The lack of tests with sufficient diagnostic value for detecting immunological causes of RPL has wide implications for the identification of patients for specific treatments or inclusion in randomized controlled trials. The failure to find significant beneficial effects of immunotherapeutic treatments such as prednisone [80] or intravenous immunoglobulin [81] in randomized controlled trials has by many researchers been attributed to the non-selection of patients for these trials due to the presence of immune biomarkers such as high NK cell cytotoxicity levels. We believe that as long as the diagnostic specificity of the immune tests is not well established, patients for treatment or participation in randomized trials must still be selected based on their reproductive history, e.g., a poor spontaneous prognosis evidenced by a high number of previous pregnancy losses.

In our view, not one but several disturbances or disruptions of pathways relating to immune interactions are probably causing many cases of RPL; the reproductive process is too important to be vulnerable to the disruption of only one immune pathway. We think that disturbances in several immune pathways (caused by SNPs or CNVs disrupting DNA sequences) in conjunction with immunizing events in previous pregnancies, such as a substantial transfer of fetal antigens (cells) into the maternal circulation [82], can promote pro-inflammatory reactions or breakage of autotolerance. This will predispose to RPL and other adverse pregnancy outcomes and ultimately lead to atherosclerotic or autoimmune disease.

This suggested complexity of the pathogenesis of RPL will be a challenge for future research in the area, which is further complicated by the fact that almost half of all pregnancy losses in RPL women are due to embryonal aneuploidy with no immunological background. We find it important for researchers to acknowledge this complexity instead of narrow-sightedly dividing the patients into subgroups, each suggested to be caused by one specific (simple) immunological or non-immunological etiology.

Large epidemiological studies have now documented that RPL patients carry a substantial risk of developing later atherosclerotic disease [78, 79], which may be due to chronic activation of pro-inflammatory pathways. Research in the immunological abnormalities associated with RPL therefore both has the potential to disclose pathways leading to pregnancy loss that may be modified by specific therapies but it may also identify biomarkers, which can be used for identifying those patients who are in the greatest risk of contracting cardiovascular disease in order that preventive measures can be initiated.