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  2. Abstract


To assess the true prevalence of congenital complete heart block (CCHB) in infants of anti-Ro/SSA–positive women known to have connective tissue disease (CTD) and, secondarily, to evaluate the prevalence of other electrocardiographic abnormalities in these newborns at birth.


A prospective study was conducted in 4 referral hospitals. One hundred anti-Ro/SSA–positive mothers were followed up before they became pregnant and during the index pregnancy. Counterimmunoelectrophoresis and immunoblotting were used to test for antibodies to extractable nuclear antigens.


Of the 100 women with anti-Ro/SSA antibodies, 2 had infants who developed CCHB in utero (2%). The CCHB was detected at 22 weeks and 20 weeks, respectively. One of the 2 mothers had primary Sjögren's syndrome (SS), and the other had undifferentiated CTD (UCTD). No case of CCHB occurred among the infants of 53 mothers with systemic lupus erythematosus (SLE). No fetal death occurred due to CCHB. In 2 centers, electrocardiography was recorded in 24 unselected newborns, and 4 were found to have sinus bradycardia.


The prevalence of CCHB in newborns of prospectively followed up women already known to be anti-Ro/SSA positive and with known CTD was 2%. This finding is useful with regard to preconception counseling of these women. The risk of delivering an infant with CCHB may be higher in mothers with primary SS or UCTD than in those with SLE. Additional electrocardiographic abnormalities such as sinus bradycardia and prolongation of the QT interval may be present in their children.

The so-called neonatal lupus syndromes, whose most important manifestation is congenital complete heart block (CCHB), are closely linked to the presence of anti-Ro/SSA antibodies (1, 2). Mothers known to have autoimmune disease are therefore at risk of delivering an affected infant, and for preconception counseling, it would be useful to have precise data about the risk of delivering a child with CCHB. However, existing data are imprecise, since they mainly come from one retrospective study (3), that indicated a risk of 5%, or from one prospective study including only systemic lupus erythematosus (SLE) patients (4), that showed a risk of 0%. Anti–52-kd Ro/SSA and anti-La/SSB antibodies have been reported to be more strongly associated with CCHB than was anti–60-kd Ro/SSA alone (5–7). Furthermore, recent experimental data suggest that anti-Ro/SSA antibodies may have a wider range of electrophysiologic effects in the fetal heart than was previously recognized, interfering with the calcium channels and possibly affecting not only the atrioventricular node, but also the sinus node (8, 9). We therefore conducted a prospective study in 4 hospitals, to evaluate the occurrence of CCHB in the offspring of consecutively selected anti-Ro/SSA–positive women with known connective tissue disease (CTD). The secondary aim was to assess other electrocardiographic abnormalities. To achieve maximal specificity, we included only women who were found to be anti-Ro/SSA positive by counterimmunoelectrophoresis (CIE).


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This prospective study was performed in 4 referral hospitals in Italy: Spedali Civili starting in 1985 (47 women), University of Padua starting in 1990 (26 women), Niguarda Hospital starting in 1995 (17 women), and Milan University starting in 1995 (10 women). All 4 hospitals are tertiary referral centers with CTD/pregnancy clinics. All of the mothers were being monitored regularly at the hospital before becoming pregnant. The only selection criterion was the presence of anti-Ro/SSA antibodies in the mother's serum before she became pregnant. The 100 women were studied during their 118 pregnancies (18 repeat pregnancies), 108 of which ended with the delivery of 112 living newborns (4 twin pregnancies). Fifty-three of the mothers had SLE, 19 had undifferentiated CTD (UCTD), 25 had primary Sjögren's syndrome (SS), 1 had systemic sclerosis, 1 had mixed CTD, and 1 had primary antiphospholipid syndrome (APS); the mean age at the first delivery was 31.2 years (range 25–40 years). Diagnoses were in accordance with the American College of Rheumatology criteria for SLE (10) and the European criteria for SS (11).

Every woman with a CTD seen in any of the 4 referral hospitals was tested for anti-Ro/SSA antibodies before becoming pregnant, and positivity for these antibodies was confirmed during the index pregnancy; in all cases this positivity remained very stable over the years. All women who were confirmed to be anti-Ro/SSA positive by CIE were included in this study. During the same period, 219 women with a CTD who were anti-Ro/SSA negative were followed up during their pregnancies in the 4 referral hospitals; 104 of these women had SLE, 76 had primary APS, and 39 had other diagnoses (UCTD, rheumatoid arthritis, etc.). CCHB did not occur in the offspring of any of these women.

All of the women were closely followed up by a high-risk pregnancy obstetric team, monthly until the eighteenth week, and then every 2–4 weeks. Instrumental monitoring included fetal echocardiography and Doppler velocimetry. The diagnosis of CCHB was obtained during fetal life (echocardiographic demonstration of atrioventricular dissociation). The study protocol included 1 last assessment 4 weeks after delivery. None of the women in the study was lost to followup.

Identification of antibodies

Antibodies to Ro/SSA were determined by CIE and immunoblotting, using as substrate a human spleen extract prepared according to the method of Clark et al (12). Antibodies to other cellular antigens were detected by CIE using a rabbit thymus extract (Pel-Freez, Rogers, AR) as described (13). The fine specificity of the 52-kd and 60-kd anti-Ro/SSA response was determined by immunoblotting. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis was performed in order to distinguish the anti-La response (48 kd) from anti–52 kd reactivity, using a commercial slab gel apparatus (10.5% slab gel with an acrylamide/bisacrylamide ratio of 19:1) (Mini protein Dual Slab gel; Bio-Rad, Richmond, CA).


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One hundred eighteen consecutive pregnancies in 100 women were studied. Seven pregnancies ended within 10 weeks and 3 ended after 10 weeks; cardiac activity of the fetus was not recorded in these cases. One hundred twelve babies were born from the remaining 108 pregnancies (4 twin births). Two babies had CCHB (1 male and 1 female), giving a risk of 2 per 100 first observed pregnancies (2%), or 2 per 112 living births (1.8%), or 2 per 118 total pregnancies (1.7%). No case of CCHB was observed among the 18 repeat pregnancies. The CCHB was detected at 22 weeks and 20 weeks, respectively; before detection of the block, 1 mother, with primary SS, was taking fluocortolon 10 mg (equivalent to prednisone 12.5 mg) daily because of previous thrombocytopenia, and the other, with UCTD, was receiving no treatment. These 2 mothers were prescribed dexamethasone (4 mg/day) after detection of the block. In both cases there was evidence of intrauterine growth retardation but no signs of hydrops or heart failure, and a cesarean delivery was performed in both cases at 38 weeks. The female baby had a pacemaker inserted at the age of 8 months and is doing well. The male baby had a pacemaker inserted at age 3 years and is also doing well.

In 2 centers (Niguarda Hospital and Milan University), an electrocardiogram was routinely obtained in all of the newborns; 24 electrocardiograms obtained within 3 days of birth were available for analysis. Four cases of sinus bradycardia were recorded (heart rate below the third centile for age). Details are reported in Table 1. Three of these cases have been described recently (14). In all 4 cases, the most frequent possible causes of bradycardia in newborns (electrolyte abnormalities and drug interference) were excluded. The bradycardia spontaneously resolved within 2 weeks in all cases, with no sequelae. A prolongation of the QT interval was observed in 9 cases, as recently described by our group (15), and this was generally in electrocardiograms recorded some weeks after birth.

Table 1. Details of the 4 cases of sinus bradycardia
 Case 1Case 2Case 3Case 4
Sex of the newbornMaleFemaleFemaleMale
Weeks of gestation40394138
Modality of deliverySpontaneousSpontaneousSpontaneousCesarean
Weight at birth, gm3,3902,6703,2002,340
Apgar score at 1 minute/5 minutes9/99/109/109/10
Lower heart rate, beats/minute85907090
Days after birth when bradycardia detected1222

As noted above, the presence of anti-Ro/SSA antibodies had been confirmed by CIE in all mothers. Anti-La/SSB were present in 28 cases. Four mothers showed immunoblot reactivity to the 52-kd component of Ro/SSA alone, 30 to both the 52-kd and 60-kd components, 52 to the 60-kd component only, and 7 did not have reactivity on immunoblot. Fifty-five mothers had anti–52-kd Ro/SSA and/or anti-La/SSB. One of the 2 mothers of infants with CCHB was positive for 52-kd and 60-kd anti-Ro/SSA and negative for anti-La/SSB, while the other was positive for 60-kd anti-Ro/SSA and anti–La/SSB. The prevalence of CCHB was therefore 2 of 55 (3.6%) in the infants of mothers who were positive for anti–52-kd Ro/SSA and/or anti-La/SSB and 0 of 45 in the infants of mothers who were negative for both anti–52-kd Ro/SSA and anti-La/SSB. It is noteworthy that no mother with SLE had a baby with CCHB; this might be because the prevalence of anti–52-kd Ro/SSA in these mothers is typically low. One mother who had delivered 2 healthy babies, in 1996 and 1998, herself abruptly developed a complete “idiopathic” atrioventricular heart block in 1999, at the age of 29, requiring implantation of a pacemaker. This woman was positive for anti–60-kd Ro/SSA and negative for anti-La/SSB.


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This is the first reported prospective study of the prevalence of CCHB in the offspring in a large cohort of unselected anti-Ro/SSA–positive women. The rate we identified, 2 per 100 women, is particularly useful in terms of preconception counseling of these women, who are often unjustifiably alarmed by too-high estimates of this risk (3). One prospective study (4) assessed this prevalence in a cohort of women with SLE, but only 38 infants were delivered to mothers who were anti-Ro/SSA positive; none of these infants had CCHB. These low numbers precluded any precise estimate of the risk; furthermore, in SLE, which was the only CTD investigated in that study, anti–60-kd is the prevalent anti-Ro/SSA specificity. A previous higher estimate of the risk of having a child with CCHB (5%) among anti-Ro/SSA–positive mothers with SLE was biased by the retrospective nature of the study (3): it is now recognized that the majority of women bearing children with neonatal lupus do not have recognized SLE and are often asymptomatic or oligosymptomatic at the time of delivery. These women would not have been identified as having SLE had the fetal abnormality not occurred (retrospective diagnosis). On the other hand, the most severe cases of CCHB, leading to early death in utero, might have been missed in a retrospective study.

We only studied mothers who had been found to be anti-Ro/SSA positive by CIE, a method with high specificity and rather low sensitivity, to exclude women with low or borderline titers of anti-Ro/SSA. Our results therefore apply only to mothers who are anti-Ro/SSA positive by CIE and cannot be extrapolated to, for instance, those with a low-positive anti-Ro/SSA reaction by enzyme-linked immunosorbent assay, for whom the risk, if any, should be even lower.

Studies of large series of CCHB patients have shown that anti–52-kd Ro/SSA and anti-La/SSB might be more strongly associated with CCHB than other specificities (5–7). We observed only 2 cases of CCHB, and this low figure does not allow us to draw any firm conclusion regarding antibody specificity and the subsequent occurrence of CCHB.

In this prospective study, CCHB, the main manifestation of the entity misleadingly named “neonatal lupus” (5, 13), was observed only in the offspring of women with primary SS or UCTD, and not in the offspring of any of the 53 women with SLE. This finding, which might be related to the low prevalence of anti–52-kd Ro/SSA in SLE, further illustrates that this maternal/fetal syndrome appears to be more closely related to primary SS and UCTD than to classic SLE (7).

Experimental data from studies of human fetal hearts and of mice suggest a wider range of electrophysiologic effects of anti-Ro/SSA antibodies. Mazel et al observed sinus bradycardia in the offspring of mice exposed to anti-Ro/SSA antibodies, consistent with the effects of anti-Ro/SSA antibodies on calcium channels involved in the electrogenesis of the atrioventricular node and of the sinus node (8). Our study extends these findings also to human newborns, where we observed a high percentage of sinus bradycardia, as recently described (14). We also have recently reported on the QT prolongation seen in these babies (15); notably, in that study no case of sinus bradycardia was observed among 7 control anti-Ro/SSA–negative newborns. In the present study, there was also 1 mother who developed an “idiopathic” complete heart block almost 2 years after the delivery of a healthy baby; the baby's electrocardiogram result was completely normal. There may therefore be a wider pattern of electrophysiologic abnormalities in these newborns and their mothers, consistent with recent experimental data regarding the electrophysiologic effects of anti-Ro/SSA antibodies (8, 9).

In conclusion, we found a 2% prevalence of CCHB in the offspring of unselected anti-Ro/SSA–positive mothers prospectively followed up since the beginning of the index pregnancy. This risk may be higher among women with primary SS and UCTD than women with SLE. Our findings could be useful in terms of preconception counseling of women with CTD and anti-Ro/SSA antibodies.


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