Outcome of pregnancies in patients with anti-SSARo antibodiesA study of 165 pregnancies with special focus on electrocardiographic variations in the children and comparison with a control group.

ARTHRITIS & RHEUMATISM
Vol. 50, No. 10, October 2004, pp 3187–3194
DOI 10.1002/art.20554
© 2004, American College of Rheumatology
Outcome of Pregnancies in Patients With
Anti-SSA/Ro Antibodies
A Study of 165 Pregnancies, With Special Focus on Electrocardiographic
Variations in the Children and Comparison With a Control Group
Nathalie Costedoat-Chalumeau,1 Zahir Amoura,1 Jean-Marc Lupoglazoff,2 Du Le Thi Huong,1
Isabelle Denjoy,2 Danièle Vauthier,1 Djamel Sebbouh,1 Olivier Fain,3 Sophie Georgin-Lavialle,1
Pascale Ghillani,1 Lucile Musset,1 Bertrand Wechsler,1 Pierre Duhaut,4
and Jean-Charles Piette1
at the time of EKG, age of the mothers, or treatments
received by the mothers during their pregnancies. Seven
of 137 children developed cutaneous neonatal lupus
syndrome; 1 child developed CHB (CHB risk of 1 in 99
[1%] if only the first prospectively observed pregnancy
in women without a history of CHB is included in the
analysis). For EKGs recorded during the first 2 months
of life, the mean ⴞ SD PR interval was 96 ⴞ 16 msec in
the anti-SSA–positive group and 96 ⴞ 13 msec in the
anti-SSA–negative group (P ⴝ 0.84), with mean QTc
values of 397 ⴞ 27 and 395 ⴞ 25 msec (P ⴝ 0.57) and
mean heart rates of 141 ⴞ 23 and 137 ⴞ 21 beats per
minute (P ⴝ 0.20), respectively. No difference in the PR
interval, QTc interval, or heart rate was observed for
EKGs obtained between 2 and 4 months of life.
When EKGs obtained at 0–2 months were compared
with those obtained at 2–4 months, a physiologic prolongation of the QTc interval was observed in both study
groups. No sudden infant death or symptomatic arrhythmia occurred during the first year of life.
Conclusion. The EKG findings in children of
anti-SSA–positive and anti-SSA–negative mothers were
not significantly different. Our results suggest that the
prolongation of the QTc interval and sinus bradycardia
that have recently been reported in children of mothers
with anti-SSA antibodies occur independently of the
anti-SSA antibodies. The pathologic nature of these
EKG variations was not confirmed by our controlled
study.
Objective. Aside from congenital heart block
(CHB), sinus bradycardia and prolongation of the corrected QT (QTc) interval have been reported in infants
born to mothers with anti-SSA antibodies. To assess the
pathologic nature of these manifestations, this study
focused on electrocardiographic (EKG) variations in
these children, comparing them with findings in a
control group.
Methods. We studied 165 consecutive pregnancies
in 106 anti-SSA–positive women with connective tissue
diseases (CTDs). EKGs obtained on 58 children of this
group were compared with those obtained on 85 infants
born to mothers with CTD who were negative for both
anti-SSA and anti-SSB.
Results. No statistically significant difference was
seen between the 2 study groups with regard to gestational age, prematurity, birth weight, age of the children
Presented in part at the 67th Annual Scientific Meeting of the
American College of Rheumatology, Orlando, FL, October 2003.
1
Nathalie Costedoat-Chalumeau, MD, Zahir Amoura, MD,
Du Le Thi Huong, MD, Danièle Vauthier, MD, Djamel Sebbouh, MD,
Sophie Georgin-Lavialle, MD, Pascale Ghillani, MD, Lucile Musset,
MD, Bertrand Wechsler, MD, Jean-Charles Piette, MD: Centre
Hospitalier Universitaire Pitié-Salpêtrière, Paris, France; 2Jean-Marc
Lupoglazoff, MD, PhD, Isabelle Denjoy, MD: Centre Hospitalier
Universitaire Robert Debré, Paris, France; 3Olivier Fain, MD: Hôpital
Jean Verdier, Bondy, France; 4Pierre Duhaut, MD: Hôpital Nord,
Amiens, France.
Address correspondence and reprint requests to Nathalie
Costedoat-Chalumeau, MD, Service de Médecine Interne, Centre
Hospitalier Universitaire Pitié-Salpêtrière, 47-83 Boulevard de
l’Hôpital, 75651 Paris Cedex 13, France. E-mail: nathalie.
costedoat@psl.ap-hop-paris.fr.
Submitted for publication April 3, 2004; accepted in revised
form June 22, 2004.
Mothers known to have anti-SSA/Ro and/or antiSSB/La antibodies are at risk of delivering an infant with
3187
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COSTEDOAT-CHALUMEAU ET AL
neonatal lupus erythematosus syndrome, which is characterized by transient lupus dermatitis, hepatic and
hematologic abnormalities, or isolated congenital heart
block (CHB) (1,2). The skin rash, hepatitis, and thrombocytopenia generally resolve without sequelae. In contrast, the heart block is permanent, often requires insertion of a pacemaker (3,4), and may be complicated by
late-onset cardiomyopathy (5). When anti-SSA antibodies are present in the sera of mothers with connective
tissue diseases (CTDs), the incidence of CHB has been
reported to be 2% of live births (6), with a 95%
confidence interval of 0.2–7%. The risk of occurrence of
CHB in a subsequent child is estimated to be 10–16%
(4,7,8). More recently, other cardiac manifestations,
such as sinus bradycardia (6) and prolongation of the
corrected QT (QTc) interval (9,10), have been reported
in infants without CHB who are born to anti-SSA–
positive mothers.
The assumption that these new cardiac manifestations are pathologic should be questioned. In a study
of 4,205 healthy newborns, Schwartz et al (11) demonstrated a physiologic and transient prolongation of the
QTc interval at 2 months of life. Additionally, sinus
bradycardia is common in healthy infants during the first
days of life (12–15). Comparison of electrocardiographic
(EKG) findings with the findings in a carefully selected
control group is mandatory before any conclusions can
be drawn about EKG variations identified in infants,
inasmuch as pathologic prolongation of the QTc interval
may be life-threatening (16) and require treatment with
␤-blockers (9,16).
We have conducted a study in which the EKG
findings in 58 consecutive infants born to mothers with
CTDs associated with anti-SSA antibodies were compared with those in 85 consecutive control infants born
to mothers with CTDs but without anti-SSA and antiSSB antibodies. Both groups were comparable for gestational age, prematurity, birth weight, age of the children at EKG recording, age of the mothers, and
treatments received by the mothers during their pregnancies. These 58 children were issued from a large
series of 165 consecutive pregnancies. We additionally
report the outcome of these 165 pregnancies occurring
in 106 anti-SSA–positive women.
PATIENTS AND METHODS
Mothers. This study was performed at a single center,
the Pitié-Salpêtrière Hospital, between January 1991 and June
2002. All of the mothers were being monitored regularly at the
hospital before they became pregnant. During pregnancies, the
patients were closely monitored by an internist and an obstetric
team specializing in high-risk pregnancies. Patients were evaluated monthly until 32 weeks of gestation and then every 2
weeks thereafter. Instrument monitoring included repeated
fetal echocardiography and Doppler velocimetry.
One hundred six women with anti-SSA antibodies were
followed up during 165 consecutive pregnancies. All patients
were positive for anti-SSA antibodies, and 45 of them (42%)
were also positive for anti-SSB antibodies. Sixty-three of the
patients met the American College of Rheumatology (ACR)
criteria for systemic lupus erythematosus (SLE) (17), 29 met
the European Study Group criteria for primary Sjögren’s
syndrome (18), 1 had mixed connective tissue disease, and 13
had unclassified CTD. In addition, 12 of the patients with SLE
fulfilled the Sapporo criteria for definite antiphospholipid
syndrome (19). Thirteen pregnancies occurred in 7 women
who had previously given birth to a child with CHB.
Children. Each child was carefully examined during
the neonatal period by a pediatrician. During followup, data
were gathered from the mothers about the health of each child
at a mean age of 20 months (range 12–120 months). Mothers
were asked if the findings of their child’s medical examinations
were normal, especially the findings of complete medical
examinations that were systematically performed at 4 months,
9 months, and 24 months. These medical appointments are
mandatory in France.
Autoantibody determinations. The presence of antiSSA and/or anti-SSB antibodies was determined by counterimmunoelectrophoresis and/or by using INNO-LIAT ANA
Update (Innogenetics, provided by InGen, Rungis, France), a
semiquantitative line immunoassay for the detection of antibodies against 52-kd Ro, 60-kd Ro, and La.
EKG studies. Since 1999, standard 12-lead EKGs were
systematically obtained within the 2 first months of life in
children born to mothers with CTDs, whatever the mother’s
anti-SSA antibody status. EKGs recorded on the first and
second days of life were excluded from this study because
spontaneous variations in the QTc interval are maximal during
the first 2 days of life (16). Since publication of the report by
Cimaz et al (9), additional EKGs were performed after the
0–2-month period. These EKGs were performed when the
mothers attended our department for followup of their CTDs.
EKGs were always recorded when the child was awake.
Analysis of EKG tracings. To address the physiologic
(11) or pathologic (9,10) nature of the variations in EKG
findings, children were grouped according to age: 0–2 months,
2–4 months, and 4–12 months. A prospective subgroup was
also evaluated. The prospective subgroup consisted of children
in whom a total of 3 EKGs had been performed, 1 for each age
period as the study subjects (i.e., 0–2 months, 2–4 months, and
4–12 months).
Measurement of the PR interval, QT interval, and
heart rate on all EKGs were performed by a pediatric cardiologist who was blinded to the antibody status and diagnosis in
the mothers as well as the age of the children. Because of the
current limitations of electronic measurements in newborns,
the EKG intervals were hand measured, as recently recommended (20). QT intervals were measured and corrected for
heart rate (QTc) according to Bazett’s formula (i.e., dividing
the value of the QT interval by the square root of the preceding
R-R interval).
EKG CHANGES IN CHILDREN OF MOTHERS WITH ANTI-SSA/Ro
3189
Table 1. Main features of the mothers and children and the treatments given to the mothers, by anti-SSA antibody status of
the mothers*
Mothers
No. of subjects
Age, mean ⫾ SD years
Treatment during pregnancy, no (%) of pregnancies
Aspirin, 100 mg/day
Prednisone
Hydroxychloroquine
Low molecular weight heparin
Children
No. of subjects
Premature birth, no. (%)
Full-term birth, no. (%)
Gestational age, mean ⫾ SD weeks
Birth weight, mean ⫾ SD gm
Age at EKG, mean ⫾ SD days
Anti-SSA–positive
group
Anti-SSA–negative
group
P
53
31.2 ⫾ 5
73
31.4 ⫾ 4.1
0.75
48 (83)
44 (76)
39 (67)
16 (8)
75 (88)
56 (66)
56 (66)
24 (28)
0.35
0.20
0.87
0.93
58
9 (16)
49 (84)
38.3 ⫾ 1.8
3.002 ⫾ 536
13 ⫾ 14
85
23 (27)
62 (73)
38 ⫾ 1.4
3,013 ⫾ 471
15 ⫾ 16
0.10
0.10
0.06
0.86
0.31
* The number of mothers differs from the total numbers of pregnancies and children because some mothers had 2 children that
were included in the study. Anti-SSA–positive mothers had connective tissue diseases (CTDs) and anti-SSA antibodies.
Anti-SSA–negative mothers had CTDs but neither anti-SSA nor anti-SSB antibodies. EKG ⫽ electrocardiogram.
Anti-SSA–positive study group. The anti-SSA–positive
group consisted of 58 consecutive infants born to 53 mothers
with a CTD and anti-SSA antibodies (i.e., a subgroup of the
106 anti-SSA–positive mothers described above). Only the
children of mothers who had anti-SSA antibodies as determined by counterimmunoelectrophoresis were included. All of
the infants had an EKG performed between 0 and 2 months of
life, 19 had an additional EKG between 2 and 4 months, and 20
had an additional EKG between 4 and 12 months.
The diagnoses in this group of mothers were as follows:
SLE as defined by the ACR criteria (n ⫽ 28), primary
Sjögren’s syndrome as defined by the European Study Group
criteria (n ⫽ 16), unclassified CTD (n ⫽ 9). Three of the
patients with SLE fulfilled the Sapporo criteria for definite
antiphospholipid syndrome. Twenty-four mothers were also
positive for anti-SSB antibodies (45%). As soon as pregnancy
was diagnosed, the mothers were given aspirin (100 mg/day; 48
pregnancies), prednisone (44 pregnancies), hydroxychloroquine (39 pregnancies), and/or low molecular weight heparin
(16 pregnancies) (Table 1). The mean gestational age at birth
of their infants was 38.3 ⫾ 1.8 weeks.
The prospective subgroup of newborns in the anti-SSA–
positive group who had an EKG performed during each of the
same age periods as the other subjects consisted of 8 infants.
Anti-SSA–negative control group. The anti-SSA–
negative group consisted of 85 consecutive children born to 73
mothers with a CTD but without anti-SSA or anti-SSB antibodies.
All infants had an EKG performed between 0 and 2 months of
life, 24 had an additional EKG between 2 and 4 months, and 29
had an additional EKG between 4 and 12 months.
For this group, the diagnoses in the mothers were as
follows: SLE as defined by the ACR criteria (n ⫽ 53) and
miscellaneous/unclassified CTD (n ⫽ 12). Twenty of the SLE
patients fulfilled the Sapporo criteria for definite antiphospholipid syndrome. As soon as pregnancy was diagnosed, mothers
were given aspirin (100 mg/day; 75 pregnancies), prednisone (56
pregnancies), hydroxychloroquine (56 pregnancies), and/or low
molecular weight heparin (24 pregnancies) (Table 1). The mean
gestational age at birth of their infants was 38 ⫾ 1.4 weeks.
The prospective subgroup of newborns in the antiSSA–negative control group who had an EKG performed
during each of the same age periods as the other subjects
consisted of 12 infants.
Definitions. Gestational age was determined according
to the date of the mother’s last menstrual period as well the
ultrasonographic findings during the first trimester of pregnancy. Spontaneous abortion was defined as spontaneous
termination of a pregnancy prior to 20 weeks’ gestation.
Stillbirth was defined as spontaneous termination of a pregnancy after 20 weeks’ gestation. Premature birth was defined
as termination of the pregnancy by a live birth before 37 weeks’
gestation. Full-term birth was defined as termination of a
pregnancy by a live birth at or after 37 weeks’ gestation.
Statistical analysis. A study distribution was performed for all continuous variables, and Wilcoxon’s rank sum
test was used to compare data when the distribution was not
normal. Chi-square test or Fisher’s exact test, when required,
was computed for dichotomous variables. Data are presented
as the mean ⫾ SD. P values less than 0.05 were considered
significant.
RESULTS
Outcome of anti-SSA–positive pregnancies. One
hundred sixty-five pregnancies, including 2 twin pregnancies, occurred in 106 women with anti-SSA antibodies. One hundred thirty-seven living children were delivered. The outcomes of the individual pregnancies were
as follows: spontaneous abortion in 24, stillbirth in 3,
therapeutic abortion in 3, premature birth in 27 (including the 2 twin pregnancies), and full-term birth in 108.
The 135 live births occurred at a mean gestational age of
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COSTEDOAT-CHALUMEAU ET AL
Table 2. EKG findings in the children, by age group and by the anti-SSA antibody status of the mothers*
Ages 0–2 months‡
Feature†
Age, mean ⫾ SD days
PR interval, msec
Mean ⫾ SD
Range
QTc interval, msec
Mean ⫾ SD
Range
Heart rate, beats per
minute
Mean ⫾ SD
Range
Ages 2–4 months
Ages 4–12 months
SSA⫹
(n ⫽ 58)
SSA⫺
(n ⫽ 85)
P
SSA⫹
(n ⫽ 19)
SSA⫺
(n ⫽ 24)
P
SSA⫹
(n ⫽ 20)
SSA⫺
(n ⫽ 29)
P
13 ⫾ 14
15 ⫾ 16
0.31
92 ⫾ 18
82 ⫾ 24
0.15
219 ⫾ 86
264 ⫾ 88
0.08
96 ⫾ 16
70–140
96 ⫾ 13
80–140
0.84
95 ⫾ 15
80–120
97 ⫾ 14
80–120
0.56
100 ⫾ 16
80–140
94 ⫾ 12
80–120
0.20
397 ⫾ 27
325–467
395 ⫾ 25
346–462
0.57
411 ⫾ 32
354–457
418 ⫾ 24
375–485
0.78
371 ⫾ 33
295–417
397 ⫾ 27
366–477
0.02
141 ⫾ 23
90–188
137 ⫾ 21
100–200
0.20
146 ⫾ 18
120–200
146 ⫾ 19
109–187
0.55
135 ⫾ 13
109–176
138 ⫾ 16
111–188
0.49
* Anti-SSA–positive mothers had connective tissue diseases (CTDs) and anti-SSA antibodies. Anti-SSA–negative mothers had CTDs but neither
anti-SSA nor anti-SSB antibodies. QT intervals were measured on electrocardiographic (EKG) tracings and were corrected for heart rate (QTc)
according to Bazett’s formula (see Patients and Methods for details).
† Normal EKG values in healthy infants are as follows (20,27): mean heart rate, 129 beats per minute (range 90–166) at ages 3–7 days, 149 (range
107–182) at ages 7–30 days, and 129 (range 90–166) at ages 1–3 months; mean PR interval, 107 msec (range 80–160) at ages 0–1 day, 100 (range
80–140) at ages 3–7 days, 100 (range 70–140) at ages 7–30 days, and 100 (range 70–130) at ages 1–3 months; and mean ⫾ SD QTc interval, 400 ⫾
20 msec (97.5 percentile of 440) at age 4 days. By the second month, there is a physiologic prolongation of the QTc interval (mean 410 msec), which
is followed by a progressive decline (11,20), such that by the sixth month, the QTc interval returns to the values recorded during the first week.
‡ EKGs recorded during the first and second days of life were excluded from the analyses.
37.9 ⫾ 2.2 weeks (range 30–41 weeks). The mean weight
of the 137 newborns was 2,930 ⫾ 595 gm (range
1,300–4,250). One premature twin died of pulmonary
hypoplasia at 15 days of life. We observed neither
sudden infant death nor symptomatic arrhythmia (other
than CHB) during the first year of life in the 136
remaining children.
Fetal malformations. Five fetuses were diagnosed
as having severe malformations. A therapeutic abortion
was performed in 3 cases (indications were Down syndrome in 1, univentricular malformation in 1, and pulmonary hypoplasia associated with cardiac dilation and severe
intrauterine growth restriction in 1). One child was born
with Down syndrome. Another child was born with a
transposition of the great arteries, with ventricular septal
defect and pulmonary stenosis. This child underwent successful surgical correction at 10 days of life. No concomitant CHB was observed in these 5 fetuses, and the mothers
had no history of CHB in previous pregnancies.
One child born to a mother who had previously
delivered a child with CHB had a ventricular septal
defect that was discovered in utero. No surgical correction was required.
Neonatal lupus erythematosus syndrome. Seven
children (4 girls and 3 boys) born to 6 mothers had
neonatal lupus erythematosus syndrome, which was
characterized by transient lupus dermatitis. Treatment
of the mothers during their pregnancies had included
prednisone in 4, aspirin in 5, and hydroxychloroquine in
2. In addition to anti-SSA antibodies, 3 of the 6 mothers
also had anti-SSB antibodies.
One case of third-degree CHB was observed at
22 weeks of gestation during the first pregnancy in an
untreated patient who was receiving followup care for
primary Sjögren’s syndrome. Betamethasone was
started, but there was no regression of the CHB and this
treatment was subsequently tapered and stopped. A boy
weighing 3,160 gm was delivered at 39 weeks of gestation. His EKG at birth confirmed the presence of complete
CHB; the QTc interval was normal (354 msec). This EKG
was excluded from the EKG study. A pacemaker was
inserted during the child’s first week of life, and he is doing
well at age 1 year. No other CHB or other manifestation of
neonatal lupus erythematosus syndrome occurred in this
series, giving a risk of CHB of 1 in 99 (1%) if only the first
prospectively observed pregnancy in women without a
history of CHB are considered.
Comparison of EKG findings in the anti-SSA–
positive study group and the anti-SSA–negative control
group. EKGs were available within the 2 first months of
life in 58 anti-SSA–positive and 85 anti-SSA–negative
children. As detailed in Table 1, no statistically significant differences were seen between the 2 groups with
regard to the age of the mothers or treatments received
by the mothers during their pregnancies, the gestational
age, prematurity, and birth weight in the children, and
the age of the children at the EKG recording.
EKG CHANGES IN CHILDREN OF MOTHERS WITH ANTI-SSA/Ro
3191
Figure 1. Variation in the corrected QT (QTc) interval, by age of the children and by anti-SSA antibody
status in the mothers. The evolution of the QTc interval values during the first year of life is shown for A,
both antibody status groups, B, the anti-SSA–positive group, and C, the anti-SSA–negative group. Values
are the mean and SD. P values were calculated as described in Patients and Methods.
The results of the EKG analyses are detailed in
Table 2 for each of the neonatal age groups, by anti-SSA
antibody status.
EKG findings at ages 0–2 months. The mean ⫾ SD
PR interval was 96 ⫾ 16 msec (range 70–140) in the 58
infants of the anti-SSA–positive group and 96 ⫾ 13 msec
(range 80–140) in the 85 infants of the anti-SSA–
negative group (P ⫽ 0.84). The QTc interval in these 2
groups was 397 ⫾ 27 msec (range 325–467) and 395 ⫾ 25
msec (range 346–462), respectively (P ⫽ 0.57) (Figure
1A). The heart rate was 141 ⫾ 23 beats per minute
(range 90–188) and 137 ⫾ 21 beats per minute (range
100–200) in the respective groups (P ⫽ 0.20). All PR and
heart rate values where within the range of normal
except for a borderline heart rate (90 beats per minute)
in a child in the anti-SSA–positive group. Three of the 58
children in the anti-SSA–positive group and 5 of the 85
in the anti-SSA–negative group had a QTc interval that
was ⬎440 msec (the 97.5 percentile on the fourth day of
life) (P ⫽ 0.85), with QTc values of 443, 453, and 467
msec, respectively, in the anti-SSA–positive group and
443, 443, 443, 443, and 462 msec, respectively, in the
anti-SSA–negative group.
Results were not significantly modified when
EKGs recorded at 1 and 2 days of life were included in
the study (data not shown). In the anti-SSA–positive
group, no variations in the PR interval, QTc interval, or
heart rate were observed based on the presence (n ⫽ 27)
or absence (n ⫽ 31) of anti-SSB antibodies (data not
shown). EKGs were available for 6 siblings of children
with CHB. The PR interval, QTc interval, and heart rate
in the 6 siblings were not different from those in the
children of the whole anti-SSA–positive group (data not
shown).
EKG findings at ages 2–4 months. EKGs were
obtained between 2 and 4 months of life in 19 anti-SSA–
positive and 24 anti-SSA–negative infants. No difference
in the mean ⫾ SD values for the PR interval, the QTc
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COSTEDOAT-CHALUMEAU ET AL
Figure 2. Variations in the corrected QT (QTc) interval in the prospective subgroups, by age of the
children and by anti-SSA antibody status in the mothers. The evolution of the QTc interval values during
the first year of life are shown separately for the anti-SSA–positive group (n ⫽ 8) and the anti-SSA–
negative group (n ⫽ 12).
interval, and the heart rate were observed between the 2
groups (Table 2 and Figure 1A).
EKG findings at ages 4–12 months. For EKGs
recorded between 4 and 12 months of life, no difference
in the PR interval or the heart rate was observed
between the 2 study groups (Table 2 and Figure 1A).
The mean QTc interval was slightly shorter in the
anti-SSA–positive group (371 ⫾ 33 msec) than in the
anti-SSA–negative group (397 ⫾ 27) (P ⫽ 0.02).
EKG findings in the prospective subgroups. When
the EKG analysis was restricted to the 8 anti-SSA–
positive and the 12 anti-SSA–negative children who had
3 successive EKGs, no significant between-group differences were observed in the PR interval, the QTc interval, or the heart rate in any of the 3 periods studied (i.e.,
0–2, 2–4, or 4–12 months) (Figure 2).
Analysis of variations in the QTc interval by age
group. In the anti-SSA–positive group, the mean QTc
interval was 397 ⫾ 27 msec (range 325–467) between 0
and 2 months of life and reached 411 ⫾ 32 msec (range
354–457) between 2 and 4 months (P ⫽ 0.05) (Figure
1B). A similar prolongation was observed in anti-SSA–
negative infants, with a QTc interval of 395 ⫾ 25 msec
(range 346–462) and 418 ⫾ 24 msec (range 375–485) at
0–2 months and 2–4 months, respectively (P ⫽ 0.003)
(Figure 1C). We observed neither sudden infant death
nor symptomatic arrhythmia during the first year of life
in both groups.
DISCUSSION
We report a single-center study of 165 consecutive pregnancies in 106 women with anti-SSA antibodies.
Seven of the 137 children (5.1%) developed transient
and benign cutaneous neonatal lupus erythematosus
syndrome. One child had CHB (1%). These findings are
consistent with the 2% prevalence of CHB found in a
recent prospective study (6).
Because EKG variations in infants without CHB
born to anti-SSA–positive mothers have been described
(6,9), our study focused on variations in the QTc interval, the PR interval, and the heart rate. However, since
the pathologic nature of these EKG variations is questionable (11,21), we compared the anti-SSA–positive
group with a carefully defined control group of infants
born to mothers with CTDs but without anti-SSA and
anti-SSB antibodies. The 2 groups were similar with
regard to the age of the mothers and the treatments
received by the mothers during their pregnancies, the
gestational age, prematurity, and birth weight of the
children, and the age of the children at the time of the
EKG recordings. We studied 58 EKGs recorded within
the first 2 months of life in infants of mothers with
anti-SSA antibodies and 85 EKGs in control infants of
mothers without anti-SSA antibodies. A pediatric cardiologist who was blinded to the SSA and SSB antibody
status read the EKGs. No differences in the QTc
interval, the PR interval, or the heart rate were found
EKG CHANGES IN CHILDREN OF MOTHERS WITH ANTI-SSA/Ro
between these 2 groups. No differences where found
when we compared these 3 values at 2–4 months of life
or at 4–12 months of life, except for a slight shortening
of the QTc interval at 4–12 months in the anti-SSA–
positive group compared with the anti-SSA–negative
group. This result contrasts with previous reports (9,10).
The observed difference might have occurred by chance
in the 12 statistical tests performed and seems devoid of
clinical relevance.
Within the 2 first months of life, 3 of the 58
anti-SSA–positive children and 5 of the 85 anti-SSA–
negative children had a QTc interval ⬎440 msec (the
97.5 percentile at the fourth day of life) (P ⫽ 0.85). The
higher QTc in the anti-SSA–positive group was 467
msec, compared with 462 msec in the anti-SSA–negative
group.
Discrepancies between our QTc findings and
those of previous studies may be explained by the
physiologic prolongation of the QTc interval in healthy
infants at the age of 2 months, which has previously been
reported (11). When we compared EKGs obtained
during the 2–4-month age period with those obtained
during the 0–2 month age period, we found a significant
prolongation of the mean QTc intervals. Interestingly,
this prolongation was present in both the anti-SSA–
positive and the anti-SSA–negative groups, indicating
that it was independent of the anti-SSA antibody status.
Our findings are consistent with those of Schwartz et al
(11), whose prospective study of 4,205 healthy newborns
identified a significant increase in the mean QTc interval
between day 4 of life (397 ⫾ 18 msec) and the second
month of life (409 ⫾ 15 msec) (P ⬍ 0.0001). Unfortunately, the ages of the infants at the time of the EKG
recordings were different in both groups in the 2 previous studies. In the study by Cimaz et al (9), the median
age was 90 days in the anti-SSA–positive group (when
the QTc interval is physiologically prolonged [11]) and 7
days in anti-SSA–negative group. In the study by Gordon et al (10), the mean ages were 65.4 months and 1.8
months in the respective groups. Apart from a lack of
close matching of the control groups with the study
groups, the small sample size of the previous studies may
also account for the discrepancies with our results (9,10):
the control group in each of the 2 other studies consisted
of 7 children, whereas our study included 81 children in
the control group.
We also found that after an initial prolongation,
the QTc interval shortened after 4 months of life in both
groups, as has been noted by Schwartz et al (11). These
physiologic variations may also explain why in the studies by Cimaz et al, the observed prolongation of the QTc
3193
interval in the 21 EKGs of anti-SSA–positive children at
a median of 90 days of life (9) was no longer present at
1 year of life (22). Because we considered these variations to be physiologic, we did not treat any of these
children. No sudden infant death, symptomatic arrhythmia, or other notable symptoms occurred during the first
year of life of the 136 infants we followed up.
Sinus bradycardia has recently been reported as
another EKG abnormality in infants without CHB born
to anti-SSA–positive mothers. Brucato et al (6) reported
that among 24 otherwise healthy children whose EKGs
were obtained within the first 3 days of life, 4 had sinus
bradycardia, with a mean heart rate of 84 beats per
minute (range 70–90). Spontaneous resolution was observed within 15 days. The existence of sinus bradycardia
has been reported in 2 infants with anti-SSA antibodies
(23) and is supported by findings in an experimental
animal model (24) and a recent in vitro study (25).
However, the pathologic nature of sinus bradycardia in
newborns should be considered cautiously. Several reports have previously demonstrated that the cardiac rate
of normal newborns may present major physiologic
variations. These variations have highlighted the inappropriateness of applying standard definitions of sinus
bradycardia to newborns (12–15). For example, an analysis of cardiac rates on EKGs performed during a
24-hour period in 134 healthy newborns demonstrated
that 109 had sinus bradycardia at their lowest heart rate,
with a mean minimum rate of 85 beats per minute (12).
Based on the recent European guidelines for the interpretation of neonatal EKGs (20), sinus bradycardia was
not observed among the 58 children in our series,
although 1 child had a borderline heart rate of 90 beats
per minute at 4 days of life. Comparison with the 85
control EKGs did not reveal any significant difference in
the mean heart rate between the anti-SSA–positive and
the anti-SSA–negative groups.
Miscellaneous cardiac structural lesions have
been previously reported in 16–42% of children with
CHB born to anti-SSA–positive mothers (4,7). The
occurrence of these lesions has never been studied in the
absence of CHB. In our series, 2 therapeutic abortions
were performed because of major cardiac abnormalities,
which in 1 case, was associated with pulmonary hypoplasia. In addition, 1 child required neonatal surgery for
transposition of the great arteries, and 1 sibling of a child
with CHB had a ventricular septal defect. Taken together, the rate of anatomic abnormalities of the heart
was 4 (2.8%) of 141 “appraisable pregnancies” (i.e.,
gestational age ⬎20 weeks). This frequency of cardiac
malformations is significantly higher than that in the
3194
COSTEDOAT-CHALUMEAU ET AL
general population (0.54% of all births, including fetal
deaths and induced abortions, in the European Concerted Action on Congenital Anomalies and Twins
[EUROCAT] registry [26]; P ⫽ 0.008 by Fisher exact
test). This point deserves further prospective study that
includes data from therapeutic abortions.
In conclusion, we observed only 1 case of CHB in
a series of 165 consecutive pregnancies in women with
anti-SSA antibodies. The EKG findings in infants of the
anti-SSA–positive group were not significantly different
from those in infants of the anti-SSA–negative group.
We did not confirm either a prolongation of the QTc
interval or sinus bradycardia in infants without CHB
who were born to anti-SSA–positive mothers. Although
there are several methodologic limitations to our study,
its reassuring conclusions, based on a large group of
patients and controls, are of interest for patients of
childbearing age who have anti-SSA antibodies, as well
as for their physicians.
ACKNOWLEDGMENTS
The authors thank Dr. Janine Goujard for assistance in
providing the data from the EUROCAT registry and Dr.
Gilles Lefebvre for medical assistance.
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