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.код для вставкиСкачать
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. email@example.com. 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 3188 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 3190 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 3192 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 ) 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 ; 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. REFERENCES 1. Kitridou RC. The neonatal lupus syndrome. In: Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 1040–59. 2. Buyon JP. Neonatal lupus: bedside to bench and back. Scand J Rheumatol 1996;25:271–6. 3. 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