Increased production of Th1 cytokines such as TNFalpha plus IFNgamma 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, TNFalpha is currently the most feasible and uncorrected abnormality. Two recently published observational cohort-controlled studies of the addition of anti-TNFalpha 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-TNFalpha 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-TNFalpha drugs may offer a new safe and effective approach to treating patients with Th1-cytokine-dependent infertility and recurrent miscarriages.
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