Recurrent Early Pregnancy Losses
Immunologic Problems

Autoimmunity (Self Antigens)

In autoimmunity, a humoral or cellular response is directed against a specific component of the host. The lupus anticoagulant and anticardiolipin antibodies are antiphospholipid antibodies, which arise as the result of an autoimmune disease. The lupus anticoagulant is present in a variety of clinical conditions, not just with lupus erythematosus. The antiphospholipid antibodies are directed against platelets and the vascular endothelium and cause thrombosis, spontaneous miscarriage, and fetal wastage. These antibodies block prostacyclin formation, which results in unbalanced thromboxane activity, leading to vasoconstriction and thrombosis. In several series, 10–16% of women with recurrent miscarriages have had antiphospholipid antibodies.  These antibodies are also associated with fetal growth retardation and fetal death in addition to recurrent miscarriages, and when present, there is a high rate of second-trimester fetal deaths. The mechanism of pregnancy loss is probably decidual and placental insufficiency due to the thrombotic tendency. Annexin-V is a phospholipid-binding protein that inhibits coagulation; the levels of annexin-V on trophoblasts and endothelial cells are reduced in the presence of antiphospholipid antibodies.

Despite activating thrombosis, the antiphospholipid antibodies prolong the prothrombin time and the partial thromboplastin time. The activated partial thromboplastin time is a relatively sensitive screening test, but we also obtain a kaolin clotting time. The anticardiolipin antibody and lupus anticoagulant can be identified and titered by specific immunoassays; other individual antiphospholipid antibodies have not been associated with recurrent miscarriages.  The antiphospholipid antibodies all produce the same clinical impact and have identical effects on clotting tests. Although the prevalence is uncertain, patients with recurrent miscarriages should be screened with the activated partial thromboplastin time, a kaolin clotting time, lupus anticoagulant, and the anticardiolipin antibody.  It is not clinically helpful to measure antinuclear antibodies, IGA antibodies, or leukocyte antibodies.

Our preferred treatment for significant titers of antiphospholipid antibodies consists of the combination of low-dose aspirin (80 mg daily) and low-dose heparin as soon as pregnancy is diagnosed. Treatment is not always successful. Studies of low-dose aspirin alone do not demonstrate a favorable effect on pregnancy outcome in either women with unexplained recurrent losses or in women with detectable anticardiolipin antibodies. Others advocate the addition of a glucocorticoid in a dose sufficient to restore the clotting studies to normal.  However, the addition of glucocorticoids is not very effective in eliminating the anticardiolipin antibody, and in a randomized trial, a combination of prednisone and aspirin (100 mg daily) was no better than placebo treatment. Many of these patients develop preeclampsia, often very severe, but approximately 75% of patients with antiphospholipid antibodies will deliver a viable infant in a treated pregnancy. Because of the risks associated with anticoagulation, aspirin and heparin treatment should be confined to women with recurrent pregnancy losses who have antiphospholipid antibodies. Indeed, it can be argued that treatment should be offered only to women with antiphospholipid antibodies who have experienced both first-trimester and second-trimester losses.

Alloimmunity (Foreign Antigens)

Alloimmunity refers to all causes of pregnancy losses related to an abnormal maternal immune response to antigens on placental or fetal tissues.  Normally, maintenance of pregnancy may require the formation of blocking factors (probably complexes of antibody and antigen) that prevent maternal rejection of fetal antigens. It has been argued that couples with repetitive miscarriages have an increased sharing of human leukocyte antigens (HLA), a condition that would not allow the mother to make blocking antibodies.

Immunotherapy to stimulate antibody formation has been offered to produce a favorable maternal immune response in order to protect the developing embryo. Women with recurrent miscarriages have been treated with infusions of their partner's lymphocytes. In one study, 77% of women receiving their husband's cells gave birth compared to 37% receiving their own cells. Critics of this study have contended that success in the control group raises the question of the adequacy of matching in the selection of control patients. Others have claimed good results with transfusion of leukocyte-rich, erythrocyte-rich donor blood (3 transfusions every 4–8 weeks) or with intravenous immunoglobulin or seminal plasma vaginal suppositories.

Women have been selected for immunotherapy by HLA typing, but its use is no longer supported. Many investigators have failed to confirm that sharing of HLA antigens is found to a greater degree in couples with recurrent miscarriages. This agrees with experiments in animals where sharing of HLA antigens has not been found to affect reproduction. The sharing of genetic loci may be a broader problem that includes genetic loci critical for embryonic development, and the antigens available for measurement serve only as markers for a more fundamental genetic immunologic failure in pregnancy. There is also concern that immunization of mothers may affect placenta and fetus. There is no specific immunologic test or clinical method which will predict the need for treatment.

Immunotherapy remains experimental with potential risks of adverse consequences on the immune systems of mother and child. At least 5 randomized placebo-controlled studies have failed to demonstrate a beneficial effect of immunotherapy. In a study of women with 5 or more early miscarriages, paternal leukocyte immunization appeared to have a beneficial effect; suggesting that 25% of multiple aborters (without a live birth) would benefit. In a re-analysis of the world-wide raw data, the difference in birth rate between treatment and control groups amounted to 10%, a difference so small that it may not be clinically significant. Our recommendation is that women with an extreme number of recurrent early pregnancy losses should be referred to a center operating an immunotherapy protocol.