The autoimmune disorder rheumatoid arthritis occurs in about 1%–2% of the population. The disease is more prevalent in women than men by about a 3:1 ratio, but in the reproductive years, the ratio may be as high as 6:1. During pregnancy, the incidence is about 1 in 1,000.
RA is characterized by production of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1 in the synovial cavity, and irreversible damage to soft tissues and bones. Drug therapy of RA involves using disease-modifying antirheumatic drugs (DMARDs) to prevent or lessen this damage. The therapy can be categorized as biologic DMARDs, synthetic DMARDs, and anti-inflammatory agents.
Biologic DMARDs include three agents that inhibit TNF-α—adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade)—and one interleukin-1 receptor antagonist, anakinra (Kineret). Although the human pregnancy data for these four drugs are lacking, animal reproduction data suggest they pose a low risk for developmental toxicity (growth retardation, structural defects, functional/behavioral defects, or death).
The safest course is to avoid these agents during the first trimester, but with their long elimination half-lives, inadvertent exposures during organogenesis of unplanned pregnancies is likely.
Synthetic DMARDs include azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold compounds, hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate, penicillamine, and sulfasalazine (Azulfidine).
The two immunosuppressants, azathioprine and cyclosporine, do not appear to cause congenital defects, but they may be associated with growth retardation. There is limited human pregnancy experience with the gold compounds—auranofin (Ridaura), aurothioglucose (Solganal), and gold sodium thiomalate (Aurolate)—but the animal data suggest the risk for developmental toxicity is low.
Hydroxychloroquine is probably compatible in pregnancy, but there is limited pregnancy experience with the high doses commonly used in RA. The drug has a very long elimination half-life from maternal tissues (weeks to months), so stopping the drug when pregnancy is confirmed will not prevent embryo/fetal exposure.
Leflunomide, a pyrimidine synthesis inhibitor, causes dose-related teratogenicity and toxicity in animals at doses much lower than those used in humans. Human pregnancy experience is too limited to determine the risk to the embryo or fetus, and the drug is contraindicated in pregnancy. Exposure of unplanned pregnancies will probably occur because the drug and its active metabolite may take up to 2 years to reach nondetectable plasma levels.
The folic acid antagonist methotrexate is contraindicated during pregnancy. The drug is associated with spontaneous abortions and a spectrum of congenital defects collectively termed methotrexate embryopathy. The critical exposure period for structural defects is 8–10 weeks after the first day of the last menstrual period. Exposure after this period is associated with fetal toxicity and mortality. The critical dose is thought to be 10 mg or more per week.
Another folate antagonist, sulfasalazine, does not seem to cause developmental toxicity, but supplemental folic acid (1 mg/day) should be used if there is a risk of unplanned pregnancy or if pregnancy occurs. The drug has caused bloody diarrhea in a nursing infant, so breast-feeding should be done with caution. Penicillamine, a chelating agent associated with a risk of fetal connective tissue defects (cutis laxa), should be avoided during pregnancy.
The NSAIDs, which include aspirin, have considerable potential for embryo/fetal toxicity: spontaneous abortions when used around the time of conception, fetal renal toxicity, and premature closure of the ductus arteriosus in the third trimester. Aspirin use near term may increase the risk of bleeding in the mother and the infant. The use of prednisone during organogenesis carries a low risk for oral clefts and prolonged use in pregnancy has been associated with growth retardation.
The biologic DMARDs, gold compounds, hydroxychloroquine, NSAIDs (except high-dose aspirin), and prednisone are probably compatible with breast-feeding. The other agents are either contraindicated (methotrexate) or should be avoided because of potential toxicity. High-dose aspirin and sulfasalazine have been associated with toxicity in nursing infants.
The Organization of Teratology Information Services is conducting a study of pregnancy exposure to rheumatoid arthritis drugs. Health care professionals can call the toll-free number (877-311-8972) for information about enrolling patients in this study.