Rheumatoid Arthritis Drugs During Pregnancy and Lactation: A Review of Safety Guidelines

Rheumatoid arthritis (RA) is a life-long autoimmune disease affecting women 3 times more frequently than men, with a high occurrence between the ages of 18 and 44.¹ Although a majority of women with RA were previously thought to achieve remission during pregnancy, recent studies indicate remission occurs in only 20% to 40% of cases.²

Only limited data are available regarding the safety of antirheumatic drugs during pregnancy, mainly because of the exclusion of pregnant women from drug trials. Available data are mainly gathered from case reports and large registries of patients taking multiple medications or presenting with other immune diseases in addition to RA, thus limiting conclusions applicable to patients with RA.³

In addition, in June 2015, the United States Food and Drug Administration removed from all drug labeling the pregnancy categories (A, B, C, D, and X), because of a lack of clear guidance regarding the degree of risk to the fetus.³ The Pregnancy and Lactation Labeling Rule now replaces these categories to provide a clearer understanding of drug-associated risks during pregnancy.⁴

Below is pregnancy-related safety information regarding the use of common drugs used to manage RA:

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

There is conflicting evidence indicating that NSAIDs may increase the risk for spontaneous abortion; therefore, conservative recommendations call for limited use in the first trimester.^2,3 

NSAID use during the third trimester of pregnancy has been found to increase the risk for premature closure of the ductus arteriosus (odds ratio [OR], 15.04; 95% CI, 3.29-68.68) in a 2006 meta-analysis and is therefore advised against during that period.⁵

During lactation, NSAIDs are considered safe, except in mothers of infants with thrombocytopenia in whom they should be avoided.²

Glucocorticoids

The glucocorticoids prednisone and prednisolone are the drugs of choice because of their high metabolism by placental dehydrogenase.² However, glucocorticoids have been found to increase the risk for oral clefts (OR, 3.35; 95% CI, 1.97-5.69), therefore minimizing the dose during the first trimester is recommended.⁵

Minimizing the dose in the third trimester is also recommended because of an increased risk for gestational diabetes mellitus, hypertension, premature rupture of membranes, and intrauterine growth restriction.²

Glucocorticoids are considered safe in lactation, although recommendations are to delay feeding until 4 hours after taking glucocorticoids to lessen infant exposure.²

Methotrexate

Methotrexate is contraindicated during pregnancy because of an increased risk for spontaneous abortion and heart, central nervous system, and skeletal embryopathy.⁶ Recommendations are to cease methotrexate 3 months before conception and take folic acid before conceiving and also during the first trimester.² If unplanned pregnancy occurs while a patient is on methotrexate, the drug should be discontinued and the patient should be counseled on risk management.²

Hydroxychloroquine

Hydroxychloroquine, an immunomodulating antimalarial drug, is considered safe during pregnancy with no associated risk for genital anomalies, although most of the data available are from studies in patients with systemic lupus erythematosus.^2,3

Sulfasalazine

Sulfasalazine is a disease-modifying antirheumatic drug (DMARD) generally considered safe to use during pregnancy, according to studies in patients with inflammatory bowel disease (IBD).²

Taking folate during preconception and pregnancy is recommended, as sulfasalazine may affect the absorption of folate.²

Leflunomide  

Leflunomide, a pyrimidine antagonist, is contraindicated during pregnancy because of its teratogenic and embryotoxic properties, as indicated by animal studies.² Because of the drug’s long half-life, it should be discontinued 2 years before conception or washed out with cholestyramine (8 g 3 times/day for 11 days).² If unplanned pregnancy occurs while a patient is taking leflunomide, the drug should be discontinued and the patient should be counseled on risk management.²