Copenhagen Phase IV Unit (Phase4CPH), Department of Clinical Pharmacology and Center for Clinical Research and Prevention, Copenhagen University Hospital Bispebjerg and Frederiksberg, Copenhagen, Denmark.
Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
PLoS Med. 2021 Nov 22;18(11):e1003851. doi: 10.1371/journal.pmed.1003851. eCollection 2021 Nov.
The prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths.
A population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates.
Based on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy.
在育龄期和怀孕期间，女性的抑郁患病率和抗抑郁药物暴露率都很高。度洛西汀是一种选择性 5-羟色胺和去甲肾上腺素再摄取抑制剂（SNRI），于 2004 年在美国和欧洲获批用于治疗抑郁症。度洛西汀的胎儿安全性尚未得到充分证实。本研究评估了孕期暴露于度洛西汀与重大和轻微先天畸形以及死产风险之间的关联。
这是一项基于瑞典和丹麦登记处数据的基于人群的观察性研究。纳入了 2004 年至 2016 年期间医学出生登记处中所有的出生和死产。畸形诊断在出生后 1 年内确定。采用逻辑回归分析。通过多回归、倾向评分（PS）匹配和敏感性分析来解决潜在的混杂因素。混杂变量包括社会人口学信息（收入、教育、年龄、出生年份和国家）、合并症和合并用药、既往精神科就诊情况以及与分娩相关的信息（孕期吸烟和既往自然流产和死产）。度洛西汀暴露组与 4 个对照组进行比较：（1）度洛西汀无暴露组；（2）选择性 5-羟色胺再摄取抑制剂（SSRIs）暴露组；（3）文拉法辛暴露组；（4）在妊娠前而非妊娠期间暴露于度洛西汀的组。暴露定义为在妊娠早期和整个妊娠期间分别开具度洛西汀处方。畸形和死产的分析分别使用了结局。主要和次要畸形以及死产的结局来自国家患者登记处。队列包括超过 200 万例分娩，其中有 1512 例度洛西汀暴露的妊娠。在调整后的和 PS 匹配分析中，各组间均未发现重大畸形、轻微畸形或死产的风险增加。度洛西汀暴露与度洛西汀无暴露 PS 匹配分析显示，主要畸形的比值比（OR）为 0.98（95%置信区间[CI]为 0.74 至 1.30，p=0.909），次要畸形的 OR 为 1.09（95%CI 为 0.82 至 1.45，p=0.570），死产的 OR 为 1.18（95%CI 为 0.43 至 3.19，p=0.749）。对于个别畸形亚型，一些发现具有统计学意义，但由于事件数量极少，统计学不确定性较大。该研究的主要局限性是没有获得度洛西汀的用药指征和抑郁严重程度的直接测量值，无法将其作为协变量纳入。
基于这项来自瑞典和丹麦的基于人群的观察性注册研究，孕期暴露于度洛西汀与重大或轻微先天畸形或死产的风险增加无关。
