Anti-HY responses in pregnancy disorders

Cellular and humoral immune responses against male-specific minor histocompatibility (HY) antigens are important in the pathogenesis of graft-versus-host reactions and can be detected in women who have previously given birth to a boy. However, the importance of these responses for pregnancy outcome is unclear.

Review of the current knowledge about the impact of anti-HY immunity on pregnancy outcome in terms of risk of miscarriage, placental abruption and low birth weight.

Women with secondary recurrent miscarriage (RM) more often have given birth to a boy compared with a girl prior to a series of miscarriages (P<0.0001) and a firstborn boy seems significantly to reduce the chance of a subsequent live in these patients (P=0.0003). Human leukocyte antigen (HLA) class II alleles known to restrict CD4 T-cell-mediated anti-HY responses were investigated among 358 patients with secondary RM and 203 of their children born prior to the miscarriages. The chance of a subsequent live birth in secondary RM patients with firstborn boys compared with firstborn girls was significantly lower in women with HY-restricting HLA class II alleles [OR: 0.17 (0.1-0.4), P=0.0001]. In patients without these alleles, the chance of live birth was similar in those with firstborn boys and girls, respectively. In early pregnancy, both antibodies against HLA and HY antigens were found with increased prevalence in secondary patients with RM and in particular in those with a firstborn boy compared with controls (P=0.005). The presence of these antibodies was associated with a low subsequent live birth rate, and the presence of HY antibodies was associated with a low male/female ratio (12% boys versus 88% girls) in subsequent live births (P=0.03). Register-based population studies suggested that births of boys also are associated with subsequent adverse obstetric outcomes also in the background population.

Findings strongly indicate that aberrant maternal immune reactions against fetal HY antigens playing a role in secondary RM and other pregnancy complications. We propose pathogenetic pathways for these conditions that in our view best explain the findings.