Association of Endometrial HAND2 Expression with β2-Glycoprotein I Antibodies in Recurrent Pregnancy Loss

Background: Recurrent pregnancy loss (RPL) is frequently linked to antiphospholipid antibodies, yet many affected women are seronegative for the classical (Sydney) criteria antibodies. In a previously characterized cohort, an extended antiphospholipid antibody panel was positive in 79% of women with RPL, with the strongest associations for antibodies against prothrombin, annexin V and β2-glycoprotein I. Whether this association reflects molecular endometrial dysfunction was unclear. Objective: To examine endometrial expression of ten decidualization- and inflammation-related genes in women with RPL, stratified by APL status, focusing on the dominant antibody specificity: anti-β2-glycoprotein I. Methods: Thirty-nine women with RPL (≥2 losses), a subsample of a published 100-patient cohort, underwent mid-luteal Pipelle endometrial biopsy followed by RT-PCR for C4BPA, CXCL1, HAND2, HPRT1, IFNG, IL15, IL8 (CXCL8), MMP10, TNC and VEGFB. Antibodies were measured by antiphospholipid 10 Dot line immunoblot (Generic Assays, Germany). The analysis used Mann–Whitney U, Fisher’s exact test, Benjamini–Hochberg correction and ROC analysis. Results: Antibody prevalence in the subsample matched the parent cohort (Pearson r = 0.999). Of ten transcripts, only HAND2 showed a nominally significant reduction in APL+ women (median ΔCt −2.04 vs. −1.30; p = 0.037; rank-biserial r = −0.47); this signal did not survive Benjamini–Hochberg correction (q = 0.372). The signal was specific to anti-β2GPI (p = 0.064; AUC 0.700), not to annexin V or prothrombin. A cut-off of HAND2 ΔCt ≤ −1.60 identified APL+ status with 73% sensitivity, 78% specificity and OR 9.62 (95% CI 1.64–56.4; p = 0.015). HAND2 clustered with IL15 (ρ = 0.65) and VEGFB (ρ = 0.70). Conclusions: Anti-β2-glycoprotein I antibodies, the dominant APL specificity in RPL, are associated with reduced endometrial HAND2 expression. This exploratory data outline a candidate molecular pathway linking extended antiphospholipid serology to impaired endometrial receptivity.