Association of human leukocyte antigen-G and -F with recurrent miscarriage and implantation failure: A systematic review and meta-analysis

Problem: The immune system plays an essential role in embryonic implantation and pregnancy, but the molecular details remain controversial. In the past four decades, human leukocyte antigen (HLA)-G and -F have garnered significant attention.

Method of study: MEDLINE, EMBASE, Web of Science, and the Cochrane Trials Registry were searched from their inception dates until December 2022. Studies were selected following PRISMA guidelines. Meta-analyses were used to assess the relationship of soluble HLA-G (sHLA-G) and HLA-G 3'-untranslated region polymorphisms with recurrent miscarriage (RM) and recurrent implantation failure (RIF). Narrative synthesis was conducted to determine the association of RM with other single nucleotide polymorphisms (SNPs) and HLA-G protein in tissues and of RIF with HLA-F. Risk-of-bias was assessed using ROBINS-I. Publication bias was assessed using Egger's and Begg's tests.

Results: Finally, 42 articles were eligible for inclusion in the systematic review (32 in the meta-analysis; 13 in narrative synthesis). We found a significant association between the 14-bp ins/del HLA-G polymorphism and RM risk, but no definitive association with RIF risk. Women with RM had lower blood concentrations of sHLA-G during pregnancy and non-pregnancy than did controls. For women in the RIF group, no significant difference was found.

Conclusion: HLA-G protein and gene expression levels may be closely related to RM. The relevance of HLA-G to RIF is still being determined. A narrative synthesis of current studies has shown that HLA-F is likely associated with RIF.