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

Abstract

ProblemThe 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 StudyMEDLINE, 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.ResultsFinally, 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.ConclusionHLA‐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.