Antiphospholipid antibodies and reproductive outcome: the current state of affairs

Antiphospholipid antibodies were first linked to pregnancy loss more than 20 years ago, and the condition known as antiphospholipid syndrome is perhaps the most convincing 'immunologic' disturbance other than anti-erythrocyte and anti-platelet alloimmunization disorders. Specific criteria for the antiphospholipid syndrome have been delineated, the anticardiolipin assay has been standardized, and authorities agree on laboratory criteria defining lupus anticoagulant. Nonetheless, considerable confusion exists regarding antiphospholipid syndrome and related reproductive problems. The state of affairs primarily derives from two problems: the first is the premature introduction of non-standardized antiphospholipid assays into clinical use without rigorous standardization and prior to convincing proof of clinical utility. As a result, well-intending, but less well-versed clinicians sometimes make the diagnosis of antiphospholipid syndrome in women who are negative for lupus anticoagulant and anticardiolipin antibodies. This is especially confusing in the face of of growing evidence that the relevant in vivo antiphospholipid antigen is formed by a complex between beta 2-glycoprotein 1 and phospholipids. A second major problem is that of unwarranted discrepancies in the clinical and laboratory features of patients considered to have a diagnosis of antiphospholipid syndrome. This problem is most apparent in the case selection for pregnancy-loss treatment series and trials. Many series have included women with predominantly pre-embryonic and embryonic pregnancy losses, while others included a large majority of patients with one or more second or third trimester pregnancy losses. Some treatment trials purposefully excluded patients with a history of thrombosis or systemic lupus erythematosus, features found in nearly 50% of patients in other series. Though most authorities require the presence of either lupus anticoagulant or medium-to-high titer IgG anticardiolipin antibodies to make a diagnosis of antiphospholipid syndrome, in some series no more than half of the study patients had lupus anticoagulant and as many as 20% had only IgM anticardiolipin antibodies. It is very unlikely that patients with such disparate clinical and laboratory findings have the same autoimmune syndrome, and a stated or implicit diagnosis of antiphospholipid syndrome in such a wide variety of women is scientifically unsound and clinically dangerous. The relationship between antiphospholipid antibodies and poor reproductive outcomes must be approached through rigorous scientific study and appropriate treatments established by well-designed clinical trials.