The impact of anti-HY responses on outcome in current and subsequent pregnancies of patients with recurrent pregnancy losses

Women pregnant with a male fetus often generate cellular and humoral immune responses against male-specific minor histocompatibility (HY) antigens—however, the importance of these responses for pregnancy outcome is unclear. Epidemiologic studies have shown that the birth of a boy compared with a girl prior to a series of miscarriages significantly reduces the chance of a subsequent live birth and pregnancies with boys have an increased risk of placental abruption. This paper aims to review the current knowledge about the impact of anti-HY immunity on pregnancy outcome in terms of miscarriage and placental abruption. Our knowledge primarily comes from studies of the impact on pregnancy outcome of HLA class II alleles known to restrict CD4 T cell mediated anti-HY responses among 358 secondary recurrent miscarriage (SRM) patients and 203 of their children born prior to the miscarriages and investigation of these HLA alleles in 8 patients with recurrent severe placental abruptions. The chance of a subsequent live birth in SRM patients with firstborn boys compared to firstborn girls was significantly lower in women with HY-restricting HLA class II alleles [OR: 0.17 (0.1–0.4), p = 0.0001]. Most patients with recurrent placental abruptions had firstborn boys and significantly more of these patients carried HLA haplotypes with HY-restricting class II alleles compared with controls (p = 0.009). These findings are strongly indicative of aberrant maternal immune reactions against fetal HY antigens playing a role in recurrent miscarriage and placental abruption. We propose pathogenetic pathways for these conditions that in our view best explain the findings.