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Congenital complete heart block and maternal connective tissue disease
International Journal of Cardiology 112 (2006) 153 – 158 www.elsevier.com/locate/ijcard
Review
Congenital complete heart block and maternal connective tissue disease N. Jayaprasad *, Francis Johnson, K. Venugopal Department of Cardiology, Medical College, Calicut, Kerala State, 673008, India Received 1 July 2005; received in revised form 12 November 2005; accepted 27 November 2005 Available online 30 June 2006
Abstract Congenital Complete Heart Block can be isolated or can occur in association with other structural heart diseases. Isolated Congenital Complete Heart Block (CCHB) is due to transplacental transfer of autoantibodies from mothers with connective tissue disease. Congenital heart block is usually complete, but incomplete blocks, sinus bradycardia and QTc prolongation are also reported. Anti SS A and Anti SS B antibodies transferred from mothers have inflammatory and arrhythmogenic effects in the fetal conduction system. Cardiac manifestations reported include dilated cardiomyopathy, endocardial fibroelastosis and mitral insufficiency. Low ventricular rate, QT prolongation and arrhythmias on monitoring are high risk features. CCHB has a mortality of 30%, and 60% of infants require pacemaker therapy. Fetal echocardiography is useful in early diagnosis. Prophylactic steroid therapy is controversial. Beta adrenergic agonists were tried in mothers with fetuses having congenital heart block to increase fetal heart rate. Early pacemaker therapy is indicated in patients with symptomatic bradycardia and ventricular dysfunction. The indications for pacing in congenital heart block continue to evolve with advances in techniques and most of these children will ultimately require permanent pacemakers by adulthood. D 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Congenital Complete Heart Block; Neonatal lupus; QT prolongation; Pacemaker; Autoantibody
1. Introduction Congenital complete heart block (CCHB) is an uncommon disorder with an incidence of about 1/20,000 in liveborn infants [1]. This is a condition associated with high mortality and morbidity and requires a high index of suspicion for early diagnosis and therapy. Congenital complete heart block was first reported by Morquio in 1901 [2]. CCHB can occur in the setting of structurally normal heart or in association with structural heart disease. Structural heart disease most strongly associated with CCHB is left isomerism with associated atrioventricular septal defect and congenitally corrected transposition of great arteries [3,4]. CCHB associated with structural heart disease has got a far worse prognosis compared to isolated CCHB both pre and postnatally. The association between isolated CHB and maternal connective tissue disease was * Corresponding author. Tel.: +91 9846810902. E-mail address: [email protected] (N. Jayaprasad). 0167-5273/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.11.115
described by Hull et al. in the late 1960s [5]. This association was shown to be due to the circulating anti SSA/Ro and anti SSB/La antibodies in most of the mothers of these affected infants. These antibodies are associated with a spectrum of abnormalities in the newborns affecting the skin, liver and blood elements, and are known as neonatal lupus syndromes [6,7]. CCHB occurs between 16 and 24 weeks of gestation in fetuses with structurally normal hearts [8]. CCHB carries a mortality of about 30% and as many as 60% of affected children require pacemakers [9]. Although nearly every mother with an affected child has circulating anti-SSA/Ro and/or anti-SSB/La antibodies, only about 2% of mothers with antibodies will have a child with CCHB [10]. The risk of recurrence of CCHB in a subsequent pregnancy is about 10% to 16% [11,12]. Although CCHB was described mainly in children of mothers with SLE, it can occur with other connective tissue diseases like Sjogren’s syndrome, etc. Nearly half of the mothers do not have connective tissue disease when children are born with complete heart block even though
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most of them have autoantibodies. Many of these asymptomatic mothers progress to a connective tissue disease like SLE, Sjogren’s syndrome or undifferentiated connective tissue disease later [9]. Up to 10% of fetuses with CCHB and structurally normal heart have mothers without autoimmune connective tissue disease or antibodies.
2. Neonatal lupus syndrome Neonatal lupus is due to transmission of autoantibodies from a mother with connective tissue disease through the placental barrier to her fetus. The most important clinical feature of neonatal lupus is congenital heart block (CHB), which is usually complete (i.e. third degree) and irreversible. Other abnormalities of cardiovascular system, skin, liver, etc. are described and these manifestations are together called neonatal lupus syndromes. Hematological abnormalities like anemia and thrombocytopenia are described [7]. Hepatic involvement includes asymptomatic increase in liver enzymes, cholestasis, etc. [6]. Manifestations other than complete heart block are usually transient and do not need treatment. Abnormalities in other systems are present at birth in some cases but not clinically evident until several weeks in other children.
3. Cardiac manifestations of lupus syndrome Clinical manifestations of congenital complete heart block mainly depend on ventricular rate. Fetuses with very low ventricular rates present with fetal hydrops or neonatal heart failure. Dilated cardiomyopathy with cardiac failure in infancy has a poor prognosis with high perinatal and neonatal mortality [11]. Other cardiac manifestations have been reported, including incomplete atrioventricular (AV) blocks and sinus bradycardia [13,14]. This occurrence suggests that sinus node may also be involved along with AV node. A high incidence of QT prolongation without CCHB is reported in infants from mothers with anti-SSA/ Ro antibodies [15]. Since a prolonged corrected QTc is associated with increased risk of sudden death; some of these infants were subsequently treated with a h-blocker in order to prevent arrhythmias. QTc prolongation is usually not long lasting and disappears as soon as the maternal autoantibodies are cleared from the baby’s blood [16]. Other related cardiac pathology described among these children include late onset dilated cardiomyopathy, endomyocardial fibroelastosis and mitral insufficiency [17 – 19]. Some patients may develop endocardial fibroelastosis without CCHB. Nield et al. have recently reported endocardial fibroelastosis (EFE) predominantly involving the left ventricle in 13 children with CCHB [18]. EFE was diagnosed in half of them before birth. All these children had severe left ventricular dysfunction leading ultimately to death or cardiac transplantation.
4. Pathogenesis The exact mechanism of causation of autoantibody related CCHB is not completely understood but it usually occurs in fetuses without cardiac structural anomalies. Transplacental passage of autoantibodies from mothers with autoimmune disorders is now widely recognized as the most likely mechanism in the pathogenesis of the disease [20]. The main autoantibodies detected both in children with complete congenital heart block and their mothers are anti-Ro/SS-A and anti-La/SS-B antibodies [21]. Anti-SSA/Ro antibodies recognize 2 proteins: a 60-kDa protein and a 52-kDa protein [22]. SSB/La is a 48-kDa protein having the function of facilitating the maturation of RNA polymerase III transcripts. Transplacental passage of the maternal autoantibodies is thought to occur at approximately 12 weeks of gestation. These antibodies against Ro and La intracellular ribonuclear proteins bind specific cells of the fetal conduction system. The most common lesion in complete congenital heart block is discontinuity between the atrium and the atrioventricular node [23]. The interruption may occasionally be situated between the atrioventricular node and the main His bundle, or within the bundle, itself [24]. Maternal antibodies to all components of the Ro/La system are efficiently transported across the placenta. Antibodies can cause myocarditis, hemorrhage and necrosis of the conduction system. This can lead to fibrosis and even calcification of the conduction system [25]. The concentration of anti La/SS-B and anti Ro/ SS-A antibodies in the mother well correlated with that in children [26]. Immunohistochemical reports have shown deposition of IgG and complement in the myocardial tissues. Mononuclear cell infiltration can also occur [27,28]. All these show that inflammation may be the initiating event, which can ultimately lead to fibrosis and calcification of the conduction system. How the intracellular protein targets SSA/Ro and SSB/ La, become accessible to maternal autoantibodies is not definitely understood. Apoptosis is described as a mechanism, which causes surface expression of these intracellular antigens in human fetal myocytes [29]. Binding by autoantibodies leads to induction of inflammation and phagocytosis of the apoptotic cells. Secretion of tumor necrosis factor-alfa (TNF-alfa) may mediate inflammation [30]. A similar pathogenesis is implicated in patients with endocardial fibroelastosis and congenital complete heart block. Immunohistochemical staining demonstrated significant deposition of IgG and also of IgM and the presence of T cells in majority of them. This suggests that immune process involving these antibodies directed against fetal myocyte antigens is the pathogenic mechanism. Maternal autoantibody-induced EFE can occur in the presence of CHB despite adequate ventricular pacing and is associated with high rate of mortality among affected fetuses and infants. Another mechanism of complete heart block is arrhythmogenic effect of the autoantibodies itself. Anti-SSA/Ro and anti SSB/La IgG antibodies isolated from the sera of
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mothers whose children have CCHB are arrhythmogenic in the human fetal heart by inhibiting L-type calcium channels. The inhibitory effect of antibodies on L-type Ca2+ channels is indirectly supported by the induction of AV block in the Langendorff-perfused heart and directly supported by the patch-clamp experiments in isolated myocytes. The abnormalities in conduction at the AV node were reproduced in fetuses born to mice immunized with the 52-kDa SSA/Ro recombinant protein [31]. Prolonged exposure of fetal Ca2+ channels to the maternal anti-SSA/Ro-SSB/La antibodies may lead to internalization and degradation of the channel, cell death and ultimately fibrosis. Brucato et al. described sinus bradycardia in infants without CHB born to anti-SSA/ Ro-positive mothers [14]. In another study, maternal antibodies from mothers of children with CHB were shown to decrease ICa.L and ICa.T, two important currents in sinus node responsible for spontaneous pacemaker activity in rabbit SA node cells. In addition, positive IgG caused sinus bradycardia in single SA node myocytes [32].
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ventricular rate during rest, sleep and activity and to look for ventricular arrhythmias. In children and adults, exercise testing can be done to assess chronotropic incompetence. Maternal antibodies to 52 -kDa and 60-kDa SS-A, and to 48-kDa SS-B can be determined by time-resolved fluoroimmunoassay (TR-FIA) and antinuclear antibodies (ANA) by immunofluorescense (IF). Although maternal autoantibodies are present in most patients with prenatally diagnosed CCHB, the incidence is less in postnatally diagnosed cases. High titer antibodies to SSA and SSB indicate increased risk of having an affected child [36]. Low heart rate detected in an undiagnosed fetus can be misinterpreted by obstetricians as a sign of fetal distress resulting in emergency caesarian section, the baby will then have CCHB and prematurity and the prognosis will be poor.
6. Outcome 6.1. Mortality
5. Diagnosis CCHB is suspected when routine auscultation for fetal heart sounds reveals a slow heart rate. Prenatally identified either on routine obstetrical ultrasound or on screening of mothers with known autoantibodies. Fetal echocardiographic study should be done routinely starting from 16 to 18 weeks of pregnancy in pregnant ladies with autoantibodies. Fetal mechanical PR interval prolongation based on Doppler flow recordings in the left ventricular outflow tract helps in detecting AV conduction delay [33]. The mechanical PR interval is measured from onset of mitral Fa_ wave to the beginning of LV ejection wave. When conduction time is markedly prolonged, atrial contraction can occur during ventricular ejection causing a tall reverse Fa_ wave in superior venacava and a deep retrograde wave in ductus venosus but no Fa_ wave on mitral Doppler wave form [34]. Another Doppler method is comparing simultaneous flow velocity wave forms in aorta and superior venacava. Mmode tracing of atrial and ventricular free wall, atrial wall and opening of aortic valve or mitral Fa_ wave and aortic opening can identify fetal atrioventricular block [35]. Fetal echocardiogram is useful to rule out major associated structural lesions of the heart. In isolated congenital complete heart block in addition to evidence of complete heart block other abnormalities like myocarditis may be seen. In cases with very low ventricular rate, decreased cardiac contractility on fetal echocardiogram as well as cardiac dilatation, tricuspid regurgitation, pericardial effusion or hydrops fetalis may be evident. In the postnatal period electrocardiography performed will reveal AV dissociation with low ventricular rate. As the site of block is usually at or above AV node, the escape ventricular complexes are usually narrow. Twenty-four-hour holter monitoring is indicated in all patients to assess
Waltuck and Buyon reported the total mortality of CCHB to be 19%, of whom 27% died in utero and 45% died within the first 3 months after delivery [9]. Groves et al. showed that heart rate less than 55 beats/min is associated with greater likelihood of poor outcome [37]. Fetal hydrops was associated with poor outcome. Early infancy is the time of greatest risk of death in CHB. Eronen et al. reported a total mortality of 16% of which 73% occurred in the first 12 months of life. Poor outcome was associated with intrauterine hydrops, low fetal and neonatal heart rate, low birth weight, male sex and neonatal problems attributable to prematurity or neonatal lupus [11]. 6.2. Morbidity Congenital complete heart block is associated with high neonatal morbidity. In the study by Eronen et al. [11], the incidence of neonatal complications was as follows. Fetal hydrops—27% Cardiac failure without hydrops—21% Pace maker therapy as a new born—53% Neonatal lupus—18% Waltuck and Buyon reported pacemaker therapy in 63% of live-born children with 33% within the first 9 days of life [9]. Late onset dilated cardiomyopathy developing despite the early institution of cardiac pacing has been reported in infants with congenital CHB [17]. Dilated cardiomyopathy occurred in 23% of children in the series by Eronen et al. with a mortality of more than 60%. Michaelsson et al. described high incidence of unpredictable Stokes-Adams disease and acquired mitral insufficiency [19]. Mitral regurgitation was a predictor of future Stokes –Adams attacks. Early pacemaker implantation was shown to reduce mortality and may reduce
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the incidence of mitral regurgitation. Ventricular rate was found to decrease with age. A high incidence of QTc prolongation was also seen which was associated with Stokes –Adams attacks. Ventricular tachycardia and fibrillation were the indications for pacing in 6% of children undergoing pacemaker therapy after the newborn period [11]. Indicators of poor prognosis in adults with CCHB include low ventricular rate, QTc prolongation, and frequent ectopies on holter monitoring as well as a low ventricular rate response during heavy work [38 –41]. Ventricular rate less than 40 per minute in the young and less than 35 per minute in elderly is associated with poor prognosis. 6.3. Maternal outcome Outcome in mothers of these children was assessed in few studies. McCune et al. assessed the health status of mothers and children with neonatal lupus syndrome in a follow-up study of 21 families [42]. The average follow-up was 4.5 years. All mothers eventually developed symptoms of a connective tissue. In the study by Waltuck and Buyon, out of 52 mothers and their children with isolated congenital heart block, 23 women were asymptomatic, 15 had systemic lupus erythematosus, 8 had the Sjogren syndrome and 11 had an undifferentiated autoimmune syndrome at the time of diagnosis of complete heart block [9]. After a median follow-up of 3.7 years, 11 (48%) of the 23 initially asymptomatic mothers developed symptoms of a connective tissue disease. Six developed an undifferentiated connective tissue disease, two developed Sjogren syndrome and three developed systemic lupus erythematosus. One mother with Sjogren syndrome progressed to systemic lupus erythematosus. Recurrence rate in the subsequent pregnancies was 16%.
7. Management 7.1. Treatment of mother/fetus Obstetric management of a mother with anti-Ro/SSASSB/La positivity include serial echocardiograms and
obstetric sonograms, performed at least every 2 weeks starting from 16 weeks of gestation [43]. The goal is to detect early fetal abnormalities that might precede complete AV block and that might be a target of preventive therapy. Prophylactic steroid therapy in antibody positive mothers was investigated. But it is not recommended owing to the too-low risk and the potential side-effects [43 – 45]. Once fetal diagnosis is made, drug therapy to the mother may be tried, in order to diminish the autoimmune response, cardiac inflammatory injury and to increase fetal heart rate. Use of corticosteroids is controversial. Steroid therapy is thought to be effective in reducing inflammation and features like hydrops, pleural effusions, ascites, etc. [46]. Because of possible maternal side-effects, steroids are given only if the block is incomplete or is of recent onset, or if a complete block is accompanied by signs of fetal distress such as hydrops, effusions, ascites or heart failure. Dexamethasone in a dose of 4 mg daily was used. Established complete heart block does not respond to steroid. Steroid therapy is associated with potential maternal side effects like oligohydramnios, hypertension, etc. [46]. But Jaeggi et al. found steroids to be effective and demonstrated 90% survival rates in patients treated with transplacental steroids compared to 46% in the untreated group [47]. Maternal administration of beta adrenergic agonists can produce fetal tachycardia Administration of salbutamol to mother increased heart rate and cardiac function in fetus with complete heart block [48]. Schmidt et al. reported an increase in fetal heart rate of 15% to 50% in four fetuses treated with terbutaline, ritodrine or isoprenaline, but only one survived to delivery [49]. Maternal treatment with salbutamol may help to prolong gestation so that preterm delivery can be avoided. It may be given in a dose of 2 mg 6 – 10 times daily to the mother. Follow-up is required to look for progression of heart block, dilated cardiomyopathy and development of hydrops. Other therapeutic interventions that have been advocated include prophylactic plasmapheresis, fetal pacing, etc. [50]. Early delivery should be considered if there is evidence of fetal distress or compromised ventricular function [51]. There is a high likelihood of delivery by caesarian section due to the
Table 1 Recommendations for pacing in children and adolescents with congenital heart block Class 1
Class IIa
Class IIb
Class III
1. Advanced second- or third-degree AV block associated with symptomatic bradycardia, ventricular dysfunction or low cardiac output. 2. Congenital third-degree AV block with a wide QRS escape rhythm, complex ventricular ectopy or ventricular dysfunction. 3. CCHB in the infant with a ventricular rate less than 50 to 55 bpm or with congenital heart disease and a ventricular rate less than 70 bpm. 4. CCHB with sustained pause-dependent VT, with or without prolonged QT, in which the efficacy of pacing is thoroughly documented. 1. Congenital third-degree AV block beyond the first year of life with an average heart rate less than 50 bpm, abrupt pauses in ventricular rate that are two or three times the basic cycle length, or associated with symptoms due to chronotropic incompetence. 2. Long-QT syndrome with 2:1 AV or third-degree AV block. 1. Congenital third-degree AV block in the asymptomatic infant, child, adolescent, or young adult with an acceptable rate, narrow QRS complex and normal ventricular function. 2. Neuromuscular diseases with any degree of AV block, with or without symptoms, because there may be unpredictable progression of AV conduction disease. 1. Asymptomatic type I second-degree AV block. 2. Asymptomatic sinus bradycardia in the adolescent with longest RR interval less than 3 s and minimum heart rate more than 40 bpm.
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inability to monitor fetal well being during labor by fetal heart rate. 7.2. Postnatal treatment Postnatal treatment includes treatment of cardiac failure as well as pacemakers for babies with significant bradycardia, such as those with a heart rate less than 55 bpm. Many neonates are asymptomatic with adequate ventricular rates and needs no treatment. They should be observed closely for lowering of heart rate in the initial 5 –10 days as there is a risk that the mean heart rate may fall and child may become symptomatic. Even though antibodies are present in the infants no definite data is available regarding immune modification treatment in the postnatal period. Beta agonists like isoprenaline can be used to increase heart rate temporarily. ACC/AHA guidelines are useful in selecting patients for permanent pacemaker implantation in congenital heart block [52] (Table 1). In several studies, it has been observed that pacemaker implantation may improve long-term survival and prevent syncopal episodes among asymptomatic patients with congenital complete AV block. Periodic evaluation of ventricular function is required in patients with congenital AV block, even after pacemaker implantation [52]. There is controversy regarding the route and mode of pacing in young children. Previously most centers were advocating epicardial implantation of pacing leads in children < 5 years of age and < 30 kg weight [53]. The reasons for avoiding endocardial approach are risk of venous occlusion, growth related lead problems and need for future lead extractions and lead replacement [54]. An increasing number of centers are now using endocardial pacing in children older than 1 year of age and weighing > 8 kg [55]. A trend from epicardial towards endocardial pacing is steadily increasing in the recent years with successful implantation in even smaller children [56]. If epicardial pacing is necessary, steroid-eluting leads may be considered as they lessen the increase in stimulation threshold. Dual chamber cardiac pacing which maintains atrio ventricular synchrony is the optimal pacing mode in many children and young adults [57]. Clinical studies have suggested benefit from dual chamber pacing in terms of survival, quality of life, cardiac output and incidence of pacemaker syndrome. Although dual-chamber pacing improves cardiac function in patients with complete congenital heart block by restoring physiological heart rate and atrioventricular synchronization, prolonged ventricular dyssynchrony induced by long-term endovenous right ventricular pacing is associated with deleterious LV remodeling, LV dilatation, LV asymmetrical hypertrophy and low exercise capacity [58]. Late onset dilated cardiomyopathy occurring despite pacing has got a poor prognosis with many requiring cardiac transplantation. These children require close monitoring of ECG, monitoring of adequate functioning of the pacemaker and serial assessment of ventricular function. Patients with
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CCHB without pace maker do need a close, at least yearly, follow-up with 12 lead ECG, 24-h Holter monitoring and echocardiography. Indications for pace maker therapy in congenital complete heart block continue to evolve, based on improved definition of the natural history of the disease as well as advances in pacemaker technology and diagnostic methods.
8. Conclusion Isolated congenital complete heart block is associated with high mortality and morbidity. In majority, autoantibodies can be detected which are transmitted transplacentally from mothers with connective tissue diseases. Low ventricular rate, fetal hydrops, associated dilated cardiomyopathy, mitral insufficiency and endocardial fibroelastosis are having a poor outcome. Transplacental steroid and sympathomimetic therapy are tried with variable results. Early pacemaker therapy can improve outcome. References [1] Michaelsson M, Engle MA. Congenital complete heart block: an international study of the natural history. Cardiovasc Clin 1972;4: 85 – 98. [2] Morquio L. Sur une maladie infantile et familiale characterisee par des modifications permanentes du pouls des attaques syncopales et eptileptiformes et la mort subite. Arch Med Inf 1901;4:467 – 9. [3] Jaeggi ET, Hornberger LK, Smallhorn JF, Fouron JC. Prenatal diagnosis of complete atrioventricular block associated with structural heart disease: combined experience of two tertiary care centers and review of the literature. Ultrasound Obstet Gynecol 2005;26:16 – 21. [4] Berg C, Geipel A, Kohl T, et al. Atrioventricular block detected in fetal life: associated anomalies and potential prognostic markers. Ultrasound Obstet Gynecol 2005;26:4 – 15. [5] Hull D, Binns BAO, Joyce D. Congenital heart block and widespread fibrosis due to maternal erythematosus. Arch Dis Child 1966;41:688 – 90. [6] Laxer RM, Roberts EA, Gross KR, et al. Liver disease in neonatal lupus erythematosus. J Pediatr 1990;116:238 – 42. [7] Watson R, Kang JE, May M, Hudak M, Kickler T, Provost TT. Thrombocytopenia in the neonatal lupus syndrome. Arch Dermatol 1988;124:560 – 3. [8] Buyon JP, Waltuck J, Kleinman C, et al. In utero identification and therapy of congenital heart block. Lupus 1995;4:116 – 21. [9] Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: outcome in mothers and children. Ann Intern Med 1994;120:544 – 51. [10] Buyon JP. Congenital complete heart block (review). Lupus 1993; 2:291 – 5. [11] Eronen M, Siren MK, Ekblad H, et al. Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000;106:86 – 91. [12] Buyon J, Hiebert R, Copel J, et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity, and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol 1998;31:1658 – 66. [13] Cimaz R, Airoldi ML, Careddu P, et al. Transient neonatal bradycardia without heart block associated with anti-Ro antibodies. Lupus 1997; 6:487 – 8. [14] Brucato A, Cimaz R, Catelli L, Meroni PL. Anti-Ro associated sinus bradycardia in new-borns. Circulation 2000;102:E88-9.
158
N. Jayaprasad et al. / International Journal of Cardiology 112 (2006) 153 – 158
[15] Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL. QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum 2000;43: 1049 – 53. [16] Cimaz R, Meroni PL, Brucato A, et al. Concomitant disappearance of electrocardiographic abnormalities and of acquired maternal auto antibodies during the first year of life in infants who had QT interval prolongation and anti-SSA/Ro positivity without congenital heart block at birth. Arthritis Rheum 2003;48:266 – 8. [17] Moak JP, Barron KS, Hougen TJ, et al. Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol 2001;37:238 – 42. [18] Nield LE, Silverman ED, Taylor GP, et al. Maternal anti-Ro and antiLa antibody-associated endocardial fibroelastosis. Circulation 2002; 105:843 – 8. [19] Michaelsson M, Jonzon A, Riesenfeld T. Isolated congenital complete atrioventricular block in adult life: a prospective study. Circulation 1995;92:442 – 9. [20] Buyon JP, Winchester RJ. Complete congenital block: a model of passively acquired autoimmunity. Arthritis Rheum 1990;33: 609 – 14. [21] Buyon JP. Neonatal lupus. Curr Opin Rheumatol 1996;8:485 – 90. [22] Wang D, Buyon JP, Zhu W, et al. Defining a novel 75-kDa phosphoprotein associated with SS-A/Ro and identification of distinct human autoantibodies. J Clin Invest 1999;104:1265 – 75. [23] Ho SY, Esscher E, Anderson RH, Michaelsson M. Anatomy of congenital complete heart block and relation to maternal anti-Ro antibodies. Am J Cardiol 1986;58:291 – 4. [24] Anderson RH, Wenick ACG, Losekoot TG, Becker AE. Congenitally complete heart block. Circulation 1977;56:90 – 8. [25] Michaelsson M. Congenital complete atrioventricular block. Prog Pediatr Cardiol 1995;4:1 – 7. [26] Buyon JP, Waltuck J, Caldwell K, et al. Relationship between maternal and neonatal levels of antibodies to 48 kDa SSB(La), 52 kDa SSA(Ro), and 60 kDa SSA(Ro) in pregnancies complicated by congenital heart block. J Rheumatol 1994;21:1943 – 50. [27] Litsey SE, Noonan JA, O’Connor WN, Cottrill CM, Mitchell B. Maternal connective tissue disease and congenital heart block. Demonstration of immunoglobulin in cardiac tissue. N Engl J Med 1985;312:98 – 100. [28] Fesslova V, Mannarino S, Salice P, et al. Neonatal lupus: fetal myocarditis progressing to atrioventricular block in triplets. Lupus 2003;12:775 – 8. [29] Miranda ME, Tseng CE, Rashbaum W, et al. Accessibility of SSA/Ro and SSB/La antigens to maternal auto antibodies in apoptotic human fetal cardiac myocytes. J Immunol 1998;161:5061 – 9. [30] Miranda-Carus ME, Askanase AD, Clancy RM, et al. Anti-SSA/Ro and anti-SSB/La auto antibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of TNF-alpha by macrophages. J Immunol 2000;165:5345 – 51. [31] Mohamed Boutjdir, Long Chen, et al. Arrhythmogenicity of IgG and anti-52-kD SSA/Ro affinity-purified antibodies from mothers of children with congenital heart block. Circ Res 1997;80:354 – 62. [32] Keli Hu, Yongxia Qu, Yuankun Yue, Mohamed Boutjdir. Functional basis of sinus bradycardia in congenital heart block. Circ Res 2004;94:e32 – 8. [33] Rosenthal D, Friedman DM, Buyon J, Dubin A. Validation of the Doppler PR interval in the fetus. J Am Soc Echocardiogr 2002;15: 1029 – 30. [34] Raboisson MJ, Fouron JC, Sonesson SE, Nyman M, Proulx F, Gamache S. Fetal Doppler echocardiographic diagnosis and successful steroid therapy of Luciani-Wenckebach phenomenon and endocardial fibroelastosis related to maternal anti-Ro and anti-La antibodies. J Am Soc Echocardiogr Apr 2005;18(4):375 – 80. [35] Fouron JC, Proulx F, Miro J, Gosselin J. Doppler and M-Mode ultrasonography to time fetal atrial and ventricular contractions. Obstet Gynecol 2000;96:732 – 6.
[36] Julkunen H, Miettinen A, Walle TK, Chan EK, Eronen M. Autoimmune response in mothers of children with congenital and postnatally diagnosed isolated heart block: a population based study. J Rheumatol Jan 2004;31(1):183 – 9. [37] Groves AMM, Allan LD, Rosenthal E. Outcome of isolated congenital complete heart block diagnosed in utero. Heart 1996;75:190 – 4. [38] Levy AM, Camm AJ, Keane JF. Multiple arrhythmias detected during nocturnal monitoring in patients with congenital complete heart block. Circulation 1977;55:247 – 53. [39] Winkler RB, Freed MD, Nadas A. Exercise-induced ventricular ectopy in children and young adults with complete heart block. Am Heart J 1980;99:87 – 92. [40] Esscher E, Michaelsson M. Q-T interval in congenital complete heart block. Pediatr Cardiol 1983;4:121 – 4. [41] Solti F, Szatma´ry L, Vecsey T, Re´nyi-Va´mos F, Bodor E. Congenital complete heart block associated with QT prolongation. Eur Heart J 1992;13:1080 – 3. [42] McCune AB, Weston WL, Lee LA. Maternal and fetal outcome in neonatal lupus erythematosus. Ann Intern Med 1987;106:518 – 23. [43] Brucato A, Cimaz R, Stramba-Badiale M. Neonatal lupus. Clin Rev Allergy Immunol 2002;3:279 – 99. [44] Buyon JP, Clancy RM. Maternal auto antibodies and congenital heart block. Mediators, markers, and therapeutic approach. Semin Arthritis Rheum 2003;33:140 – 54. [45] Costedoat-Chalumeau N, Amoura Z, Le Thi Hong D, et al. Questions about dexamethasone use for the prevention of anti-SSA related congenital heart block. Ann Rheum Dis 2003;63:1010 – 2. [46] Breur JMPJ, Visser GHA, Kruize AA, Stoutenbeek P, Meijboom EJ. Treatment of fetal heart block with maternal steroid therapy: case report and review of the literature. Ultrasound Obstet Gynecol 2004;24:467 – 72. [47] Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger LK. Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 2004;110(12):1542 – 8. [48] Groves AMM, Allan LD, Rosenthal E. Therapeutic trial of sympathomimetics in three cases of complete heart block in the fetus. Circulation 1995;92:3394 – 6. [49] Schmidt KG, Ulmer HE, Silverman NH, Kleinman CS, Copel JA. Perinatal outcome of fetal complete atrioventricular block: a multicenter experience. J Am Coll Cardiol 1991;17:1360 – 6. [50] Carpenter RJ, Strasburger JF, Garson A, Smith RT, Deter RL, Engelhardt HT. Fetal ventricular pacing for hydrops secondary to complete atrioventricular block. J Am Coll Cardiol 1986;8:1434 – 6. [51] Donofrio MT, Gullquist SD, Mehta ID, Moskowitz WB. Congenital complete heart block: fetal management protocol, review of the literature, and report of the smallest successful pacemaker implantation. J Perinatol 2004 [Feb];24(2):112 – 7. [52] Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2002 [Nov 6];40(9):1703 – 19. [53] Maginot KR, Mathewson JW, Bichell DP. Application of pacing strategies in neonates and infants. Prog Pediatr Cardiol 2000;11: 65 – 75. [54] Friedman RA, Fenrich AC, Kertesz NJ. Congenital complete atrioventricular block. PACE 2001;24. [55] Serwer GA. Permanent pacing in children: acute lead implantation and long term follow-up. Prog Pediatr Cardiol 1995;4:31 – 41. [56] Rao V, Williams WG, Hamilton RH. Trends in pediatric cardiac pacing. Can J Cardiol 1995;11:993 – 9. [57] Karpawich PP, Perry BL, Farooki ZQ, et al. Pacing in children and young adults with nonsurgical atrioventricular block: comparison of single-rate ventricular and dual-chamber modes. Am Heart J 1987;113:316 –21. [58] Thambo JB, Bordachar P, et al. Detrimental ventricular remodeling in patients with congenital complete heart block and chronic right ventricular apical pacing. Circulation 2004;110:3766 – 72.
Review
Congenital complete heart block and maternal connective tissue disease N. Jayaprasad *, Francis Johnson, K. Venugopal Department of Cardiology, Medical College, Calicut, Kerala State, 673008, India Received 1 July 2005; received in revised form 12 November 2005; accepted 27 November 2005 Available online 30 June 2006
Abstract Congenital Complete Heart Block can be isolated or can occur in association with other structural heart diseases. Isolated Congenital Complete Heart Block (CCHB) is due to transplacental transfer of autoantibodies from mothers with connective tissue disease. Congenital heart block is usually complete, but incomplete blocks, sinus bradycardia and QTc prolongation are also reported. Anti SS A and Anti SS B antibodies transferred from mothers have inflammatory and arrhythmogenic effects in the fetal conduction system. Cardiac manifestations reported include dilated cardiomyopathy, endocardial fibroelastosis and mitral insufficiency. Low ventricular rate, QT prolongation and arrhythmias on monitoring are high risk features. CCHB has a mortality of 30%, and 60% of infants require pacemaker therapy. Fetal echocardiography is useful in early diagnosis. Prophylactic steroid therapy is controversial. Beta adrenergic agonists were tried in mothers with fetuses having congenital heart block to increase fetal heart rate. Early pacemaker therapy is indicated in patients with symptomatic bradycardia and ventricular dysfunction. The indications for pacing in congenital heart block continue to evolve with advances in techniques and most of these children will ultimately require permanent pacemakers by adulthood. D 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Congenital Complete Heart Block; Neonatal lupus; QT prolongation; Pacemaker; Autoantibody
1. Introduction Congenital complete heart block (CCHB) is an uncommon disorder with an incidence of about 1/20,000 in liveborn infants [1]. This is a condition associated with high mortality and morbidity and requires a high index of suspicion for early diagnosis and therapy. Congenital complete heart block was first reported by Morquio in 1901 [2]. CCHB can occur in the setting of structurally normal heart or in association with structural heart disease. Structural heart disease most strongly associated with CCHB is left isomerism with associated atrioventricular septal defect and congenitally corrected transposition of great arteries [3,4]. CCHB associated with structural heart disease has got a far worse prognosis compared to isolated CCHB both pre and postnatally. The association between isolated CHB and maternal connective tissue disease was * Corresponding author. Tel.: +91 9846810902. E-mail address: [email protected] (N. Jayaprasad). 0167-5273/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.11.115
described by Hull et al. in the late 1960s [5]. This association was shown to be due to the circulating anti SSA/Ro and anti SSB/La antibodies in most of the mothers of these affected infants. These antibodies are associated with a spectrum of abnormalities in the newborns affecting the skin, liver and blood elements, and are known as neonatal lupus syndromes [6,7]. CCHB occurs between 16 and 24 weeks of gestation in fetuses with structurally normal hearts [8]. CCHB carries a mortality of about 30% and as many as 60% of affected children require pacemakers [9]. Although nearly every mother with an affected child has circulating anti-SSA/Ro and/or anti-SSB/La antibodies, only about 2% of mothers with antibodies will have a child with CCHB [10]. The risk of recurrence of CCHB in a subsequent pregnancy is about 10% to 16% [11,12]. Although CCHB was described mainly in children of mothers with SLE, it can occur with other connective tissue diseases like Sjogren’s syndrome, etc. Nearly half of the mothers do not have connective tissue disease when children are born with complete heart block even though
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most of them have autoantibodies. Many of these asymptomatic mothers progress to a connective tissue disease like SLE, Sjogren’s syndrome or undifferentiated connective tissue disease later [9]. Up to 10% of fetuses with CCHB and structurally normal heart have mothers without autoimmune connective tissue disease or antibodies.
2. Neonatal lupus syndrome Neonatal lupus is due to transmission of autoantibodies from a mother with connective tissue disease through the placental barrier to her fetus. The most important clinical feature of neonatal lupus is congenital heart block (CHB), which is usually complete (i.e. third degree) and irreversible. Other abnormalities of cardiovascular system, skin, liver, etc. are described and these manifestations are together called neonatal lupus syndromes. Hematological abnormalities like anemia and thrombocytopenia are described [7]. Hepatic involvement includes asymptomatic increase in liver enzymes, cholestasis, etc. [6]. Manifestations other than complete heart block are usually transient and do not need treatment. Abnormalities in other systems are present at birth in some cases but not clinically evident until several weeks in other children.
3. Cardiac manifestations of lupus syndrome Clinical manifestations of congenital complete heart block mainly depend on ventricular rate. Fetuses with very low ventricular rates present with fetal hydrops or neonatal heart failure. Dilated cardiomyopathy with cardiac failure in infancy has a poor prognosis with high perinatal and neonatal mortality [11]. Other cardiac manifestations have been reported, including incomplete atrioventricular (AV) blocks and sinus bradycardia [13,14]. This occurrence suggests that sinus node may also be involved along with AV node. A high incidence of QT prolongation without CCHB is reported in infants from mothers with anti-SSA/ Ro antibodies [15]. Since a prolonged corrected QTc is associated with increased risk of sudden death; some of these infants were subsequently treated with a h-blocker in order to prevent arrhythmias. QTc prolongation is usually not long lasting and disappears as soon as the maternal autoantibodies are cleared from the baby’s blood [16]. Other related cardiac pathology described among these children include late onset dilated cardiomyopathy, endomyocardial fibroelastosis and mitral insufficiency [17 – 19]. Some patients may develop endocardial fibroelastosis without CCHB. Nield et al. have recently reported endocardial fibroelastosis (EFE) predominantly involving the left ventricle in 13 children with CCHB [18]. EFE was diagnosed in half of them before birth. All these children had severe left ventricular dysfunction leading ultimately to death or cardiac transplantation.
4. Pathogenesis The exact mechanism of causation of autoantibody related CCHB is not completely understood but it usually occurs in fetuses without cardiac structural anomalies. Transplacental passage of autoantibodies from mothers with autoimmune disorders is now widely recognized as the most likely mechanism in the pathogenesis of the disease [20]. The main autoantibodies detected both in children with complete congenital heart block and their mothers are anti-Ro/SS-A and anti-La/SS-B antibodies [21]. Anti-SSA/Ro antibodies recognize 2 proteins: a 60-kDa protein and a 52-kDa protein [22]. SSB/La is a 48-kDa protein having the function of facilitating the maturation of RNA polymerase III transcripts. Transplacental passage of the maternal autoantibodies is thought to occur at approximately 12 weeks of gestation. These antibodies against Ro and La intracellular ribonuclear proteins bind specific cells of the fetal conduction system. The most common lesion in complete congenital heart block is discontinuity between the atrium and the atrioventricular node [23]. The interruption may occasionally be situated between the atrioventricular node and the main His bundle, or within the bundle, itself [24]. Maternal antibodies to all components of the Ro/La system are efficiently transported across the placenta. Antibodies can cause myocarditis, hemorrhage and necrosis of the conduction system. This can lead to fibrosis and even calcification of the conduction system [25]. The concentration of anti La/SS-B and anti Ro/ SS-A antibodies in the mother well correlated with that in children [26]. Immunohistochemical reports have shown deposition of IgG and complement in the myocardial tissues. Mononuclear cell infiltration can also occur [27,28]. All these show that inflammation may be the initiating event, which can ultimately lead to fibrosis and calcification of the conduction system. How the intracellular protein targets SSA/Ro and SSB/ La, become accessible to maternal autoantibodies is not definitely understood. Apoptosis is described as a mechanism, which causes surface expression of these intracellular antigens in human fetal myocytes [29]. Binding by autoantibodies leads to induction of inflammation and phagocytosis of the apoptotic cells. Secretion of tumor necrosis factor-alfa (TNF-alfa) may mediate inflammation [30]. A similar pathogenesis is implicated in patients with endocardial fibroelastosis and congenital complete heart block. Immunohistochemical staining demonstrated significant deposition of IgG and also of IgM and the presence of T cells in majority of them. This suggests that immune process involving these antibodies directed against fetal myocyte antigens is the pathogenic mechanism. Maternal autoantibody-induced EFE can occur in the presence of CHB despite adequate ventricular pacing and is associated with high rate of mortality among affected fetuses and infants. Another mechanism of complete heart block is arrhythmogenic effect of the autoantibodies itself. Anti-SSA/Ro and anti SSB/La IgG antibodies isolated from the sera of
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mothers whose children have CCHB are arrhythmogenic in the human fetal heart by inhibiting L-type calcium channels. The inhibitory effect of antibodies on L-type Ca2+ channels is indirectly supported by the induction of AV block in the Langendorff-perfused heart and directly supported by the patch-clamp experiments in isolated myocytes. The abnormalities in conduction at the AV node were reproduced in fetuses born to mice immunized with the 52-kDa SSA/Ro recombinant protein [31]. Prolonged exposure of fetal Ca2+ channels to the maternal anti-SSA/Ro-SSB/La antibodies may lead to internalization and degradation of the channel, cell death and ultimately fibrosis. Brucato et al. described sinus bradycardia in infants without CHB born to anti-SSA/ Ro-positive mothers [14]. In another study, maternal antibodies from mothers of children with CHB were shown to decrease ICa.L and ICa.T, two important currents in sinus node responsible for spontaneous pacemaker activity in rabbit SA node cells. In addition, positive IgG caused sinus bradycardia in single SA node myocytes [32].
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ventricular rate during rest, sleep and activity and to look for ventricular arrhythmias. In children and adults, exercise testing can be done to assess chronotropic incompetence. Maternal antibodies to 52 -kDa and 60-kDa SS-A, and to 48-kDa SS-B can be determined by time-resolved fluoroimmunoassay (TR-FIA) and antinuclear antibodies (ANA) by immunofluorescense (IF). Although maternal autoantibodies are present in most patients with prenatally diagnosed CCHB, the incidence is less in postnatally diagnosed cases. High titer antibodies to SSA and SSB indicate increased risk of having an affected child [36]. Low heart rate detected in an undiagnosed fetus can be misinterpreted by obstetricians as a sign of fetal distress resulting in emergency caesarian section, the baby will then have CCHB and prematurity and the prognosis will be poor.
6. Outcome 6.1. Mortality
5. Diagnosis CCHB is suspected when routine auscultation for fetal heart sounds reveals a slow heart rate. Prenatally identified either on routine obstetrical ultrasound or on screening of mothers with known autoantibodies. Fetal echocardiographic study should be done routinely starting from 16 to 18 weeks of pregnancy in pregnant ladies with autoantibodies. Fetal mechanical PR interval prolongation based on Doppler flow recordings in the left ventricular outflow tract helps in detecting AV conduction delay [33]. The mechanical PR interval is measured from onset of mitral Fa_ wave to the beginning of LV ejection wave. When conduction time is markedly prolonged, atrial contraction can occur during ventricular ejection causing a tall reverse Fa_ wave in superior venacava and a deep retrograde wave in ductus venosus but no Fa_ wave on mitral Doppler wave form [34]. Another Doppler method is comparing simultaneous flow velocity wave forms in aorta and superior venacava. Mmode tracing of atrial and ventricular free wall, atrial wall and opening of aortic valve or mitral Fa_ wave and aortic opening can identify fetal atrioventricular block [35]. Fetal echocardiogram is useful to rule out major associated structural lesions of the heart. In isolated congenital complete heart block in addition to evidence of complete heart block other abnormalities like myocarditis may be seen. In cases with very low ventricular rate, decreased cardiac contractility on fetal echocardiogram as well as cardiac dilatation, tricuspid regurgitation, pericardial effusion or hydrops fetalis may be evident. In the postnatal period electrocardiography performed will reveal AV dissociation with low ventricular rate. As the site of block is usually at or above AV node, the escape ventricular complexes are usually narrow. Twenty-four-hour holter monitoring is indicated in all patients to assess
Waltuck and Buyon reported the total mortality of CCHB to be 19%, of whom 27% died in utero and 45% died within the first 3 months after delivery [9]. Groves et al. showed that heart rate less than 55 beats/min is associated with greater likelihood of poor outcome [37]. Fetal hydrops was associated with poor outcome. Early infancy is the time of greatest risk of death in CHB. Eronen et al. reported a total mortality of 16% of which 73% occurred in the first 12 months of life. Poor outcome was associated with intrauterine hydrops, low fetal and neonatal heart rate, low birth weight, male sex and neonatal problems attributable to prematurity or neonatal lupus [11]. 6.2. Morbidity Congenital complete heart block is associated with high neonatal morbidity. In the study by Eronen et al. [11], the incidence of neonatal complications was as follows. Fetal hydrops—27% Cardiac failure without hydrops—21% Pace maker therapy as a new born—53% Neonatal lupus—18% Waltuck and Buyon reported pacemaker therapy in 63% of live-born children with 33% within the first 9 days of life [9]. Late onset dilated cardiomyopathy developing despite the early institution of cardiac pacing has been reported in infants with congenital CHB [17]. Dilated cardiomyopathy occurred in 23% of children in the series by Eronen et al. with a mortality of more than 60%. Michaelsson et al. described high incidence of unpredictable Stokes-Adams disease and acquired mitral insufficiency [19]. Mitral regurgitation was a predictor of future Stokes –Adams attacks. Early pacemaker implantation was shown to reduce mortality and may reduce
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the incidence of mitral regurgitation. Ventricular rate was found to decrease with age. A high incidence of QTc prolongation was also seen which was associated with Stokes –Adams attacks. Ventricular tachycardia and fibrillation were the indications for pacing in 6% of children undergoing pacemaker therapy after the newborn period [11]. Indicators of poor prognosis in adults with CCHB include low ventricular rate, QTc prolongation, and frequent ectopies on holter monitoring as well as a low ventricular rate response during heavy work [38 –41]. Ventricular rate less than 40 per minute in the young and less than 35 per minute in elderly is associated with poor prognosis. 6.3. Maternal outcome Outcome in mothers of these children was assessed in few studies. McCune et al. assessed the health status of mothers and children with neonatal lupus syndrome in a follow-up study of 21 families [42]. The average follow-up was 4.5 years. All mothers eventually developed symptoms of a connective tissue. In the study by Waltuck and Buyon, out of 52 mothers and their children with isolated congenital heart block, 23 women were asymptomatic, 15 had systemic lupus erythematosus, 8 had the Sjogren syndrome and 11 had an undifferentiated autoimmune syndrome at the time of diagnosis of complete heart block [9]. After a median follow-up of 3.7 years, 11 (48%) of the 23 initially asymptomatic mothers developed symptoms of a connective tissue disease. Six developed an undifferentiated connective tissue disease, two developed Sjogren syndrome and three developed systemic lupus erythematosus. One mother with Sjogren syndrome progressed to systemic lupus erythematosus. Recurrence rate in the subsequent pregnancies was 16%.
7. Management 7.1. Treatment of mother/fetus Obstetric management of a mother with anti-Ro/SSASSB/La positivity include serial echocardiograms and
obstetric sonograms, performed at least every 2 weeks starting from 16 weeks of gestation [43]. The goal is to detect early fetal abnormalities that might precede complete AV block and that might be a target of preventive therapy. Prophylactic steroid therapy in antibody positive mothers was investigated. But it is not recommended owing to the too-low risk and the potential side-effects [43 – 45]. Once fetal diagnosis is made, drug therapy to the mother may be tried, in order to diminish the autoimmune response, cardiac inflammatory injury and to increase fetal heart rate. Use of corticosteroids is controversial. Steroid therapy is thought to be effective in reducing inflammation and features like hydrops, pleural effusions, ascites, etc. [46]. Because of possible maternal side-effects, steroids are given only if the block is incomplete or is of recent onset, or if a complete block is accompanied by signs of fetal distress such as hydrops, effusions, ascites or heart failure. Dexamethasone in a dose of 4 mg daily was used. Established complete heart block does not respond to steroid. Steroid therapy is associated with potential maternal side effects like oligohydramnios, hypertension, etc. [46]. But Jaeggi et al. found steroids to be effective and demonstrated 90% survival rates in patients treated with transplacental steroids compared to 46% in the untreated group [47]. Maternal administration of beta adrenergic agonists can produce fetal tachycardia Administration of salbutamol to mother increased heart rate and cardiac function in fetus with complete heart block [48]. Schmidt et al. reported an increase in fetal heart rate of 15% to 50% in four fetuses treated with terbutaline, ritodrine or isoprenaline, but only one survived to delivery [49]. Maternal treatment with salbutamol may help to prolong gestation so that preterm delivery can be avoided. It may be given in a dose of 2 mg 6 – 10 times daily to the mother. Follow-up is required to look for progression of heart block, dilated cardiomyopathy and development of hydrops. Other therapeutic interventions that have been advocated include prophylactic plasmapheresis, fetal pacing, etc. [50]. Early delivery should be considered if there is evidence of fetal distress or compromised ventricular function [51]. There is a high likelihood of delivery by caesarian section due to the
Table 1 Recommendations for pacing in children and adolescents with congenital heart block Class 1
Class IIa
Class IIb
Class III
1. Advanced second- or third-degree AV block associated with symptomatic bradycardia, ventricular dysfunction or low cardiac output. 2. Congenital third-degree AV block with a wide QRS escape rhythm, complex ventricular ectopy or ventricular dysfunction. 3. CCHB in the infant with a ventricular rate less than 50 to 55 bpm or with congenital heart disease and a ventricular rate less than 70 bpm. 4. CCHB with sustained pause-dependent VT, with or without prolonged QT, in which the efficacy of pacing is thoroughly documented. 1. Congenital third-degree AV block beyond the first year of life with an average heart rate less than 50 bpm, abrupt pauses in ventricular rate that are two or three times the basic cycle length, or associated with symptoms due to chronotropic incompetence. 2. Long-QT syndrome with 2:1 AV or third-degree AV block. 1. Congenital third-degree AV block in the asymptomatic infant, child, adolescent, or young adult with an acceptable rate, narrow QRS complex and normal ventricular function. 2. Neuromuscular diseases with any degree of AV block, with or without symptoms, because there may be unpredictable progression of AV conduction disease. 1. Asymptomatic type I second-degree AV block. 2. Asymptomatic sinus bradycardia in the adolescent with longest RR interval less than 3 s and minimum heart rate more than 40 bpm.
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inability to monitor fetal well being during labor by fetal heart rate. 7.2. Postnatal treatment Postnatal treatment includes treatment of cardiac failure as well as pacemakers for babies with significant bradycardia, such as those with a heart rate less than 55 bpm. Many neonates are asymptomatic with adequate ventricular rates and needs no treatment. They should be observed closely for lowering of heart rate in the initial 5 –10 days as there is a risk that the mean heart rate may fall and child may become symptomatic. Even though antibodies are present in the infants no definite data is available regarding immune modification treatment in the postnatal period. Beta agonists like isoprenaline can be used to increase heart rate temporarily. ACC/AHA guidelines are useful in selecting patients for permanent pacemaker implantation in congenital heart block [52] (Table 1). In several studies, it has been observed that pacemaker implantation may improve long-term survival and prevent syncopal episodes among asymptomatic patients with congenital complete AV block. Periodic evaluation of ventricular function is required in patients with congenital AV block, even after pacemaker implantation [52]. There is controversy regarding the route and mode of pacing in young children. Previously most centers were advocating epicardial implantation of pacing leads in children < 5 years of age and < 30 kg weight [53]. The reasons for avoiding endocardial approach are risk of venous occlusion, growth related lead problems and need for future lead extractions and lead replacement [54]. An increasing number of centers are now using endocardial pacing in children older than 1 year of age and weighing > 8 kg [55]. A trend from epicardial towards endocardial pacing is steadily increasing in the recent years with successful implantation in even smaller children [56]. If epicardial pacing is necessary, steroid-eluting leads may be considered as they lessen the increase in stimulation threshold. Dual chamber cardiac pacing which maintains atrio ventricular synchrony is the optimal pacing mode in many children and young adults [57]. Clinical studies have suggested benefit from dual chamber pacing in terms of survival, quality of life, cardiac output and incidence of pacemaker syndrome. Although dual-chamber pacing improves cardiac function in patients with complete congenital heart block by restoring physiological heart rate and atrioventricular synchronization, prolonged ventricular dyssynchrony induced by long-term endovenous right ventricular pacing is associated with deleterious LV remodeling, LV dilatation, LV asymmetrical hypertrophy and low exercise capacity [58]. Late onset dilated cardiomyopathy occurring despite pacing has got a poor prognosis with many requiring cardiac transplantation. These children require close monitoring of ECG, monitoring of adequate functioning of the pacemaker and serial assessment of ventricular function. Patients with
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CCHB without pace maker do need a close, at least yearly, follow-up with 12 lead ECG, 24-h Holter monitoring and echocardiography. Indications for pace maker therapy in congenital complete heart block continue to evolve, based on improved definition of the natural history of the disease as well as advances in pacemaker technology and diagnostic methods.
8. Conclusion Isolated congenital complete heart block is associated with high mortality and morbidity. In majority, autoantibodies can be detected which are transmitted transplacentally from mothers with connective tissue diseases. Low ventricular rate, fetal hydrops, associated dilated cardiomyopathy, mitral insufficiency and endocardial fibroelastosis are having a poor outcome. Transplacental steroid and sympathomimetic therapy are tried with variable results. Early pacemaker therapy can improve outcome. References [1] Michaelsson M, Engle MA. Congenital complete heart block: an international study of the natural history. Cardiovasc Clin 1972;4: 85 – 98. [2] Morquio L. Sur une maladie infantile et familiale characterisee par des modifications permanentes du pouls des attaques syncopales et eptileptiformes et la mort subite. Arch Med Inf 1901;4:467 – 9. [3] Jaeggi ET, Hornberger LK, Smallhorn JF, Fouron JC. Prenatal diagnosis of complete atrioventricular block associated with structural heart disease: combined experience of two tertiary care centers and review of the literature. Ultrasound Obstet Gynecol 2005;26:16 – 21. [4] Berg C, Geipel A, Kohl T, et al. Atrioventricular block detected in fetal life: associated anomalies and potential prognostic markers. Ultrasound Obstet Gynecol 2005;26:4 – 15. [5] Hull D, Binns BAO, Joyce D. Congenital heart block and widespread fibrosis due to maternal erythematosus. Arch Dis Child 1966;41:688 – 90. [6] Laxer RM, Roberts EA, Gross KR, et al. Liver disease in neonatal lupus erythematosus. J Pediatr 1990;116:238 – 42. [7] Watson R, Kang JE, May M, Hudak M, Kickler T, Provost TT. Thrombocytopenia in the neonatal lupus syndrome. Arch Dermatol 1988;124:560 – 3. [8] Buyon JP, Waltuck J, Kleinman C, et al. In utero identification and therapy of congenital heart block. Lupus 1995;4:116 – 21. [9] Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: outcome in mothers and children. Ann Intern Med 1994;120:544 – 51. [10] Buyon JP. Congenital complete heart block (review). Lupus 1993; 2:291 – 5. [11] Eronen M, Siren MK, Ekblad H, et al. Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000;106:86 – 91. [12] Buyon J, Hiebert R, Copel J, et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity, and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol 1998;31:1658 – 66. [13] Cimaz R, Airoldi ML, Careddu P, et al. Transient neonatal bradycardia without heart block associated with anti-Ro antibodies. Lupus 1997; 6:487 – 8. [14] Brucato A, Cimaz R, Catelli L, Meroni PL. Anti-Ro associated sinus bradycardia in new-borns. Circulation 2000;102:E88-9.
158
N. Jayaprasad et al. / International Journal of Cardiology 112 (2006) 153 – 158
[15] Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL. QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum 2000;43: 1049 – 53. [16] Cimaz R, Meroni PL, Brucato A, et al. Concomitant disappearance of electrocardiographic abnormalities and of acquired maternal auto antibodies during the first year of life in infants who had QT interval prolongation and anti-SSA/Ro positivity without congenital heart block at birth. Arthritis Rheum 2003;48:266 – 8. [17] Moak JP, Barron KS, Hougen TJ, et al. Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol 2001;37:238 – 42. [18] Nield LE, Silverman ED, Taylor GP, et al. Maternal anti-Ro and antiLa antibody-associated endocardial fibroelastosis. Circulation 2002; 105:843 – 8. [19] Michaelsson M, Jonzon A, Riesenfeld T. Isolated congenital complete atrioventricular block in adult life: a prospective study. Circulation 1995;92:442 – 9. [20] Buyon JP, Winchester RJ. Complete congenital block: a model of passively acquired autoimmunity. Arthritis Rheum 1990;33: 609 – 14. [21] Buyon JP. Neonatal lupus. Curr Opin Rheumatol 1996;8:485 – 90. [22] Wang D, Buyon JP, Zhu W, et al. Defining a novel 75-kDa phosphoprotein associated with SS-A/Ro and identification of distinct human autoantibodies. J Clin Invest 1999;104:1265 – 75. [23] Ho SY, Esscher E, Anderson RH, Michaelsson M. Anatomy of congenital complete heart block and relation to maternal anti-Ro antibodies. Am J Cardiol 1986;58:291 – 4. [24] Anderson RH, Wenick ACG, Losekoot TG, Becker AE. Congenitally complete heart block. Circulation 1977;56:90 – 8. [25] Michaelsson M. Congenital complete atrioventricular block. Prog Pediatr Cardiol 1995;4:1 – 7. [26] Buyon JP, Waltuck J, Caldwell K, et al. Relationship between maternal and neonatal levels of antibodies to 48 kDa SSB(La), 52 kDa SSA(Ro), and 60 kDa SSA(Ro) in pregnancies complicated by congenital heart block. J Rheumatol 1994;21:1943 – 50. [27] Litsey SE, Noonan JA, O’Connor WN, Cottrill CM, Mitchell B. Maternal connective tissue disease and congenital heart block. Demonstration of immunoglobulin in cardiac tissue. N Engl J Med 1985;312:98 – 100. [28] Fesslova V, Mannarino S, Salice P, et al. Neonatal lupus: fetal myocarditis progressing to atrioventricular block in triplets. Lupus 2003;12:775 – 8. [29] Miranda ME, Tseng CE, Rashbaum W, et al. Accessibility of SSA/Ro and SSB/La antigens to maternal auto antibodies in apoptotic human fetal cardiac myocytes. J Immunol 1998;161:5061 – 9. [30] Miranda-Carus ME, Askanase AD, Clancy RM, et al. Anti-SSA/Ro and anti-SSB/La auto antibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of TNF-alpha by macrophages. J Immunol 2000;165:5345 – 51. [31] Mohamed Boutjdir, Long Chen, et al. Arrhythmogenicity of IgG and anti-52-kD SSA/Ro affinity-purified antibodies from mothers of children with congenital heart block. Circ Res 1997;80:354 – 62. [32] Keli Hu, Yongxia Qu, Yuankun Yue, Mohamed Boutjdir. Functional basis of sinus bradycardia in congenital heart block. Circ Res 2004;94:e32 – 8. [33] Rosenthal D, Friedman DM, Buyon J, Dubin A. Validation of the Doppler PR interval in the fetus. J Am Soc Echocardiogr 2002;15: 1029 – 30. [34] Raboisson MJ, Fouron JC, Sonesson SE, Nyman M, Proulx F, Gamache S. Fetal Doppler echocardiographic diagnosis and successful steroid therapy of Luciani-Wenckebach phenomenon and endocardial fibroelastosis related to maternal anti-Ro and anti-La antibodies. J Am Soc Echocardiogr Apr 2005;18(4):375 – 80. [35] Fouron JC, Proulx F, Miro J, Gosselin J. Doppler and M-Mode ultrasonography to time fetal atrial and ventricular contractions. Obstet Gynecol 2000;96:732 – 6.
[36] Julkunen H, Miettinen A, Walle TK, Chan EK, Eronen M. Autoimmune response in mothers of children with congenital and postnatally diagnosed isolated heart block: a population based study. J Rheumatol Jan 2004;31(1):183 – 9. [37] Groves AMM, Allan LD, Rosenthal E. Outcome of isolated congenital complete heart block diagnosed in utero. Heart 1996;75:190 – 4. [38] Levy AM, Camm AJ, Keane JF. Multiple arrhythmias detected during nocturnal monitoring in patients with congenital complete heart block. Circulation 1977;55:247 – 53. [39] Winkler RB, Freed MD, Nadas A. Exercise-induced ventricular ectopy in children and young adults with complete heart block. Am Heart J 1980;99:87 – 92. [40] Esscher E, Michaelsson M. Q-T interval in congenital complete heart block. Pediatr Cardiol 1983;4:121 – 4. [41] Solti F, Szatma´ry L, Vecsey T, Re´nyi-Va´mos F, Bodor E. Congenital complete heart block associated with QT prolongation. Eur Heart J 1992;13:1080 – 3. [42] McCune AB, Weston WL, Lee LA. Maternal and fetal outcome in neonatal lupus erythematosus. Ann Intern Med 1987;106:518 – 23. [43] Brucato A, Cimaz R, Stramba-Badiale M. Neonatal lupus. Clin Rev Allergy Immunol 2002;3:279 – 99. [44] Buyon JP, Clancy RM. Maternal auto antibodies and congenital heart block. Mediators, markers, and therapeutic approach. Semin Arthritis Rheum 2003;33:140 – 54. [45] Costedoat-Chalumeau N, Amoura Z, Le Thi Hong D, et al. Questions about dexamethasone use for the prevention of anti-SSA related congenital heart block. Ann Rheum Dis 2003;63:1010 – 2. [46] Breur JMPJ, Visser GHA, Kruize AA, Stoutenbeek P, Meijboom EJ. Treatment of fetal heart block with maternal steroid therapy: case report and review of the literature. Ultrasound Obstet Gynecol 2004;24:467 – 72. [47] Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger LK. Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 2004;110(12):1542 – 8. [48] Groves AMM, Allan LD, Rosenthal E. Therapeutic trial of sympathomimetics in three cases of complete heart block in the fetus. Circulation 1995;92:3394 – 6. [49] Schmidt KG, Ulmer HE, Silverman NH, Kleinman CS, Copel JA. Perinatal outcome of fetal complete atrioventricular block: a multicenter experience. J Am Coll Cardiol 1991;17:1360 – 6. [50] Carpenter RJ, Strasburger JF, Garson A, Smith RT, Deter RL, Engelhardt HT. Fetal ventricular pacing for hydrops secondary to complete atrioventricular block. J Am Coll Cardiol 1986;8:1434 – 6. [51] Donofrio MT, Gullquist SD, Mehta ID, Moskowitz WB. Congenital complete heart block: fetal management protocol, review of the literature, and report of the smallest successful pacemaker implantation. J Perinatol 2004 [Feb];24(2):112 – 7. [52] Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2002 [Nov 6];40(9):1703 – 19. [53] Maginot KR, Mathewson JW, Bichell DP. Application of pacing strategies in neonates and infants. Prog Pediatr Cardiol 2000;11: 65 – 75. [54] Friedman RA, Fenrich AC, Kertesz NJ. Congenital complete atrioventricular block. PACE 2001;24. [55] Serwer GA. Permanent pacing in children: acute lead implantation and long term follow-up. Prog Pediatr Cardiol 1995;4:31 – 41. [56] Rao V, Williams WG, Hamilton RH. Trends in pediatric cardiac pacing. Can J Cardiol 1995;11:993 – 9. [57] Karpawich PP, Perry BL, Farooki ZQ, et al. Pacing in children and young adults with nonsurgical atrioventricular block: comparison of single-rate ventricular and dual-chamber modes. Am Heart J 1987;113:316 –21. [58] Thambo JB, Bordachar P, et al. Detrimental ventricular remodeling in patients with congenital complete heart block and chronic right ventricular apical pacing. Circulation 2004;110:3766 – 72.