Safety of RA drug treatments in pregnant and nursing women
A majority of drugs have the ability to cross the placenta and come in contact with a developing fetus. Those that pose a danger to the fetus are called teratogenic. Many drugs may also enter breast milk during lactation and may pose a risk to the nursing infant.
Even though the symptoms of RA may improve for many women during pregnancy, many pregnant women with RA may still need to use pain control medications and medications to control inflammation. While the safest course of action is to avoid use of all drugs during pregnancy, this may not be possible. The US FDA has classified medications used to treat RA according to their possible effects on the fetus and has determined whether it is safe to nurse an infant while taking a given drug.
FDA classification system for drug safety during pregnancy
The FDA classification system for the safety of drugs during pregnancy categorizes drugs from A to D and X, based on evidence from studies conducted in animals and humans, where A is no evidence of risk to the human fetus, D some evidence risk to the human fetus, and X is a high level of risk to the human fetus.1
US FDA categories for drug safety during pregnancy
- Well-controlled, adequate studies (in humans) failed to demonstrate fetal risk during first trimester
- No evidence of risk after first trimester
- Animal studies failed to demonstrate fetal risk, but no there are no well-controlled, adequate studies in humans
- Animal studies have shown a fetal risk, but well-controlled, adequate studies (in humans) failed to demonstrate fetal risk during first trimester or later
- Animal studies have shown a fetal risk, but there are no well-controlled, adequate studies (in humans) and drug benefits may be acceptable, despite the potential risks
- There are no animal reproductive studies or well-controlled, adequate studies (in humans)
- There is evidence of fetal risk from adverse event data from investigational or marketing experience, but drug benefits may be acceptable, despite the potential risks
- Animal or human studies (or marketing experience) demonstrate positive fetal risk or fetal abnormalities, and risk clearly outweighs possible benefit
Adapted from Hazes JM, Coulie PG, Geenen V, et al. Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use. Rheumatol (Oxford) 2011;50:1955-68.
Safety of different classes of RA drugs in pregnancy
For some drugs commonly used to treat RA, safety data may be lacking due to the difficulty and ethical considerations associated with testing these drugs in pregnant women. For many drugs used in RA, the risk during pregnancy varies according to the stage of pregnancy.
NSAIDs and aspirin
Non-steroidal anti-inflammatory drugs (NSAIDS) (including naproxen, ibuprofen, ketoprofen), as well as low-dose aspirin (and other salicylates), when given from conception to the start of the third trimester are considered to present minimal fetal risk. These drugs are pregnancy category B drugs during the first stages of pregnancy. After 30 weeks of gestation, NSAIDs and high-dose aspirin may increase the risk of a type of fetal heart problem and high-dose aspirin may increase the risk for fetal bleeding or bruising. Therefore, in the later stages of pregnancy these drugs become pregnancy category C drugs.2
There is some risk that NSAIDs may interfere with implantation after conception, therefore it may be advisable to avoid NSAID use until pregnancy is confirmed. Additionally, there is a small increased risk of miscarriage with NSAID use before 20 weeks of gestation.2
Corticosteroids include short-acting agents (prednisone, prednisolone, and methylprednisolone) and long-acting agents (dexamethasone and betamethasone). These drugs vary according to the concentrations they reach in the fetus. As a group, they are considered pregnancy category C drugs, with evidence of birth defects (mostly cleft palate) in both animal and human studies. Use of corticosteroids during pregnancy in patients with RA has been associated with increased risk of premature delivery. Despite these risks, corticosteroids are considered relatively safe throughout pregnancy when given at low doses (below 15 mg/day). They should be avoided, if possible, during the first trimester, when risk for defects of the hard palate are highest. Prednisone and prednisolone are preferred in pregnant women because they are inactivated as they cross the placenta.1,2
Disease-modifying anti-rheumatic drugs (DMARDs) vary widely according to their safety in pregnancy.
Sulfasalazine is considered a pregnancy category B drug. There is little evidence of fetal risk with sulfasalazine, as long as the expectant mother is also taking a multivitamin with 0.4 mg or more of folic acid.2
The immunosuppressive agent azathioprine is considered a pregnancy category D drug, with some evidence of increased risk of fetal abnormalities in human studies. If the benefits of treatment with azathioprine (for instance, to maintain remission during pregnancy) outweigh the risks, this drug may be continued during pregnancy.2
The DMARDs methotrexate and leflunomide are both considered pregnancy category X drugs and should not be taken during pregnancy. With both drugs, there is increased risk for birth defects and miscarriages. Methotrexate should be discontinued at least three months prior to becoming pregnancy and leflunomide should be avoided for two years before pregnancy.2
Anti-malarial drugs (hydroxychloroquine, chloroquine) are considered pregnancy category C drugs. While there is evidence of risk for damage to the eye and ear, if the benefits of these drugs in controlling RA symptoms are judged to outweigh the risks, they may continue to be used during pregnancy.1,2
A variety of biologic agents are used to treat RA, including TNF-inhibitors (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol), abatacept, rituximab, anakinra, tofacitinib, and toclizumab, which act against a variety of targets to inhibit immune response. Since many of these agents are quite new, there is limited data to determine their safety during pregnancy.
TNF-inhibitors (those listed above) are considered pregnancy category B drugs, with a low risk for birth defects, miscarriages, and preterm births. Because of the limited safety data available, discontinuation of TNF-inhibitor therapy is recommended at the time of conception. There is evidence that anti-TNF antibodies are not transferred to the fetus during the first trimester of pregnancy. In patients who experience RA flares during pregnancy, treatment with TNF-inhibitor therapy may be resumed, with an understanding that there may be an increased risk of birth defects and other negative outcomes.1,2
For the biologics, including abatacept, rituximab, anakinra, tofacitinib, and toclizumab, there is limited data to judge safety during pregnancy. Therefore, each of these drugs is considered a pregnancy category C drug. When planning pregnancy, it is recommended that these drugs be discontinued 10 weeks before conception.1,2
RA drugs and risk during pregnancy
- First part of pregnancy
- After 30 weeks of gestation
- Use during first trimester associated with increased risk of oral cleft
- No increased risk of congenital malformations
- Combine with folate supplements
- Can be continued to maintain remission during pregnancy
- Compatible with pregnancy
- Risk for eye and ear abnormalities higher with chloroquine
Safety of RA drugs during breast-feeding
NSAIDs and aspirin
NSAIDS (including naproxen, ibuprofen, ketoprofen) are found in breast milk in small amounts and aspirin and other salicylates are generally considered safe to use during nursing. However, caution should be exercised when using these drugs during breastfeeding.2
Corticosteroids do enter breast milk. However, their use during lactation has been approved by the American Academy of Pediatrics in cases where their use is justified by the potential health benefit for the mother.2
Sulfasalazine enters breast milk in very small amounts. Use of the drug during lactation has been judged to be safe.2
Azathioprine is excreted into breast milk and the manufacturer notes that the drug should not be used in nursing women.2
Both methotrexate and leflunomide are contraindicated (should not be used) in women who are lactating.2
Hydroxychloroquine and chloroquine are excreted into breast milk in small amounts and have been deemed safe by the American Academy of Pediatrics.1,2
There is insufficient data for determining the safety of TNF-inhibitors (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) and other biologics, including abatacept, rituximab, anakinra, tofacitinib, and toclizumab, in lactating mothers.2