First‐degree heart block in the fetus of an anti‐SSA/Ro–positive mother: Reversal after a short course of dexamethasone treatment

Isolated congenital heart block is almost invariably associated with the presence of antibodies to SSA/Ro and SSB/La antigens in the maternal circulation. Once established, third‐degree congenital heart block is permanent. However, a lesser degree of autoantibody‐associated heart block in a fetus can be reversed if it is recognized and treated early enough with fluorinated glucocorticosteroids. The only method available clinically for the recognition of first‐degree heart block in a fetus is measurement of the mechanical PR interval by pulsed Doppler echocardiography. This is the first report of a fetus in whom a diagnosis of first‐degree heart block and the consequent decision to intervene were based solely on this technique. In addition, the first‐degree heart block resolved completely after only 2 weeks of dexamethasone treatment, and the heart rhythm remained stable throughout the remainder of the pregnancy despite early discontinuation of therapy due to oligohydramnios.     

Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies

OBJECTIVE: To prospectively investigate the development of fetal heart block in anti-SSA/Ro 52-kd-positive women, and to evaluate the usefulness of serial Doppler echocardiography in detecting early signs of congenital heart block. METHODS: Twenty-four women with anti-SSA/Ro 52-kd antibodies and consequently increased risk for fetal heart block were followed up weekly, between 18 and 24 weeks of gestation, with two Doppler echocardiographic methods designed to estimate the time delay between hemodynamic events caused by atrial and ventricular depolarizations. Two hundred eighty-four women with normal pregnancies served as controls. Anti-Ro 52-kd, anti-Ro 60-kd, and anti-La antibodies were investigated by immunoblotting and enzyme-linked immunosorbent assay using recombinant proteins. RESULTS: In anti-Ro 52-kd-positive women, fetal atrioventricular (AV) time intervals were longer and heart rates were slightly lower compared with those in controls. Eight of 24 fetuses had signs of first-degree block. One of these fetuses had progression to complete block, and another showed recovery from second-degree block to first-degree block with betamethasone treatment. In the remaining 6 fetuses, spontaneous normalization occurred before or shortly after birth. Fetuses with normal AV time intervals at 18-24 weeks had normal electrocardiographic results at birth. CONCLUSION: Anti-Ro 52-kd-positive pregnant women frequently carry fetuses with Doppler echocardiographic signs of first-degree AV block. These blocks revert spontaneously in the majority of fetuses, but progression to a more severe degree of block may occur in some. Serial Doppler echocardiographic measurement of AV time intervals is suggested as a useful method for surveillance of these high-risk pregnancies.     

Isolated congenital heart block

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.     

Congenital heart block: clinical features and therapeutic approaches

Isolated congenital heart block is strongly associated with anti-Ro antibodies. It occurs in 2% of anti-Ro antibody positive pregnancies with a recurrence rate of 17-19%. Mortality is high in the first year of life (12-41%) and is predominantly due to dilated cardiomyopathy. A prolonged QTc occurs in 15-22% 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 first-degree heart block. Both first and second-degree heart block detected in utero respond to therapy with fluorinated 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 fluorinated steroids for established complete heart block is conflicting, although their use in cases where there is evidence of hydrops, poor ventricular function or both is not controversial.     

Epidemiology, etiology, detection, and treatment of autoantibody-associated congenital heart block in neonatal lupus

Neonatal lupus syndrome is a model of passively acquired autoimmunity in which the pregnant woman’s serum contains specific antibodies to 52 or 60 kd SSA/Ro and/or 48 kd SSB/La, which cross the placenta and are associated with the development of congenital heart block in the fetus and/or a transient rash or various liver and blood cell abnormalities in the newborn. To date, congenital heart block is a permanent condition that entails significant morbidity and mortality, with nearly all affected infants requiring pacemakers and with an 80% cumulative probability of survival at 3 years of age. An intensive search is on for the specific etiopathophysiology and for new clinical tools to approach and treat this disease.     

A Newborn with Congenital Complete Atrioventricular Block,Lissencephaly, and Skeletal Abnormalities: A Case of Suspected Cytomegalovirus Infection

We present a case of congenital complete atrioventricular block in a preterm microcephalic male with multiple additional congenital anomalies, including spinal and rib abnormalities. The heart was structurally normal, and maternal tests for autoimmune disorders were negative. The brain had an immature lissencephalic appearance, suggestive of an insult early in gestation. Genetic testing was normal, virtually excluding chromosomal disorders that are known to cause lissencephaly. Viral studies were suggestive of cytomegalovirus infection during early gestation, and we believe that the patient's clinical presentation was most likely the result of an early cytomegalovirus infection. The finding of complete atrioventricular block in a patient with presumed cytomegalovirus infection would represent a very rare complication. “Isolated” complete atrioventricular block in a fetus should be considered an incentive for an extensive work-up in search for a possible etiology, rather than accepted as a final diagnosis.     

An overview on systemic lupus erythematosus pregnancy

A systemic lupus erythematosus (SLE) pregnancy is no longer regarded as unacceptable, with an early diagnosis, a mild disease condition, and good interdisciplinary collaboration ensuring intense surveillance of pregnant SLE patients. The key point is a sufficiently long period of disease quiescence before conception. A low dose of prednisone is preferable during pregnancy. Nevertheless, 20% of disease flare-up still happens interpartum or postpartum, even in such well-planned pregnancies, although usually with only mild severity. Pregnancy during an active disease stage, especially active nephritis, should always be avoided. Substantial renal function damage may occur, and there is a relatively high prevalence of preeclampsia, which may further compromise the mother as well as the fetus. It is well documented that antiphospholipid syndrome and antiphospholipid antibodies are strongly associated with fetal wastage. Low-dose aspirin or heparin is indicated for a favorable fetal outcome. Women with positive anti-SSA and/or anti-SSB should be aware of the danger of congenital heart block in their infants. Cytotoxic drugs applied in the early stage of pregnancy are dangerous to the fetus. A rather long-term follow-up is required to make a precise evaluation of the maternal SLE influence on the offspring.     

A combination therapy to treat second-degree anti-Ro/La-related congenital heart block: a strategy to avoid stable third-degree heart block?

While mainly based on the use of fluorinated steroids, there is no standard management of anti-Ro/La-related congenital heart block (CHB). This is a report concerning two consecutive cases of anti-Ro/La-related second-degree block treated with betamethasone (4?mg/day), weekly plasmapheresis, and intravenous immunoglobulins (IVIGs; 1?g/kg) administered every 15 days, a therapy that was begun shortly after CHB was detected and continued until delivery. The newborns were also treated with IVIG (1?g/kg) soon after birth and continued fortnightly until the anti-Ro/La antibody levels became undetectable. In both cases second-degree AV block reverted to a stable sinus rhythm with a first-degree atrioventricular (AV) block. Moreover, there was no recurrence of CHB when therapy was suspended, as confirmed by a 29 month and an eight month follow-up, respectively.     

Echocardiography and fetal heart sounds in the diagnosis of fetal heart block.

A 32-week fetus was demonstrated phonocardiographically and echocardiographically to have a regular atrial rate of 150 per minute and a regular ventricular rate of 39 per minute, indicating complete heart block. The diagnosis was suspected when two groups of heart sounds at two distinct rates were heard on auscultation, and was confirmed by the postnatal ECG. The maternal history was significant for the presence of systemic lupus erythematosus. The basis for the echocardiographic diatnosis of complete heart block, the presence of atrial heart sounds in complete heart block, and the relationship of maternal SLE to congenital heart block are discussed.     

Neonatal lupus: basic research and clinical perspectives

Neonatal lupus, although quite rare, carries a significant mortality and morbidity when the fetal heart is the targeted organ. Anti-SSA/Ro-SSB/La antibodies are present in more than 85% of mothers whose fetuses are identified with congenital heart block (CHB) in a structurally normal heart, but the risk for a woman who has the candidate antibodies to have a child who has CHB is approximately 2%. Although the precise pathogenic mechanism of injury remains unknown, it is clear that the antibodies alone are insufficient to cause disease, and fetal factors are likely contributory. In vivo and in vitro evidence supports a pathologic cascade, involving apoptosis of cardiocytes, surface translocation of Ro and La antigens, binding of maternal autoantibodies, secretion of profibrosing factors (eg, tumor growth factor ) from the scavenging macrophages, and modulation of cardiac fibroblasts to a myofibroblast-scarring phenotype. The spectrum of cardiac abnormalities encompasses varying degrees of block identified in utero and late-onset cardiomyopathy. Better echocardiographic measurements that identify first-degree block in utero may be the optimal approach for pregnant women at risk; prophylactic therapies, including treatment with intravenous immunoglobulin, await larger trials.     

Congenital atrioventricular block and maternal autoimmune diseases

Congenital heart block is rare; it is acquired in utero, definitive and, more often than not, complete. It can be diagnosed by the appearance of fetal bradycardia around the 23rd week of gestation, during ultrasonographic monitoring of pregnancy. Heart block is usually associated with the presence of anti-Ro and/or anti-La antibodies in the mother's serum. These maternal immunological abnormalities can be isolated or associated with an autoimmune disease, usually systemic lupus erythematosus, but also Sj?gren's syndrome, or more rarely still, an as yet unclassified connective tissue disease. Anti-Ro and anti-La antibodies cross the placental barrier and react with a fetal heart, leading to acute fetal myocarditis by the 17th week of gestation. When severe, it is lethal, otherwise it can result in degeneration and endocardial fibroelastosis, disrupting conduction and leading to congenital heart block. The ideal treatment would be prevention with corticosteroids. When the mother is Ro or La antibody-positive before pregnancy, elimination of these circulating antibodies can be attempted by treatment with 0.5 mg/kg body wt/d of prednisolone for 3 months. If the treatment is successful, corticotherapy can be prescribed early in the pregnancy to try to protect the fetus. However, there is not always a relationship between maternal anti-Ro antibodies and fetal heart block. If the Ro/La antibody-positive woman is already pregnant, but before her 17th week, it is possible to prescribe dexamethasone, which crosses the placenta and remains active, sometimes in association with plasmapheresis.     

Complete heart block in a case of pregnancy

In summary we wish to emphasize the relatively infrequent occurrence of acceptable cases of congenital complete heart block as reported in American literature. A review of the literature reveals that only twenty-six cases of complete heart block in pregnant women have been reported.A report of a patient with congenital complete heart block who experienced normal pregnancy and uneventful recovery has been presented. This report adds emphasis to the current belief that patients with complete heart block who become pregnant should be allowed to continue a normal pregnancy, provided that the associated congenital defects do not constitute an indication for therapeutic abortion.It is our hope that the report of this case of congenital complete heart block in pregnancy may stimulate interest in this rare condition and ultimately lead to better understanding and proper recognition of this entity.     

Finding the “PR‐fect” Solution: What Is the Best Tool to Measure Fetal Cardiac PR Intervals for the Detection and Possible Treatment of Early Conduction Disease?

In the absence of structural heart disease, the great majority of cases with complete congenital heart block will be associated with the maternal autoantibodies directed to components of the SSA/Ro—SSB/La ribonucleoprotein complex. Usually presenting in fetal life before 26 weeks' gestation, once third‐degree (complete) heart block develops, it is irreversible. Therefore, investigators over the past several years have attempted to predict which fetuses will be at risk for advanced conduction abnormalities by identifying a biomarker for less severe or incomplete disease, in this case, PR interval prolongation or first‐degree atrioventricular block. In this state‐of‐the‐art review, we critically analyze the various approaches to defining PR interval prolongation in the fetus, and then analyze several clinical trials that have attempted to address the question of whether complete heart block can be predicted and/or prevented. We find that, first and foremost, definitions of first‐degree atrioventricular block vary but that the techniques themselves are all similarly valid and reliable. Nevertheless, the task of predicting those fetuses at risk, and who are therefore candidates for treatment, remains challenging. Of concern, despite anecdotal evidence, there is currently no conclusive proof that a prolonged PR interval predicts complete heart block.     

Congenital heart block

1. 1. Studies of eight cases of congenital heart block, including the first published case of mitral atresia with congenital heart block, are presented.

2. 2. Review of the literature revealed that of the seventeen cases of congenital heart block reported with postmortem findings interventricular septal defect, with or without other anomalies, was the most common associated congenital lesion, being present in twelve cases, while patent ductus arteriosus was found in six and coarctation of the aorta in four cases as part of the malformation. Congenital heart block may occur in patients who show no clinical evidence of associated heart disease.

3. 3. The diagnostic value of the electrocardiogram in differentiating congenital from acquired heart block is stressed. The ventricular rate in congenital heart block is generally 40 to 80 beats per minute and the QRS complex is usually supraventricular in form. This is in contrast to the somewhat slower ventricular rate and idioventricular form of the QRS complex usually found in acquired heart block.

4. 4. Cardiac catheterization in two of our patients revealed that (a) when atrial contraction occurs during ventricular systole, the “a” waves were considerably higher than those recorded when atrial contraction occurs during ventricular diastole; (b) direct pulmonary artery, right ventricular and brachial artery pressures revealed the influence of the atrial contractions. The possible mechanisms of the hemodynamic observations are discussed.

5. 5. The prognosis of congenital heart block is primarily that of the associated heart disease, when present.

     

Prevention of congenital heart block in children of SSA-positive mothers

The incidence of congenital heart block (CHB) in the offspring of anti-Ro-positive women is approximately 1-2%, and the risk of recurrence is 10 times higher in the following pregnancies. Non-fluorinated steroids (prednisone, prednisolone and methylprednisolone) are recommended only for maternal indications, not for prevention of CHB in anti-Ro/SSA-positive women. Fluorinated steroids (dexamethasone or bethametasone) are not metabolized by the placenta and are available to the fetus in an active form. Routine prophylactic therapy with fluorinated steroids is not recommended even in women who previously had children with CHB or skin rash since this therapy has its own side-effects. Intravenous immunoglobulin had been used to prevent the development of CHB in 8 high risk mothers (anti-Ro/SSA positive and previous pregnancy with CHB), and in one case CHB recurred (12.5%). At present, the only sure recommendation that can be made in these women is that in the presence of reliable positivity for anti-Ro/SSA antibodies serial echocardiograms and obstetric sonograms should be performed at least every 2 weeks starting from the 16th week of gestational age: the goal is to detect early fetal abnormalities, such as premature atrial contractions or moderate pericardial effusion, that might precede complete atrioventricular block and that might be a target of preventive therapy. Fluorinated steroids should not be used in the absence of symptoms; in the presence of alarming symptoms, betamethasone seems safer than dexamethasone.     

Importance of the immune response to the Ro/La particle in the development of congenital heart block and neonatal lupus erythematosus

Previous studies have suggested a role for anti-Ro antibodies in the pathogenesis of neonatal lupus erythematosus (NLE). We reexamined the role of the immune response to the Ro/La particle in the development of NLE using newer and more definitive assay techniques. All 15 infants with congenital heart block and NLE had both anti-Ro and anti-La antibodies. Of 8 patients with cutaneous NLE alone, 2 had anti-Ro antibodies alone while the remaining 6 had both anti-Ro and anti-La antibodies. One woman gave birth to 2 children; one had both Ro and La antibodies and developed congenital heart block, the other had only anti-Ro and anti-U1RNP antibodies and was clinically normal. Our study demonstrates that the presence of anti-Ro and anti-La antibodies define the immune response that is associated with the development of congenital heart block of NLE.     

Progressive fetal atrioventricular block in heterotaxy syndrome

We report a fetus with left isomerism, in whom the atrioventricular block progressed from low grade second degree to complete block and fetal hydrops. While it is known that there is a high incidence of heart block in the fetus with left isomerism, as far as we are aware, ours is the first report of Wenckebach type block documented in the fetus by Doppler echocardiography, and demonstration of the progression of heart block during fetus life in the setting of left isomerism.     

Phonocardiography of the human fetus

From our work evidence has been obtained of the variability of normal heart sounds before and after birth. An early systolic murmur is almost universal in early infancy, according to our criteria for the recognition of a murmur.Among thirty-three subjects upon whom fetal heart sound observations were made, twelve presented no murmurs, seventeen showed an early systolic murmur only. Seven showed other systolic and diastolic murmurs which apparently could not be used as indications of congenital heart lesions as seen after birth, and may represent currents through the patent foramen ovale and ductus arteriosus.One case illustrated certain criteria of a congenital heart lesion before birth. These criteria agreed in general with those of Hoehne but were more specific in recognition of the particular valve lesion noted in this case, namely pulmonic stenosis. The unique feature of this case was a high-pitched murmur throughout the whole of systole. This was totally unlike any of the murmurs recorded by us either in children or adults in cases other than those diagnosed clinically as classical pulmonic stenosis.A surprising fact disclosed in this investigation was that in the normal fetus with a patent foramen ovale and ductus arteriosus, murmurs were not consistently found. Presumably it requires either abnormal pressure relationships, developmental defects occurring relatively early in intrauterine life, or both, to produce the auditory signs of a congenital lesion of the recognizable patent ductus arteriousus type as seen after birth. This theory is not original but receives support from the observations here recorded.     

Pacing in preterm with hydrops fetalis due to congenital complete heart block

Hydrops fetalis due to congenital complete heart block (CCHB) is a rare condition. The outcome of the preterm fetus with hydrops fetalis due to CCHB is poor, and is frequently associated with significant morbidity and mortality. The management of this condition is difficult. We report our experience in a hydropic preterm using staged pacing by applying left ventricular epicardial pacing with a temporary pacemaker and subsequently, left ventricular epicardial pacing with a permanent pacemaker.