Lupus (2007) 16, 642646

http://lup.sagepub.com

REVIEW

Congenital heart block: clinical features and therapeutic approaches

PA Gordon*
Department of Rheumatology, Kings College Hospital, London, UK

Isolated congenital heart block is strongly associated with anti-Ro antibodies. It occurs in 2% of antiRo antibody positive pregnancies with a recurrence rate of 1719%. Mortality is high in the rst year of life (1241%) and is predominantly due to dilated cardiomyopathy. A prolonged QTc occurs in 1522% of cases and minor structural defects such as atrial septal defects and patent arterial ducts are well recognized. The mechanical PR interval can now be measured in utero allowing for the detection of rst-degree heart block. Both rst and second-degree heart block detected in utero respond to therapy with uorinated steroids. Complete congenital heart block is not reversible. Progression from a normal PR interval to complete heart block can occur within a week. IVIG is under investigation for the prevention of recurrence of congenital heart block, while dexamethasone should not be used for this purpose due to unacceptable toxicity. Data on the use of uorinated steroids for established complete heart block is conicting, although their use in cases where there is evidence of hydrops, poor ventricular function or both is not controversial. Lupus (2007) 16, 642646. Key words: neonatal lupus; SSA/RO; pregnancy; connective tissue diseases

Introduction
Neonatatal lupus is disease of passive immunity, which presents in the fetal and neonatal period, and is strongly associated with maternal anti-52kD Ro, anti-60kD Ro and anti-La antibodies. Classically it is characterized by congenital heart block or the neonatal lupus rash. However many other features have been described including hepatitis,1 thrombocytopenia,2 neutropenia3 and central nervous system involvement.4 Isolated congenital heart block is caused by brous replacement of the atrioventricular node and therefore persists throughout life whilst the other manifestations resolve in the rst months of life as the maternal IgG antibodies are cleared from the childs circulation. Isolated congenital heart block occurs in the region of 2% pregnancies of anti-Ro antibody positive women, however the risk is slightly higher in women who are additionally anti-La antibody positive -in the order of 3%.5,6 Congenital heart block can usually rst be detected in the fetus between 1824 weeks of gestational age.
*Correspondence: Dr Patrick A Gordon, Consultant Rheumatologist, Department of Rheumatology, 2nd Floor Hambledon Wing, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK. E-mail: patrick.gordon@kingsch.nhs.uk
2007 SAGE Publications, Los Angeles, London, New Delhi and Singapore

Mortality The early outcome for congenital heart block was considered good until a paper by Machado and colleagues demonstrated that early mortality was high in fetal and neonatal life at 25%.7 Later studies have conrmed a high early mortality in congenital heart block, with mortality by the end of the rst year of life varying from 12% to 41%.812 The majority of deaths occur in utero or within the rst three months of life.1012 Therefore studies including patients diagnosed at or after birth may underestimate early mortality. For example Jaeggi and colleagues reported a one year mortality of 41% in 29 congenital heart block cases diagnosed prenatally but only 3% in 33 cases diagnosed after birth.12 A single centre series of 64 antenatally diagnosed cases, the largest such series to date, reported a one year mortality of 24%.11 The main cause of early death is cardiac failure secondary to cardiomyopathy.9,13 Eronen et al. reported cardiac failure as the cause of death in nine of 11 children dying before one year of age, with dilated cardiomyopathy conrmed on post-mortem in 10.9 Predictors of early mortality include a fetal heart rate 55, delivery prior to 34 weeks and hydrops.10,12,14 Although mortality is highest in the rst year of life, there is a signicant mortality even beyond this age and particularly in the rst four years of life. Buyon and
10.1177/0961203307079041

Congenital heart block PA Gordon

643

colleagues reported a mortality of 3/89 (3%) between one and two years, 2/74 (3%) between two and three years and no deaths in those followed up more than three years.10 In Eronen et al.s cohort of 91 cases, 3/78 (4%) patients surviving beyond one year died between one and four years of age, and all had dilated cardiomyopathy.9 There was one further relevant death reported in this cohort a sudden death in association with a dilated heart at 41 years.9 Moak et al. described a series of 16 patients with congenital heart block who developed a late onset cardiomyopathy despite early pacing.15 Four of these died from cardiac failure, eight required cardiac transplantation and four recovered without intervention.15 Pacing in congenital heart block Many children with congenital heart block (3353%) require pacing as newborns.9,10 Due to the long-term risk of sudden death the vast majority of patients are paced by the time they reach adult life.9 Data from several studies suggest that right ventricular apex pacing may cause left ventricular dysfunction secondary to asynchronous right and left ventricular contraction and relaxation.1518 Thus, late onset cardiomyopathy, in at least some congenital heart block patients, may be due to right ventricular apex pacing rather than the underlying disease process. Earlier age and higher rate of pacing may accentuate this problem. Prolonged QTc A prolonged QTc is a recognized feature of congenital heart block1921 and occurs in the region of 1522% of patients.9,21 Due to the risk of torsades de pointes these patients should be paced and treated with a beta-blocker. A prolonged QTc has been reported to occur in isolation in children born to anti-Ro positive mothers, although prospective studies do not suggest this is a common occurrence.2224 Structural cardiac defects Minor cardiac structural abnormalities have been described in between 17% and 42% cases of isolated congenital heart block.911 The majority are atrial septal defects and patent arterial ducts but other defects including small muscular ventricular septal defects, pulmonary stenosis, mitral valve defects and a hypoplastic right ventricle have been described. Lesser degrees of congenital heart block Both rst and second degree heart block have been reported and these may progress to more advanced

atrioventricular nodal block.25 In view of this, all children born to anti-Ro antibody positive mothers should have EKGs performed to exclude rst and second degree heart block. However, even a normal EKG at birth cannot exclude the subsequent development of second degree heart block.26 There are reports of anti-Ro antibody associated cardiomyopathy in the absence of heart block.27 Additionally, a case has been reported of a child of an anti-Ro positive mother who had no clinical or electrophysiological features of cardiomyopathy or heart block but on post mortem had brosis with calcication in the AV groove.25

Recurrence rate and twins

The recurrence rate of congenital heart block in subsequent pregnancies is low at 1719%.28 This low recurrence rate occurs despite the apparent stability of the anti-Ro and La antibodies over time. There are many examples in the literature of twins, including monozygotic twins discordant for congenital heart block.3032

Maternal disease
There are gures varying between 29% and 66% in the percentage of mothers of children with congenital heart block who are asymptomatic at the time of the index delivery.13,33,34 A proportion of these women remain asymptomatic in the long-term, although again gures vary from 43% to 86%.13,33,34 Symptomatic patients generally have SLE, Sjogrens syndrome, SLE with secondary Sjogrens syndrome or an undifferentiated autoimmune syndrome. The mothers of congenital heart block children do not appear to have an increased risk of developing cardiac conduction defects.35

Therapy
Preventative therapy As the incidence of congenital heart block is only 2% in the offspring of unselected anti-Ro antibody positive mothers preventative therapy cannot be advocated for this group. However, in women with a previous child with congenital heart block the risk is greater, in the region of 1719%.28 Graham Hughes has proposed that in this group of patients maternal administration of intravenous immunoglobulins (IVIG) may reduce the risk of recurrences. In a murine model Tran and colleagues demonstrated reduced transplacental transfer of anti-Ro
Lupus

Congenital heart block PA Gordon

644

and La antibodies in mice treated with IVIG.36 They also demonstrated reduced formation of IgG-apoptotic cell complexes in the fetal hearts of mice treated with IVIG compared to those treated with saline.36 In a pilot study Kaaja and colleagues treated eight pregnant women with IVIG in an attempt to prevent recurrence of congenital heart block.37 One of the eight women delivered a child with congenital heart block; as such this study was inconclusive. To conrm or refute the efcacy of IVIG in preventing congenital heart block a multinational open label study is currently underway based at The Lupus Unit, St. Thomas Hospital, London, UK (for further details contact sandy.hampson@kcl.ac.uk). Another potential strategy to prevent recurrence in subsequent pregnancies was immunosuppression with uorinated steroids, which cross the placenta. However, the toxicity of these agents precludes their use as a preventative therapy. In a study of women with a previous child with congenital heart block, dexamethasone prophylaxis was given in six pregnancies upon the diagnosis of the pregnancy.38 None of the fetuses developed heart block. However, two of the six pregnancies ended in spontaneous abortions and a further two in stillbirth. Both surviving children had intrauterine growth restriction and mild adrenal insufciency. There is also evidence from other studies that dexamethasone is toxic to the human fetus causing reduced birth weight, left ventricular myocardial hypertrophy and delayed psychomotor development.3941 Therapy in established disease Jaeggi and colleagues proposed the routine use of dexamethasone once congenital heart block is diagnosed in utero.42 This was based on their historical data where in a seven year period (19972003) 19/21, 90% of congenital heart block cases were treated in utero with dexamethasone and the overall one year survival was 86% compared to the preceding seven year period (19901996) when 3/16, 19% were treated with dexamethasone and the overall one year survival was 44%. Across the 14-year period, mortality was signicantly lower in fetuses treated with dexamethasone at diagnosis (P 0.015) with reduced mortality due to the immune mediated complications of hepatitis, myocarditis and endocardial broelastosis (P 0.01). However, data taken from the same period at Guys Hospital, London has not supported the hypothesis that the improved survival can be attributed to dexamethasone therapy.43 In the same seven year period (19972003) they did not treat any of their 14 cases of congenital heart block with dexamethasone but still had an overall one year survival of 93% compared to the preceding seven year period (19901996) when
Lupus

7/26, 27% fetuses where treated with dexamethasone and the overall survival was 77%. As such a prospective study is needed to establish the role of routine dexamethasone therapy in congenital heart block. At present, given the potential toxicity of dexamethasone to the fetus it is perhaps advisable to take a conservative approach and reserve the use of uorinated steroids for cases where there is evidence of hydrops, poor ventricular function, or both.43 In compromised fetuses with a heart rate below 55 bpm maternal administration of -sympathomimetic agents may be considered.42,44,45 Early detection and therapy of heart block Once complete congenital heart block occurs, it cannot be reversed by immunosuppressive therapy. However, lesser degrees of heart block may respond to therapy. Saleeb and colleagues performed a retrospective study of treatment with uorinated glucocorticoids.46 In this study a total of 28 mothers were treated with dexamethasone or betamethasone and 22 were not. Twenty-one treated fetuses and 18 untreated fetuses were in complete congenital heart block at presentation and all remained in complete heart block regardless of therapy. In contrast, all four fetuses that presented in second-degree congenital heart block and were treated with steroid reverted to rst-degree heart block by birth. Two of these children remained in rst-degree heart block at four years of age; one alternated between rst and second-degree heart block at two years of age and the fourth was in second-degree heart block at four years of age. Two fetuses that presented in second-degree congenital heart block were not treated; both progressed to complete heart block postnatally. New ultrasound methods allow measurement of the fetal atrioventricular time interval which provides a mechanical PR interval and therefore it is now possible to detect rst-degree heart block in utero.47 If the natural history of congenital heart block involves the development of lesser degrees of heart block progressing to complete congenital heart block, detection of rst-degree congenital heart block could theoretically provide a window of opportunity where therapeutic intervention is benecial, either reversing the heart block or preventing progression to complete congenital heart block. The PRIDE (PR interval and dexamethasone evaluation) study is assessing this possibility by frequent measurement of the mechanical PR interval, weekly from 16 to 26 weeks gestation and then biweekly until 34 weeks, in pregnancies where the mother is anti-Ro antibody positive.48 In this study a fetus is considered to have rst-degree heart block if the PR is greater than 150 msec. To date 88 fetuses

Congenital heart block PA Gordon

645

have been assessed. Conduction abnormalities occurred in six of these fetuses; three (19%) in the 16 women with a previous child with congenital heart block and three (5%) in the 56 women with no previous history of neonatal lupus. Three fetuses developed complete congenital heart block; all three had had a normal PR interval at their preceding assessment at 1, 1.5 and 2 weeks prior to the rst detection of complete congenital heart block. Three children developed rst-degree congenital heart block. In one case the mechanical PR interval was normal at 30 weeks gestation and the child was born with rst-degree heart block at 32 weeks gestation. The other two cases were detected at 19 and 22 weeks and resolved following dexamethasone therapy. Sonesson et al. assessed the mechanical PR interval of the fetuses of 24 anti-52kD Ro antibody positive women and 284 antibody negative women weekly from 18 to 24 weeks gestation.49 In this study a prolonged PR interval was dened as a PR interval greater than the 95% condence interval for the normal fetuses. It varied according to the fetal gestation but was always shorter than the 150 msec used for the PRIDE study. In total eight of the 24 anti-Ro antibody exposed fetuses developed a prolonged PR interval at some stage. One fetus progressed from rst-degree heart block to complete congenital heart block. A second developed second-degree heart block (PR interval normal at preceding assessment) and then converted to rst-degree block following betamethasone therapy. Three of the remaining six fetuses had rst-degree heart block at birth, which resolved without therapy within a few weeks of birth. Only one of these six fetuses had a PR interval longer than 150 msec in utero on one occasion. Thus even with intense monitoring lesser degrees of heart block are frequently not detected prior to the development of complete congenital heart block, providing little opportunity for intervention. Second-degree heart block detected in utero responds to treatment with uorinated steroids. Whilst rst-degree heart block detected in utero resolves following uorinated steroid therapy, its natural history is unclear with many cases resolving spontaneously.

References
1 Lee L, RJ S, Buyon J. Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry. Arthritis Rheum 2001; 44: 340. 2 Watson R, Kang JE, May M, Hudak M, Kickler T, Provost TT. Thrombocytopenia in the neonatal lupus syndrome. Arch Dermatol 1988; 124: 560563. 3 Kanagasegar S, Cimaz R, Kurien BT, Brucato A, Scoeld RH. Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions. J Rheumatol 2002; 29: 187191.

4 Prendiville JS, Cabral DA, Poskitt KJ, Au S, Sargent MA. Central nervous system involvement in neonatal lupus erythematosus. Pediatr Dermatol 2003; 20: 6067. 5 Gordon P, Khamashta MA, Rosenthal E et al. Anti-52 kDa Ro, anti-60 kDa Ro, and anti-La antibody proles in neonatal lupus. J Rheumatol 2004; 31: 24802487. 6 Brucato A, Frassi M, Franceschini F et al. Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum 2001; 44: 18321835. 7 Machado MV, Tynan MJ, Curry PV, Allan LD. Fetal complete heart block. Br Heart J 1988; 60: 512515. 8 Brucato A, Franceschini F, Gasparini M et al. Isolated congenital complete heart block: longterm outcome of mothers, maternal antibody specicity and immunogenetic background. J Rheumatol 1995; 22: 533540. 9 Eronen M, Siren MK, Ekblad H, Tikanoja T, Julkunen H, Paavilainen T. Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000; 106: 8691. 10 Buyon JP, 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: 16581666. 11 Gordon PA, Khamashta MA, Hughes GR, Rosenthal E, Simpson J, Sharland G. Early Outcome in anti-Ro antibody associated congenital heart block. Arthritis Rheum 2001; 44: S161. 12 Jaeggi ET, Hamilton RM, Silverman ED, Zamora SA, Hornberger LK. Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrioventricular block. A single institutions experience of 30 years. J Am Coll Cardiol 2002; 39: 130137. 13 Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: outcome in mothers and children. Ann Intern Med 1994; 120: 544551. 14 Groves AM, Allan LD, Rosenthal E. Outcome of isolated congenital complete heart block diagnosed in utero. Heart 1996; 75: 190194. 15 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: 238242. 16 Karpawich PP, Rabah R, Haas JE. Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block. Pacing Clin Electrophysiol 1999; 22: 13721377. 17 Tantengco MV, Thomas RL, Karpawich PP. Left ventricular dysfunction after long-term right ventricular apical pacing in the young. J Am Coll Cardiol 2001; 37: 20932100. 18 Janousek J, Tomek V, Chaloupecky V, Gebauer RA. Dilated cardiomyopathy associated with dual-chamber pacing in infants: improvement through either left ventricular cardiac resynchronization or programming the pacemaker off allowing intrinsic normal conduction. J Cardiovasc Electrophysiol 2004; 15: 470474. 19 Solti F, Szatmary L, Vecsey T, Renyi-Vamos F Jr, Bodor E. Congenital complete heart block associated with QT prolongation. Eur Heart J 1992; 13: 10801083. 20 Garson A Jr, Dick M 2nd, Fournier A et al. The long QT syndrome in children. An international study of 287 patients. Circulation 1993; 87: 18661872. 21 Esscher E, Michaelsson M. Q-T interval in congenital complete heart block. Pediatr Cardiol 1983; 4: 121124. 22 Gordon PA, Khamashta MA, Rosenthal E, Hughes GR. The effect of anti-Ro antibody on the fetus in the abscence of overt congenital heart block. Arthritis Rheum 2002; 46: S318. 23 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: 10491053. 24 Costedoat-Chalumeau N, Amoura Z, Lupoglazoff JM et al. 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. Arthritis Rheum 2004; 50: 31873194. 25 Askanase AD, Friedman DM, Copel J et al. Spectrum and progression of conduction abnormalities in infants born to mothers with antiSSA/Ro-SSB/La antibodies. Lupus 2002; 11: 145151.

Lupus

Congenital heart block PA Gordon

646 26 Gordon PA, Khamashta MA, Hughes GR, Rosenthal E. A normal ECG at birth does not exclude signicant congenital cardiac conduction disease associated with maternal anti-Ro antibodies. Rheumatology (Oxford) 2001; 40: 939940. 27 Nield LE, Silverman ED, Smallhorn JF et al. Endocardial broelastosis associated with maternal anti-Ro and anti-La antibodies in the absence of atrioventricular block. J Am Coll Cardiol 2002; 40: 796802. 28 Julkunen H, Eronen M. The rate of recurrence of isolated congenital heart block: a population-based study. Arthritis Rheum 2001; 44: 487488. 29 Hughes G. The eradication of congenital heart block. Lupus 2004; 13: 489. 30 Watson RM, Scheel JN, Petri M et al. Neonatal lupus erythematosus. Report of serological and immunogenetic studies in twins discordant for congenital heart block. Br J Dermatol 1994; 130: 342348. 31 Harley JB, Kaine JL, Fox OF, Reichlin M, Gruber B. Ro (SS-A) antibody and antigen in a patient with congenital complete heart block. Arthritis Rheum 1985; 28: 13211325. 32 Cooley HM, Keech CL, Melny BJ, Menahem S, Morahan G, Kay TW. Monozygotic twins discordant for congenital complete heart block. Arthritis Rheum 1997; 40: 381384. 33 Julkunen H, Eronen M. Long-term outcome of mothers of children with isolated heart block in Finland. Arthritis Rheum 2001; 44: 647652. 34 Press J, Uziel Y, Laxer RM, Luy L, Hamilton RM, Silverman ED. Longterm outcome of mothers of children with complete congenital heart block. Am J Med 1996; 100: 328332. 35 Gordon PA, Rosenthal E, Khamashta MA, Hughes GR. Absence of conduction defects in the electrocardiograms of mothers with children with congenital complete heart block. J Rheumatol 2001; 28: 366369. 36 Tran HB, Cavill D, Buyon JP, Gordon TP. Intravenous immunoglobulin and placental transport of anti-Ro/La antibodies: comment on the letter by Kaaja and Julkunen. Arthritis Rheum 2004; 50: 337338; author reply 338. 37 Kaaja R, Julkunen H. Prevention of recurrence of congenital heart block with intravenous immunoglobulin and corticosteroid therapy: comment on the editorial by Buyon et al. Arthritis Rheum 2003; 48: 280281; author reply 281282. 38 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; 62: 10101012. 39 Lajic S, Wedell A, Bui TH, Ritzen EM, Holst M. Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 1998; 83: 38723880. 40 Bloom SL, Shefeld JS, McIntire DD, Leveno KJ. Antenatal dexamethasone and decreased birth weight. Obstet Gynecol 2001; 97: 485490. 41 Zecca E, Papacci P, Maggio L et al. Cardiac adverse effects of early dexamethasone treatment in preterm infants: a randomized clinical trial. J Clin Pharmacol 2001; 41: 10751081. 42 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: 15421548. 43 Rosenthal E, Gordon PA, Simpson JM, Sharland GK. Letter regarding article by Jaeggi et al., transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 2005; 111: e287288; author reply e287288. 44 Groves AM, Allan LD, Rosenthal E. Therapeutic trial of sympathomimetics in three cases of complete heart block in the fetus. Circulation 1995; 92: 33943396. 45 Robinson BV, Ettedgui JA, Sherman FS. Use of terbutaline in the treatment of complete heart block in the fetus. Cardiol Young 2001; 11: 683686. 46 Saleeb S, Copel J, Friedman D, Buyon JP. Comparison of treatment with uorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus. Arthritis Rheum 1999; 42: 23352345. 47 Glickstein J, Buyon J, Kim M, Friedman D. The fetal Doppler mechanical PR interval: a validation study. Fetal Diagn Ther 2004; 19: 3134. 48 Friedman DM, Kim MY, Copel JA, Davis C, Buyon JP. Utility of cardiac monitoring in fetuses at risk of congenital heart block. The PR interval and dexamethasone evaluation (PRIDE) prospective study. Arthritis Rheum 2006; 54: S689. 49 Sonesson SE, Salomonsson S, Jacobsson LA, Bremme K, WahrenHerlenius M. Signs of rst-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies. Arthritis Rheum 2004; 50: 12531261.

Lupus