Intravenous Immunoglobulin Intravenous immunoglobulins (IVIgs) are composed of pooled samples of immunoglobulins harvested from a large number of blood donors. Studies on the use of IVIg therapy in the treatment of recurrent pregnancy loss are based on the theory that some recurrent pregnancy loss patients have an overzealous immune reactivity to their implanting fetus. IVIgs do have immunosuppressive effects, but the mechanisms underlying this immune modulation are only partially understood. These mechanisms may include decreased autoantibody production and increased autoantibody clearance, T-cell and Fc-receptor regulation, complement inactivation, enhanced T-cell suppressor function, decreased T-cell adhesion to the extracellular matrix, and downregulation of TH1 cytokine synthesis (391–394). Based on a large number of relatively small studies using a variety of treatment protocols, there remains no conclusive evidence to suggest that use of IVIg in the treatment of patients with unexplained (and presumed immunologic) recurrent pregnancy loss has any benefit (383,395–399). This includes a recent trial using IVIg in women with secondary recurrent pregnancy loss that was ended early because interim analyses revealed no effect (395). The Cochrane review of immune therapy for recurrent pregnancy loss also addressed IVIg therapy and reported that its use did not alter pregnancy outcomes in patients with otherwise unexplained recurrent pregnancy loss (381,388). Improved posttreatment pregnancy rates may be seen, however, when IVIg is used in those specific patients with autoimmune-mediated pregnancy loss associated with APS (400,401). Therapy with IVIgs for recurrent pregnancy loss is expensive, invasive, and time-consuming, requiring multiple intravenous infusions over the course of pregnancy (402). Side effects of IVIg therapy include nausea, headache, myalgias, and hypotension. More serious adverse effects include anaphylaxis (particularly in patients with IgA deficiency) (403).
Progesterone As mentioned earlier, progesterone also has known immunosuppressive effects (220–223,227,228). A number of studies using in vitro cellular systems relevant to the maternal–fetal interface have now demonstrated that progesterone either inhibits TH1 immunity or causes a shift from TH1-to TH2-type responses (208,227,228,404). Although the mechanism of action remains unclear, a recent Cochrane review concluded that progesterone supplementation was effective in the treatment of recurrent, but not isolated, spontaneous pregnancy loss (405,406). The review makes no recommendations on dosage, timing of initiation, nor route of progesterone administration. Progesterone has been administered both intramuscularly and intravaginally for the treatment of recurrent pregnancy loss. It is thought that vaginal administration may increase local, intrauterine concentrations of progesterone better than systemic administration. Vaginal formulations may therefore provide a better method of attaining local immunosuppressive levels of progesterone while averting any adverse systemic side effects.