Evaluation of Th1-Th2 balance in patients with recurrent implantation failure; a systematic review and meta-analysis

Recurrent implantation failure (RIF) remains a major barrier in assisted reproduction, and systemic immune imbalance, particularly between T helper (Th) 1 and Th2 pathways, has been implicated. We performed a systematic review and meta-analysis to assess peripheral blood Th1- and Th2-related markers in RIF compared with healthy fertile (HF) and IVF-successful (IS) women. We systematically searched PubMed, Scopus, and Web of Science up to June 2025 for studies that assessed circulating Th1/Th2 cells or cytokines. Compared with HF, RIF patients showed a higher frequency of Th1(IFN-γ) cells (Standardized mean difference (SMD) = 0.37, 95% confidence interval (CI) = 0.08 to 0.66, p = 0.01), while Th2(IL-4) cells did not differ. In cytokine analyses with IS controls, IFN-γ was significantly elevated in RIF (SMD = 0.91, 95% CI = 0.19 to 1.63, p = 0.01), whereas TNF-α, IL-4, and IL-10 showed no significant differences. Among ratio outcomes, IFN-γ/IL-10 (SMD = 0.70, 95% CI = 0.40 to 1.00, p < 0.00001) and TNF-α/IL-10 (SMD = 0.40, 95% CI = 0.11 to 0.69, p = 0.006) were increased in RIF, while IL-4-based ratios were not differed significantly. Our results point to an association between Th1/Th2 imbalance and RIF. Confirmation in larger, standardized studies is needed to strengthen the evidence and determine clinical applicability.