The clinical spectrum of autoimmune congenital heart block

Abstract

Autoimmune congenital heart block (CHB) is an immune-mediated acquired disease that is associated with the placental transference of maternal antibodies specific for Ro and La autoantigens. The disease develops in a fetal heart without anatomical abnormalities that could otherwise explain the block, and which is usually diagnosed in utero, but also at birth or within the neonatal period. Autoantibody-mediated damage of fetal conduction tissues causes inflammation and fibrosis and leads to blockage of signal conduction at the atrioventricular (AV) node. Irreversible complete AV block is the principal cardiac manifestation of CHB, although some babies might develop other severe cardiac complications, such as endocardial fibroelastosis or valvular insufficiency, even in the absence of cardiac block. In this Review, we discuss the epidemiology, classification and management of women whose pregnancies are affected by autoimmune CHB, with a particular focus on the autoantibodies associated with autoimmune CHB and how we should test for these antibodies and diagnose this disease. Without confirmed effective preventive or therapeutic strategies and further research on the aetiopathogenic mechanisms, autoimmune CHB will remain a severe life-threatening disorder.

Figure 1

Maternal and fetal factors associated with the development of CHB. Fetal heart block can be associated with maternal metabolic diseases, drugs, viral myocarditis or transference of maternal autoantibodies, or with fetal anatomical heart abnormalities and genetic channelopathies. *Factors associated with an increased risk of heart structural abnormalities. ^‡Factors associated with a higher risk of development of myocarditis. Abbreviations: ACE, angiotensin-converting enzyme; RNP, ribonucleoprotein; SSA, Sjögren-syndrome-related antigen A; SSB, Sjögren-syndrome-related antigen B; SSRI, selective serotonin reuptake inhibitor.

Figure 2

Ratios of autoantibody positivity and negativity amongst CHB-affected mothers.^– Data taken from our systematic review (Box 2). Most affected mothers were positive for anti-Ro/SSA antibodies, but only around half were positive for anti-La/SSB antibodies. Two-thirds of affected mothers were positive for anti-Ro60 antibodies when tested using r.Ro60 antigen, whereas almost all were positive when tested using n.Ro60 antigen. Abbreviations: n, native; r, recombinant SSA, Sjögren-syndrome-related antigen A; SSB, Sjögren-syndrome-related antigen B.

Figure 3

Proportions of isolated and multiple autoantibody positivity. 288 CHB-affected mothers were tested for anti-Ro52, anti-Ro60 and anti-La autoantibodies.^,,,,, Approximately half the mothers were triple positive. Much lower percentages were reported for double positivity of Ro52⁺Ro50⁺, Ro52⁺La⁺ and Ro60⁺La⁺, and less again for isolated Ro52, Ro60 or La positivity. Only three (1%) mothers tested negative for all three autoantibodies.

Figure 4

Maternal autoimmune diseases associated with CHB. Of 856 CHB-affected mothers who were autoantibody positive, approximately half were asymptomatic Ro/La carriers. 121 (14%) had UAD (lacking fulfillment of the current criteria for systemic autoimmune diseases), 113 (13%) had pSS, 113 (13%) had SLE, 20 (2%) had Sjögren syndrome associated with SLE, and 13 (1.5%) had other ADs (including RA in 5, mixed connective tissue disease in 3, SSc in 2, autoimmune thyroiditis in 1, dermatomyositis in 1 and haemolytic anaemia in 1 case). Data from our systematic review.^{–,–,–,–,,,–,–,,} Abbreviations: AD, autoimmune disease; aSS, Sjögren syndrome associated with other systemic autoimmune diseases; CHB, congenital heart block; pSS, primary Sjögren syndrome; RA, rheumatoid arthritis; SSc, systemic sclerosis; SLE, systemic lupus erythematosus; UAD, undifferentiated autoimmune disease.

Figure 5

Demographics of autoimmune CHB. Data taken from our systematic review show that negative pregnancy outcomes included prematurity (<37 weeks; n = 138 of 360, 38%)^,,,,, IUGR (n = 5 of 62, 8%),^,,, and Caesareans (n = 55 of 73, 75%).^,,,, The gender of live births was 54% female (n = 362) and 46% male (n = 307).^,,,,, The mean weight of live births was 2,409.56 g (1,260–3,950 g; n =9),^,, and a pacemaker was required in 519 of 809 cases (64%).^{,,,,,,,,,,,,,,,–} Graphs depict a | age at diagnosis of CHB (n =280),^{,,,,,,,,,,,,,} b | CHB type (n =772),^{,,,–,,,,,,,,,} c | other cardiac complications (n =875),^{,,,,,,,,,,,,,,,} and d | mortality (n =188).^{,,,,,,,,,,,,,,,,,,,} Abbreviations: CHB, congenital heart block; EFE, endocardial fibroelastosis; IUGR, intrauterine growth restriction.

Figure 6

Autoantibody sequential studies and clinical evaluation of women who have babies with CHB of any degree, EFE or congenital valvular disease in an otherwise structurally-normal fetal heart. For women with negative results in Ro/La commercial tests, we recommend extending immunological studies to include anti-Ro52 and anti-Ro60 antibodies using a native antigen. *Systemic autoimmune diseases more frequently identified in CHB-affected mothers. Abbreviations: CHB, congenital heart block; EFE, endocardial fibroelastosis, pSS, primary Sjögren syndrome; SLE, systemic lupus erythematosus.

Figure 7

Electrocardiogram. Typical electrocardiogram of a healthy person.