Comparative safety & effectiveness of antihypertensive medications in pregnancy

描述(申请人提供)：高血压疾病合并约占所有妊娠的6-8%，是胎儿和产妇发病率和死亡率的重要来源。大约3%-4%的孕妇在怀孕期间会接触到抗高血压药物。在美国，怀孕期间最常用的降压药是甲基多巴；然而，它是一种较老的药物，通常耐受性较差。与其他类型的药物包括α-β受体阻滞剂、β受体阻滞剂和钙通道阻滞剂相比，就重要的妊娠结局而言，它可能是一种次要的治疗方法。然而，对于其他每一个类别，都提出了重要的胎儿安全问题。因此，拟议项目的主要目标是评估这些常用药物中每一种相对于甲基多巴的相对安全性和有效性。这项研究旨在解决的临床问题是：“如果患者在怀孕期间因既往存在的或妊娠期高血压而需要门诊抗高血压药物，什么是对胎儿最安全的药物，也是最有可能确保良好妊娠结局的药物？”我们还将检查妊娠早期接触噻嗪利尿剂和血管紧张素转换酶抑制剂的安全性，这是育龄妇女在怀孕外使用的最常见的降压药类型，因此是常见的妊娠早期暴露。这项分析将解决临床问题：“对于计划怀孕或可能怀孕的妇女，考虑到胎儿早期接触药物的可能性，哪些药物可以安全使用？”这项研究将使用从医疗补助分析摘录(MAX)获得的怀孕队列进行，MAX是一个基于人口的大型索赔数据库。使用这个数据集，我们已经开发了一个超过110万个怀孕的队列，其纵向数据从孕前到产后。这一队列与门诊药房索赔和胎儿记录相关联，使其成为我们建议的那种研究的特别合适的数据源。我将在布里格姆妇女医院药物流行病学和药物经济学分部(“分部”)发达的基础设施内进行拟议的研究。该司在利用观察性数据来源进行杰出的药物安全性和有效性研究方面有着长期的记录。我将与一个由来自哈佛大学各个机构的导师和合作者组成的跨学科团队合作，这些机构在流行病学和统计学方法、围产期药物流行病学、高危产科、高血压疾病和药物政策方面拥有深厚的专业知识和国内/国际声誉。这项研究工作将得到哈佛公共卫生学院的正式课程和该司经常举行的研讨会和实验室会议的补充。这种密集的研究、指导和正规教育的结合将为我成为一名成功的产科药物流行病学独立研究员提供必要的背景。

DESCRIPTION (provided by applicant): Hypertensive disorders complicate an estimated 6-8% of all pregnancies and are a significant source of fetal and maternal morbidity and mortality. Approximately 3-4% of all pregnant women will be exposed to antihypertensive medications during pregnancy. The antihypertensive most commonly used in pregnancy in the United States is methyldopa; however, it is an older, often poorly tolerated medication. It may be an inferior therapy with respect to important pregnancy outcomes compared to other classes of agents including alpha-beta blockers, beta blockers, and calcium channel blockers. Yet, for each of these other classes, important fetal safety concerns have been raised. The primary goal of the proposed project is therefore to evaluate the comparative safety and effectiveness of each of these commonly used agents relative to methyldopa. The clinical question this study aims to address is: "If a patient requires an outpatient antihypertensive during pregnancy for pre-existing or gestational hypertension, what is the safest agent for the fetus, and the one most likely to assure a good pregnancy outcome?" We will also examine the safety of first trimester exposure to thiazide diuretics and angiotensin converting enzyme inhibitors, which are the most common types of antihypertensives used in women of reproductive age outside of pregnancy and thus common first trimester exposures. This analysis will address the clinical question: "For a woman in whom pregnancy is planned or possible, which agents can be safely used given the potential for early fetal exposure to the medication?" The study will be performed using a pregnancy cohort obtained from the Medicaid Analytic Extract (MAX), a large population-based claims database. Using this dataset, we have developed a cohort of over 1.1 million pregnancies with longitudinal data that span from the pre-pregnancy to the postpartum periods. This cohort is linked to outpatient pharmacy claims and fetal records making it an exceptionally well-suited data source for the kind of study we propose. I will perform the proposed research within the well developed infrastructure of the Division of Pharmacoepidemiology and Pharmacoeconomics ("The Division") at the Brigham and Women's Hospital. The Division has a long track record of producing outstanding drug safety and effectiveness research using observational data sources. I will work with an interdisciplinary team of mentors and collaborators drawn from across institutions at Harvard University that have deep expertise and national/international reputations in epidemiological and statistical methods, perinatal pharmacoepidemiology, high-risk obstetrics, hypertensive diseases, and drug policy. This research work will be complemented by formal coursework at the Harvard School of Public Health and frequent seminars and lab meetings at the Division. This combination of intensive research, mentoring, and formal education will provide the necessary background for me to become a successful, independent researcher in obstetric pharmacoepidemiology.