system symptoms, bundle
250–300 mg daily in three equal
Flecainide branch block, QT prolongation,
doses PO
QRS prolongation, fetal or
neonatal proarrhythmia
Nausea, maternal and/or fetal
thyroid dysfunction,
LD 1800–2400 mg daily in equal photosensitivity,
Amiodarone doses given every 6 h for 48 h; MD thrombocytopenia, bundle
200–600 mg daily PO branch block, proarrhythmia,
torsades de pointes in fetuses
with long QT syndrome
LD 500–600 mg over 20 min iv;
MD 2–6 mg/min iv Nausea, hypotension,
Procainamide Initially 1250 mg, followed in 1 h proarrhythmia, platelets
by 750 mg, then 250–1000 mg abnormalities
every 3–6 h PO
Ventricular tachycardia
Fatigue, central nervous system
symptoms, stop for loss of
Magnesium sulfate LD 2–4 g iv followed by 1–2 g/h iv patellar reflex at levels of
3.5–5.0 mmol/L cardiac
arrhythmias at high levels
LD 1.0–1.5 mg/kg iv followed by Central nervous system
Lidocaine
1–3 mg/min iv symptoms
Fatigue, bradycardia,
Propranolol 40–80 mg every 8 h PO
hypotension
Maternal effects similar to other
corticosteroids, possible negative
Dexamethasone LD 4–8 mg PO; MD 4 mg daily PO
influence on the development of
the fetal brain
LD—loading dose; MD—maintenance dose.

5. Bradyarrhythmias
The obstetric definition of fetal bradycardia is sustained FHR of less than 110 bpm for
more than 10 min [2,10]. FHR is dependent of gestational age, and it decreases significantly
as gestation progresses from an average of 141 bpm at 32 weeks of gestation to 137 bpm
J. Clin. Med. 2021, 10, 2510 12 of 22

at 37 weeks of gestation [2,8,10]. Persistent low heart rate may be normal or may be a
marker for significant conduction disease [6,9,10,54]. A persistent ventricular rate of less
than 60 bpm is usually associated with complete heart block, while rates between 60 and
90 bpm can be due to non-conducted bigeminy or second-degree block.
Persistent low fetal heart rate can be caused by sinus, low atrial or junctional brady-
cardia, blocked ectopic beats, long QT syndrome, or atrioventricular block (second or
third degree).

5.1. Sinus Bradycardia

Sinus bradycardia is rare [2,3]. It is defined by 1:1 atrioventricular conduction with a
slow atrial rate [2,3].
It can be caused by structural heart disease in heterotaxy, long QT syndrome (LQTS), or
noncardiac conditions such as maternal medication, maternal hypotension, hypoglycemia
and hypothermia, maternal conditions including fetal–maternal infections, and pregnancy
or delivery complications. The causes of sinus bradycardia are presented in Table 2. It is
important to recognize the causes of sinus bradycardia in order to avoid emergent delivery
because of presumed fetal distress [2,10]. Fetal therapy is not necessary for sinus or low
atrial bradycardia, but fetal well-being should be attentively assessed and monitored. The
nonstress test is likely to be nonreactive with sustained sinus bradycardia, but variability
may be normal.

Table 2. Causes of sinus bradycardia.

Sinus node dysfunction in left atrial isomerism

Congenital LQTS
Sinus node inflammation or fibrosis in viral myocarditis or autoimmune collagen diseases
(SSA/Ro [+] or SSA/Ro and SSB/La [+] antibodies)
Fetal distress
Fetal hypoxia
Fetal acidosis
Maternal hypotension
Maternal hypoglycemia
Maternal hypothermia and cardiopulmonary bypass
Maternal treatment with beta blockers or sedatives

5.2. Long QT Syndrome

Congenital long QT syndrome (LQTS) is a disorder of ventricular myocardial repolar-
ization caused by genetic ion channelopathies or by an imbalance in the sympathetic inner-
vation of the heart [56–59]. LQTS should be suspected in unexplained fetal demise after
20 weeks of gestation or stillbirth, particularly in cases with positive family history [10,56].
The most common presentation of LQTS in fetuses is bradycardia, but LQTS can also
present with second degree block, alternating tachycardia and bradycardia, torsades de
pointes, or ventricular tachycardia [9,10,53,54]. ECG of the parents is recommended if LQTS
is suspected in a fetus. Prenatal diagnosis is possible in families with known mutations. If
the syndrome is confirmed in the fetus or in the mother, close observation is recommended
and drugs that lengthen the QT interval are contraindicated [10]. Electrolyte and vitamin
D deficiency should be corrected [10]. Therapy is not necessary for bradycardia; magne-
sium sulphate, mexiletine, lidocaine, or betablockers can be tried for torsades de pointes
arrhythmia [57].
J. Clin. Med. 2021, 10, 2510 13 of 22

5.3. Blocked Ectopic Beats

Ectopy causing irregular fetal heart rhythm has been discussed above. Blocked
ectopic atrial beats can lead to sustained bradycardia, especially in the case of bigeminy or
trigeminy. It is very important to distinguish blocked ectopic beats from complete heart
block. In complete heart block, the atrial rhythm is regular, and in atrial ectopy with blocked
beats, the atrial rhythm is irregular. Abrupt shifts from low heart rates to approximately
120 to 160 bpm suggest blocked premature contractions during the bradycardic periods.
Reasonably close monitoring (weekly or every two weeks) should be provided by the fetal
medicine specialist as long as the atrial ectopy persists.

5.4. Heart Block

Atrioventricular block (AV block) refers to altered (delayed, intermittent, or absent)
conduction between the atria and the ventricles [2,10]. The atrial rate is regular and normal,
but the ventricular rate is slow because of the AV dissociation [2,10,51]. There are three
degrees of block: first, second, and third (complete) [2,6,10]. Congenital heart block (CHB)
is rather rare and it is usually associated with fetal structural heart disease or maternal
autoimmune disease [2,12,60].
First-degree AV block is not truly a block, but a delay of the conduction between the
atria and the ventricles, seen as prolonged PR interval. As there is no interruption of the
conduction between the atria and the ventricles, it might be more appropriate to use the
term ‘prolonged AV conduction’ rather than ‘AV block’, to describe this pathology. In
fetuses, the mechanical PR interval can be measured, as described above. When measured
at the mitral/aortic valves, the normal values for the fetal PR are 0.12 ± 0.02 s [9], with an
upper limit (cutoff) of 0.14 s, or 0.15 s if the 99th centile of the normal range at advanced
gestation is considered. Measurement of the PR interval is not routinely done during
fetal morphology assessment or during fetal echocardiography either; therefore, fetal
first-degree AV block is rarely diagnosed in the general population. In mothers with
conditions predisposing to fetal heart block, it is recommended to measure the PR interval,
between 18 to 28 weeks of gestation, so that damage to the cardiac conduction system can
be recognized early, monitored, and managed in utero, if considered necessary [61].
Second-degree heart block is uncommonly diagnosed in the fetus, as it represents a
transient phase in the deterioration of the fetal cardiac conduction system. Second-degree
AV block in the fetus often presents with lengthening of the mechanical PR interval from
one beat to the next—a Mobitz I type of second-degree block (Figure 6), which, in theory,
has a lower risk of progressing to complete atrioventricular block (CAVB). Nonetheless,
fetal second-degree AV blocks very often progress to CAVB. Referral to cardiology is
warranted. When second-degree fetal AV block is diagnosed incidentally, the mother
should be tested for anti-Ro/SSA and anti-La/SSB antibodies.
Complete atrioventricular block (CAVB) is an important cause of sustained fetal
bradycardia [2,10,12]. In CAVB, there is a complete dissociation between the atria and the
ventricles because of the absence of atrioventricular conduction (Figure 7); ventricular rate
is typically 50–80 bpm, but it can be lower. Even at typical ventricular rates and very often
at rates less than 50 bpm, cardiac dysfunction and fetal hydrops are noted.
About 50% of fetuses with CAVB have complex congenital heart disease (CHD). Het-
erotaxy (left isomerism) and cardiac malformations with L-looped ventricles (L-transposition
of great arteries) are the main types of CHD associated with CAVB [2,10,12]. Left atrial
isomerism and transposition can be sometimes recognized on ultrasound from the first
trimester of pregnancy [62–64]; yet, the unpredictable evolution to CAVB cannot be pre-
vented in such cases. Fetal and neonatal mortality is high in CAVB associated with cardiac
malformations, particularly in the setting of hydrops [60].
CAVB in structurally normal hearts is mostly due to immune-mediated inflammation
and fibrosis of the conduction system. The most frequent antibodies responsible for
CAVB in the fetus are maternal SSA/Ro and/or SSB/La antibodies, which can cross
 ognized early, monitored, and managed in utero, if considered necessary [61].
Second-degree heart block is uncommonly diagnosed in the fetus, as it represents a
transient phase in the deterioration of the fetal cardiac conduction system. Second-degree
AV block in the fetus often presents with lengthening of the mechanical PR interval from
J. Clin. Med. 2021, 10, 2510 one beat to the next—a Mobitz I type of second-degree block (Figure 6), which, in14theory,
of 22
has a lower risk of progressing to complete atrioventricular block (CAVB). Nonetheless,
fetal second-degree AV blocks very often progress to CAVB. Referral to cardiology is war-
the placenta
ranted. When [15,65]. Autoimmune
second-degree CAVB
fetal AV usually
block developsincidentally,
is diagnosed between 18 the
andmother
28 weeks of
should
gestation, the anti-Ro/SSA
be tested for highest risk period being between
and anti-La/SSB 18 and 24 weeks of gestation [10,15].
antibodies.

J. Clin. Med. 2021, 10, x FOR PEER REVIEW 15 of 23

Figure 6. Second degree fetal heart block. Arrows indicate atrial contractions.

Complete atrioventricular block (CAVB) is an important cause of sustained fetal

bradycardia [2,10,12]. In CAVB, there is a complete dissociation between the atria and the
ventricles because of the absence of atrioventricular conduction (Figure 7); ventricular rate
is typically 50–80 bpm, but it can be lower. Even at typical ventricular rates and very often
Figure Second
6. less
at rates degree
than fetal heart
50 bpm, block.
cardiac Arrows indicate
dysfunction atrialhydrops
and fetal contractions.
are noted.

Figure7.7.Complete
Figure Complete(third
(thirddegree)
degree)fetal
fetalheart
heartblock.
block.Thin
Thinarrows
arrows indicate
indicate atrial
atrial contractions,
contractions, thick
thick
arrowsindicate
arrows indicateventricular
ventricularcontractions;
contractions;there
thereis is
AVAV dissociation.
dissociation.

About 50% of fetuses with CAVB have complex congenital heart disease (CHD). Het-
erotaxy (left isomerism) and cardiac malformations with L-looped ventricles (L-transpo-
sition of great arteries) are the main types of CHD associated with CAVB [2,10,12]. Left
atrial isomerism and transposition can be sometimes recognized on ultrasound from the
first trimester of pregnancy [62–64]; yet, the unpredictable evolution to CAVB cannot be
J. Clin. Med. 2021, 10, 2510 15 of 22

Isolated non-autoimmune fetal complete atrioventricular block is rare and usually

familial. It seems to be associated with a better survival rate than the autoimmune one [66].
Third-degree block represents about 80% of cases of CHB, and the rest is evenly
distributed between first- and second-degree block.
Treatment of AV block depends on the etiology, presence and stage of heart failure, and
ventricular rate [6,10]. There are few options for prenatal therapy. In particular, congenital
heart block associated with hydrops fetalis is a life-threatening condition with no effective
treatment options. Preterm delivery at the onset of hydrops can be considered, but pacing
very small premature infants is difficult and frequently unsuccessful [2,60].
In utero therapy options for fetal heart block include: beta-sympathomimetics; in-
travenous immunoglobulin and apheresis; and fluorinated glucocorticoids [2,67,68]. Hy-
droxychloroquine is used to prevent fetal heart block and neonatal lupus in women with
anti-Ro/SSA or anti-La/SSB antibodies with a previous history of fetal heart block or
neonatal lupus [12,14]. One study has shown a higher incidence of fetal AV block in winter
months, implying that vitamin D maternal levels should be assessed, and deficiencies
corrected [69].
Beta sympathomimetics to increase heart rate and stroke volume are often used if the
fetal heart rate is less than 50–60 bpm, but no studies demonstrated improved survival
rates [2,70].
Immunoglobulins and maternal plasmapheresis have been used, with variable success,
to treat autoimmune fetal heart block [2,71–73].
The most studied medication for autoimmune fetal heart block is represented by
fluorinated glucocorticoids, which cross the placenta (oral dexamethasone 4 to 8 mg per
day or betamethasone 3 mg per day). Clinicians use glucocorticoids for various indications,
such as second degree AV block, recent onset AV block, or severe cardiac dysfunction and
hydrops (extranodal immune-mediated fetal heart disease) [2,73–75], but the efficiency of
treatment in any of the above circumstances is not proven and questionable.
In a recent meta-analysis [76], fluorinated glucocorticoids did not improve fetal or
neonatal survival, while prolonged administration of fluorinated glucocorticoids was
associated with fetal and maternal complications. However, this meta-analysis is difficult
to interpret. It analyzed all degrees of heart block together, although the natural history and
the prognostic significance of each type of block are very different. Complete heart block,
once identified, is irreversible despite all therapies attempted to date [2,77]. Second-degree
heart block may be reversible, but it also may progress to complete heart block despite
therapy. Progression from first-degree block to more advanced heart block in the fetus is
difficult to document and seems unpredictable [77]. We discuss the use of glucocorticoids
for each type of heart block separately.
There would be equipoise on the recommendation to start transplacental steroids after
a diagnosis of first-degree block. One approach is to start steroids for persistent first-degree
block [78]. The treatment is discontinued if the first-degree block progresses to complete
block and if there is no evidence of extra-nodal disease. If the block remains stable or reverts
to normal sinus rhythm, the benefits and the risks of continuing steroid treatment should
be carefully weighed. Depending on the fetal echocardiography evolution, dexamethasone
may be continued up to 26–28 weeks of gestation, when the critical period reaches the
end [78].
Second-degree fetal block is known for its tendency to progress to complete heart
block; thus, in utero glucocorticoid therapy is indicated by most experts (intravenous
immunoglobulin is an alternative treatment). However, second-degree block can revert
to sinus rhythm without treatment, and not all cases respond to treatment. Case series
document that both treated and untreated patients can progress, stabilize, or revert to
normal conduction. A 2018 systematic review and meta-analysis of five observational
studies that included 71 fetuses with second-degree immune-mediated congenital heart
block concluded that the use of fluorinated glucocorticoids should not be discouraged,
“until more robust evidence is available” [79].
J. Clin. Med. 2021, 10, 2510 16 of 22

Established third-degree fetal block is an irreversible condition caused by fibrosis and

calcification of the AV node. Management of the fetus with CAVB is primarily expectant
since the reversal of the established third-degree block has not been documented [2,77].
However, the transition from a normal rhythm to emergent complete CHB and from
emergent CHB to established CHB can happen in less than 24 h, and the treatment of
the former can revert the conduction to normal [80]. Therefore, in selected cases, daily
FHR monitoring can be crucial to diagnose and effectively treat emerging complete CHB.
One recent study proved that home monitoring is useful in detecting the emergence of
CHB [81]. Otherwise, there is no reason to use fluorinated steroids to prevent disease
progression or death in cases presenting with complete isolated heart block caused by
anti-Ro/SSA antibodies. If fetal heart injury extends beyond the AV node, on the other
hand (endocardial fibroelastosis or global cardiomyopathy), transplacental glucocorticoids
might be of benefit and improve survival [73].
There are attempts to develop in utero pacemakers [16,68,82].
Prevention of fetal heart block recurrence in subsequent pregnancy is possible. The
efficacy of hydroxychloroquine to prevent recurrent congenital heart block in fetuses of
anti-Ro/SSA-positive mothers has been shown by retrospective and prospective clinical
studies [83,84]. Hydroxychloroquine is an antimalarial drug that inhibits the ligation of
endosomal Toll-like receptors (TLRs) and it is often used in patients with systemic lupus
erythematosus. Its preemptive action, in situations others than those of mothers with
anti-Ro/SSA antibodies and history of cardiac neonatal lupus is unknown. Yet, many
clinicians are prescribing hydroxychloroquine during the first pregnancy in asymptomatic
mothers with anti-Ro/SSA antibodies or anti-La/SSB antibodies, as it has minimal side
effects for the mother [15].
Delivery of any fetus with heart block and significant bradycardia should take place
at a center where support personnel from neonatal intensive care and pediatric cardiology,
including a specialist with experience in newborn pacing, are available at the time of birth.

6. Discussion
6.1. The Fetal Medicine Specialist Point of View
When treating fetal arrhythmias, both the fetus and the mother undergo medical
intervention. Transplacental treatment of fetal arrhythmias involves giving medication—in
many instances, antiarrhythmic and proarrhythmogenic substances—to the mother, so
that the medication can reach the fetus through the placenta. For efficient management,
fetal arrhythmias have to be placed in the maternal context, in several respects. Many
reversible maternal conditions (infection, hyperpyrexia, thyroid disease, medication, and
so on) can cause abnormal fetal heart rhythm. Other maternal conditions (autoimmune
disease, long QT syndrome) can be sometimes unveiled by fetal arrhythmia. Side effects
of the antiarrhythmic medication have to be tolerated by the mother for the benefit of
the fetus.
We think that it is up to the fetal medicine specialist to integrate the maternal and
fetal care, under the circumstances. The specialist should set the short-term and the long-
term targets for fetal therapy and should be aware of pregnancy-related modifications
(particularly of renal function) affecting pharmacokinetics of antiarrhythmics or potential
maternal side-effects of medications. The doctor also has to consider that extended medical
care for a fetus with uncertain prognosis produces significant parental anxiety, often
requiring provision of psychological support. The fetal medicine specialist advises in utero
fetal therapy (as opposed to monitoring or delivery), mainly based on the risk of hydrops
and intrauterine death, but also taking into account concomitant maternal conditions or
the development of pregnancy-related conditions such as preeclampsia.
J. Clin. Med. 2021, 10, 2510 17 of 22

6.2. The Cardiologist Point of View

The role of the cardiologist consists in evaluating the risk/benefit balance from the
point of view of the maternal side effects, indicating the medication regimen and monitoring
the fetal and maternal cardiac effects of the treatment.
Different specialists use different terminologies, different types of investigations,
but they must reach the same conclusion and manage the pregnancy for the benefit of
both mother and child. There are differences between the terminology used by a fetal
specialist and a cardiologist. The fetal specialist explores the heart through ultrasound and
characterizes it using the ventriculoatrial interval, while the cardiologist is used to ECG
and its specifics.
Because of this lack of a common point of view, some discrepancies in the current prac-
tices of fetal specialists and cardiologists arise. For example, sotalol is not the first option for
maternal SVT, but it is the drug currently used for fetal tachyarrhythmias. Currently, there
are no common guidelines including both maternal and fetal pathologies. The most recent
ESC (European Society of Cardiology) Guidelines recommend the assembly of a pregnancy
heart team for better management of cardiovascular diseases during pregnancy [85]. A
cardiologist, an obstetrician, and an anesthetist are the indispensable specialists for such
a team. Similar teams should be constituted in case of high-risk fetal arrhythmias, with
the addition of a pediatric cardiologist, fetal medicine specialist, neonatologist, etc. These
teams would be essential for establishing the indications for treatment, balancing the ma-
ternal side effects with the benefit for the child, conduct the perinatal care and follow-up,
and adjudicate on the prognosis of both mother and fetus [86–88].
In conclusion, ultrasound can characterize fetal heart rhythm in detail. For tach-
yarrhythmias, the type of arrhythmia has less prognostic value than the gestational age at
diagnosis or the presence of fetal hydrops. Higher degree heart block, in fetuses with both
normal and abnormal hearts, remains difficult to treat.

Author Contributions: Conceptualization, A.V. and A.M.P.; methodology, A.M.P., M.R.P., and P.C.;
investigation, A.V., A.M.P., A.M.C., D.N., M.R.P., and G.P.; writing—original draft preparation, A.V.,
A.M.C., D.N., and M.R.P.; writing—review and editing, A.M.P., M.R.P., and G.P.; supervision, A.V.
and P.C.; project administration, A.M.P. and P.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

Appendix A

Table A1. Cardiology terminology explained for the fetal medicine specialist [86–88].

heart beat originating in an ectopic focus in the

atrial myocardium, after a long sinus pause; the
escape atrial beats sinus pause can be caused by sinus node exit
block, sinus node arrest and so on; the escape
rhythm is slower than the sinus rhythm
early activation of the atrial myocardium by an
impulse coming from an ectopic focus within the
atrial myocardium, not from the sinus node; the
premature atrial complexes/beats (PACs)
interval between the last sinus beat and the
ectopic beat is shorter than the interval between
two sinus beats
a rhythm in which every other beat (bigeminy) or
atrial bigeminy/trigeminy every third beat (trigeminy) is an ectopic beat
(PAC)
J. Clin. Med. 2021, 10, 2510 18 of 22

Table A1. Cont.

an abnormally fast heart rhythm originating

supraventricular tachycardia (SVT) above the ventricles; in a broader sense, it
includes atrial flutter and atrial fibrillation
sometimes referred to as atrial tachycardia or
primary atrial tachycardia, it is a rhythm
ectopic atrial tachycardia generated by an ectopic atrial focus, which is
faster than the normal heart rate (180 bpm in
fetuses)
tachyarrhythmia caused by the repetitive
propagation of an excitatory wave through a
reentry tachycardia
circular path, returning to its site of origin to
reactivate that site
reciprocating tachycardia reentry tachycardia
also called sporadic, it is a self-limited reentry
paroxysmal tachycardia tachycardias initated by ectopic beats and
terminated by functional block
also called sporadic, those intermittent SVTs with
paroxysmal SVT abrupt onset and offset and a regular ventricular
response, mostly due to reentry, eg AVRT
nonparoxysmal tachycardia, most often caused by
incessant tachycardia enhanced/abnormal automaticity or triggered
activity
arrhythmia present for more than 50% of the
sustained tachycardia
examination time
arrhythmia present for less than 50% of the
intermittent tachycardia
examination time
SVT in which the reentrant circuit conducts
impulses down (antegradely) through the AV
orthodromic tachycardia node and the His–Purkinje system to the
ventricles, and then up (retrogradely) through the
accessory pathway (narrow complex tachycardia)
rare SVT in which the reentrant circuit conducts
impulses down (antegradely) through the
antidromic tachycardia accesory pathway to the ventricles, and then up
(retrogradely) through the AV node (wide
complex tachycardia)
If the RP interval is less than one-half of the RR
interval, the tachycardia is considered a short RP
(short VA) tachycardia. If the P wave is retrograde,
AV reentry with the common slow—fast
conduction type is most probable. The slow—fast
pattern gives rise to retrograde P waves that is
very close or even masked by the QRS complex. If
short VA tachycardia
the P wave is morphologically abnormal, atrial
(ectopic) tachycardia with abnormal AV nodal
conduction is most probable.
With specific referral to reentry tachycardia, it is a
form of tachycardia in which the conduction from
the ventricles back to the atria is by a fast
accessory pathway.
orthodromic AVRT with a slowly conducting
permanent junctional reciprocating
accessory pathway, resulting in a long VA
tachycardia, PJRT
incessant tachycardia
J. Clin. Med. 2021, 10, 2510 19 of 22

Table A1. Cont.

delayed, intermittent, or absent conduction

heart block
between the atria and the ventricles
first-degree heart block prolonged PR interval (>0.14 s in fetuses)
an occasional non-conducted P wave, resulting in
a long RR interval
Mobitz I (Wenckebach) type: progressive slowing
of the conduction of each subsequent impulse in
the AV node, until the node fails to conduct one
second-degree heart block impulse
Mobitz II type: unpredictable failure of the
His–Purkinje pathway to conduct some of the
impulses from the atria to the ventricles; unlike
the Mobitz type I, there is no change in the PR
interval prior to the non-conducted P wave
high-degree block successive non-conducted P waves
also referred to as AV dissociation, absent
complete (third-degree) heart block
conduction beteween the atria and the ventricles

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