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

Abstract 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.