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Rheumatologists vary on when to discontinue arthritis drugs during unplanned pregnancies
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Although rheumatologists overwhelmingly agree on the use of conventional synthetic DMARDs and biologic drugs for inflammatory arthritis in patients with planned pregnancies, there appears to be little consensus on when to suspend drugs and how to handle unplanned pregnancies, according to survey data in BMC Rheumatology.
“Although, historically some [inflammatory arthritides (IA)] were recognized to improve during pregnancy, particularly RA , recent evidence suggests remission during pregnancy in less than 20% of women with RA,” Mary A. De Vera, PhD, of the University of British Columbia, and colleagues wrote. “Consequently, it is estimated that 40% to 50% of women with IA require treatment throughout the perinatal period. Managing IA pregnancy is an important clinical challenge. A 2013 U.K. survey of rheumatologists and obstetricians showed no uniform practice for using IA medications during pregnancy.”
To evaluate Canadian rheumatologists’ views on the management of inflammatory arthritis in patients who are pregnant, and to identify practice patterns and gaps in knowledge, De Vera and colleagues conducted a survey of members of the Canadian Rheumatology Association. The survey included 23 general and specific questions on the use of 12 specific conventional synthetic DMARDs, 12 biologics or small-molecule drugs and prednisone. In addition, questions gauged participants’ management of planned and unplanned pregnancies in patients.
The researchers distributed the survey to 450 members of the Canadian Rheumatology Association, including rheumatologists and rheumatology trainees. In all, 96 recipients opened the survey and 90 consented to participate. Although just 68 participants completed at least 76% of the survey, all responses were included in the final analysis. Of the participants, 57% had been practicing rheumatology for more than 10 years.
According to the researchers, there was a broad consensus among rheumatologists on the discontinuation of four conventional synthetic DMARDs, specifically in planned pregnancies. Of these, 100% agreed on ceasing cyclophosphamide, 98% agreeing on leflunomide, 96% agreed on methotrexate and 89% agreed on mycophenolate mofetil.
However, responses were markedly more varied on when to discontinue treatment in the event of an unplanned pregnancy, and there was not much agreement on how to manage them in general. Still, participants agreed that three conventional synthetic DMARDs were safe to continue in planned and unplanned pregnancies. These were azathioprine, with 84% agreement; hydroxychloroquine, with 95% agreement; and sulfasalazine, with an agreement of 77%.
There was also agreement on the use of four biologics in planned pregnancies — adalimumab (Humira, AbbVie), certolizumab (Cimzia, UCB), etanercept (Enbrel, Amgen), and infliximab (Remicade, Janssen). However, there remained uncertainty on when they should be discontinued, as well as their use in unplanned pregnancies.
“This national survey shows consensus among rheumatologists on the safety of some [conventional synthetic] DMARDs and biologics/small molecules in IA patients planning pregnancy,” De Vera and colleagues wrote. “However, there was limited knowledge on when to discontinue these medications and what to do in unplanned pregnancies. Findings are timely as they establish baseline practice patterns and identify gaps that may be addressed by recently published points and guidelines.” – by Jason Laday
Disclosures: The researchers report no relevant financial disclosures.
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David A. McLain, MD, FACP, FACR
How do you treat inflammatory arthritis in pregnancy? The authors from British Columbia surveyed Canadian rheumatologists through an online survey to understand their practice patterns for pregnant inflammatory arthritis (IA) patients. IA includes rheumatoid arthritis (RA) and lupus, which disproportionately affect women, often in the childbearing years.
The authors note that it is often said that IA, particularly RA, improves with pregnancy, but recent evidence suggests this occurs in less than 20% of women with RA. Other studies estimate that 40-50% of women with IA need treatment during the perinatal period. A 2013 study of rheumatologists and obstetricians in the United Kingdom indicated no uniform practice for the treatment of IA in pregnancy. The present survey was administered in March 2016 to 450 rheumatologists and had a 20% response rate with 68 answering all questions.
Most conventional DMARDs were not considered safe in pregnancy by the rheumatologist respondents: leflunomide (98%), methotrexate (98%), cyclophosphamide (95%) and mycophenolate mofetil (82%) were not considered safe. There was consensus that all of these drugs except leflunomide should be stopped 3 months before attempting pregnancy. Leflunomide had a variable response and this was thought to be due to the ability of cholestyramine to eliminate the drug in 11 days.
However, rheumatologist respondents considered two DMARDs safe in pregnancy: azathioprine (81%) and hydroxychloroquine (93%). In the 1979 FDA Drugs in Pregnancy and Lactation classification, azathioprine was a “D” and hydroxychloroquine was a “C”. Since the 1979 classification, there are numerous studies (mostly from gastroenterology) with azathioprine that suggest it is safe in pregnancy.
The 1979 FDA pregnancy and lactation rule has been supplanted by a new system in 2015 that no longer contains a classification letter but a discussion of data; this system will be applied to new drugs after 2015, phased in for drugs approved since 2001, but not applied to older drugs.
Sulfasalazine was also considered by many to be safe during pregnancy (73%, yet below the predetermined 80% consensus level). The FDA had assigned sulfasalazine as a “B” but “D” if used for prolonged periods or near term with an increased risk of kernicterus in the newborn.
Notably, there was a diversity of opinion with regards to the use of biologics and small molecules in pregnancy: None of the 12 agents reached the consensus level of 80%. The closest was Certolizumab (61%) but this survey was prior publication of the CRIB and CRADLE studies and the FDA acceptance of the label change for the use in pregnancy and breastfeeding. The other TNF inhibitor agents had a 30-40% consensus for use during pregnancy by the respondents. None of the other biologics or small molecules (only apremilast and tofacitinib were queried) achieved a consensus rate above 11%.
The respondents did reach a consensus on the use of ibuprofen and naproxen during certain trimesters (83.6%, 82.9% respectively). Increased risks of malformations and miscarriage are associated with NSAID use in early pregnancy. Conversely, exposure to NSAIDs after 30 weeks' gestation is associated with an increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios. The Quebec Pregnancy Registry found 7.5% of spontaneous abortions in women exposed to NSAIDs and 2.6% in controls.
This report reviews the practice patterns of Canadian rheumatologists in women with IA who are pregnant; as such, there is no new science as to the safety of these agents vs. controls. However, it does allow us to review the data available and the views of our colleagues.
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