Use of disease-modifying anti-rheumatic drugs (DMARDs) before becoming pregnant does not increase the risk of miscarriage or birth defects in women with juvenile idiopathic arthritis (JIA), or female partners of male JIA patients, a study in Germany has found.
However, those exposed to DMARDs, especially to methotrexate or leflunomide, more often decide to have elective abortions, afraid of malformations in the fetus. Researchers say this fear may not be justified, which underlines the need for proper counseling for youth with rheumatic diseases regarding the use of medications at conception and pregnancy.
The study, “Pregnancy outcomes in DMARD-exposed patients with juvenile idiopathic arthritis—results from a JIA biologic registry,” was published in the journal Rheumatology.
DMARDs are a standard of care for inflammatory arthritis, namely JIA. Some of these medications can cause liver damage, others may not be safe when taken along with vaccines, and some are not recommended if one is pregnant or trying to become pregnant.
As JIA often persists into adulthood, it is important for female patients who wish to become pregnant, or male patients who look to become fathers, to understand if exposure to DMARDs — prior or current — represents significant risks for pregnancy.
Some studies suggest that women with JIA have more pregnancy complications, including preterm birth and congenital malformations. However, the underlying reasons for that are uncertain, and could be due to the disease itself rather than its treatment.
To shed light on disease activity and DMARDs’ potential harmful effects for pregnancy, researchers compared pregnancy outcomes in pregnant women with JIA, or partners of male patients who had taken or were taking DMARDs, at the time of conception, compared to those not using these medications.
The study included a total of 191 pregnancies, 152 of which were female patients and 39 involving male patients as partners. Participants were enrolled in the German JIA biological registry (BiKeR) and its follow-up registry (JuMBO).
To assess pregnancy course, researchers collected physician- and patient-reported outcomes and conducted telephone interviews with patients.
Most patients had polyarticular JIA, characterized by inflammation in five or more joints (61%). Patients’ average age at time of first pregnancy was 24.1 years, at a mean disease duration of 13.8 years.
Patients had been using DMARDs for a mean of 9.5 years, and nearly all (90%) also had received biologics.
About half of the pregnancies were unplanned and occurred during DMARD exposure: 44.1% in females and 66.7% involving male patients.
At the time they got pregnant, 30 women were using biologic DMARDs, 13 were taking chemical-based DMARDs, and 24 were using a combination of both. Etanercept (sold as Enbrel, Erelzi) was the most-used biologic.
Most women stopped using DMARDs shortly after conception, a median of seven weeks after. Other medications being taken up to becoming pregnant were nonsteroidal anti-inflammatory drugs (NSAIDs) in 30.2% of the patients, folic acid in 13.8%, and costicosteroids in 30.9%.
For pregnancies in which patients were fathers, 26 of 39 (67%) were exposed to DMARDs by the time of conception.
Of all 191 pregnancies, 24 (12.6%) were ended by elective termination and 138 (72%) resulted in live birth. Noticeably, more women who used DMARDs had elective abortions compared to women who had not.
Of the 22 elective pregnancy terminations in women with JIA, 11 were due to fear of malformation in women exposed to methotrexate (brand names Trexall, Resuvo among others, and generic) or leflunomide (brand name Arava, also available as generic). Three others were due to medical recommendations for starting on TNF inhibitors, and one was due to a fetal malformation (without exposure to medications). The remainder were for personal reasons.
Of the 19 pregnancies in women with post-conception methotrexate exposure, 42.1% were terminated, 15.8% ended in a spontaneous abortion, and 42.1% led to a healthy live birth without congenital anomalies. The three pregnancies that occurred during treatment with leflunomide were terminated.
“Whether the high rate of elective terminations among [methotrexate]- or [leflunomide]-exposed pregnancies is justified, however, is questionable,” the researchers wrote.
Recent studies have not shown that leflunomide is a major teratogen agent (i.e., which induces malformations), or that low-dose methotrexate after conception increases the risk of embryo defects typically associated with the compound.
Nevertheless, this does not exclude the fact that risks and caution are warranted, researchers noted. In the case of inadvertent exposure during early pregnancy, “treatment should be stopped immediately, folate supplementation continued, and … a detailed [ultrasound] examination of the fetus should be done,” they wrote.
However, pregnancy and birth complications did not significantly differ between DMARD-exposed and -unexposed pregnancies, either in mothers or fathers with JIA.
Rates of miscarriage (13.1%) and newborns with major congenital anomalies (3.6%) “were not suggestive of increased risk compared with expected background rates,” which range from 8.9-16.0% and from 2.4-3.7%. “However, the rates of premature birth (12.3%) and caesarean section (37.7%) were slightly above those in the German birthing population,” the researchers note.
Neither disease activity nor type of JIA were correlated with pregnancy outcomes. Overall, 40.3% and 41.5% of women had a moderate or high disease activity before pregnancy, respectively, which was maintained relatively stable throughout pregnancy.
“This study found that, despite long-term and often intrapregnancy exposure to DMARDs, most pregnancy outcomes were within the range expected for the general population,” the researchers wrote.
It is important to stress that “approximately every fifth DMARD-exposed pregnancy was electively terminated, including every fourth pregnancy in DMARD-exposed women and every second pregnancy in [methotrexate]- or [leflunomide]-exposed women.”
“These findings underline the importance of addressing family planning in rheumatological practice and the need for adequate information and counseling of young people with rheumatic diseases on drug safety at conception and pregnancy,” the researchers concluded.