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Signs of first-degree heart block occur in one-third of fetuses of pregnant women with antiSSARo 52-kd antibodies.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 4, April 2004, pp 1253–1261
DOI 10.1002/art.20126
© 2004, American College of Rheumatology
Signs of First-Degree Heart Block Occur in One-Third of
Fetuses of Pregnant Women With
Anti–SSA/Ro 52-kd Antibodies
Sven-Erik Sonesson, Stina Salomonsson, Lilly-Ann Jacobsson, Katarina Bremme, and
Marie Wahren-Herlenius
block. One of these fetuses had progression to complete
block, and another showed recovery from second-degree
block to first-degree block with betamethasone treatment. In the remaining 6 fetuses, spontaneous normalization occurred before or shortly after birth. Fetuses
with normal AV time intervals at 18–24 weeks had
normal electrocardiographic results at birth.
Conclusion. Anti–Ro 52-kd–positive pregnant
women frequently carry fetuses with Doppler echocardiographic signs of first-degree AV block. These blocks
revert spontaneously in the majority of fetuses, but
progression to a more severe degree of block may occur
in some. Serial Doppler echocardiographic measurement of AV time intervals is suggested as a useful
method for surveillance of these high-risk pregnancies.
Objective. To prospectively investigate the development of fetal heart block in anti–SSA/Ro 52-kd–
positive women, and to evaluate the usefulness of serial
Doppler echocardiography in detecting early signs of
congenital heart block.
Methods. Twenty-four women with anti–SSA/Ro
52-kd antibodies and consequently increased risk for
fetal heart block were followed up weekly, between 18
and 24 weeks of gestation, with two Doppler echocardiographic methods designed to estimate the time delay
between hemodynamic events caused by atrial and ventricular depolarizations. Two hundred eighty-four
women with normal pregnancies served as controls.
Anti–Ro 52-kd, anti–Ro 60-kd, and anti-La antibodies
were investigated by immunoblotting and enzymelinked immunosorbent assay using recombinant proteins.
Results. In anti–Ro 52-kd–positive women, fetal
atrioventricular (AV) time intervals were longer and
heart rates were slightly lower compared with those in
controls. Eight of 24 fetuses had signs of first-degree
Several rheumatic conditions are associated with
increased risk of pregnancy complications and fetal loss.
Congenital heart block (CHB) without associated cardiac malformation is a rare disease in the general
population, with an incidence in newborn babies of
1/15,000–1/20,000 (1). There is, however, a well-known
association between CHB and placental transfer of the
maternal anti-SSA/Ro and anti-SSB/La autoantibodies
(2,3). Women with these antibodies are commonly diagnosed as having Sjögren’s syndrome (SS), systemic lupus
erythematosus (SLE), or rheumatoid arthritis (RA), but
they may also be asymptomatic. With circulating anti-Ro
and/or anti-La antibodies in maternal sera, there is a
2–5% risk of giving birth to a child with CHB (4,5), while
the risk of giving birth to a second child with CHB is
12–25% (6–9). More recent studies also suggest that the
risk is higher in women in whom the anti-Ro activity is
targeted to the 52-kd component of the antigen rather
than to the 60-kd component (9–11). CHB is most
frequently diagnosed at 18–24 weeks of gestation, when
Supported by the Swedish Research Council, Karolinska
Institutet, Sigurd and Elsa Golje’s Foundation, the Swedish Society for
Medical Research, the Freemason’s Foundation, Signe and Reinhold
Sund’s Foundation, the Samariten Foundation, the General Maternity
Hospital Foundation, Queen Silvia’s Jubilee Foundation, Prof. Nanna
Svartz’ Foundation, King Gustaf V’s 80-Year Foundation, the Börje
Dahlin Foundation, the Clas Groschinsky Foundation, the Emil and
Wera Cornell Foundation, the Heart-Lung Foundation, and the
Swedish Rheumatism Association.
Sven-Erik Sonesson, MD, PhD, Stina Salomonsson, MSc,
Lilly-Ann Jacobsson, RT, Katarina Bremme, MD, PhD, Marie
Wahren-Herlenius, MD, PhD: Karolinska Institutet, Stockholm, Sweden.
Address correspondence and reprint requests to Sven-Erik
Sonesson, MD, PhD, Fetal Cardiology Unit, Pediatric Cardiology
Q1:03, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm,
Sweden. E-mail: sven-erik.sonesson@ks.se.
Submitted for publication September 11, 2003; accepted in
revised form December 17, 2003.
1253
1254
SONESSON ET AL
Table 1. Pregnant anti-SSA/Ro–positive women included in the study*
Most severe degree of
AV block in fetus†
Diagnosis of mother (n)
SS (8)
SLE (11)
RA (2)
Undifferentiated autoimmune syndrome (1)
Asymptomatic (2)
I
II
III
2
3
–
–
1
–
–
–
1
–
–
–
1
–
–
Positive for autoantibodies‡
Anti–Ro 52-kd
8
11
2
1
of
of
of
of
8
11
2
1
2 of 2
Anti–Ro 60-kd
5
5
1
0
of
of
of
of
8
11
2
1
1 of 2
Anti-La
6
7
0
0
of
of
of
of
8
11
2
1
1 of 2
* AV ⫽ atrioventricular; SS ⫽ Sjögren’s syndrome; SLE ⫽ systemic lupus erythematosus; RA ⫽ rheumatoid arthritis.
† Measured by Doppler echocardiography. Most severe degree of block recorded in each fetus is shown.
‡ By enzyme-linked immunosorbent assay with recombinant antigen.
it results in fetal bradycardia (6,12). CHB has been
associated with substantial perinatal mortality (20–
30%), and the majority of children born alive require a
pacemaker at an early age (6,7,13–15).
Early treatment with fluorinated glucocorticoids
has been demonstrated to improve atrioventricular
(AV) conduction in fetuses with second-degree AV
block and to improve cardiac function in complete AV
block (12,16–20). A complete heart block is, however,
commonly considered permanent, but it still remains to
be determined whether a third-degree block might be
reversible if therapy is initiated immediately upon occurrence.
Assuming that CHB is a gradually progressing
disease, a method to diagnose a first-degree AV block
should have the potential for early detection of CHB,
before it becomes complete. Using standard fetal echocardiographic techniques, atrial and ventricular depolarizations can be identified indirectly by their mechanical
(M-mode) or hemodynamic (Doppler) consequences.
Recent experimental (21) and clinical (22) studies have
demonstrated the superiority of the Doppler technique
compared with the M-mode approach for measuring
fetal AV time intervals and thus for diagnosing firstdegree AV block. Reference values obtained by using
different Doppler techniques have been established
(23,24).
Based on these observations and ideas, we devised a protocol for early surveillance of pregnancies at
risk for fetal CHB. In addition to the goal of providing
early therapy to fetuses developing CHB, a second goal
was to investigate whether and to what extent these
fetuses demonstrated Doppler echocardiographic abnormalities suggesting first-degree AV block. Such observations would indicate that measuring AV time intervals could be a useful and reliable method for early
detection of fetal CHB.
PATIENTS AND METHODS
Patients. From December 1999 through March 2003,
24 women (Table 1) with a mean ⫾ SD age of 31.2 ⫾ 4.7 years
and singleton pregnancies were recruited to undergo weekly
fetal echocardiographic examinations between 18 and 24
weeks of gestation. Inclusion criteria were a positive SSA
finding on routine serology with a verified positive anti–Ro
52-kd finding by enzyme-linked immunosorbent assay
(ELISA). Eight women had SS as defined by the revised
European criteria (25), 11 had SLE (2 with secondary SS [25])
according to the 1982 revised criteria of the American College
of Rheumatology (ACR; formerly, the American Rheumatism
Association) (26), 2 had RA according to the 1987 revised
criteria of the ACR (27), 1 had an undifferentiated autoimmune syndrome, and 2 were asymptomatic. Gestational age
had been determined by ultrasound biometry before 18 weeks
of gestation. All women gave informed consent to participate,
and the study was approved by the Ethics Committee at
Karolinska Hospital.
Serologic analyses. Production and purification of
recombinant Ro 52-kd, Ro 60-kd, and La proteins were
performed as described previously (28). The proteins were
used in ELISA and Western blotting for detection of antibodies as described previously (11).
Echocardiographic studies. All fetal echocardiographic recordings and measurements were performed by the
same examiner (S-ES) using a Sequoia ultrasound system with
a 6C2 transducer (Acuson Computed Sonography, Mountain
View, CA). At the first examination, a complete fetal echocardiographic study was performed to identify fetuses with cardiac
malformations. At this and at the following examination, AV
time intervals were measured by using two different Doppler
techniques that have previously been described in detail (24).
Briefly, Doppler recordings were made in a 5-chamber
view from a position recording velocities in both the mitral
valve and the left ventricular/aortic outflow. The AV time
interval was measured from the intersection of the mitral E
and A waves to the beginning of the ventricular ejection wave
(MV-Ao). To obtain a real-time picture suitable for simultaneous recordings of the superior vena cava and aorta Doppler
velocities (SVC-Ao recordings), a 4-chamber view in a vertical
position was first obtained, and thereafter 90° rotation allowed
a longitudinal view of both the ascending aorta and the SVC in
ANTI-Ro ANTIBODIES AND FETAL HEART BLOCK
1255
Figure 1. Longitudinal observations of atrioventricular (AV) time intervals in 24 fetuses with anti–Ro 52-kd–positive mothers. Open squares
represent the fetus with progression to complete block and open circles represent the fetus with second-degree block that reversed to first-degree
block (see Results). Solid circles represent the other 22 fetuses. Straight lines denote the linear regression and 95% confidence limits for individual
observations on normal fetuses. A, Results obtained measuring the AV time interval from the beginning of the retrograde venous a wave to the
beginning of the aortic ejection wave. B, Results obtained measuring the AV time interval from the intersection of the mitral E and A waves to the
beginning of the ventricular ejection wave. ms ⫽ milliseconds; GA ⫽ gestational age.
close proximity to each other. The gate of the pulsed Doppler
was then opened enough to encompass both vessels. On these
simultaneous SVC-Ao recordings, the AV time interval was
measured from the beginning of the retrograde venous a wave
to the beginning of the aortic ejection wave. Measurements of
corresponding complete cardiac cycles were used to calculate
heart rate from both the MV-Ao and the SVC-Ao recordings.
Three consecutive beats were measured for all intervals and
averaged.
Two hundred eighty-four women with normal pregnancies served as controls. The majority of these controls have
already been described (24). During the time period of investigating the pregnancies in the present study, an additional 20
normal pregnancies with gestational ages of 17–22 weeks were
studied. All AV time interval measurements made on these
fetuses fitted well with previously obtained data and were
included in the normal reference values.
Statistical analysis. Statistical analysis was performed
using the Mann-Whitney U test (Statistica 6.0; StatSoft, Tulsa,
OK). Repeated observations made on the anti–Ro 52-kd–
positive pregnancies were divided into 3 gestational age periods. Within each of these periods, an average value for each
individual pregnancy was calculated and compared with the
single observations made on control pregnancies of the same
gestational age. P values less than 0.05 were considered
significant.
RESULTS
Longitudinal Doppler echocardiographic observations of fetuses of anti–Ro 52-kd–positive mothers.
Twenty-four anti–Ro 52-kd–positive, singleton-pregnant
women (Table 1) were followed between gestational
weeks 18 and 24 with fetal echocardiography, and in
some cases also at earlier and later weeks. All 24 fetuses
had structurally normal hearts and normal hemodynamic findings at the first examination. Longitudinal
observations made on these fetuses are illustrated in
Figure 2. Longitudinal observations of heart rate (HR) in 24 fetuses
with anti–Ro 52-kd–positive mothers. Open square represents the
fetus with progression to complete block and open circles represent the
fetus with second-degree block that reversed to first-degree block (see
Results). Solid circles represent the other 22 fetuses. Straight lines
denote the linear regression and 95% confidence limits for individual
observations on normal fetuses. bpm ⫽ beats per minute; GA ⫽
gestational age.
1256
SONESSON ET AL
Figure 3. Observations of AV time intervals in 24 fetuses with anti–Ro 52-kd–positive mothers, plotted against HR. A, Results obtained measuring
the AV time interval from the beginning of the retrograde venous a wave to the beginning of the aortic ejection wave. B, Results obtained measuring
the AV time interval from the intersection of the mitral E and A waves to the beginning of the ventricular ejection wave. Straight lines denote the
linear regression and 95% confidence limits for individual observations on normal fetuses. See Figures 1 and 2 for definitions.
Figures 1 and 2. For both Doppler methods used, there
was a clear tendency toward prolonged AV time intervals in these fetuses compared with normal control
fetuses. Actually, as many as 8 of the 24 fetuses under
study had values outside the 95% confidence interval for
normal fetuses, suggesting an intrauterine first-degree
AV block in one-third of these fetuses. One fetus
progressed from an abnormal AV time interval to
complete AV block in 6 days. Despite betamethasone
treatment until delivery, the block was still complete at
birth. Another fetus progressed from a normal AV time
interval to second-degree AV block in 3 weeks. After a
few days of betamethasone treatment, there was recuperation to a first-degree block. Disregarding these 2
fetuses with second-degree or complete AV block, the
remaining 22 fetuses had heart rates within the normal
Table 2. Heart rates (HRs) and atrioventricular (AV) time intervals obtained with two different
Doppler techniques in patients and controls at 3 gestational age (GA) periods*
GA period, weeks
17–19
HR, bpm
Patients
Controls
MV-Ao AV time
interval, msec
Patients
Controls
SVC-Ao AV-time
interval, msec
Patients
Controls
20–22
23–25
147 ⫾ 6.8 (21)
148 ⫾ 6.5 (57)
143 ⫾ 4.7 (21)†
147 ⫾ 6.5 (58)
142 ⫾ 5.0 (22)‡
146 ⫾ 7.0 (32)
123 ⫾ 10.8 (21)§
114 ⫾ 8.5 (55)
125 ⫾ 11.7 (21)§
111 ⫾ 8.3 (56)
129 ⫾ 10.9 (22)§
115 ⫾ 9.7 (31)
118 ⫾ 11.7 (14)
112 ⫾ 7.9 (15)
123 ⫾ 11.3 (19)§
110 ⫾ 7.8 (38)
126 ⫾ 11.6 (22)‡
116 ⫾ 9.9 (22)
* Values are the mean ⫾ SD (no. of patients or controls). bpm ⫽ beats per minute; MV-Ao ⫽
measurement from the intersection of the mitral E and A waves to the beginning of the ventricular
ejection wave; SVC-Ao ⫽ measurement from the beginning of the retrograde venous a wave to the
beginning of the aortic ejection wave.
† P ⬍ 0.05 versus controls.
‡ P ⬍ 0.01 versus controls.
§ P ⬍ 0.001 versus controls.
ANTI-Ro ANTIBODIES AND FETAL HEART BLOCK
1257
Figure 4. Doppler recordings obtained by measuring the atrioventricular (AV) time interval from the intersection of the mitral E and A waves (E
and A, respectively) to the beginning of the ventricular ejection wave. Mitral inflow is shown downward. Aortic outflow is shown upward. A, A case
with abnormally long time delay (boxed area) between the mitral A wave and the aortic outflow wave, indicating first-degree block. B, Second-degree
block in which every second A wave is superimposed on the mitral E wave (E⫹A). C, Complete block with asynchrony between mitral A waves and
aortic outflow waves. m/s ⫽ meters per second (sweep speed 100 mm/second in A and B; 50 mm/second in C).
range, but with a tendency toward lower values (Figure
2). Individual AV time estimates did not show any
correlation with heart rate (Figure 3).
Transient prolonged AV conduction time is common in fetuses of anti–Ro 52-kd–positive mothers. In
the women with anti–Ro 52-kd antibodies, fetal AV time
intervals measured with the MV-Ao approach were
longer than those in normal fetuses during all 3 gestational age periods (Table 2). With the SVC-Ao approach, which included somewhat fewer observations
during the first period, this finding could be demonstrated only for the second and third periods. A slightly
lower heart rate could also be found in fetuses with
anti–Ro 52-kd–positive mothers during the two later
1258
SONESSON ET AL
Figure 5. Doppler recordings obtained by measuring the atrioventricular (AV) time interval from the beginning of the retrograde venous a wave
(a) to the beginning of the aortic ejection wave. Flow through the superior vena cava toward the heart is shown upward. Aortic outflow is shown
downward. Note the small retrograde venous a wave corresponding to atrial contraction. Shown are the same cases illustrated in Figure 4. A, A case
with abnormally long time delay (boxed area) between the venous a wave and the aortic outflow wave, indicating first-degree block. B, Second-degree
block in which every second a wave is followed by an aortic outflow wave. C, Complete block with asynchrony between venous a waves and aortic
outflow waves. m/s ⫽ meters per second (sweep speed 100 mm/second in A and B; 50 mm/second in C).
gestational age periods (Table 2). The usability of the
suggested fetal Doppler echocardiographic approaches
to distinguish between different degrees of AV block is
demonstrated in Figures 4 and 5, which illustrate recordings from fetuses included in the study.
All women included in the study have delivered
their babies, 21 at term and 3 at gestational ages of
33–35 weeks. Results of electrocardiograms (EKGs),
usually performed during the first days after birth, were
normal in 19 babies and showed a first-degree AV block
in 4. Three of these babies had had Doppler echocardiographic signs of first-degree block as fetuses, and
ANTI-Ro ANTIBODIES AND FETAL HEART BLOCK
the fourth was the fetus with second-degree block that
had converted to first-degree block during betamethasone treatment. Within a few weeks, these 4 babies also
had normal EKG results. The fetus diagnosed as having
complete block was delivered by cesarean section at term.
EKG performed after birth confirmed the diagnosis. All of
the babies are alive and well.
DISCUSSION
Isolated complete congenital heart block is associated with transfer of maternal anti-Ro/SSA autoantibodies to the fetus. The final stage—a complete thirddegree AV block—of the presumed gradual
development from normal conduction activity is usually
discovered before 24 weeks of gestation. However, little
is yet known about the natural progression of this
conduction failure, nor is it known whether an observed
first-degree block will unconditionally lead to more
advanced disease.
An objective of the present study was to determine whether fetuses at risk for developing complete
AV block had signs of first-degree block, as documented
by fetal Doppler echocardiography. With each of two
different techniques, this could be demonstrated in 8 of
24 fetuses. A higher degree of block also occurred in two
of these fetuses. In one fetus, there was a progression
from first-degree block to complete block, while in the
other, recovery from second-degree block to first-degree
block was observed, with subsequent complete normalization. Interestingly, 6 fetuses had indirect signs of
first-degree block without progressing to a higher degree
of AV conduction abnormality. Three of these fetuses
had normal EKG results at birth, and 3 still had firstdegree AV block. A few weeks after birth, the latter 3
babies also had normal EKG results. No later occurring
conduction abnormalities were found in the 16 fetuses
with normal AV time intervals during early midtrimester, and they all had normal EKG results at birth.
To our knowledge, these observations are the
first reported prospective data to support the idea that
CHB is a gradually developing disease starting with a
first-degree block. Our findings also indicate that firstdegree AV block can be present in the fetus without
progressing to complete AV block, and that a firstdegree block is spontaneously reversible. To our knowledge, Doppler echocardiographic signs of first-degree
AV block have previously only been described in a single
fetus initially noted to have a myocardial dysfunction
that resolved during dexamethasone therapy (20); in
1259
addition, this fetus was retrospectively shown to have
had prolonged mechanical time intervals (29).
Treatment with fluorinated steroids in a few
fetuses diagnosed as having second-degree AV block has
been demonstrated to improve AV conduction, and our
observations of one fetus are in accordance with these
previous findings. A complete AV block is commonly
considered irreversible. This conclusion is based on
cases in which bradycardia was the indication for fetal
echocardiography and the time delay from the occurrence of the block to treatment was unknown. We know
that another fetus in our study had signs of a first-degree
AV block, but remained in a one-to-one conduction,
only 6 days before a complete block was diagnosed and
treatment with betamethasone was started. Still, the
complete block remained, suggesting that complete
block is irreversible even when treatment is started
within a few days of occurrence.
The use of fluorinated steroid as prophylactic or
symptomatic treatment of CHB carries potential risks
for both the mother and her fetus (16,30). Thus, observing that first-degree AV block seems to be reversible in
the majority of cases, we currently consider this degree
of block, without signs of endocardial fibroelastosis, to
be an indication for closer surveillance without starting
treatment with fluorinated steroids.
Excluding the two fetuses with second-degree or
complete block, a slightly lower heart rate was still
demonstrated in fetuses with anti–Ro 52-kd–positive
mothers compared with that in control fetuses. This
observation is interesting, since it might be an indication
that the sinus node is also affected by maternal antibodies. This assumption is supported by experimental data
showing that anti-Ro antibodies have effects on calcium
currents in cardiocytes (31) and by autopsy data showing
that in 2 of 7 babies who died of CHB, the sinuatrial
nodes were hypoplastic and, in the case of another of
these babies, surrounded by extensive fibrosis (32).
Furthermore, sinus bradycardia has been described in
infants of mothers with anti-Ro antibodies (5), but, to
our knowledge, not previously in the fetus.
Fetal heart rate has been inversely correlated
with AV time intervals (24). Hence, AV time intervals
were plotted against heart rate to investigate whether
the slight bradycardia found in the fetuses in our study
could explain the prolongation in AV time intervals. No
relationship was demonstrated, which confirmed that
the abnormally long AV time intervals found in the
fetuses of anti–Ro 52-kd–positive mothers were not an
effect of a decrease in heart rate.
Our data may be interpreted as supporting the
1260
idea that the development of complete congenital heart
block is a 2-stage process. In the first step, the maternal
autoantibodies are transferred through the placenta and
bind structures in the developing fetal heart, leading to
a first-degree AV block. Our data indicate that occurrence of first-degree block is much more common than
previously appreciated; they also show that this state is
spontaneously reversible with further maturation of the
fetus. In some cases, however, a second phase is entered
and progression to complete heart block commences.
Factors involved in this second phase may be mainly
fetal and related to the immunogenetic profile of the
individual. A predisposition to an intense inflammatory
reaction to the antibody deposition might lead to the
subsequent mononuclear cell infiltration and fibrosis,
with a permanent injury as the outcome.
Our study demonstrates the usability of fetal
Doppler echocardiography in the surveillance of fetuses
at risk for CHB. By measuring AV time intervals,
indirect signs of first-degree block can be documented,
and different levels of block can also be distinguished by
using these described techniques (Figures 4 and 5).
Reference values for both techniques used in the present
study have recently been reported (24). To minimize the
risk of unexpected methodologic changes with time, new
control pregnancies were tested against the original data
from that study, and, after analysis, the resulting data
were included in the reference data used in the present
study.
Although the two Doppler methods used in the
present study do not show any systematic differences
when compared directly, each has advantages and disadvantages. On the one hand, the advantage of the
MV-Ao approach is that these recordings are easier to
obtain. On the other hand, in fetuses with long time
intervals and/or higher heart rates, when the mitral E
and A waves are difficult to separate, measuring the AV
time interval may be very difficult. Recordings with the
SVC-Ao approach require greater technical skill, but
measurements are easier to perform. With this technique, AV time intervals are also less dependent on
heart rate (24).
In summary, our data demonstrate that anti–Ro
52-kd–positive pregnant women frequently carry fetuses
with Doppler echocardiographic signs of first-degree
AV block. In the majority of these fetuses, a spontaneous normalization occurred before or shortly after birth.
Still, the long-term prognosis for these infants remains
to be established. Two of 8 fetuses in whom signs of
first-degree block were documented also had higher
degrees of block. Fetuses with normal AV time intervals
SONESSON ET AL
at 18–24 weeks seemed to maintain normal AV conduction throughout pregnancy. Serial Doppler echocardiographic measurement of AV time intervals is suggested
as a most useful instrument for surveillance of pregnancies at risk for fetal CHB.
ACKNOWLEDGMENT
The authors want to thank Professor J. C. Fouron,
University of Montreal, Montreal, Quebec, Canada, for use of
the reference data.
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women, block, antibodies, fetuses, heart, signs, pregnant, third, one, first, degree, occurs, antissaro
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