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HLA Mismatches and Pregnancy: Research Review

A short overview of the role of HLA mismatches in fertility and the science behind it.

March 31, 2022 Pregmune Team
HLA Mismatches

HLA mismatches are assessed as part of the parental histocompatibility section of the IRMA report. Parental histocompatibility examines the impact of human leukocyte antigens (HLAs) on pregnancy.

HLAs are diverse proteins displayed on human cells like a barcode – unique for everyone. The immune system uses HLAs to differentiate “self” from “non-self.” Half of a developing embryo’s HLAs come from the father, and a certain amount of mismatch between parental HLAs is a good thing.

A mother’s immune system needs to develop tolerance to the embryo to maintain a healthy pregnancy. Part of this process lies in recognizing that the embryo is genetically unique. However, if the embryo inherits paternal HLAs that are too similar to the maternal HLAs, the immune system might not develop a strong tolerance. This test determines if there are enough mismatches between the maternal and paternal HLA Class II alleles.


Human Leukocyte Antigen (HLA) genes [commonly referred to as the major histocompatibility complex (MHC) genes], are a cluster of genes present on the chromosome 6and are involved in antigen presentation to T cells to initiate an immune response.

In most cases, this immune reaction leads to the destruction of cells displaying “non-self” peptides.

There are two groups of HLA molecules, the class I includes HLA-A, -B, -C and the class II that includes HLA-DR, -DQ, and -DP.

HLA molecules play a key role in organ transplantation and are associated with many diseases including auto-immune disorders1-2.

While a mismatch in Human Leukocyte Antigen (HLA) between a donor and a recipient in organ transplantation may lead to a graft rejection, most often due to the formation of antibodies3, a certain level of difference between the mother’s and father’s HLA alleles4 (inherited by the embryo and defined as a mismatch) is necessary to actively generate immune tolerance of the embryo5. Thus, couples with significant matched alleles for HLA genes may be more prone to infertility, repeated implantation failure, and recurrent pregnancy loss6.

Published clinical data

Although still controversial, the influence of HLA sharing on pregnancy outcome has been shown in clinical studies. Prospective studies of pregnancy outcome in an inbred population of European origins named “Hutterites” previously demonstrated increased fetal loss rates among couples with matching HLA4-6.

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About Pregmune: We’re an innovative reproductive health technology company, built on a solid foundation of data gained from decades of experience and thousands of successful pregnancies. Our team of fertility specialists and scientists are using artificial intelligence to decipher the complexity of the immune system and help patients grow the families of their dreams.

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  1. Doherty PC,Zinkernagel RM. A biological role for the major histocompatibility antigens. Lancet (1975) 1(7922):1406–9.
  2. Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature (1999) 401(6756):921–3.
  3. Jucaud V. The Immunogenicity of HLA Class II Mismatches: The Predicted Presentation of Nonself Allo-HLA-Derived Peptide by the HLA-DR Phenotype of the Recipient Is Associated with the Formation of DSA. J Immunol Res. 2017; 2017:2748614.
  4. Ober C. Studies of HLA, fertility and mate choice in a human isolate. Hum Reprod Update. 1999 Mar-Apr;5(2):103-7. Review.
  5. Papúchová H, Meissner TB, Li Q, Strominger JL, Tilburgs T. The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface. Front Immunol. 2019 Dec 9;10: 2730.
  6. Ober C, Hyslop T, Elias S, Weitkamp LR, Hauck WW. Human leukocyte antigen matching and fetal loss: results of a 10-year prospective study. Hum Reprod. 1998 Jan 13(1):33-8.