Anti-TNFα therapy in immune-mediated subfertility: State of the art☆

Abstract 

Increased production of Th1 cytokines such as TNFα plus IFNγ compared to the Th2 cytokine IL-10 is linked to infertility and recurrent spontaneous abortion (RSA). In murine models, direct evidence of pathogenic mechanisms has been elucidated, and these have been validated where possible by correlation with human data. Although there are a number of potential targets that could be utilized for therapeutic benefit, TNFα is currently the most feasible and uncorrected abnormality. Two recently published observational cohort-controlled studies of the addition of anti-TNFα agents to treatment with heparin plus aspirin, with or without IVIG, in RSA and in infertile (repeat IVF failure) patients are reviewed with respect to methodological and biological rigor, and literature supporting the reliability, feasibility, and value of observational cohort-controlled trials compared to double-blind randomized controlled trials is outlined. For those who do not believe the existing data is sufficiently strong for adoption of anti-TNFα therapy, a hybrid approach is outlined for validation of efficacy in specific subsets of pregnancy failure patients. Potential side effects and key issues in informed consent are set out. Anti-TNFα drugs may offer a new safe and effective approach to treating patients with Th1-cytokine-dependent infertility and recurrent miscarriages.

Abbreviations: RSA, recurrent spontaneous abortion, NK, natural killer (cell), NKT, natural killer cell with T cell receptor, TNFα, tumor necrosis factor alpha, a cytokine, IFNγ, interferon gamma, a cytokine, IL, interleukin, Th1, T helper cell type 1 cytokine, Th2, T helper cell type 2 cytokine, Th3, T helper cell type 3 cytokine, Th17, T helper cell type 3 cytokine, FGL2, fibrinogen-line protein, mFGL2 is membrane associated as distinct from soluble FGL2, sFGL2, HA, heparin plus low-dose aspirin, EBM, evidence-based medicine, EC, endothelial cell, TF, tissue factor, MΦ, macrophage/monocyte, C3, 3rd component of complement, C5, 5th component of complement, fB, factor B, MBL, mannan-binding lectin, Fc, crystalizable end of immunoglobulin molecule, IVIG, intravenous administration of immunoglobulin G purified from pooled human plasma, sFlt-1, soluble VEGF receptor, PMNLs, polymorphonuclear leukocytes

Keywords: Anti-TNF-alpha, Infertility, Recurrent spontaneous abortion, Evidence-based medicine, Controlled clinical trials