Desai Rishi J, Bateman Brian T, Huybrechts Krista F, Patorno Elisabetta, Hernandez-Diaz Sonia, Park Yoonyoung, Dejene Sara Z, Cohen Jacqueline, Mogun Helen, Kim Seoyoung C
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02120, USA
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02120, USA.
BMJ. 2017 Mar 6;356:j895. doi: 10.1136/bmj.j895.
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. Observational cohort study. Public (Medicaid, 2001-10) or private (Optum Clinformatics, 2004-15) health insurance programs in the US. 4961 pregnant women treated with immunosuppressive drugs for rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease. 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. 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. 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 steroids, hazard ratio 0.81 (95% confidence interval 0.48 to 1.37), TNF inhibitors steroids 0.91 (0.36 to 2.26), and TNF inhibitors 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). 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.
比较妊娠期间使用全身性类固醇、非生物制剂或肿瘤坏死因子α（TNF）抑制剂与严重感染风险的相关性。观察性队列研究。美国的公共（医疗补助，2001 - 2010年）或私人（Optum临床信息学，2004 - 2015年）医疗保险计划。4961名因类风湿关节炎、系统性红斑狼疮、强直性脊柱炎、银屑病关节炎或炎症性肠病接受免疫抑制药物治疗的孕妇。根据孕期首次开具的处方，将暴露情况分为类固醇、非生物制剂或TNF抑制剂。由于TNF抑制剂不用于治疗系统性红斑狼疮，患有这种疾病的患者被排除在涉及TNF抑制剂的比较之外。主要结局是妊娠期间发生严重感染，定义为因细菌或机会性感染住院治疗。在通过倾向评分精细分层对混杂因素进行调整后，使用Cox比例风险回归模型得出风险比。使用逻辑回归模型对至少开具过一张类固醇处方的女性进行剂量反应分析。4961名接受免疫抑制药物治疗的孕妇中有71名（0.2%）发生了严重感染。本研究纳入的2598名类固醇使用者、1587名非生物制剂使用者和776名TNF抑制剂使用者中，每100人年严重感染的粗发病率分别为3.4（95%置信区间2.5至4.7）、2.3（1.5至3.5）和1.5（0.7至3.0）。在这三类免疫抑制药物使用者中，妊娠期间严重感染风险未观察到统计学上的显著差异：非生物制剂与类固醇相比，风险比为0.81（95%置信区间0.48至1.37）；TNF抑制剂与类固醇相比，风险比为0.91（0.36至2.26）；TNF抑制剂与非生物制剂相比，风险比为1.36（0.47至3.93）。在剂量反应分析中，较高的类固醇剂量与妊娠期间严重感染风险增加相关（每日平均泼尼松等效毫克剂量每增加一个单位的系数 = 0.019，P = 0.02）。患有全身性炎症疾病的孕妇使用类固醇、非生物制剂和TNF抑制剂时，严重感染风险相似。然而，高剂量使用类固醇是妊娠期间严重感染的独立危险因素。
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