Stimulation of the maternal immune system using alloantigens on either paternal or pooled donor leukocytes has been promoted for patients with immunologic recurrent pregnancy loss, and a number of reports support possible mechanisms for potential therapeutic value (371–375). Both individual clinical trials and meta-analyses, however, continue to report conﬂicting results concerning the efficacy of leukocyte alloimmunization in patients with recurrent pregnancy loss (25,364,365,372,376–379). This most certainly reﬂects the remarkable heterogeneity in study design, patient selection, and therapeutic protocols, as well as the typically small numbers of enrolled subjects in these investigations. One of the largest trials evaluating the efficacy of leukocyte immunization in patients with unexplained recurrent pregnancy loss is a part of the Recurrent Miscarriage (REMIS) study (380). This investigation was large (over 90 patients per treatment arm), prospective, placebo controlled, randomized, and double blinded. It demonstrated no efficacy for paternal leukocyte immunization in couples with unexplained recurrent pregnancy loss. The most recent and best of the meta-analyses definitively rejects use of this therapy in patients with recurrent loss (381). Leukocyte immunization also poses a significant risk to both the mother and her fetus (344,345,382). Several cases of graft-versus-host disease, severe intrauterine growth retardation, and autoimmune and isoimmune complications have been reported (25,378,382–386). In addition, alloimmunization to platelets contained in the paternal leukocyte preparation is associated with cases of potentially fatal fetal thrombocytopenia. The routine use of this therapy for recurrent abortion cannot be clinically justified at this time. The procedure should be performed only as part of an appropriately controlled trial using informed consent. All costs associated with this treatment should be borne by the investigators until its efficacy has been demonstrated.
Other immunostimulating therapies have been proposed and abandoned. Intravenous preparations consisting of syncytiotrophoblast microvillus plasma membrane vesicles have been used to mimic the fetal cell contact with maternal blood that normally occurs in pregnancy (387). The efficacy of this therapy has not been established (381,387,388). The use of third-party seminal plasma suppositories has also been attempted, based on the misconception that TLX was part of an idiotype–anti-idiotype control system (389,390). Third-party seminal plasma suppositories for recurrent abortion have no scientifically credible rationale and should not be used.
Immunosuppressive and other immunoregulating therapies have been advocated for cases in which abortion was believed to result from antiphospholipid antibodies or inappropriate cellular immunity toward the implanting fetus. Again, study design problems, including small numbers of recruited patients, lack of prestratification by maternal age and number of prior losses before randomization, and other methodologic and statistical inaccuracies preclude definitive statements regarding therapeutic efficacy for most of the proposed immunosuppressive approaches.