Human Molecular Genetics Advance Access originally published online on February 17, 2009
Human Molecular Genetics 2009 18(9):1684-1691; doi:10.1093/hmg/ddp077
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Association of HY-restricting HLA class II alleles with pregnancy outcome in patients with recurrent miscarriage subsequent to a firstborn boy
1 The Fertility Clinic 4071, University Hospital Copenhagen, Blegdamvej 9, Rigshospitalet, DK-2100 Copenhagen Ø, Denmark 2 Department of Clinical Immunology, Aalborg Hospital DK-9000, Aalborg, Denmark 3 Department of Immunohematology and Blood Transfusion and 4 Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 5 Department of Immunology, University Medical Center, Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands and 6 Department of Clinical Immunology, University Hospital of Copenhagen, Rigshospitalet, DK-2200 Copenhagen N, Denmark
* To whom correspondence should be addressed. Tel: +45 20868723; Fax: +45 35454946; Email: henriette.svarre.nielsen{at}rh.regionh.dk
Received January 20, 2009; Accepted February 13, 2009
Healthy females, pregnant with a boy, generate immune responses against male-specific minor histocompatibility (HY) antigens. The clinical importance of these responses is evident in stem cell transplantation. Birth of a boy prior to a series of miscarriages reduces the chance of a subsequent live birth. This study explores the putative impact of known HY-presenting HLA alleles on future pregnancy outcome in women with at least three consecutive miscarriages following a birth [secondary recurrent miscarriage (SRM)]. HLA-A, -B, -DRB1, DRB3-5 and DQB1 genotyping was performed in 358 SRM patients and in 203 of their children born prior to the miscarriages. The subsequent live birth in women with boys prior to the miscarriages compared with girls is lower in women with HY-restricting HLA class II alleles [odds ratio (OR): 0.17 (0.1–0.4), P = 0.0001]. One HY-restricting HLA class II allele in women with firstborn boys significantly reduces the chances of a live birth [OR: 0.46 (0.2–0.9), P = 0.02]. Two HY-restricting HLA class II alleles further reduced this chance [OR: 0.21 (0.1–0.7), P = 0.02]. HY-restricting HLA class II did not reduce the chances of a live birth in SRM women with firstborn girls. HY-restricting HLA class II alleles are associated with a decreased chance of a live birth in SRM women with firstborn boys. These findings strongly indicate an aberrant maternal immune reaction against fetal HY-antigens in SRM. The results may shed light on the as-yet unknown immunological causes of SRM and may help understand the successful maternal acceptance of the fetal semi-allograft.