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Isolated congenital heart block, frequently seen in mothers who have connective-tissue disease, can be transmitted to the fetus through transplacental passage of anti-Ro/SSA and anti-La/SSB autoantibodies. Even if the antibodies appear transiently in the fetal circulation, the block is permanent and can require pacemaker implantation. Complete congenital heart block is seen in 1% to 5% of neonates born to mothers who carry these autoantibodies. Herein, we report the case of a baby—born to a 31-year-old asymptomatic woman—who manifested congenital heart block in utero, at 30 weeks of gestation. During gestation and following birth, no further problems were detected. At her last follow-up appointment, 8 years later, the girl still had no clinical symptoms, and exercise increased her heart rate despite complete heart block. We report this case for its unique presentation, and we discuss isolated congenital heart block within the context of the inadequate literature on its pathogenesis and treatment.
Isolated congenital heart block (CHB) is an autoimmune disease that usually develops at some point between 16 and 24 weeks of gestation, coincident with the increased transfer of maternal immunoglobulin G (IgG) antibodies into the fetal circulation. A generally accepted mean incidence of isolated CHB is 1 in 17,000 live births.1–3 However, this incidence increases dramatically to about 5% of 1st pregnancies among mothers with lupus erythematosus and to 18% of subsequent pregnancies.2,4 The target antigens of anti-Ro/SSA and anti-La/SSB (anti-Ro/La) are sequestered intracellularly and found in fetal cardiac tissue, including that of the conduction system. Fetal tissue damage has been shown to be mediated by anti-Ro and anti-La, independently or together.5–7
These autoantibodies have been thought to cause myocarditis, hemorrhage, and necrosis in cells specific to the fetal conduction system, and this damage has been shown to block atrium–atrioventricular (AV) node conduction. Furthermore, anti-Ro/La causes calcification and fibrosis in the conduction system, thereby causing 1st-, 2nd-, and 3rd-degree heart block.8 The other cardiac manifestations of neonatal lupus syndrome are heart failure with dilated cardiomyopathy and long QT syndrome without CHB. Clinical manifestations depend upon the ventricular rate. Should the fetus have a very low heart rate, fetal hydrops or neonatal heart failure may occur. Some newborns can compensate for a low heart rate; however, most need pacemaker implantation.6,7,9
The hallmark of isolated CHB is irreversible AV block, unaccompanied by other cardiac structural or anatomic abnormalities. Even though CHB is persistent, in a few isolated cases AV nodal rhythm has returned to sinus rhythm spontaneously.10
Our patient experienced a clinical course totally different from others reported in the medical literature. We report this case for its unique presentation, and afterwards we discuss CHB and the matter of whether these patients need permanent pacing.
A healthy, asymptomatic 31-year-old woman was referred to our pediatric cardiology clinic at 30 weeks of gestation after detection of a decreased fetal heart rate upon routine obstetric ultrasonographic examination. The fetal echocardiographic study, performed in our clinic, revealed CHB. After referral for further study, the mother was diagnosed with systemic lupus erythematosus. Fetal echocardiography revealed a structurally normal heart with a ventricular rate of 74 to 90 beats/min, an atrial rate of 130 to 140 beats/min, and no pericardial effusion.
The female baby, born via cesarean section in the 38th week of gestation, weighed 2,190 g and was 47 cm in length. After delivery, her heart rate was 70 to 110 beats/min. Electrocardiography revealed complete AV block, with an atrial rate of 150 beats/min and a ventricular rate of 70 to 90 beats/min (Fig. 1). Holter monitoring showed complete AV block, but during monitoring the ventricular rate increased to 120 beats/min. Results of laboratory examination showed that the hemoglobin level was 14.9 g/dL, and the blood was negative for antinuclear, anti-ds DNA, and anti-La/SSB antibodies, but positive for anti-Ro/SSA; there was no increase in hepatic transaminase levels and no thrombocytopenia. Echocardiographic evaluation showed normal left ventricular systolic and diastolic function. The mother's blood samples were positive for antinuclear antibodies and anti-Ro/SSA but were negative for anti-La/SSB and anti-DNA (Table I).
This child, up to the time of her last examination at the age of 8 years, remained in complete AV block. Symptoms of heart failure and growth retardation in infancy and early childhood were not detected. Holter monitoring at the age of 4 years showed complete AV block, with a minimum heart rate of 39 beats/min (Fig. 2) and a mean heart rate of 43 to 50 beats/min; but during exercise, the ventricular rate increased to a peak of 110 beats/min (Fig. 3). At her 8-year follow-up visit, the girl remained well and had no complaints. Her weight and height fell between the 50th and 75th percentiles. Although her CHB was permanent, our patient manifested no effort dyspnea and performed all ranges of exercise without difficulty. During exercises, her heart rate increased and her serum samples became negative for anti-Ro/SSA antibody.
Isolated CHB is associated mainly with neonatal lupus syndrome, but it can be observed in children whose mothers have other connective-tissue diseases, such as Sjögren's syndrome. Nearly half of the mothers do not have connective-tissue disease when their children are born with CHB, but most of them have anti-Ro/La autoantibodies.11 Congenital heart block requires a pacemaker in two thirds of the affected pediatric population. In less than 10% of cases, congenital AV block is 1st or 2nd degree at birth, and, in 50% of these cases, it progresses to 3rd-degree block after birth.7
Most cases of isolated CHB are detected in utero and are associated with anti-Ro/La autoantibodies. Under normal physiologic conditions, the cognate antigens are intracellular and therefore inaccessible to the circulating antibodies. Two plausible explanations for the pathogenesis of isolated CHB should be considered. The 1st explanation presents dual possibilities: the cognate antigens Ro/SSA and La/SSB are transported to the cellular surface as a consequence of an event such as viral infection, ultraviolet light exposure, or apoptosis12–15; alternatively, the anti-Ro/La autoantibodies cross-react with a surface antigen on the sarcolemma of the cardiomyocyte. The 2nd possibility is that maternal antibodies react with components on the cellular surface. To date, the muscarinic receptor laminin, the serotonin receptor 5-hydroxytryptamine4, and the L-type calcium channels are the sarcolemmic proteins found to be involved in this process.12,13,16–18
Lazzerini and colleagues, in their study of the electrophysiologic and molecular mechanisms of CHB,7 concluded that anti-Ro/SSA antibodies might display direct arrhythmogenic activity. Anti-Ro/SSA antibodies are found—more than other antibodies—to be associated with isolated CHB.7 In our case, the sera of both mother and child were positive for the anti-Ro/SSA antibody.
Antibodies against the Ro/SSA and La/SSB ribonucleoproteins are detectable in several autoimmune diseases, especially in systemic lupus erythematosus and Sjögren's syndrome. These antibodies play an important role in the pathogenesis of many rhythm disorders. Patients who have experienced the transplacental passage of anti-Ro/SSA antibodies are vulnerable to sinus bradycardia,1 as well as to CHB. Mazel and colleagues19 have observed sinus bradycardia in mice injected with IgG obtained from the mothers of children with CHB. Dubin and co-authors20 found that babies with congenital junctional ectopic tachycardia and congenital complete AV block had mothers with elevated anti-Ro/La titers. They hypothesized that the circulating autoantibodies, in fetal or neonatal life, had inflamed the conduction system, which in turn had induced the arrhythmia.
Nevertheless, children whose mothers have displayed anti-Ro/La negativity have shown the presence of CHB. Indeed there is suspicion regarding the association of anti-Ro/La antibodies with CHB.21 In a study by Brucato and colleagues,21 CHB was observed in 20% of mothers with anti-Ro/La negativity. Schmidt22 and Maeno23 and their associates reported anti-Ro/La negativity in 35% of the mothers whom they evaluated. Spontaneous regression of AV block was possible in mothers who had anti-Ro negativity and children with CHB. Infant mortality rates were similar among mothers who had anti-Ro positivity, anti-Ro negativity, and children with CHB.21
Fetal heart rate is an important indicator of the prognosis of the disease during the newborn period. Veille and Covitz9 have suggested that to adapt to persistent bradycardia, both the right and left ventricles increase in size. In the same study, when the ventricular rate decreased to 38 beats/min, fractional shortening decreased, and this resulted in ascites and pericardial effusion.9 Among patients with a prenatal diagnosis of CHB, certain features appear to result in a particularly poor outcome. Premature birth, low birth weight, low ventricular rate, significant structural heart disease, evidence of ventricular dysfunction or associated cardiomyopathy, and the presence of hydrops fetalis are poor prognostic signs. Ascites and anasarca-type edema are also associated with poor outcome, and pacemaker implantation is indicated in infants with cardiac failure and a heart rate of under 55 beats/min. In the presence of hydrops fetalis, the reported mortality rates for infants born with CHB have exceeded 80%.2,6,24 The clinical presentation of CHB in utero or in the neonatal period is itself a grave indication: the overall mortality rate even in neonates and infants with structurally normal hearts has been estimated at 19% to 31%.2,8,10
Previous studies have proposed various therapeutic regimens for use in CHB.1,23–26 These include β-sympathomimetic drugs to increase the fetal heart rate; plasmapheresis and steroids to target the antibody-mediated and inflammatory components; and digoxin or furosemide to prevent hydrops. The studies conducted to date take the form of case series; controlled clinical trials are not yet available. The usefulness of steroid treatment and other treatment options is still under debate.1,23–26 Recent studies27–29 suggest that high-risk newborns should be delivered before full term; after birth, therapy typically includes aggressive medical management, coupled with pacing in those infants who do not respond to medical treatment alone. Premature birth, low birth weight, poor hemodynamic status, and metabolic acidosis adversely affect the performance and success of pacing. Planned early pacing of high-risk neonates who have CHB potentially reduces the adverse consequences of profound bradycardia and asystole, which often occur soon after birth, within the context of increasing metabolic demand. In cases of isolated CHB, Glatz and colleagues28 have recommended early diagnosis and the use of maternal steroids, followed by planned delivery and, for severely affected newborns, the early placement of temporary epicardial pacing leads. Temporary epicardial ventricular pacing wires, implanted through a minimally invasive approach, can serve as a successful bridge to a permanent pacemaker.
Kelle and associates30 have shown that the implantation of an epicardial pacemaker in neonates with CHB is technically feasible and results in excellent outcomes in patients with structurally normal hearts. There is still discussion about whether the pacing should be permanent or temporary, and about whether placement should be transvenous or epicardial. Studies on this topic take the form of isolated case reports.23–30
Our patient had a ventricular rate of 70 to 90 beats/min, whereas normal newborns have a heart rate of 94 to 155 beats/min.31 Despite her low heart rate, her weight and height were within normal limits. Signs of heart failure were not observed, and no treatment was given during or after delivery. There were no indications of fatigue or decreased effort capacity during the follow-up period. At 4 years of age, the heart rate of the patient was approximately 43 to 50 beats/min during rest. Nonetheless, the ventricular rate increased dramatically (up to 110 beats/min) to provide the cardiac output necessary during maximum effort. It is very interesting and rather bizarre that AV node responses to exercise resulted in accelerated heart rate. The patient has displayed great variation in her ventricular heart rate. Although the CHB was detected in fetal life, no symptoms were observed during the postnatal period, infancy, or childhood. These results have indeed surprised us. The literature on this subject suggests that, when CHB is persistent, the ventricular rate shows no increase during exercise. Although conduction system abnormalities are present in more than 85% of babies born to mothers with anti-Ro/SSA and anti-La/SSB antibodies, only about 2% of such newborns develop CHB. Although these antibodies are directly involved in the pathogenesis of CHB, we infer that other factors—perhaps environmental, fetal, individual maternal, and genetic—can predispose patients to CHB (or not). Additional studies are needed to clarify these individual differences that result in variant degrees of AV node dysfunction.
Address for reprints: Ayse Yildirim, MD, Kartal Kosuyolu Yuksek Ihtisas Egitim & Arastirma Hastanesi, Denizer Caddesi Cevizli Kavsagi No:2, 34846 Kartal, Istanbul, Turkey