Congenital heart block: evidence for a pathogenic role of maternal autoantibodies

Abstract

During pregnancy in autoimmune conditions, maternal autoantibodies are transported across the placenta and may affect the developing fetus. Congenital heart block (CHB) is known to associate with the presence of anti-Ro/SSA and anti-La/SSB antibodies in the mother and is characterized by a block in signal conduction at the atrioventricular (AV) node. The mortality rate of affected infants is 15% to 30%, and most live-born children require lifelong pacemaker implantation. Despite a well-recognized association with maternal anti-Ro/La antibodies, CHB develops in only 1% to 2% of anti-Ro-positive pregnancies, indicating that other factors are important for establishment of the block. The molecular mechanisms leading to complete AV block are still unclear, and the existing hypotheses fail to explain all aspects of CHB in one comprehensive model. In this review, we discuss the different specificities of maternal autoantibodies that have been implicated in CHB as well as the molecular mechanisms that have been suggested to operate, focusing on the evidence supporting a direct pathogenic role of maternal antibodies. Autoantibodies targeting the 52-kDa component of the Ro antigen remain the antibodies most closely associated with CHB. In vitro experiments and animal models of CHB also point to a major role for anti-Ro52 antibodies in CHB pathogenesis and suggest that these antibodies may directly affect calcium regulation in the fetal heart, leading to disturbances in signal conduction or electrogenesis or both. In addition, maternal antibody deposits are found in the heart of fetuses dying of CHB and are thought to contribute to an inflammatory reaction that eventually induces fibrosis and calcification of the AV node, leading to a complete block. Considering that CHB has a recurrence rate of 12% to 20% despite persisting maternal autoantibodies, it has long been clear that maternal autoantibodies are not sufficient for the establishment of a complete CHB, and efforts have been made to identify additional risk factors for this disorder. Therefore, recent studies looking at the influence of genetic and environmental factors will also be discussed.

Systemic Lupus Erythematosus and Outcomes in First and Subsequent Births Based on Data From a National Birth Registry

“…Patent ductus arteriosus has been associated with the use of nonsteroidal antinflammatory drugs after gestational week 32 (37). Four newborns of patients had congenital heart block, which has been associated with the presence of anti-Ro/anti-La antibodies (38,39). Overall, the numbers of malformations among infants of patients were small, and the present study did not have power to examine the differences in specific birth defects.…”

Fetal Congenital Complete Atrioventricular Block in a Mother with Isolated Serum Anti-SSA/Ro and Anti-SSB/La Antibodies

“…6,7 Because of the rapid progression of the disease from 1st or incomplete block to 2nd and 3rd block, most of the cases are not detected until they develop complete AVB. 3,4 The first sign of our case was fetal bradycardia with a ventricular rate of 50 to 60 bpm and complete block at 23 weeks of gestation.…”

“…Autoimmune congenital AVB develops only in 1% to 2% of anti-SSA/Ro and/or anti SSB/La positive pregnancies, but its recurrence rate is 12% to 20%. 3 Congenital AVB is related to significant morbidities such as dilated cardiomyopathy, fetal hydrops and neonatal heart failure. 1 The perinatal mortality rate of congenital AVB varies between studies with a 5.5% to 25% rate of intrauterine fetal demise and a 18% to 40% rate of neonatal mortality.…”

Fetal Atrioventricular Heart Block

“…The exact pathologic mechanism of fetal heart block remains unclear. The 2 leading theories involve apoptosis (programed cell death) and cross-reactivity (6 ). According to the apoptosis theory, transferred maternal anti-Ro antibodies bind to apoptotic fetal cardiac cells that express the Ro antigen.…”