One additional group of autoantibodies that have been linked to recurrent pregnancy loss is the antithyroid antibodies (ATA). Although the data remain somewhat controversial, several investigators demonstrated an increased prevalence of these antibodies among women with a history of recurrent pregnancy loss, even in the absence of thyroid endocrinologic abnormalities (98–199,102,103,271–273).
Other antibody-mediated mechanisms for recurrent abortion have been proposed, including antisperm and antitrophoblast antibodies, as well as blocking antibody deficiency.
Although each hypothesis has minimal relevance to recurrent pregnancy loss, their discussion is warranted because therapies aimed at these disorders persist. Historically, the blocking antibody deficiency hypothesis has received the most attention (112,181). This hypothesis is based on a supposition that blocking factors (presumably antibodies) were required to prevent a maternal, cell-mediated, antifetal immune response that was believed to occur in all pregnancies. It was therefore proposed that, in the absence of these blocking antibodies, abortion occurred (273). This supposition was not consistently substantiated (274,275). For instance, maternal hyporesponsiveness in mixed lymphocyte culture with paternal stimulator cells was originally proposed to identify women with deficient blocking activity (273). Investigations based on this type of testing were continued by those who proposed that parental HLA sharing resulted in a predisposition to blocking antibody deficiency (276,277). These reports were of limited sample size, were retrospective in nature, and lacked population-based controls. One prospective, population-based control study conclusively demonstrated that HLA heterogeneity was not essential for successful pregnancy (278). However, follow-up studies showed that, in the exceedingly rare case of complete sharing of the entire HLA region, spontaneous pregnancy losses do increase (279). This particular 10-year prospective trial concluded that HLA typing is of no use in outbred populations, because only isolated and significantly inbred populations have such HLA homogeneity. Further evidence refuting the blocking antibody hypothesis for recurrent abortion comes from reports of successful pregnancies among women who do not produce serum factors capable of mixed lymphocyte culture inhibition and also among women who do not produce antipaternal cytotoxic antibodies (273,274). Those mixed lymphocyte culture results that demonstrate hyporesponsiveness in some recurrent pregnancy loss patients are now believed to represent the effect of the pregnancy loss rather than the cause of recurrent abortion (217,273–275).
One final theory that emerged from the blocking antibody investigations involved a novel HLA-linked alloantigen system. The finding that polyclonal rabbit antisera could recognize both lymphocytes and trophoblast cells suggested the existence of trophoblast–lymphocyte cross-reactive alloantigens (called TLX) (280). These TLX were, in turn, linked to maternal blocking antibody deficiency and recurrent pregnancy loss. The TLX hypothesis only has historical relevance. The theory was invalidated when TLX was found to be identical to CD46, a complement receptor that is thought to protect the placenta from complement-mediated attack (281). CD46 was not a novel alloantigen. It can be found on a wide variety of cells, thus explaining the cross-reactive nature of the original rabbit antisera.