Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi di Milano, Milan, Italy.
Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi di Milano, Milan, Italy; Psychiatry Unit 2, ASST Fatebenefratelli Sacco, Milan, Italy.
Clin Ther. 2019 Sep;41(9):1755-1766. doi: 10.1016/j.clinthera.2019.06.008. Epub 2019 Jul 29.
To date, the available data on the relationship between the use of selective serotonin reuptake inhibitors (SSRIs) or the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine and postpartum hemorrhage (PPH) are conflicting and have not been extensively investigated, especially in terms of plasma drug concentrations. We performed data mining of antidepressant-induced PPH reported to the US Food and Drug Administration's Adverse Event Reporting System database, to assess the strength of the potential association between antidepressant pharmacotherapy and PPH in pregnant women. Concurrently, we carried out a descriptive observational population (pregnant women) analysis of the correlation between the plasma concentrations of SSRIs/SNRIs used during pregnancy and the extent of bleeding at delivery.
A disproportionality analysis of individual case study reports of PPH associated with SSRIs or venlafaxine in pregnant women was performed. Reporting odds ratio was used as a measure of disproportionality analysis. Pregnant women treated with an SSRI or SNRI (venlafaxine) for depressive or anxiety disorder and who consented to plasma drug concentration monitoring at the time of delivery were recruited. Plasma drug concentration assay was performed according to validated LC-MS/MS. Based on plasma drug concentrations, patients were classified into 1 of 2 groups, in therapeutic range or below therapeutic range for the drug administered, in accordance with the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie guideline, and correlations with blood loss were identified, with PPH defined as a blood loss of >500 mL.
Only 43 Individual Case Safety Reports (ICSRs) reported at least one SSRIs or venlafaxine as suspect drug in 14 years (database analyses). Forty-three women were enrolled in the study population (observational study). In 24 patients (55.8%) the plasma drug concentration was below the therapeutic threshold. Unexpectedly, the mean blood loss in the below-range group was significantly higher than that in the in-range group. PPH occurred in 30% of women: in 9.3% and in 20.7% of patients in the in-range and below-range groups, respectively.
Although preliminary, these data indicate a rather good tolerability profile of SSRIs/SNRIs regarding postpartum bleeding. Moreover, they suggest that keeping the plasma levels of SSRIs/SNRIs low as a precautionary measure does not reduce postpartum bleeding, which was higher in the below-range group. The findings from this study suggest that the use of therapeutic drug monitoring in pregnancy, a period in which multiple variables affect drug metabolism, may allow for better treatment customization, with subsequent advantages in terms of tolerability and efficacy of treatment.
迄今为止，有关选择性 5-羟色胺再摄取抑制剂（SSRIs）或 5-羟色胺和去甲肾上腺素再摄取抑制剂（SNRI）文拉法辛与产后出血（PPH）之间关系的现有数据相互矛盾，且尚未得到广泛研究，尤其是在血浆药物浓度方面。我们对美国食品和药物管理局不良事件报告系统数据库中报告的抗抑郁药引起的 PPH 进行了数据挖掘，以评估抗抑郁药治疗与孕妇 PPH 之间的潜在关联强度。同时，我们对妊娠期间使用的 SSRIs/SNRIs 的血浆浓度与分娩时出血程度之间的相关性进行了描述性观察性人群（孕妇）分析。
对妊娠期间 SSRIs 或文拉法辛相关 PPH 的个体病例研究报告进行了不相称性分析。报告比值比被用作不相称性分析的衡量标准。招募了因抑郁或焦虑障碍而接受 SSRIs 或 SNRI（文拉法辛）治疗且在分娩时同意进行血浆药物浓度监测的孕妇。根据经过验证的 LC-MS/MS 进行血浆药物浓度检测。根据血浆药物浓度，根据 Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie 指南将患者分为药物治疗范围或低于药物治疗范围的 2 组，并确定与出血量的相关性，将出血量>500mL 定义为 PPH。
在 14 年内，仅数据库分析报告了 43 份至少有 1 份 SSRIs 或文拉法辛作为可疑药物的个别病例安全报告（ICSRs）。43 名妇女被纳入研究人群（观察性研究）。在 24 名患者（55.8%）中，血浆药物浓度低于治疗阈值。出乎意料的是，低于范围组的平均出血量明显高于范围组。30%的女性发生了 PPH：范围组和低于范围组中分别有 9.3%和 20.7%的患者发生 PPH。
尽管初步结果，但这些数据表明 SSRIs/SNRIs 治疗产后出血的耐受性良好。此外，它们表明，作为预防措施，将 SSRIs/SNRIs 的血浆水平保持在低水平并不能减少产后出血，而低于范围组的出血更多。这项研究的结果表明，在妊娠期间使用治疗药物监测，在妊娠期间，多种变量会影响药物代谢，可能会更好地定制治疗方案，从而在治疗的耐受性和疗效方面带来优势。
