Methotrexate, Leflunomide Linked to Adverse Pregnancy Outcomes in RA

Published on: 

Receiving methotrexate and leflunomide within the 3 months prior to conception was linked to an increased rate of adverse pregnancy outcomes.

Data from a national health insurance database showed treatment with methotrexate and leflunomide were linked to an increased risk of adverse pregnancy outcomes (APOs) in women with rheumatoid arthritis (RA), according to a study published in Rheumatic and Musculoskeletal Diseases.1 Investigators noted results underscore the importance of necessary adjustments to medication when planning for pregnancy.

Considering RA is significantly more common in female patients and the prevalence of RA among women of childbearing age is approximately .5% — 1.0%, pregnancy and childbirth require particular attention among this patient population. Previous research has revealed patients with RA have more difficulty conceiving and report a lower number of births, which could be attributed to factors such as disease activity, medication usage, including nonsteroidal anti-inflammatory drugs (NSAIDs) and prednisone, older age, and nulliparity.2

“Patients with RA who are planning for pregnancy or lactation have limited treatment options,” wrote a group of Korean investigators. “In Korea, there is a lack of studies on pregnant patients with RA. A nationwide population-based study of Korean women with rheumatic diseases reported an increased risk of pregnancy complications, but there has been no large study of patients with RA.”

To better understand factors associated with APOs in this patient population, the Korean National Health Insurance (NHI) database identified pregnant women with RA aged 20 — 50 years between 2010 and 2020. Patients were categorized according to pregnancy outcome: the delivery cohort and the APO cohort (patients who experienced abortion or stillbirth). Medication utilization patterns, including conventional synthetic disease-modifying antirheumatic drug (csDMARDs), tumor necrosis factor inhibitors (TNFs), NSAIDs, oral glucocorticoids, and Janus kinase inhibitors (JAKs), were compared among groups and factors linked to APOs were identified using multivariable logistic regression analysis. Demographic information collected included age, household income, type of insurance, and institution.

Delivery was defined as 39 weeks since the conception date before the procedure code of delivery or 35 weeks before the diagnostic codes for preterm delivery. APO was defined as 10 weeks since the conception date before the diagnostic code of abortion or 38 weeks before the diagnostic codes of stillbirth.

In total, 5729 pregnancies were included in the analysis, with 4576 patients placed in the delivery group and 1152 placed in the APO group. The mean maternal age among all patients was 33.7 years (33.3 years in the delivery cohort and 33.7 years in the APO cohort).

Among both groups, hydroxychloroquine was the most prescribed csDMARD during the preconception period and pregnancy. However, the prescription rates of all DMARDs, as well as NSAIDs and oral glucocorticoids, decreased rapidly during the pregnancy period. This rate subsequently rapidly increased in the year post-delivery or pregnancy termination.

The use of methotrexate and leflunomide was stopped earlier prior to pregnancy in the delivery group when compared with the APO group. According to multivariable analysis, receiving methotrexate (adjusted OR [aOR]: 2.14, 95% confidence interval [CI] 1.57 — 2.92) and leflunomide (aOR: 2.68, 95% CI 1.39 — 5.15) within the 3 months prior to conception was linked to an increased rate of APOs.

Other factors related to APO were patients aged 30 — 39 years (aOR: 1.33, 95% CI 1.07 — 1.66) and 40 — 49 years (aOR: 5.35, 95% CI 4.16 — 6.89). Patients treated in a community hospital or clinic also had a slightly risk of APOs when compared with those in a tertiary referral hospital (aOR: 1.33, 95% CI 1.13 — 1.56).

Investigators noted although disease activity may have influenced APOs, data on disease activity were unavailable in NHI data. Additionally, the conception date could not be precisely determined using the database.

“It is crucial for patients with RA to engage in thorough consultations with their physicians regarding pregnancy planning, and to maintain medical supervision throughout pregnancy to effectively monitor and control disease activity,” investigators concluded.


  1. Song YJ, Cho SK, Jung YS, et al. Medication utilisation trends during pregnancy and factors influencing adverse pregnancy outcomes in patients with rheumatoid arthritis. RMD Open. 2024;10(1):e003739. Published 2024 Mar 22. doi:10.1136/rmdopen-2023-003739
  2. Smeele HTW, Dolhain R. Current perspectives on fertility, pregnancy and childbirth in patients with rheumatoid arthritis. Semin Arthritis Rheum 2019;49:S32–5. doi:10.1016/j.semarthrit.2019.09.010