Treatment of Immune-Mediated Atrioventricular Block

Treatment of Immune-Mediated Atrioventricular Block

Helena M. Gardiner

Bettina F. Cuneo


Among mothers with anti-Ro/SSA antibodies, fetal atrioventricular (AV) block is rare; the AV block phenotype and natural history are variable; and data on outcomes are scant, anecdotal, and retrospective. Not surprisingly, practice variation is considerable, and there are no evidence-based guidelines to direct treatment strategies. Thus, questions remain as to whether treatment can prevent AV block, alter the progression of 1° or 2° AV block to 3° AV block, or decrease the likelihood of dilated cardiomyopathy.1,2,3,4,5,6,7,8 What is known is that 3° AV block is immutable, fetuses with 3° AV block are at high risk for perinatal demise, and survivors face lifelong cardiac pacing. This chapter will summarize published data on both prophylaxis of anti-Ro/SSA antibody-positive pregnancies and the treatment of 1°, 2°, and 3° fetal AV block.


Several prophylactic strategies have been proposed including administration of transplacental fluorinated steroids, plasmapheresis, and intravenous immune globulin (IVIG, 1 gram (g)/kilogram (kg) at 14 and 18 weeks or 0.4 g/kg 3×/wk from 12 to 24 weeks). However, these therapies have not been successful in preventing AV block.2,9,10,11,12 In fact, due to duration of continuous treatment (from 16 weeks of gestation onward), prophylactic steroids have profound side effects including intrauterine growth restriction, hypoadrenalism, and oligohydramnios. Furthermore, they may worsen maternal diabetes mellitus.

The only prophylactic treatment shown to reduce recurrence of anti-Ro/SSA-mediated AV block is hydroxychloroquine (HCQ). HCQ inhibits activation of toll-like receptors, a class of transmembrane proteins that initiate the cellular immune response. By inhibiting ligation of toll-like receptors, the pathogenesis of immune-mediated damage to the fetal cardiac tissue is interrupted, lowering the risk of conduction system and myocardial (dilated cardiomyopathy) disease.13

FIGURE 4.3.1 Results of a retrospective study of hydroxychloroquine prophylaxis to prevent recurrence of atrioventricular (AV) block in pregnancies with offspring previously affected with AV block. DC, dilated cardiomyopathy; EFE, endocardial fibroelastosis; SR, sinus rhythm; Rx, treatment. (Adapted from Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012;126(1):76-82.)

In retrospective studies, HCQ (200 mg twice a day), initiated before 11 weeks of gestation and continued throughout pregnancy, reduced the recurrence of fetal AV block from 18% to about 9%14,15 (FIG. 4.3.1). These results were confirmed in PATCH (Preventive Approach to Congenital Heart Block with Hydroxychloroquine), a prospective study in which 5/63 (7.9%) mothers with a previously affected offspring had recurrence of fetal AV block.16 Thus, in both prospective and retrospective studies, HCQ significantly reduced the recurrence rate of AV block in anti-Ro/SSA-positive mothers, with no evidence of cardiac toxicity in the newborns.17 Currently, there are only limited data supporting the role of HCQ in mothers with no previously affected offspring.18


Based on a hypothesis that inflammation is the basis of the cardiac manifestations of maternal anti-Ro/SSA antibodies, two approaches have been implemented. Therapeutic effects of both dexamethasone and IVIG treatment have been judged in two categories: restoring normal rhythm and improving outcomes. With regard to the effects of treatment on conduction system disease, treatment advocates believe dexamethasone can halt disease progression from 1° to 2° or 2° to 3° AV block
or restore 1:1 AV conduction from 2° AV block. Improved treatment outcomes would include fewer fetuses with 3° AV block, fewer fetuses with dilated cardiomyopathy or cardiac dysfunction, and fewer premature deliveries. For example, some clinicians use dexamethasone only if cardiac dysfunction, AV valve regurgitation, pericardial effusion, or hydrops is present, regardless of conduction system disease, in the belief that treatment will prevent or improve myocardial disease.


From an immunologic perspective, elimination of candidate maternal autoantibodies and reduction of a generalized inflammatory response is the logical approach to the treatment of fetal AV block. Relevant to treating fetal disease, dexamethasone, a glucocorticoid agonist which crosses cell membranes, is only partially metabolized by placental 11β-hydroxysteroid dehydrogenase (11β-OHSD) with the remainder available to the fetus in an active form. The same is not true of prednisone, which does not transfer to the fetus. Dexamethasone binds with high affinity to specific cytoplasmic receptors which modify transcription and resultant protein synthesis to inhibit leukocyte infiltration at the site of inflammation. Dexamethasone thus interferes in the function of the mediators of the inflammatory response.19

Intravenous Immune Globulin

IVIG treatment has been of benefit in a variety of immune-mediated and inflammatory diseases in pregnant women and pediatric patients.20 It is approved by the Federal Drug Administration for primary immunodeficiency, idiopathic thrombocytopenia purpura, Kawasaki disease, B cell-chronic lymphocytic leukemia with hypogammaglobulinemia, pediatric HIV infection, and allogenic bone marrow transplant in adults.20 The major rationale for IVIG in the treatment of AV block was initially based on elimination of anti-Ro antibodies: “no antibody, no disease.”21,22 However, it remains highly speculative whether IVIG can effectively lower the level below the threshold needed to result in cardiac injury. We know that replacement doses of IVIG at 400 mg/kg do not prevent recurrence of fetal AV block.2 However, in mice at doses of 1 gm/kg, IVIG is immunomodulatory via IgG-Fc sialylation and increased surface expression of the inhibitory FcγRIIb receptor on macrophages.23 Data in humans support that IVIG inhibits phagocytosis of IgG-opsonized blood cells (in the case of AV block predicted to be cardiocytes opsonized by anti-Ro independent of Ig-Fc sialylation).22,23 Clinical results in anecdotal reports have suggested IVIG improves outcome in cardiomyopathy24 (TABLE 4.3.1), but it has not been evaluated as an adjunct treatment with dexamethasone for AV block with normal cardiac function.

Although expensive, IVIG may be an effective drug if used in treatment of emerging 3° AV block, especially in combination with dexamethasone.25,26,27,28,29 However, whether monthly doses during pregnancy or postnatal treatment is required, is unknown and proof for any rationale is lacking. We await the results of future prospective studies to develop an evidence-based treatment plan for these high-risk fetuses.



AV Block Dx

IVIG, 70 g

Neonatal Rhythm



VVI paced


VVI paced


×1 (26 wk)

Not paced


Postnatal death


2° AV block not paced


VVI paced


×2 (23 and 26 wk)



q 2 wk (23-36 wk





q 2 wk (26-39 wk)




2° and 3°

DDD paced


VVI paced


VVI paced


VVI paced


×2 (25 and 28 wk)

Postnatal death


×3 (20, 23 and 28 wk)

Postnatal death



×1 (21 wk)




×2 (25 and 30 wk)

DDD paced


DDD biV paced



1° AV block


×1 (25 wk)

DDD paced

AV, atrioventricular; biV, biventricular pacing; DDD, ventricular sensed and paced; DX, diagnosed; IUFD, in utero fetal demise; IVIG, intravenous immune globulin; NSR, normal sinus rhythm; VVI, ventricular sensed and paced, inhibited; wks, weeks; ×, times.

Adapted from Trucco SM, Jaeggi E, Cuneo B, et al. Use of intravenous gamma globulin and corticosteroids in the treatment of maternal autoantibody-mediated cardiomyopathy. J Am Coll Cardiol. 2011;57(6):715-723

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Dec 30, 2020 | Posted by in CARDIOLOGY | Comments Off on Treatment of Immune-Mediated Atrioventricular Block

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