HLA associations and HLA sharing in recurrent miscarriage: A systematic review and meta-analysis

Hum Immunol. 2015 May;76(5):362-73. doi: 10.1016/j.humimm.2015.02.004. Epub 2015 Feb 17.


Problem: The aim of this meta-analysis was to evaluate whether specific maternal HLA alleles and HLA sharing of couples are associated with the occurrence of recurrent miscarriage (RM).

Method of study: A systematic literature search was performed for studies that evaluated the association between HLA alleles, HLA sharing and RM. RM was defined as three or more consecutive unexplained miscarriages and a control group was included of women with at least one live birth and no miscarriages in their history. Meta-analyses were performed and the pooled odds ratio (OR) was calculated.

Results: We included 41 studies. Selection bias was present in 40 studies and information bias in all studies. Meta-analyses showed an increased risk of RM in mothers carrying a HLA-DRB1*4 (OR 1.41, 95% CI 1.05-1.90), HLA-DRB1*15 (OR 1.57, 95% CI 1.15-2.14), or a HLA-E*01:01 allele (OR 1.47, 95% CI 0.20-1.81), and a decreased risk with HLA-DRB1*13 (OR 0.63, 95% CI 0.45-0.89) or HLA-DRB1*14 (OR 0.54, 95% CI 0.31-0.94). Pooling results for HLA sharing showed that HLA-B sharing (OR 1.39, 95% CI 1.11-1.75) and HLA-DR sharing (OR 1.57, 95% CI 1.10-1.25) were both associated with the occurrence of RM.

Conclusion: Although the present systematic review and meta-analysis demonstrates that specific HLA alleles and HLA sharing are associated with RM, a high degree of bias was present and therefore observed results should be interpreted carefully.

Keywords: HLA alleles; HLA sharing; Meta-analysis; Recurrent miscarriage; Systematic review.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Abortion, Habitual / genetics
  • Abortion, Habitual / immunology*
  • Alleles
  • Female
  • Genetic Association Studies
  • HLA-B Antigens / genetics*
  • HLA-DRB1 Chains / genetics*
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility*
  • Humans
  • Pregnancy
  • Risk
  • Selection Bias


  • HLA-B Antigens
  • HLA-DRB1 Chains
  • HLA-E antigen
  • Histocompatibility Antigens Class I