Ondansetron and risk of congenital malformations

昂丹司琼和先天性畸形的风险

• 批准号: 9298084
• 负责人: Krista F Huybrechts
• 金额: $ 9.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298084
• 关键词: Address; Adverse effects; American College of Obstetricians and Gynecologists; Benefits and Risks; Birthing Centers; Chemotherapy-Oncologic Procedure; Cleft Palate; Cohort Studies; Collaborations; Conflict (Psychology); Congenital Abnormality; Congenital Heart Defects; Data; Data Sources; Diet; Early treatment; Effectiveness; Epidemiologic Methods; Epidemiology; Exposure to; FDA approved; Fetal safety; First Pregnancy Trimester; Heart Abnormalities; Hospitalization; Hospitals; Hyperemesis Gravidarum; Infant; Interdisciplinary Study; Life Style; Linear Models; Link; Measures; Medicaid; Metoclopramide; Nausea and Vomiting; Newborn Infant; Ondansetron; Oral; Organogenesis; Outcome; Pharmaceutical Preparations; Pregnancy; Pregnant Women; Prevention; Promethazine; Public Health Schools; Quality of life; Recommendation; Relative Risks; Reporting; Residual state; Risk; Safety; Scanning; Second Pregnancy Trimester; Series; Serotonin; Serotonin Receptors 5-HT-3; Source; Stratification; Symptoms; Teratogenic effects; Teratogens; Testing; Time; Vitamin B6; Woman; Work; active comparator; base; cancer surgery; clinical practice; clinically significant; cohort; design; effective therapy; experience; high dimensionality; improved; innovation; malformation; maternal stress; neonate; offspring; oral cleft; prenatal exposure

Abstract Nausea and vomiting occurs in up to 80% of pregnancies in the US. About one third of women with nausea and vomiting of pregnancy (NVP) have symptoms that are clinically significant, causing increased maternal stress, decreased quality of life and work loss. A small percentage will develop hyperemesis gravidarum, the most severe form of NVP, which often requires hospitalization. Early treatment of NVP is recommended to stop progression to hyperemesis gravidarum. Although not formally approved for the treatment of NVP, ondansetron - a 5-HT3 receptor antagonist blocking the effect of serotonin - rapidly became the most frequently prescribed drug for NVP in the US because of its perceived superior effectiveness and improved side-effect profile . NVP and hyperemesis gravidarum typically occur during the first trimester, the most sensitive time for exposure to teratogens. Unfortunately, the available evidence on the fetal safety of ondansetron is limited and conflicting. Some recent studies have reported a doubling in risk of cleft palate and heart defects in newborns exposed to ondansetron during pregnancy. However, residual confounding bias has been posited as a potential explanation for these findings. Such conflicting data leave pregnant women and their clinicians unsure with respect to the appropriate risk-benefit trade-off for ondansetron. The objective of the proposed study is to help fill this information gap by examining the two most important safety concerns that have been raised regarding first trimester ondansetron exposure: (1) major cardiac malformations, and (2) oral clefts. We will utilize a large national cohort of approximately 1.6 million Medicaid insured pregnant women and linked infants for 2000-2013 (the most recent Medicaid data available), which includes approximately 50,000 women exposed to ondansetron during the first trimester. We will use fine stratification on the propensity score and the high-dimensional propensity score to account for potential confounding and will conduct a series of sensitivity analyses to evaluate the impact of potential misclassification of the exposure and the outcome on the findings. This effort will make use of an existing national cohort of pregnancies and will build upon the experience of a multidisciplinary research team - a collaboration between Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health - to contribute urgently needed information on the safety of this widely used medication during pregnancy. By clarifying the risk associated with this medication, the study will have a direct impact on clinical practice.

摘要 在美国，高达80%的孕妇会出现恶心和呕吐。约三分之一的女性 有恶心和呕吐的妊娠(NVP)有临床上显著的症状， 造成母亲压力增加、生活质量下降和工作损失。一小部分 会发展为妊娠剧吐，这是NVP最严重的形式，通常需要 住院治疗。建议及早治疗NVP以阻止进展为剧吐 妊娠期。 虽然没有被正式批准用于治疗NVP，但昂丹西酮-a 5-HT3 阻断5-羟色胺效应的受体拮抗剂迅速成为最常见的 美国为NVP开出的处方药，因为它被认为具有优越的疗效和改进 副作用简介 。NVP和妊娠剧吐通常发生在妊娠的前三个月， 这是接触致畸物质最敏感的时间。 不幸的是，现有的证据表明 昂丹西酮的胎儿安全性是有限的，也是相互矛盾的。最近的一些研究报告说， 暴露于恩丹西酮的新生儿患腭裂和心脏缺陷的风险增加一倍 怀孕了。然而，残留的混杂偏倚被认为是一种潜在的解释 这些发现。这种相互矛盾的数据让孕妇和她们的临床医生不确定 尊重恩丹西酮的适当风险-利益权衡。 拟议研究的目标是通过审查两个最重要的 关于怀孕前三个月恩丹西酮暴露的重要安全问题： (1)主要心脏畸形；(2)口腔裂。我们将利用一个庞大的国家队列 2000-2013年，约有160万名医疗补助计划为孕妇和有关联的婴儿提供保险 (可获得的最新医疗补助数据)，其中包括大约50,000名女性 在怀孕的前三个月接触恩丹西酮。我们将使用精细分层对 解释潜在混淆的倾向得分和高维倾向得分 并将进行一系列敏感性分析，以评估潜在的影响 对暴露和调查结果的错误分类。 这一努力将利用现有的全国怀孕队列，并将建立在 多学科研究团队的经验-Brigham和 妇女医院和哈佛大学公共卫生学院--紧急捐款 需要关于怀孕期间广泛使用的这种药物的安全性的信息。通过澄清 与这种药物相关的风险，这项研究将对临床实践产生直接影响。