Risk of serious infections associated with use of immunosuppressive agents in pregnant women with autoimmune inflammatory conditions: cohort study

Abstract

Objective To compare the risk of serious infections associated with use of systemic steroids, non-biologic agents, or tumor necrosis factor α (TNF) inhibitors in pregnancy.Design Observational cohort study.Setting Public (Medicaid, 2001-10) or private (Optum Clinformatics, 2004-15) health insurance programs in the US.Participants 4961 pregnant women treated with immunosuppressive drugs for rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease.Exposure for observational studies Exposure was classified into steroid, non-biologic, or TNF inhibitors on first filled prescription during pregnancy. Because TNF inhibitors are not used to treat systemic lupus erythematosus, patients with this condition were excluded from comparisons involving TNF inhibitors.Main outcome measure The main outcome was occurrence of serious infections during pregnancy, defined by hospital admission for bacterial or opportunistic infections. Hazard ratios were derived using Cox proportional hazard regression models after adjustment for confounding with propensity score fine stratification. A logistic regression model was used to conduct a dose-response analysis among women filling at least one steroid prescription.Results 71 out of 4961 pregnant women (0.2%) treated with immunosuppressive agents experienced serious infections. The crude incidence rates of serious infections per 100 person years among 2598 steroid users, 1587 non-biologic users, and 776 TNF inhibitors users included in this study were 3.4 (95% confidence interval 2.5 to 4.7), 2.3 (1.5 to 3.5), and 1.5 (0.7 to 3.0), respectively. No statistically significant differences in the risk of serious infections during pregnancy were observed among users of the three immunosuppressive drug classes: non-biologics v steroids, hazard ratio 0.81 (95% confidence interval 0.48 to 1.37), TNF inhibitors v steroids 0.91 (0.36 to 2.26), and TNF inhibitors v non-biologics 1.36 (0.47 to 3.93). In the dose-response analysis, higher steroid dose was associated with an increased risk of serious infections during pregnancy (coefficient for each unit increase in average prednisone equivalent mg daily dose=0.019, P=0.02).Conclusions Risk of serious infections is similar among pregnant women with systemic inflammatory conditions using steroids, non-biologics, and TNF inhibitors. However, high dose steroid use is an independent risk factor of serious infections in pregnancy.

Fig 1

Adjusted cumulative incidence plots for serious infections after exposure to immunosuppressive treatments during pregnancy in women with autoimmune inflammatory conditions, Medicaid data 2000-10 and Optum Clinformatics data 2004-15. Comparison of non-biologics versus steroids done in patients with autoimmune inflammatory conditions, including ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus (SLE). Tumor necrosis factor α (TNF) inhibitors are not indicated for the treatment of SLE and therefore patients with only SLE were excluded from comparisons concerning TNF inhibitors

Fig 2

Adjusted comparative risk estimates for serious infections after exposure to immunosuppressive treatments in pregnancy stratified by disease types, and pooled using inverse variance meta-analysis, Medicaid data 2000-10 and Optum Clinformatics data 2004-15. TNF=tumor necrosis factor α

Fig 3

Dose-response analysis for average daily dose of steroids (in prednisone milligram equivalents) during pregnancy in women with autoimmune inflammatory conditions and serious infection risk, Medicaid data 2000-10 and OptumClinformatics data 2004-15. Plotted lines derived from a model that adjusted for indications (ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus), additional immunosuppressive drugs used in pregnancy (non-biologics or tumor necrosis factor α inhibitors), and the insurance program. The average daily dose variable was statistically significant (coefficient=0.019 per 1 mg, P=0.02), indicating increasing risk of serious infections with increasing steroid doses