Autoimmune phenomena seem to play a major role in the pathogenesis of unexplained pregnancy loss. The strong association of antibodies against ribonucleoproteins and neonatal lupus syndrome became soon apparent. Neonatal lupus syndrome, a classical model of passively acquired autoimmunity, results from the transplacental transfer of IgG anti-Ro/SSA between the 20th and the 24th week of pregnancy causing histopathological damage on developing tissues. It consists of congenital heart block (CHB), non-scarring cutaneous lesions, hepatitis, haemolytic anaemia and thrombocytopenia. A recent report supports that a significantly greater number of mothers whose children had CHB were asymptomatic compared with mothers of children with cutaneous disease. Specific maternal MHC class II genes seem to correlate with specific outcomes in neonatal lupus syndrome. A Japanese study suggests that certain maternal specific haplotypes were associated with CHB and cutaneous lesions.
The exact mechanism through which antibodies against ribonucleoproteins affect the fetal conductive system remains largely unknown. Maternal ÉgG anti-Ro/SSA and anti-La/SSB antibodies have been isolated from affected fetal hearts, while studies on human and animal models revealed possible arrhythmogenic effects of these antibodies. Apoptosis is proposed as a mechanism of translocation of intracellular Ro/SSA and La/SSB antigens to the cell surface of fetal cardiac myocytes, where they can be bound by cognate autoantibodies. In addition, it was shown experimentally that embryonic expression of certain constituents of the Ro/SSA molecule occurred some weeks before the clinical detection of CHB. Particularly, hYRNAs molecules between the 6th and 16th week of gestation, while an alternative 52b protein, recognised by the sera of mothers whose children had CHB, between 14–16 weeks. Finally, antibodies against a human endogenous retrovirus (ERV-3), which is expressed in fetal tissues particularly in the heart, were found to be elevated in mothers of children with CHB. IgG antibodies against a 57 kd protein and calreticulin are also proposed as additional risk factors in the pathogenesis of neonatal lupus syndromes.
Based on the hypothesis that unexplained pregnancy loss in autoimmune patients may represent intrauterine expression of neonatal lupus, several studies explored the possible association of anti-Ro/SSA autoantibodies and pregnancy loss in autoimmune patients. In initial studies such association was confirmed only among black women with SLE. Subsequently, in a large cohort study it was revealed that although the presence of anti-Ro/SSA antibodies did not affect the pregnancy outcome in SLE patients, it was strongly correlated with recurrent pregnancy loss in non-SLE patients, including patients with Sjögren’s syndrome, rheumatoid arthritis and scleroderma. In a further study, a clear gradation risk between recurrent pregnancy loss and the number of different Ro/SSA peptides (Ro52, Ro60, p57) recognised by the sera of autoimmune patients was demonstrated. It is of interest that the association of these peptides with adverse pregnancy outcome did not alter by the presence of other autoimmune factors as antithyroid and anticardiolipin antibodies. Particularly, the presence of antibodies against thyroglobulin appears to be an independent marker of recurrent pregnancy loss in these patients.
Management of CHB remains largely empirical. Several anecdotal reports have supported the use of steroid and non-steroid treatment including theophylline, salbutamol, furosemide, plasmapheresis and intrauterine fetal heart pacing with various results. Both therapeutic modalities improved hydrops fetalis, but only steroids seemed to reverse incomplete CHB. Recent study suggests the use of fluorinated steroids-which are minimally metabolised in the placenta- in fetuses with unstable conduction defects or hydropic changes. In conclusion, it is evident that pregnancy in anti-Ro/SSA positive women remains a diagnostic, pathogenetic, family counselling and therapeutic challenge.
Abstract presented by H. M. Moutsopoulos
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