The risk for CHB in an anti-Ro-positive pregnancy is 1% to 2%, and a reported recurrence rate of 12% to 20% [1
], despite persisting maternal antibodies, indicates that additional factors (maternal or fetal or both) are critical for the establishment of heart block (Figure ).
Figure 2 Maternal and fetal risk factors in congenital heart block (CHB). Environmental and genetic factors that have been implicated in the development of CHB to date are depicted. Whereas maternal major histocompatibility complex (MHC) genes influence the generation (more ...)
Genetic polymorphisms influencing fetal susceptibility to CHB in anti-Ro/La-positive pregnancies were first investigated in a group of 40 children with CHB by using a candidate gene approach, focusing on two known polymorphisms of the genes encoding the pro-inflammatory and pro-fibrotic cytokines tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta (TGFβ). The TGFβ polymorphism assessed was found significantly more frequently in children with CHB than in their unaffected siblings, whereas the TNFα polymorphism studied was found at an increased frequency in both affected and non-affected children in comparison with healthy controls [70
]. These findings, however, have not yet been replicated in a large group of CHB cases. More recently, Clancy and colleagues [71
] performed a genome-wide association study of individuals who have CHB and who were born to anti-Ro/La-positive mothers. The authors reported a significant association with polymorphisms in the HLA region and at the location 21q22. Although these data need to be replicated in another cohort, they may provide clues for the design of functional studies addressing the pathogenic mechanisms of CHB and the role of the identified SNPs in susceptibility to CHB. However, one should be careful in the interpretation of the observed genetic associations from the case control studies, as these are performed by comparing CHB cases with healthy controls from the general population. Therefore, the associations may reflect simply the genetic bias present in the mothers, who may have SLE or SS or, even if asymptomatic, are genetically and immunologically distinct from the general population in terms of MHC haplotype and autoantibodies to the Ro/La autoantigens.
Given the rarity of CHB in the general population, studies of genetic influences in the human disease are difficult and may not be powerful enough to identify rare variants associated with the condition. Therefore, animal models may provide another source of information, an approach used by Strandberg and colleagues [55
], who recently demonstrated an influence of both maternal and fetal MHC genes in the development of CHB. Using congenic rat strains and a Ro52 immunization model of heart block, the authors showed that generation of pathogenic anti-Ro52 antibodies is restricted by maternal MHC and that the fetal MHC locus regulates susceptibility and determines the fetal disease outcome in anti-Ro52-positive pregnancies [55
Maternal and fetal factors other than genetic differences have also been suggested to contribute to the development of heart block. Although neither fetal gender nor maternal disease severity has been associated with CHB [22
], it has been proposed that maternal age may have an influence on the outcome of anti-Ro52-positive pregnancies [72
]. As the number of cases included in the latter study was too small to distinguish between possible effects of maternal age and parity, we have now addressed this issue in a larger cohort. Analyzing risk factors for the development of heart block in a population-based study, we found that the risk for CHB increased with maternal age but was not influenced by parity [17
]. Although this finding raises the possibility that age-related risk factors associated with pregnancy complications contribute to the risk of CHB, it is also possible that the increasing risk for heart block with increasing maternal age reflects the appearance or increased serum levels of anti-Ro/La autoantibodies in women over time. Interestingly, we also found that the seasonal timing of the pregnancy influenced the outcome, and we found an increased proportion of affected pregnancies among all pregnancies for which the susceptibility weeks (18 to 24 weeks of pregnancy) took place during the late winter season in Sweden. Whereas an association between the winter season, decreased sun exposure, and vitamin D levels comes readily to mind, other events linked to the winter season, such as viral infections, may also influence the development of heart block. Indeed, maternal infections occurring during pregnancy have been suggested to play a role in CHB, and a recent report by Tsang and colleagues [73
] described cell surface exposure of the Ro antigen in fetal cardiomyocytes following cytomegalovirus infection.