A firstborn boy and maternal HLA class II polymorphism negatively affect pregnancy prognosis in recurrent pregnancy loss

Immune system aberrations are suggested to explain the pathology in most patients with unexplained secondary recurrent pregnancy loss (sRPL). Stimulation of the maternal immune system by male-specific antigens (HY) on fetal/trophoblast cells entering the maternal circulation in women carrying male-specific minor histocompatibility restricting (HY-r) HLA class II alleles has been suggested to be a possible trigger of sRPL. These HY-r HLA molecules on antigen-presenting cells may trigger a cellular immune response against the HY-antigens causing repeated fetal rejection. We evaluated if a firstborn boy is more frequent than a girl among unexplained sRPL patients, and if the pregnancy prognosis is affected negatively by a firstborn boy compared to a firstborn girl in combination with carriage of HY-r HLA class II alleles. Patients with chromosomal abnormalities, uterine malformations, 12 weeks or birth, 1=PL). Logistic regression was adjusted for maternal age and number of PL (continuous), and smoking habits (binary), all assessed at first consultation, and stratified according to carriage of HY-r HLA class II alleles. HLA-DRB1 typing by DNA-based techniques was performed in all participants at the diagnostic work-up. HY-r HLA class II alleles were in accordance with the literature defined as HLADRB1*07, -DRB1*15 and DRB1*01/10 (in linkage disequilibrium with HLA-DQB1*0501/0502). We expected that 51% of sRPL patients had delivered a firstborn boy based on the distribution in the Danish background population. Significantly more sRPL patients had a firstborn boy compared to the expected (60% versus 51%, p=0.01). In women carrying ≥1 HY-r HLA class II alleles, a firstborn boy was associated with a significantly higher risk for a new pregnancy loss after admission (72.4%) compared to a firstborn girl (27.6%) (OR 2.9, 95% 1.1-7.7, p=0.03). When all sRPL patients or only sRPL patients with 0 HY-r HLA class II alleles were included, a firstborn boy was not a significant risk factor (OR 1.6, 95% CI 0.8-3.5, p=0.21 and OR 0.5, 95% CI 0.1-2.0, p=0.35). In the adjusted analysis, the ORs of a new pregnancy loss was enhanced in sRPL patients with a firstborn boy carrying ≥1HY-r HLA class II alleles compared to sRPL patients carrying ≥1HY-r allele with a firstborn girl (OR 3.4, 95% CI 1.1- 10.2, p=0.03), while a firstborn boy had no impact on pregnancy outcome in patients carrying 0 HY-r alleles (OR = 0.7, 95% CI 0.2-3.1, p=0.64). The frequency of a firstborn boy is significantly increased in sRPL patients, and in sRPL with ≥1HY-r HLA class II alleles a firstborn boy is associated with a negative reproductive prognosis. These results are in concordance with previous findings in a previously published cohort of Danish sRPL patients and suggest that a harmful immune response triggered by male cells from a prior pregnancy may cause sRPL in prone women.