AUTOIMMUNE CAUSES OF RPL

In some instances, there is a failure in normal control mechanisms that prevent an immune reaction against self, resulting in an autoimmune response. Autoantibodies to phospholipids, thyroid antigens, nuclear antigens and others have been investigated as possible causes for pregnancy loss. Antiphospholipid  (aPL) antibodies include the lupus anticoagulant, Anti–beta 2 glycoprotein I antibodies, and anticardiolipin antibodies. An increasing number of studies suggest that antibodies to phosphatidyl serine are also associated with pregnancy loss. Women with systemic lupus erythematosus and aPL have increased risks for miscarriage compared to those with lupus and negative aPL. The Recurrent Pregnancy Loss Center in Memphis has published over 100 manuscripts on the diagnosis and treatment of immunological causes of RPL.

 

 

 

Antiphospholipid Antibody Syndrome (APS):

APS is an autoimmune condition characterized by the production of moderate to high levels of antiphopolipid antibodies (APS) and certain clinical features. The presence of antiphospholipid antibodies during pregnancy is a major risk factor for adverse pregnancy outcome. In large meta-analysis of studies of couples with recurrent miscarriage, the incidence of antiphospholipid antibody syndrome was between 15% and 20% compared to about 5% in nonpregnant women without a history of obstetrical complications.

Several mechanisms have been proposed by which aPL might mediate pregnancy loss. Classically, it was believed that aPL antibodies induced thromboses in vessels surrounding the placental-maternal unit, resulting in placental infarction and fetal death. However, recent data suggests that the primary mechanism by which aPL antibodies lead to miscarriage may be via a deleterious effect conferred directly on trophoblastic cells and/or endothelial cells. aPL antibodies can interact with cultured human vascular endothelial cells with resultant injury and/or activation. Furthermore, aPL have been demonstrated to inhibit secretion of human placental chorionic gonadotropin and to inhibit the expression of trophoblast cell adhesion molecules (alpha 1 and alpha 5 integrins, E and VE cadherins. These mechanisms could explain RPL secondary to aPL antibodies early in the first trimester.

Antiphospholipid antibody syndrome (APS) is treated with a combination of low dose heparin (5000 to 10,000 units subcutaneously every 12 hours) and low dose aspirin (81 mg orally daily) appears to be effective and may reduce pregnancy loss by 54% in women with APS. Aspirin alone does not appear to reduce miscarriage rates. Unfractionated heparin is preferred to low molecular weight heparin (LMWH) based on available data. In 1996, the Recurrent Pregnancy Loss Center published the first study that established APS as a cause of RPL in the first trimester. This landmark paper, published in the American Journal of Obstetrics and Gynecology, also established heparin and aspirin as the treatment of choice.  The data from our study is foundation of the current recommendations for treatment by the American College of Obstetricians  and Gynecologists as well as the American Society for Reproductive Medicine.

 

 

Treatment with steroids is not recommended based on current evidence. Aspirin should be started preconceptually and heparin should be started after the first positive pregnancy test. Treatment should be continued until the time of delivery because these women are at an increased risk for thrombosis. Post-partum thromboprophylaxis is reasonable for a short interval to prevent thrombosis when the risk is high. The adverse reactions associated with heparin include bleeding, thrombocytopenia and osteoporosis with fracture. Calcium (600 mg twice daily) with added vitamin D supplementation (400 IU daily) and weight–bearing exercise are encouraged to decrease the risk of osteoporosis. In any pregnant woman starting on heparin, the platelet count should be monitored weekly for the first 2 weeks after initiation, and after any dosage change. Women with APS should avoid the use of estrogen-containing oral contraceptives in the future, should avoid the use of tobacco products, should maintain a normal weight, and should take aspirin 81mg daily unless contraindicated.

 

Antinuclear Antibodies 

Approximately 10-15% of all women will have detectable antinuclear antibodies regardless of their history of pregnancy loss.  Their chance of successful pregnancy outcome is not dependent on the presence or absence of antinuclear antibodies.  Treatments such as steroids have been shown to increase the maternal and fetal complications without benefiting live births. Thus, routine testing and treatment for antinuclear antibodies is not indicated.

 

Antithyroid Antibodies 

Hypothyroidism is easily diagnosed with a sensitive TSH test and patients should be treated to become euthyroid (defined for the purposes of RPL as between 1.0 and 2.5 uIU/mL) before attempting a next pregnancy. It has also been suggested that thyroid antibodies are elevated in women with recurrent pregnancy loss. A retrospective study of 700 patients with recurrent pregnancy loss demonstrated that 158 women had antithyroid antibodies but only 23 of those women had clinical hypothyroidism on the basis of an abnormal TSH value. The presence of antithyroid antibodies may imply abnormal T-cell function, and therefore, more of an immune dysfunction rather than an endocrine disorder may be responsible for the pregnancy losses. The Endocrine Society recommends that patients with RPL be treated to keep a TSH level of between 1.0 and 2.5 uIU/mL in the first trimester [30]. For TSH levels found to be between 2.5-10 mIU/mL, a starting levothyroxine dose of at least 50 μg/d is recommended.