Human Molecular Genetics Advance Access published online on February 17, 2009
Human Molecular Genetics, 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, Rigshospitalet, DK-2100 Copenhagen Ø, Denmark 2 Department of Clinical Immunology, Aalborg Hospital, DK-9000 Aalborg, Denmark 3 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, he Netherlands 4 Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 5 Department of Immunology, University Medical Center, Utrecht, Postbox 85500, 3508GA, Utrecht, The Netherlands 6 Department of Clinical Immunology, University Hospital of Copenhagen, Rigshospitalet, DK2200 Copenhagen N, Denmark
* Correspondence to: The Fertility Clinic 4071, University Hospital Copenhagen, Blegdamvej 9, DK-2100 Copenhagen O, Telephone: +45 20868723 FAX: +45 35454946 Email: henriette.svarre.nielsen{at}rh.regionh.dk
Received January 20, 2009; Revised February 10, 2009; Accepted February 13, 2009
Background: 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 miscarriages (SRM)).
Methods: HLA-A, -B, -DRB1, DRB3-5, DQB1 genotyping was performed in 358 SRM patients and in 203 of their children born prior to the miscarriages.
Results: The subsequent live birth in women with boys prior to the miscarriages compared to girls is lower in women with HY-restricting HLA class II alleles (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.
Conclusion: 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 reactions against fetal HY-antigens in SRM. The results may shed light on the as yet unknown immunological causes of SRM and may help to understand the successful maternal acceptance of the fetal semi-allograft.