Safety Guidelines Issued for Use of RA Drugs During Pregnancy and Lactation
Continued monitoring of pregnant women with RA is recommended.
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
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 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, 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 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, 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
The immunosuppressant azathioprine is considered relatively safe to use during pregnancy but not during lactation.3 A recent meta-analysis of 312 women with IBD taking azathioprine showed no increased risk for spontaneous abortion or low birth weight. However, an increased risk for congenital abnormalities was found in women taking the drug when compared with women with IBD not on medications (OR, 2.95; 95% CI, 1.03-8.43).8
Tumor Necrosis Factor (TNF) Inhibitors/Anti-TNF Therapy
TNF inhibitors include infliximab, etanercept, adalimumab, golimumab, and certolizumab. Certolizumab may have a safety advantage, as smaller amounts of the drug are known to pass into fetal circulation.9
TNF inhibitors have not been associated with congenital anomalies in recent studies, including 2 systematic reviews.10,11 However, there is a concern that immunosuppression from TNF inhibitors may be transmitted to the infant after birth.2 Therefore, live vaccines are not recommended until 6 months after birth if TNF inhibitors were used during pregnancy.2
TNF inhibitor use during periconception is considered low risk. In severe cases, use has been continued until the third trimester, although long-term safety data in children are lacking.2 Theoretic safety risk during lactation is low.2
A recent large systematic review on pregnancy outcomes (including preterm birth, spontaneous abortion, and low birth weight) in women with multiple immune-related diseases showed similar outcomes when comparing the use of anti-TNF-α agents and non-use of these agents.12 Rheumatology Advisor spoke with Atsushi Sakuraba, MD, PhD, from the University of Chicago Medical Center in Illinois about the study. “We knew that the risks for TNF users were comparable to non-TNF users, but we've shown that there is a higher risk in TNF users compared to the general population. While it is difficult to ascertain the risks of the disease itself and medications, this is important information for the treating physician and patient when discussing birth outcomes.”
When asked if he would recommend withholding anti-TNF-α agents during the third trimester, he replied: “No, withholding these drugs in the severe patient may not be a good option as it may lead to flares, and in the more stable patient, I would recommend adjusting the timing of the last dose or hold one dose right before delivery to minimize transmission of the drug to the newborn.”
Ashima Makol, MD, assistant professor of medicine and consultant in rheumatology at the Mayo Clinic in Rochester, Minnesota, also talked with Rheumatology Advisor about withholding anti-TNF-α agents during the third trimester. “We know that the highest amounts of anti-TNF agents cross the placenta during the second and third trimester, therefore use during conception and the first trimester seems most safe. Etanercept and certolizumab have the lowest rate of transplacental passage and may be used with less concern. My suggestion is to hold anti-TNF therapy in the third trimester and then restart during the postpartum period at 3 to 4 weeks unless there are any concerns for postpregnancy complications.”
Rituximab is a monoclonal antibody with recommendations to wait 12 months after discontinuation before attempting pregnancy.2,3 Insufficient data are available endorsing rituximab use during pregnancy or justifying its use during lactation.2,3
Abatacept is a cytotoxic T-lymphocyte antigen. After taking abatacept, it is recommended to wait 14 weeks before attempting pregnancy2,3 and to avoid its use during lactation because there are insufficient data.2
Tocilizumab is an interleukin-6 receptor antibody, with recommendations to wait 3 months before attempting pregnancy. It should be avoided during lactation because of insufficient data.1,2
Anakinra, Tocilizumab, Tofacitinib
Insufficient data are available to support the safe use of these medications during pregnancy.3
Continued monitoring of pregnant women with RA is recommended. In addition, studies further investigating the safety of RA drugs — particularly DMARDs — before and during pregnancy, and during lactation are mandated to provide patients with clearer guidance.
- Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010;62:1576-1582.
- Krause ML, Makol A. Management of rheumatoid arthritis during pregnancy: challenges and solutions. Open Access Rheumatol. 2016;8:23-36.
- Ngian GS, Briggs AM, Ackerman IN, Van Doornum S. Safety of anti-rheumatic drugs for rheumatoid arthritis in pregnancy and lactation. Int J Rheum Dis. 2016;19:834-843.
- Brucker MC, King TL. The 2015 US Food and Drug Administration Pregnancy and Lactation Labeling Rule. J Midwifery Womens Health. 2017;62:308-316.
- Koren G, Florescu A, Costei AM, Boskovic R, Moretti ME. Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother. 2006;40:824-829.
- Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 2000;62(6):385-392.
- Methotrexate [package insert]. http://www.pfizer.ca/sites/g/files/g10017036/f/201410/Methotrexate_0.pdf. 2011. Accessed September 26, 2017.
- Mozaffari S, Abdolghaffari AH, Nikfar S, Abdollahi M. Pregnancy outcomes in women with inflammatory bowel disease following exposure to thiopurines and antitumor necrosis factor drugs: a systematic review with meta-analysis. Hum Exp Toxicol. 2015;34:445-459.
- Fechtenbaum M, Md Yusof MY, Emery P. Certolizumab pegol in rheumatoid arthritis: current update. Expert Opin Biol Ther. 2014;14:841-850.
- Nielsen OH, Loftus EV Jr, Jess T. Safety of TNF-α inhibitors during IBD pregnancy: a systematic review. BMC Med. 2013;11:174.
- Marchioni RM, Lichtenstein GR. Tumor necrosis factor-α inhibitor therapy and fetal risk: a systematic literature review. World J Gastroenterol. 2013;19:2591-2602.
- Komaki F, Komaki Y, Micic D, Ido A, Sakuraba A. Outcome of pregnancy and neonatal complications with anti-tumor necrosis factor-α use in females with immune mediated diseases; a systematic review and meta-analysis. J Autoimmun. 2017;76:38-52.