Stephen A. Paget, MD, FACP, FACR

Disclosures

June 26, 2003

Question

What are the considerations in patients with systemic autoimmunity who may need a fertility drug to achieve pregnancy?

Response from Stephen A. Paget, MD, FACP, FACR

Normal decline in female fertility begins in the mid-30s and becomes marked after age 40. Fertility is usually normal in connective tissue diseases, with the possible exception of systemic sclerosis (where decreased fertility both before and after time of clinical diagnosis has been suggested). However, patients with autoimmune disorders, particularly those with systemic lupus erythematosus, may be treated with cytotoxic agents such as cyclophosphamide, and, as a result, fertility may decline at a significantly younger age. Risk of amenorrhea with cyclophosphamide is directly related to patient age and cumulative drug dose. Patients with vasculitis are also treated with cyclophosphamide; however, these patients are more commonly male and older. Few other disease-modifying drugs affect long-term fertility.

Advances in rheumatic disease management have resulted in a more chronic course of disease for many patients. Both improved disease control and the increasing availability of assisted reproductive techniques (ART) for couples with infertility make the issue of ART use in people with connective tissue disease (CTD) a common one today. Assisted reproductive techniques include ovarian stimulation with or without in vitro fertilization (IVF) and subsequent embryo transfer into the uterus. Ovarian induction (OI) is accomplished by hormonal manipulation, which may include administration of gonadotropins, gonadotropin-releasing hormone agonists, follicle-stimulating hormones, and luteinizing hormone. Ovulation occurs after administration of human chorionic gonadotropin (hCG). Multiple oocytes are retrieved through transvaginal ultrasound-guided follicular puncture; after IVF, which may involve a variety of specialized techniques, embryos are replaced by transcervical transfer. Ovarian hyperstimulation syndrome, a potential complication of OI/IVF, may predispose to thrombosis in severe cases.

The potential risks of the use of OI (fertility drugs) in patients with autoimmune disorders include hormone-associated flare or thrombosis. It is primarily in patients with SLE where a proinflammatory effect of estrogen on disease activity is of concern. In theory, risk of thrombosis may be greatest for patients with antiphospholipid antibody (aPL), since high estrogen levels exert an additional prothrombotic effect. While OI/IVF cycles are often successful in CTD patients, concerns -- especially in SLE and antiphospholipid syndrome (APS) patients -- are valid, and complications are seen.

Guballa and colleagues[1] reviewed histories of 19 women with SLE and/or APS who underwent 68 cycles of OI/IVF. Four of 19 patients had a flare of SLE, and 2 patients developed ovarian hyperstimulation syndrome, but no thromboses occurred. Huong and associates[2] similarly reported 21 women with 114 cycles of OI. Eight of the 21 were diagnosed with SLE only after developing a complication of OI. Five women who concealed their diagnosis of SLE had higher rates of both fetal loss and lupus flare. Lupus exacerbation was more common in patients treated with subcutaneous or intramuscular gonadotropins than with oral clomiphene.

While few data exist documenting the effect of fertility therapy on the medical/disease status of autoimmune disease patients, it seems likely that the women at greatest risk are those with SLE and/or APS. Major risks are of autoimmune disease flare and of thrombosis. Recommendations similar to those regarding pregnancy in autoimmune disease seem reasonable: Patients should be evaluated prior to the procedure for appropriate risk factors, and counseled regarding relative risk vs benefit. OI/IVF should be deferred in patients with active lupus or other CTD (ie, active disease manifested by arthritis, fever, cytopenias, or internal organ inflammation such as nephritis). Disease control should be achieved prior to the institution of fertility drug. Prophylactic therapy with low-dose aspirin in patients with asymptomatic aPL should be considered. Patients with APS and a history of thrombosis require subcutaneous heparin.

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