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Risks and Benefits of Disease-Modifying Antirheumatic Treatment for Systemic Lupus Erythematosus Exacerbations in Pregnant Women

1 January 2008


The direct correlation between systemic lupus erythematosus (SLE) and increased risk of disease activity during pregnancy is concerning to both maternal health and fetal condition. Disease-modifying antirheumatic drugs (DMARDS) have been shown to decrease disease activity in systemic lupus erythematosus (SLE) patients and effectively treat exacerbations however treatment may increase risk of fetal demise due to teratogenic effects. The potential benefits and harms to both maternal and fetal health upon taking disease-modifying antirheumatic drugs (DMARDS) during pregnancy is a clinical question that has yet to be answered, and recommendation of exacerbation treatments is currently being explored by practicing physicians.

Background: Systemic Lupus Erythematosus (SLE) is a multi system autoimmune connective tissue disorder that is more common in women of childbearing years. Majority of studies show an increased risk of disease exacerbation during pregnancy which becomes life threatening for both mother and fetus, especially if exacerbations are not treated, resulting in spontaneous abortion, stillbirth, preterm delivery, fetal growth retardation, fetal loss rates, pre-eclampsia, and gestational hypertension. Main risk factors for adverse pregnancy course and outcome are: active disease, nephritis with proteinuria, hypertension, and maternal serum antibodies to SS-A/Ro, SS-B/La, cardiolipin, [beta]2-glycoprotein I and lupus anticoagulant. Studies show that prevention and treatment of exacerbation during pregnancy is highly effective in lowering risk of fetal demise, in fact although systemic lupus erythematosus (SLE) pregnancies are high risk, pregnancy during inactive disease state has a high success rate of normal outcome. It is therefore essential to treat symptoms of exacerbation as they appear in systemic lupus erythematosus (SLE) patients during pregnancy. Exacerbations are effectively treated with disease-modifying antirheumatic drugs (DMARDS) however this classification of drugs has been known to have teratogenic effects and therefore poses a concern to medical providers in treating active disease during pregnancy.

Disease-modifying antirheumatic drugs (DMARDS) are commonly used in the treatment of systemic lupus erythematosus (SLE) and have been shown to be extremely effective in the treatment of systemic lupus erythematosus (SLE) exacerbations. The most commonly used disease-modifying antirheumatic drugs (DMARDS) include: cyclophosphamide, methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), and azathioprine (AZA). Treatments are often started at an early age therefore women of reproductive age are at risk for exposure to disease-modifying antirheumatic drugs (DMARDS) at time of conception and pregnancy. Due to lack of information and studies on the teratogenic effects of disease-modifying antirheumatic drug (DMARDS) exposure to fetus during pregnancy, it makes treatment and safety of medication exposure questionable. It has become increasingly important to investigate and explore the benefits and risks in treating pregnant patients with disease-modifying antirheumatic drugs (DMARDS).

Objective: To explore current literature and investigate potential harms and benefits of using disease-modifying antirheumatic drugs (DMARDS) treatments during systemic lupus erythematosus (SLE) exacerbation during pregnancy, and provide clarity to treatment recommendations in this demographic.

Methods: An extensive review of literature was constructed using Ovid and PubMed in conjunction with manually reviewing references cited from collected articles. Search words included: Systemic Lupus Erythematosus (SLE), Pregnancy, Lupus exacerbation, Azathioprine (AZA), Sulfasalazine (SSZ), Methotrexate (MTX), Hydroxycholoroquine (HCQ), Cyclophosphamide, Disease modifying antirheumatic drugs (DMARDS), lupus nephritis, and immunosuppression medications. Articles from 1997-2008 were used in composing a thorough literature review of this topic. Four articles were extensively reviewed and results were compared. Several complimentary articles of disease-modifying antirheumatic (DMARDS) treatments during pregnancy were also compared and reviewed.

Results: Current literature review found that treatment with disease-modifying antirheumatic drugs (DMARDS) is crucial in the treatment of lupus exacerbation during pregnancy however the potential benefits and harms must be thoroughly reviewed before initialization of treatment. Review of the literature showed that each individual drug of the disease-modifying antirheumatic drug (DMARDS) group had different effects on the fetus and mother, therefore each drug was individually studied.

Studies showed that hydroxychloroquine (HCQ) is an extremely useful agent in managing certain aspects of clinical systemic lupus erythematosus (SLE), showing that in small doses no fetal anomalies have been identified, however at supratherapeutic doses there may be ocular or auditory damage.4 Studies also showed that discontinuing hydroxychloroquine (HCQ) during pregnancy could possibly produce flares in patients with systemic lupus erythematosus (SLE), which could then be detrimental to the pregnancy. There is limited evidence that shows any benefit from initiating hydroxychloroquine (HCQ) therapy during pregnancy.

Studies showed that methotrexate (MTX) use during pregnancy is conflicting, a critical period and dose for exposure is proposed, however high rates of pregnancy loss indicates risk to fetus. Therefore in each individual patient, consideration regarding use before and during pregnancy has to be made.

Sulfasalazine (SSZ) is presently listed as a Category B drug on the FDA Pregnancy Risk Classification, however further research needs to be done for safety of this medication. A limited amount of studies were found regarding this medication, however the articles that were found showed no major teratogenic effects upon women taking sulfasalazine (SSZ) during pregnancy.6

Studies of azathioprine (AZA) showed that upon standard doses of medications no increase risk of congenital abnormalities were shown; however there were some contradictive studies that resulted in pregnancy loss while on azathioprine (AZA) during active systemic lupus erythematosus (SLE) disease. It is indecisive if the increase in pregnancy loss was due to active disease state or medication and therefore further studies are needed to evaluate this factor.

Cyclophosphamide studies were found to show an increased risk of fetal malformation due to cell death in utero. Several studies showed first trimester miscarriages upon exposure to cyclophosphamide. In the past, cyclophosphamide recommendations were to avoid exposure to medication during the first and second trimester due to fetal malformation, however recent studies now recommend avoiding during the third trimester as well, due to intrauterine fetal demise upon exposure.

Conclusion: In conclusion disease-modifying antirheumatic (DMARDS) treatments are crucial in the treatments of systemic lupus erythematosus (SLE) exacerbations; in accordance with use during pregnancy it is important to evaluate the patient and the disease individually, weighing the benefits and harms to both the mother and fetus. Recommended disease-modifying antirheumatic (DMARDS) treatment is based on observational studies and known teratogenic effects of medications therefore each medication is individually explored in its use for systemic lupus erythematosus (SLE) exacerbation. Review of literature strongly indicates hydroxychloroquine (HCQ) for safe use during pregnancy as well as azathioprine (AZA) in treating systemic lupus erythematosus (SLE) exacerbation during pregnancy. Studies indicated high risk of fetal demise and/or teratogenic congenital abnormalities upon the use of methotrexate (MTX) and cyclophosphamide therefore use during pregnancy is not recommended. Sulfasalazine (SSZ) articles were limited and recommendation of use was based on limited information, therefore more research is needed at this time upon use during pregnancy. Overall, weighing potential benefits and harms to both the mother and the fetus prior to establishing treatment of exacerbation during pregnancy is the primary importance in treating exacerbations at this time.


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