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Rheumatology Advance Access originally published online on April 20, 2007
Rheumatology 2007 46(8):1285-1289; doi:10.1093/rheumatology/kem073
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases—a multicentre prospective study

M. Gerosa1, R. Cimaz2, M. Stramba-Badiale3, K. Goulene3, E. Meregalli2, L. Trespidi4, B. Acaia4, R. Cattaneo5, A. Tincani5, M. Motta6, A. Doria7, F. Zulian8, O. Milanesi8, A. Brucato9, P. Riboldi1,10 and P. L. Meroni1,10

1Allergy, Clinical immunology and Rheumatology Unit IRCCS Istituto Auxologico Italiano,2Department of Paediatrics, Fondazione Policlinico Mangiagalli,3Cardiology Unit IRCCS Istituto Auxologico Italiano and4Department of Obstetrics and Gynaecology, Fondazione Policlinico Mangiagalli, Milan,5Rheumatology Unit and6Division of Paediatrics, Spedali Civili and University of Brescia, Brescia,7Division of Rheumatology and8Department of Pediatrics, University of Padua, Padua and9Division of Internal Medicine, Niguarda Hospital10Department of Internal Medicine, University of Milan, Milan, Italy.

Correspondence to: Pier Luigi Meroni, Allergy, Clinical Immunology & Rheumatology Unit, IRCCS Istituto Auxologico Italiano, Via Spagnoletto, 3, 20149 Milan, Italy. E-mail: pierluigi.meroni{at}unimi.it


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. To assess the prevalence of congenital heart block (CHB) and electrocardiographic (ECG) abnormalities in infants of anti-Ro/SSA-positive women.

Methods. Sixty anti-Ro-positive and 36 anti-Ro-negative patients were prospectively followed before/during pregnancy and underwent weekly fetal echocardiography from 18th to 26th weeks of gestational age. Infants’ ECG and/or ECG-Holter were performed at 1, 3, 6 and 12 months. ECG of 200 consecutive neonates were used as a healthy control group.

Results. One of 61 fetuses of anti-Ro-positive mothers developed CHB (20th week); another anti-Ro-positive baby developed second degree atrioventricular (AV) block (30th week). The prevalence of transient first degree AV block detected post-natally was significantly higher in the anti-Ro-positive group, in comparison with healthy controls (P = 0.002). No differences in corrected QT (QTc) interval prolongation prevalence (≥440 ms) was observed between the anti-Ro-positive and -negative groups, but both were significantly higher than that of the control population (P < 0.001). ECG-Holter showed QTc prolongation in 59% of infants of anti-Ro-positive and in 60% of infants of anti-Ro-negative mothers. Holter QTc was ≥470 ms in four infants of anti-Ro-positive group and two of anti-Ro-negative group. Known acquired causes of QTc prolongation were excluded.

Conclusions. This prospective study confirms the low occurrence of CHB in newborns from anti-Ro-positive mothers. ECG abnormalities (first degree AV block and QTc interval prolongation) are frequent in infants of mothers with autoimmune diseases, independently of maternal disease, autoantibody profile and treatment during pregnancy.

KEY WORDS: Anti-SSA/Ro antibodies, ECG abnormalities, Neonatal lupus, QT prolongation, Systemic autoimmune diseases


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Congenital heart block (CHB) is the most important and life-threatening clinical manifestation of neonatal lupus syndrome (NLS), a rare congenital disease due to the transplacental passage of maternal autoantibodies into the fetal bloodstream during gestation [1].

In the last decade, several studies have provided experimental evidence that autoantibodies against the extractable nuclear antigens SSA/Ro and SSB/La play a pivotal role in the pathogenesis of CHB. In vivo studies have demonstrated that passive immunization of animals with anti-Ro/La antibodies could induce CHB [2]. Although the exact mechanism of antibody-mediated damage remains unclear, in vivo and in vitro data suggest that a cascade of immune-mediated inflammatory events, ending in fetal myocardial fibrosis, is involved in the pathogenesis of CHB [2–7]. More recently, other conduction abnormalities, such as sinus bradycardia and first and second degree atrioventricular (AV) block have been described in infants born from anti-SSA/Ro (and anti-SSB/La)-positive mothers [8–10] and we have reported a high prevalence of corrected QT (QTc) interval prolongation in infants born from anti-SSA/Ro-positive mothers [11]. This alteration was transient and disappeared in concomitance with autoantibody clearance, suggesting a potential link between anti-SSA/Ro antibodies and QTc prolongation [12]. This finding may be relevant, since QTc interval prolongation is associated with a higher risk for sudden death in the newborns [13]. In addition, conduction abnormalities such as QTc interval prolongation have been found in adult patients with systemic lupus erythematosus (SLE) and in patients with autoimmune diseases and anti-SSA/Ro antibodies [14, 15]. These clinical findings are in agreement with the experimental data showing that total IgG and/or anti-52-kD SSA/Ro affinity-purified antibodies from mothers of children with CHB might induce sinus bradycardia and arrhythmogenic effects other than complete AV block in experimental animal models [4–6]. Nevertheless, contrasting data are reported in the literature and the real incidence and pathogenesis of these rhythm disorders are still debated. A recent study by Costedoat-Chalumeau et al. [16] did not find significant differences in the electrocardiographic (ECG) findings between anti-SSA/Ro-positive and -negative children. However, the study was mainly retrospective. Thus, larger and prospective studies are needed to assess the real prevalence of these ECG abnormalities in the population of infants born from mothers with autoimmune diseases.

The aim of the present study was to assess the prevalence of ECG abnormalities in a larger population of infants born from mothers positive or negative for anti-SSA/Ro antibodies, enrolled in a controlled, multicentre, prospective study.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Acknowledgements
 References
 
Mother
The present study enrolled patients seen from January 2000 to December 2004 in four tertiary referral hospitals for connective tissue diseases and pregnancy clinics in Italy: Fondazione Policlinico Mangiagalli of Milan, Department of Internal Medicine, University of Milan; Spedali Civili of Brescia; Padua Hospital; and Niguarda Hospital in Milan. Ninety-six mothers, regularly monitored at the centres before pregnancy, were prospectively enrolled in the study and followed up during 96 pregnancies. Informed consent was obtained from the mothers and the protocol was approved by the ethical committee of the centres. Sixty women were anti-SSA/Ro-positive: 22 were affected by SLE, 14 by primary Sjögren's syndrome (SS), 10 by undifferentiated connective tissue disease (UCTD), three by autoimmune thyroiditis, one by subacute cutaneous lupus erythematosus (SCLE), one by autoimmune hepatitis, one by Werlhof disease and eight were asymptomatic, with occasional finding of autoantibody positivity during a clinical work-up because of previous miscarriages. One mother had a previous history of intrauterine death at 25 weeks of gestation because of fetal CHB. An additional group represented by 36 anti-SSA/Ro-negative women was studied: 18 were affected by SLE, seven by primary anti-phospholipid syndrome (PAPS), five by UCTD, two by rheumatoid arthritis, one by discoid lupus erythematosus, one by erythema nodosum, one by systemic sclerosis and one by autoimmune thyroiditis (Table 1).


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  		TABLE 1. Mothers’ characteristics

 
Diagnoses were in accordance with the American College of Rheumatology (ACR) criteria for SLE [17], the European criteria for SS [18], the recently proposed criteria by Doria et al. [19] for UCTD and the revised Sidney criteria for PAPS [20]. The ongoing therapy and autoantibody profile of the two groups are summarized in Table 1. All mothers were followed up monthly during pregnancy. Anti-SSA/Ro-positive mothers underwent weekly fetal echocardiography from the 18th to the 24th week of gestation. For anti-SSA/Ro-negative mothers, a single fetal echocardiography was performed at 24th week of gestation.

Children
Of the 97 babies born from the mothers of the study, 71 were followed up during their first year of life, 25 dropped out of the study because of mother's refusal of further investigation and one has not been included in further follow-up because he underwent pacemaker implantation for CHB. The followed-up babies underwent clinical evaluation at 1, 3, 6 and 12 months of age. Blood tests and a standard 12-lead ECG and/or ECG-Holter were performed and serum samples for autoantibody detection were collected on the same day of clinical evaluation. ECGs collected from 200 consecutive neonates, during the first month of life, born from healthy mothers, through January 2000 to December 2004, were used as a healthy control group.

Autoantibody detection
Serum samples of all the mothers were tested for anti-nuclear antibodies (ANA) by indirect immunofluorescence on Hep2 cells, anti-dsDNA antibodies by immunofluorescence on Chritidia luciliae and/or by Farr assay and anti-phospholipid antibodies, as previously described [21]. The presence of anti-SSA/Ro 52–60 kD and anti-SSB/La antibodies was confirmed by at least two of four different methods among counterimmunoelectrophoresis (CIE), solid-phase ELISA, western blot and INNO-LIATM ANA Update (Innogenetics NV, Gent, Belgium). The only patient displaying anti-Ro positivity with only one method was excluded from the study. CIE was performed using a human spleen extract as substrate, as described [22]. Solid-phase ELISA was performed with a commercial kit (Varelisa, Phadia, Italy) using SSA/Ro52 and 60 kD human recombinant antigens, in accordance with manufacturer's instructions. Western blot utilized as substrate a cytoplasmic extract from HeLa cells [23]. INNO-LIATM is a line immunoassay that uses recombinant 52 kD Ro and 48kD La antigens and purified human 60 kD Ro protein and it has been performed and validated as described [24]. The presence of other autoantibodies directed against extractable nuclear antigens was assessed by the same methods.

ECG analysis
The standard 12-lead ECGs were analysed by a single investigator who was blinded to the infant's antibody status, according to the European Society of Cardiology guidelines for the interpretation of the neonatal ECG [25]. PR, QT and RR intervals were measured in lead 2 from five non-consecutive beats and QTc was automatically calculated according to Bazett's formula.

Twenty-four-hour ECG-Holter recordings
A 24 h ECG-Holter monitoring was recorded at 1 month of life and at the subsequent follow-up visits. All recordings were obtained using portable battery-operated three-channel Holter recorder (Ela Medical recorder). The digitized three-channel ECG signals were processed by Elatec Holter analysis software and a dedicated algorithm (ElaMedical, Mountrouge, France) converted the 24 h recording into 2880 templates obtained at 30 s intervals. For each template, an algorithm automatically measured the QT and the RR intervals (ms). The program provided for each hour the mean and the S.D. of RR intervals and of QT intervals corrected for heart rate according to the Bazett's formula (QTc).

Statistical analysis
Data are presented as the mean ± S.D. Comparison of the means was performed by independent-samples t-test. Analysis of the frequency of the different ECG abnormalities was performed by chi-square test.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Acknowledgements
 References
 
Pregnancies
The characteristics of the pregnancy outcomes are summarized in Table 2. One pregnancy, of the anti-Ro-positive group, ended in spontaneous abortion within the 10th week of gestation. Two twin pregnancies out of 60 occurred in the anti-SSA/Ro-positive women. A third-degree heart block was diagnosed at 20th week of gestation during the twin pregnancy of a mother with a previous history of intrauterine death due to CHB. No conduction abnormalities were observed in the other twin. Dexamethasone therapy (at dosage of 4 mg once a day) was started immediately, but no conduction improvement was observed and the therapy was interrupted 2 weeks later. The twins were delivered at 34 weeks of gestation. The affected one, a male weighting 1640 g, underwent pacemaker implantation during the second month of life. A second-degree AV block (AV conduction 3 : 1, 2 : 1) was diagnosed at 30 weeks of gestation in another male fetus of an anti-Ro-positive mother. The block reverted after maternal betamethasone therapy (at dosage of 2 mg once a day for 4 weeks) and the ECG of the baby during the first trimester of life was normal.


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  		TABLE 2. Pregnancy outcome

 
ECG abnormalities between 20 and 90 days of life
An ECG was recorded between 20 and 90 days of life in 71 babies, 46 born from anti-SSA/Ro-positive and 25 from anti-SSA/Ro-negative mothers. Heart rate, PR and QTc intervals were analysed for each ECG and compared with those of the healthy control group and the results are summarized in Table 3. Bradycardia was not observed in any child. Statistical analysis did not show any significant difference in the mean values of all the ECG parameters among the three groups. However, the prevalence of first degree AV block (PR ≥ 140 ms) was significantly higher in the anti-SSA/Ro-positive group, compared with that of the healthy group (P = 0.002) (Table 3). None of these babies had cardiac malformations that could explain AV conduction abnormalities.


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  		TABLE 3. ECG findings in the children between 20 and 90 days after birth

 
The mean QTc interval did not differ between the three groups (P = NS). However, when we considered the individual values, prevalence of a QTc interval ≥440 ms was greater in the two groups of babies born from mothers with autoimmune diseases when compared with the group of healthy infants. The prevalence of QTc ≥440 ms was similar in the two pathological groups (Table 3). None of the infants with QTc interval prolongation had plasma electrolyte alterations and none of them was taking medications known to affect ventricular repolarization. No differences in mothers’ ages, women's treatment during pregnancy, gestational age or birth weight were detected in infants with QTc interval prolongation when compared with those with normal values (data not shown). The prevalence of QT interval prolongation in babies born from mothers taking hydroxychloroquine or steroids during pregnancy did not differ with that found in infants born from mothers taking other therapies, independently from autoantibody profile.

Holter analysis between 20 and 90 days of life
Forty-eight neonates, 27 born from anti-SSA/Ro-positive mothers and 21 born from anti-SSA/Ro-negative women, underwent ECG-Holter during the first month of life and the QTc interval values were analysed. The mean 24 h QTc was similar in infants born from anti-SSA/Ro-positive mothers and in those of the anti-Ro-negative group (438 ± 30 and 446 ± 34 ms, respectively). However, a high percentage of babies of both groups showed a QTc interval ≥440 ms (59 and 60%, respectively), and in seven cases (15%), four of anti-SSA/Ro-positive and three of anti-SSA/Ro negative group, QTc was ≥470 ms. Four babies, one of the anti-SSA/Ro-positive and three of the anti-SSA/Ro-negative group, were treated with propranolol at a dosage of 2 mg/kg/day. The treatment was started when QTc interval was ≥470 ms on the ECG or ≥500 ms on the Holter recording.

ECG and Holter analysis between 3 and 5 months after birth
An ECG was recorded between 3 and 5 months after birth in 55 infants, 37 born from anti-SSA/Ro-positive mothers and 18 born from anti-SSA/Ro-negative mothers, and the results are summarized in Table 4. There was only one infant with asymptomatic bradycardia (90 bpm), in the anti-SSA/Ro-negative group. Mean heart rate and PR interval did not differ between the anti-SSA/Ro-positive and -negative groups. A first degree AV block was confirmed only in two anti-SSA/Ro-positive infants. The mean QTc interval did not differ between the two groups. Specifically, four infants, three from anti-SSA/Ro-positive and one from anti-SSA/Ro-negative group, still showed a prolonged QT interval (Table 4).


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  		TABLE 4. ECG findings during follow-up at 3, 6 and 12 months

 
Nineteen infants underwent 24-h ECG-Holter during the second trimester of life. Mean QTc was similar in the anti-SSA/Ro-positive group and in the -negative group. A QTc ≥440 was present in four babies born from anti-SSA/Ro-positive mothers and three born from anti-SSA/Ro-negative mothers. Only one infant of the anti-SSA/Ro-negative group still had a QTc interval ≥470 ms.

ECG and Holter analysis after 6 months of life
Fifty-two infants, 34 of the anti-SSA/Ro-positive and 18 of the anti-SSA/Ro-negative group underwent a follow-up ECG at 6 months (Table 4). Mean heart rate and PR interval were similar in the two groups. When the individual values were analysed, the two infants from anti-SSA/Ro-positive mothers still showed first degree AV block and only two infants, one from each group, still had a QT interval above the upper normal limits. Nineteen of these infants, 11 from anti-SSA/Ro-positive and 8 from anti-SSA/Ro-negative group underwent ECG-Holter. A QTc interval ≥440 was still present in six infants (two of the anti-SSA/Ro-positive and four of the anti-SSA/Ro-negative group), but in none of them it was ≥470 ms.

Forty-three infants, 26 born from anti-SSA/Ro-positive and 19 from anti-SSA/Ro-negative mothers, underwent the last follow-up ECG at 1 yr of age. Heart rate, PR interval and QTc were within the normal limits in all cases and the means did not differ between the two groups. Figure 1 shows the trend of QTc interval in the whole population during the first year of life.


Figure 1
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  		FIG. 1. Mean QTc values, ms (± S.D.) during follow-up (standard ECG).

 
Since statistical analysis did not reveal any difference in the prevalence of QTc interval prolongation between anti-SSA/Ro-positive and -negative patients, we analysed other mothers’ characteristics, but we did not find any correlation with a specific autoimmune profile, or clinical diagnosis (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Acknowledgements
 References
 
To our knowledge, this is the first multicentre, prospective study on the prevalence of ECG abnormalities in the offspring of a large population of women with autoimmune diseases, either positive or negative for anti-SSA/Ro antibodies.

There are conflicting data in the literature regarding a possible involvement of anti-SSA/Ro antibodies in unexplained pregnancy loss and adverse pregnancy outcome. In the past years, anti-SSA/Ro antibodies have been associated with an increased risk of abortion [26], but other authors found no such correlation [27, 28]. Our prospective study does confirm that these autoantibodies do not affect pregnancy outcome.

The risk of CHB in fetuses of anti-SSA/Ro-positive mothers is rated to be ~2% [16, 27]. In our series, only one case of CHB occurred in a mother who had a history of fetal CHB during the previous pregnancy. Owing to the well-known higher risk for CHB in women with a previous episode, we could not calculate the real incidence of this conduction disturbance in the studied population. On the other hand, if we take into account the second-degree AV block reverted by betamethasone therapy as the unique event in our prospective series, the whole risk for CHB in anti-SSA/Ro-positive women appears to be in agreement with previous findings (~2%). Furthermore, we observed a significantly higher prevalence of first-degree AV block in babies born from anti-SSA/Ro-positive mothers, in comparison with the healthy control group. Overall, these data on AV conduction abnormalities are in agreement with previous reports [10, 29].

The present prospective study shows that neonates born from mothers with autoimmune diseases show a significantly higher prevalence of QTc interval values above the upper normal limits, in comparison with a normal control group, irrespective of the presence or absence of anti-SSA/Ro antibodies. QTc interval prolongation ≥440 ms does not seem to be related to a specific autoimmune profile or clinical diagnosis. The prevalence of QTc prolongation in a multicentre prospective study on 45 000 consecutive neonates from the same geographic area was only 1.3% of neonates, similar to that of our control group [30]. In a previous study on 22 babies born from anti-SSA/Ro-positive mothers [11], we reported that 43% of cases had a QT interval above the upper normal limits (440 ms), and another group independently confirmed our findings [31]. However, these studies were limited by the relatively small sample size and lack of appropriate controls. In the present study, we have included not only an anti-Ro-negative control group, but also a large cohort of healthy newborns as controls. We also showed that the QTc prolongation disappeared at 1 yr of life [12]; this might be secondary to the autoantibody clearance from the babies’ circulation, but also to the physiological variation of QT with age, as also shown in the present series (Fig. 1). In another large study by Costedoat-Chalumeau et al. [16], the prevalence of QT interval prolongation was not associated to the presence of anti-Ro antibodies. In the present prospective study, we confirm that the high prevalence of QT interval prolongation does not differ between babies born from anti-Ro-positive mothers and those born from anti-Ro-negative mothers.

In our series, these ECG abnormalities in most cases disappeared within 6 months and completely by 1 yr (Fig. 1). A higher risk for sudden death in infants with a QTc >440 ms has been demonstrated [13]. In the present study, we did not observe any cardiac event or recorded arrhythmia. However, a beta-blocker therapy, which is highly effective in the long QT syndrome, a genetic disease due to mutations of genes encoding for ionic currents involved in the control of ventricular repolarization [32], was started and maintained during the first year of life in the four babies with a more marked QT interval prolongation. Two of these four babies also underwent genetic study that ruled out the presence of a congenital long QT syndrome.

The 24 h Holter monitoring demonstrated a higher prevalence (60% of the whole population) of QTc ≥440 ms even in babies with normal QTc interval at standard ECG. In up to 15% of these cases, QTc interval was ≥470 ms: this QT interval prolongation is associated with an increased risk of sudden death. However, the 24 h mean QTc measured on Holter recordings is the result of the variability of the duration of ventricular repolarization in the long term, which is higher in infants with prolonged QT interval [33]. This may explain the higher prevalence of QTc ≥440 ms on Holter monitoring when compared with standard ECGs in infants born from mothers with autoimmune diseases.

The 1 yr follow-up clearly demonstrated that AV conduction delay and QT interval prolongation were transient and disappeared by 1 yr of life in all cases. Since these ECG abnormalities are more prevalent in babies born from mothers with autoimmune diseases and are transient, we cannot exclude that a delay in the maturation or development of the heart, the conduction system or its neural control in relation to the maternal environment influenced by autoimmune pathology might have played a role in these abnormalities.

Since some studies have reported cardiotoxicity and conduction or repolarization abnormalities in patients treated with anti-malarial agents [34] that are also able to cross the placenta [35], we assessed the presence of possible correlations between AV conduction or QT interval prolongation and maternal therapy with hydroxychloroquine during pregnancy. The prevalence of AV conduction abnormalities or QT interval prolongation was not significantly different in the neonates born from mothers treated with anti-malarials during pregnancy and in those born from mothers who did not receive these drugs. This finding is in agreement with previous reports on hydroxychloroquine safety during pregnancy [36, 37].

In conclusion, this is the first prospective multicentre study that shows a high prevalence of transient ECG abnormalities in infants born from mothers with autoimmune disorders, independently of the autoantibody profile. Since some of these abnormalities may potentially be associated with higher risk for arrhythmias, a close cardiological follow-up during the first year of life in these infants should be recommended.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgements
References
 
This study was supported by PRIN n. MM06154388 to P.L.M. (National Coordinator) and by Ricerca Corrente 2005 Istituto Auxologico Italiano (to P.L.M.).

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 20 December 2006; revised version accepted 2 March 2007.
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