Unexplained sporadic and recurrent miscarrage in the new millennium: a critical analysis of immune mechanisms and treatments

There have been important advances in basic science investigation of mechanisms underlying spontaneous miscarriages which lend support to empirical treatments such as intravenous immunoglobulin G and allogeneic leukocyte immunotherapy. The results from clinical trials of these and other proposed treatments have been problematic. There is only one published meta-analysis of sufficient power and appropriate stratification to qualify as Level 1 evidence, and that deals only with leukocyte immunotherapy. Here we critically review current trials and their flaws, update the meta-analysis, and comment on potential new approaches. Inadequate sample size, better definition of heterogeneity, and proper stratification to minimize the effects of heterogeneity remain as problems. Verification that the experimental or test treatment was active in producing the expected alteration in immunophysiology in the recipient is lacking in most trials; use of stored rather than fresh allogeneic leukocytes appears problematic. Hidden biases that affect trial significance emerge with critical analysis, and the focus on apparent 'high quality' of design in published reports may be misleading. We conclude that there seem to be enough patients to conduct clinical trials of sufficient size to achieve adequate power to test therapies showing promise in pilot studies, but at present, the only Level 1 evidence concerns leukocyte immunotherapy which appears to increase the chance of a live birth if given to appropriate patients.