The possible role of classical human leukocyte antigens in recurrent miscarriage.

PROBLEM: If immunological factors play a role in the pathogenesis of recurrent miscarriage (RM), it is likely that associations between alleles of classical human leukocyte antigen (HLA) genes and RM exist. Our aim was to investigate HLA-C alleles in RM couples and HLA-DR and -DQ polymorphism in women with unexplained RM.

METHOD OF STUDY: HLA-C alleles were investigated in 35 RM and 30 control couples and HLA-DR and -DQ allogenotypes were investigated in 234 RM patients and 360 controls. All HLA investigations were undertaken by DNA based methods.

RESULTS: We found no difference between the RM and control couples in the degree of paternal incompatibility for maternal HLA-C alleles and the distribution of the two HLA-C supertypic specificities that are recognized differently by p58 killer cell inhibitory receptor (KIR) positive natural killer (NK) cells was similar in the two groups. In 97 women with at least four previous miscarriages, significantly higher frequencies of the HLA-DR1,DQ5 and -DR3,DQ2 haplotypes were found compared with 360 controls (P < 0.05 after correction for multiple comparisons). Among 94 RM patients followed prospectively, those with HLA-DR1 and/or -DR3 had a 62% miscarriage rate compared with only 29% among those without these alleles (P < 0.05). A large family study indicated that HLA-DR1 and/or -DR3 positive sisters and brothers' wives of probands with RM had an odds ratio of 5.0 for miscarrying their pregnancies compared with corresponding HLA-DR1 and -DR3 negative relatives. Finally, a meta-analysis of relevant studies based on a MEDLINE search showed that HLA-DR1, -DR3, and -DR4 were significantly increased in Caucasian women with RM.

CONCLUSIONS: HLA-DR1, -DR3, and maybe -DR4 show association to RM in Caucasian women whereas no association to classical HLA class I genes including HLA-C can be detected in RM couples. The mechanism by which class II alleles confer susceptibility to RM might be by predisposing to hypersecretion of certain cytokines, e.g., tumor necrosis factor (TNF)-alpha at the feto-maternal interface.