The Effect of Immunotherapy on Natural Killer Cells Level/Activity in Recurrent Pregnancy Loss (RPL) Patients: A Systematic Review and Meta‐Analysis

ABSTRACT Some studies have demonstrated that high level of natural killer (NK) cells or NK cytotoxicity was associated with unexplained recurrent pregnancy loss (RPL) and can serve as predictive indicator for subsequent miscarriage in RPL patients. This suggests that reducing the level or activity of NK cells may represent a potential therapeutic strategy. However, there remains controversy regarding the efficacy of current immunotherapies employed in clinical practice for modulating the number and function of NK cells in RPL patients. Consequently, this study aimed to systematically review and assess the impact of various immunotherapies on NK cells in RPL patients, as well as the effectiveness of improving pregnancy outcomes in RPL patients with abnormal NK cells level/activity. This systematic review and meta‐analysis was conducted following the PRISMA guidelines and recommendations of the Cochrane Collaboration. A comprehensive search was conducted on PubMed, Web of Science, EMBASE, and the Cochrane Library to identify relevant studies on immunotherapy in patients with RPL up to September 2023. Meta‐analyses were used to assess the impact of immunotherapy on NK cells level and activity in RPL patients. Narrative synthesis was conducted to evaluate the effect of immunotherapies on pregnancy outcomes in RPL patients with abnormal NK cells level/activity. Risk‐of‐bias was assessed using ROBINS‐I. A random‐effects model or a fixed‐effects model was selected according to the heterogeneity test, and standard mean differences (SMDs), risk ratio (RR) and 95% confidence interval (95% CI) were calculated. A total of 17 studies were included in this analysis. The meta‐analysis revealed that in the general population of patients with RPL, intravenous immunoglobulin (IVIg) led to a reduction in peripheral natural killer (pNK) cells level (SMD: −0.85, 95% CI: −1.41 to −0.28), lymphocyte immunotherapy (LIT) decreased pNK cell activity, and intralipid reduced both pNK cells level (SMD: −0.32, 95% CI: −0.64 to −0.01) and activity (SMD: −0.74, 95% CI: −1.06 to −0.42). The narrative synthesis illustrated the regulatory impact of immunotherapy on diverse immune cells and cytokines in RPL patients. Furthermore, IVIg and intralipid therapy could potentially enhance live birth rates in RPL patients specifically characterized by elevated pNK cells level. For RPL patients with elevated uterine NK (uNK) levels, cyclosporin A may ameliorate pregnancy outcomes, while prednisolone does not appear to have the same effect. Nevertheless, these findings should be approached with caution given the current insufficiency of evidence. Limited evidence indicated that IVIg, LIT, and intralipid reduce pNK cells level/activity in RPL patients. RPL patients with elevated NK levels may be benefit from immunotherapy, but not all immunotherapies were effective. However, interpretation of these results with caution is strongly advised due to the limited number of high‐quality evidence.