Strong anti-fetal HLA antibodies are associated with recurrent pregnancy loss with a diagnosis of chronic histiocytic intervillositis

Chronic histocytic intervillositis (CHI) occurs in 5-6 of 10,000 pregnancies and is strongly associated with early and late miscarriages. The recurrence rate is very high. It is defined by infiltration of CD68+ histiocytes into the intervillous space of the placenta.A previous small study [1] found high levels of complement-activating anti-fetal HLA antibodies in women with CHI. Seven patients in our clinic had a concomitant diagnosis of recurrent pregnancy loss (RPL) and CHI diagnosed histologically in connection to second trimester pregnancy losses. The patients had blood samples taken for HLA antibody analysis, and their live firstborn children and dead fetuses had alleles determined in 11 HLA loci. Serum was screened for HLA antibodies and their complement activating properties. The patients had a median of 5 previous pregnancy losses. All patients were positive for HLA antibodies; in 6 cases specific for alleles carried by their firstborn children or a dead fetus. In 3 cases the specificity was against HLA-B alleles, in one case against an HLA-DRB1 allele, and in two cases they were directed against both HLA class I and II alleles. The levels of the antibodies were all very high with mean flourescense intensity (MFI) between 16,000 and 40,000 and all were complement-activating. MFI levels >7000 define strong HLA antibodies. Since histiocyte accumulation in the placenta and presence of very high levels of complement-activating anti-fetal HLA antibodies characterize women with CHI, it is likely that their pregnancy losses are caused by mechanisms similar to antibody-mediated allograft rejection.