Antiphospholipid Antibody Syndrome and Recurrent Pregnancy Loss

Antiphospholipid Antibody Syndrome and Recurrent Pregnancy Loss

William H. Kutteh, M.D., Ph.D., H.C.L.D.

Antiphospholipid antibody syndrome (APS) is an autoimmune disorder that is defined by characteristic clinical features and abnormal laboratory tests (Table 1). The clinical history may include three or more pregnancy losses before 10 weeks gestation, previous arterial or venous thrombosis (blood vessel clotting) unrelated to pregnancy, or one unexplained fetal death after 10 weeks. The laboratory criteria include a positive lupus anticoagulant test, positive antiphospholipid antibodies, or positive antibodies against beta2-glycoprotein 1 (anti-beta2-GP1).

Antiphospholipid antibodies (APA) are acquired antibodies, or immunoglobulins, (IgG, IgM, and/or IgA) against a phospholipid or protein. APA were originally associated with an increased risk for progressive thrombosis (blood clot) and infarction in the placenta. However, histopathologic findings in placentas from women with APA argue that proinflammatory factors may contribute to tissue injury.

Recent data indicate that APA can act through mechanisms unrelated to coagulation imbalances. Several lines of investigation demonstrate that APA act very early to disrupt a pregnancy by inhibiting the growth of the trophoblastic cells (placenta), by blocking the production of human chorionic gonadotropin (hCG), and by increasing the inflammatory reaction at the placenta by activation of complement.

Anticardiolipin antibodies (ACA) refer to APA that are detected by an anticardiolipin ELISA laboratory test. APA normally occur in about 5% of all women with out a history of a previous obstetrical problem; however, they are found in about 20% of women with recurrent pregnancy loss (Table 2).

In vivo and in vitro studies have demonstrated that APA can trigger a reaction with exposed phospholipids on endothelial cells, can activate monocytes and platelets activation, and can produce inflammation, thrombosis, and tissue damage. These alterations can inhibit the normal exchange between maternal and fetal cells. When coupled with the normal hypercoaguable changes during pregnancy, APA are more likely to interfere with the blood supply to the developing fetus. The complications of pregnancy that may result include miscarriage, intrauterine growth restriction, and fetal death or stillbirth.

Lupus anticoagulant (LAC) is an immunoglobulin (usually IgM or IgG) that interferes with one or more of the phospholipid dependent tests of in vitro coagulation. The name is a misnomer in two ways. First, patients who have lupus anticoagulant are not necessarily more likely to develop systemic lupus erythematosus (Lupus or SLE). Second, the lupus anticoagulant is associated with an increased risk for thrombosis, rather than bleeding problems. The name better describes the way the blood is tested in the laboratory because there is a prolonged in vitro clotting assay. LAC refers to APA that are detected by functional clotting assays such as the activated Partial Thromboplastin Time (aPPT). The aPTT will be prolonged with certain coagulation disorders that have been associated with pregnancy loss. The Dilute Russell Viper Venom Time (dRVVT) is a more sensitive clotting test used to diagnose Lupus anticoagulant (Table 3).

Beta2-glycoprotein 1 is thought to be the principle target of antiphospholipid antibodies. It reacts with negatively charged surfaces, including phospholipids, and has been show to have both procoagulant and anticoagulant functions. The concordance of LAC and APA with anti-beta2-glycoprotein 1 antibodies is low, and it is possible that anti-beta2-gp 1 correlate better with the risk of thrombosis than with recurrent pregnancy loss.

Many treatments have been shown to increase the live birth rate, but the combination of aspirin 81mg with heparin has been proven to provide the highest success rates with the lowest risk profile. The live birth rate for women with APS but without treatment is approximately 20%; conversely, approximately 75% of women with APS who are treated with aspirin and heparin will deliver healthy babies (Table 4).

Heparin does not cross the placenta, so there are no adverse fetal effects of heparin therapy to the developing baby. Heparin has been used in hundreds of thousands of women during pregnancy with minimal risk to the mother and the baby. Calcium supplementation (1200mg/day) is recommended to decrease the increased bone loss associated with heparin and pregnancy. Low molecular weight heparin, which is administered once a day, has also been used to treat APS. Although it is much more expensive than regular heparin, it is associated with less bone loss than unfractionated heparin. Heparin should be continued throughout pregnancy and resumed after delivery for a few weeks to prevent thrombosis.

Aspirin 81mg daily is taken concurrently with heparin as it selectively inhibits thromboxane production. Thromboxane is a factor known to increase vasoconstriction and platelet aggregation. It is recommended to continue aspirin 81mg until three weeks before the expected delivery date to decrease the risk of bleeding during delivery. Aspirin should be discontinued in women with thrombocytopenia (low platelets). Unless there are other pregnancy complications, most women using heparin therapy will have normal prenatal care and normal vaginal deliveries.

Women diagnosed with APS have an increased lifetime risk of thrombosis (blood clots). Because of this increased risk, any modifiable change that can decrease one’s risk of thrombosis should be made (Table 5).

The manifestations of APS may involve multiple organ systems due to the vascular occlusive complications. Fortunately, these complications are rare in young women of reproductive age. Estrogen-containing birth control pills should be avoided, as estrogen is also known to increase the risk of thrombosis. Women who have APS should take a baby aspirin 81mg daily to counter the increased risk of a future thromboembolic event such as arterial and venous clots.

References

• Empson M, Lassere M, Craig JC, Scott Jr. Recurrent pregnancy loss with
  Antiphospholipid antibody: a systemic review of therapeutic trials. Obstetrics and Gynecology 99:135-144, 2002.
• Franklin RD, Kutteh WH. Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population. Human Reproduction 11:2981-2985, 2002.
• Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nature Medicine 10: 1222-1226, 2004.
• Kutteh, WH. Antiphospholipid Antibody- associated recurrent pregnancy loss: treatment with heparin and low dose aspirin is superior to low dose aspirin alone. American Journal of Obstetrics and Gynecology 174:1958-1989, 1996.
• Noble LS, Kutteh WH, Lashey N, Franklin RD, Herrada J. Antiphospholipid antibodies associated with recurrent pregnancy loss: A prospective, multicenter, controlled pilot study comparing treatment with low-molecular weight heparin versus unfractionated heparin. Fertility and Sterility 83: 684-690, 2005.
• Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies. British Medical Journal. 314:253-257, 1997.