Recurrent Pregnancy Loss and Immunological Factors
Jessica Auffant, MS IV & Mark P. Trolice, M.D.
A pregnancy loss is devastating for a woman and her family occurring in approximately 15% percent of clinically diagnosed pregnancies. This loss rate is closer to 50% of all fertilizations since many spontaneous abortions occur at 2-4 weeks before pregnancy is clinically diagnosed. This can be caused by multiple factors, the most common being genetic with up to 70% resulting from chromosomal abnormalities. Other common causes of pregnancy loss include anatomical abnormalities (uterine fibroids, septate uterus), endocrine disturbances (diabetes mellitus, thyroid dysfunction, polycystic ovarian syndrome), and autoimmune disorders (antiphospholipid syndrome - APS). Recurrent pregnancy loss (RPL) is defined as three or more clinical pregnancies losses of less then 20 weeks gestation and occurs in 1-2% of patients. An evaluation should begin sooner for women 35 years and older or for those with significant risk factors (thrombosis with a pregnancy loss).
The autoimmune causes most commonly known include the APS but also may include autoantibodies to thyroid, antinuclear antibodies, and alloimmune responses. All of these conditions are still unclear as to how they correlate exactly with fetal losses.
APS has been shown to cause RPL, thrombosis, and/or autoimmune thrombocytopenia. Antiphospholipid antibodies are of clinical significance when lupus anticoagulant, anticardiolipin antibodies, and anti-beta2 glycoprotein remain elevated six weeks apart. It is theorized that these antiphospholipid antibodies cause an increase in thromboxane-to-prostacyclin ratio leading to clotting in the placenta and fetal tissue hypoxia and damage therefore ending the pregnancy in miscarriage. Once a laboratory and clinical criteria are met, APS is diagnosed.
APS has up to a 90% fetal loss rate without therapeutic intervention. Treatment includes a low dose aspirin (81 mg daily) and low dose heparin (5,000-10,000 units SQ every 12 hours) or low molecular weight heparin daily throughout the first trimester of pregnancy. These medications are thought to help prevent thrombosis in the placenta helping maintain pregnancies. The treatment of APS, although not completely understood, has been shown to improve the chance of pregnancy in women, but fetal losses continue in some women despite adequate therapy.
There are other therapies that are still being studied and explored to further treat women with antiphospholipid syndromes. The use of corticosteroids has been thought to decrease the risk of recurrent pregnancy loss in women with suspected autoimmune origins. Steroids however have failed to currently prove their efficacy in improving pregnancy success rates verse losses. They have furthermore been shown to increase other risks in pregnancy such as gestational diabetes, premature rupture of membranes, and hypertension during pregnancy. Currently steroids are still being studied but are not recommended as treatment modalities for women with antiphospholipid syndrome.
There is also investigations looking into intravenous immunoglobulin (IVIG) therapy but this is expensive and no evidence has shown strong support in its favor to date.
Other autoimmune cause of PRL in women include the production of antithyroid antibodies and antinuclear antibodies (ANA). The antithyroid antibodies found were not associated with any thyroid dysfunction or thyroid specific disease but did show a clinically significant increase in miscarriages. It is theorized that these antibodies are not physiologically associated with the loss but are associated with a larger systemic autoimmune reaction that results in the miscarriage that is not well understood. Antinuclear antibodies have been associated pregnancy loss but further evidence is still needed to prove this nonspecific correlation. Nevertheless, low dose thyroid replacement may reduce pregnancy loss and preterm deliveries. (J Clin Endocrinol Metab 91: 2587–2591, 2006).
There are several theories about alloimmune responses (when the immune system attack abnormal fetal tissue) resulting in miscarriages in women. One theory suspects that if paternal and maternal human leukocyte antigens (HLA) are shared the mother will not produce blocking antibodies preventing rejection of the fetal antigens. Another theory suggests that maternal production of antileukocytotoxic antibodies against the father results in a fetal loss. Another alloimmune theory is that the mother fails to produce a serum blocking factor and attacks the fetus herself. Finally another theory has been described as dysregulation of the maternal-fetal immune mechanisms. The theories and studies have not proven yet to show that these are definite causes of miscarriages and are therefore being further explored. No HLA testing is currently recommended for couples undergoing immunological exploration for pregnancy losses nor do any current treatment modalities exist.
By further understanding, knowing how to diagnose, and finally to treat immunological causes of recurrent pregnancy losses that we can hopefully prevent the heartbreak and devastation women endure. The impact a lost pregnancy can have on a woman and her family can be one of the hardest events in their lives and is one that we hope to prevent in our patient’s futures.
Jessica Auffant is a fourth year medical student and Dr. Trolice is Clinical Associate Professor of Florida State University College of Medicine.