Corticosteroids during pregnancy are also associated with maternal comorbidities, including gestational diabetes, hypertension, and accelerated osteoporosis. “For this reason, the goal should always be to keep the dose as low as possible,” she said.
Azathioprine and 6-Mercaptopurine
The use of azathioprine, a nonbiologic disease-modifying antirheumatic drug, is generally limited to women with severe disease who have not responded to other treatments, Dr. Bermas stated. There are “conflicting data about the safety of this drug during pregnancy. Animal data [suggest that] the drug is teratogenic, and there have been case reports of fetal malformations, but transplant series indicate that the medication doesn't increase the rate of congenital anomalies,” she said. Small-for-gestational-age babies and premature rupture of membranes are associated with use of the drug during pregnancy.
As with azathioprine, the nucleoside analog 6-mercaptopurine is teratogenic in animals, and it is plagued by conflicting human data. Some of the human studies suggest that “there is an increased risk of congenital anomalies, but the gastrointestinal literature doesn't support this,” Dr. Bermas noted. “From a rheumatology perspective, this medication is rarely used, so I would suggest discontinuing it during pregnancy.”
Sulfasalazine
“Case reports of fetal malformations linked to sulfasalazine from the inflammatory bowel disease literature didn't pan out in larger studies,” said Dr. Bermas. “This drug can be used in pregnancy. It does cause azoospermia in men, however, so if you have a male patient who is interested in trying to get his partner pregnant, advise him to stop taking sulfasalazine for 3 months before conception for spermatogenesis.”
Penicillamine
Occasionally used in the treatment of progressive systemic sclerosis, penicillamine has been shown to interfere with collagen biosynthesis and to cause malformations in animal studies, according to Dr. Bermas. “In humans, cases of cutis laxa and connective tissue disorders have been reported with exposure to this medication,” she said. As such, “this medication should not be used during pregnancy.”
Mycophenolate Mofetil
“We had such high hopes for mycophenolate mofetil. We thought this would be one of those medications that could be safely used during pregnancy,” said Dr. Bermas. “Unfortunately, there are increased case reports of congenital anomalies, including one report of the drug being used during pregnancy in a renal transplant patient. The baby was born prematurely and was noted to have hypoplastic nails and short fifth fingers.” Although there is not a rich body of literature yet, “this medication should be avoided during pregnancy,” she said.
IVIG
Intravenous immunoglobulin is not a common drug for rheumatologic disorders, and the literature on its use in pregnancy is limited. “In one case report of an individual with steroid-resistant idiopathic thrombocytopenic purpura, IVIG was used with no adverse effects on the offspring,” said Dr. Bermas. “The medication has also been used to manage the obstetrical complications of the antiphospholipid antibody syndrome without inducing congenital malformations.” Based on the available data, IVIG, when warranted, is acceptable for use in pregnancy, she said.
Cyclosporin A
The large body of data regarding the use of cyclosporin A during pregnancy comes from the transplant literature. “These medications are not teratogenic, although they are associated with small-for-gestational-age infants and hypertension of pregnancy,” said Dr. Bermas. The drug is not widely used, but in individual cases, if the potential benefit outweighs the possible risk, clinicians may choose to continue treatment with it, she noted.
Chlorambucil and Cyclophosphamide
Both of these cytotoxic agents are teratogenic and should be avoided during pregnancy, Dr. Bermas stressed. “In life-or-death situations, cyclophosphosamide has been used in the third trimester,” she said.
Methotrexate
Because of the high risk of congenital anomalies, methotrexate is an FDA category X drug for use in pregnancy. In addition to being teratogenic, it is also abortifacient, said Dr. Bermas, noting that, in terms of gestation, the use of methotrexate during weeks 6–8 at dosages greater than 10 mg/day substantially increases the risk of fetal harm. “I recommend that patients, both men and women, discontinue methotrexate for at least 3 months prior to conception,” she said.
Leflunomide
Another FDA category X drug for use in pregnancy because of its high teratogenicity, leflunomide “has an extremely long half-life, so either you need to wash out with cholestyramine or discontinue for 2 years before conception,” said Dr. Bermas. “As a general rule, I avoid using this in women of childbearing potential.”
Anti-TNF-α Agents
Limited data exist regarding the safety of the tumor necrosis factor-? inhibitors during pregnancy, “although case reports of two infants exposed to these drugs in utero being born with anomalies potentially consistent with VACTERL [vertebral, anal, cardiac, tracheal, esophageal, renal, and limb] syndrome give clinicians pause,” said Dr. Bermas. On the other hand, animal studies reported no teratogenic or fetotoxic effects, and some reports on human pregnancy in patients taking these drugs did not show an increase in birth defects or adverse pregnancy outcomes, she said. In one large study comprising 131 patients with inflammatory chronic diseases—including 8 patients with RA—who were directly exposed to inifliximab, drug exposure during pregnancy resulted in outcomes similar to those seen in the general population of pregnant women (Am. J. Gastroenterol, 2004;99:2385–92).