A Population-Based Study to Quantify the Risks of Opioid Analgesics in Pregnancy

项目摘要 在过去的二十年里，怀孕期间处方阿片类药物的使用急剧增加。然而， 研究了用于疼痛的阿片类药物对不良妊娠结局的影响。一些数据表明， 产前阿片类镇痛药可能与某些出生缺陷的较高风险有关。然而，证据显示， 受限于不一致的研究结果、母亲对药物使用的回忆不佳以及样本量小。此外 对于这些问题，关于阿片类药物治疗后早产和小于胎龄儿的风险数据很少。 镇痛剂暴露和死产尚未研究。产前阿片类镇痛药安全使用的证据 因此没有定论。 本研究的主要目的是确定与暴露于阿片类药物治疗疼痛相关的风险， 怀孕独立于影响先前研究的偏见。我们将研究几个重要的不利因素， 可能与此类暴露相关的妊娠结局，包括特定的出生缺陷、早产， 小于胎龄儿和死胎。阿片类药物依赖的母婴结局 还将评估产前阿片类镇痛剂暴露。为了实现这一目标，我们组织了一个 2012-2017年加拿大安大略（N = 790，000）所有妊娠的基于人群的队列，其中30，262例 在怀孕期间接触阿片类镇痛药。使用现代方法，如高维 倾向评分调整和替代参照物（包括未暴露于 阿片类镇痛药和未暴露于阿片类镇痛药但产前暴露于其他镇痛药的婴儿），我们 将确定特定阿片类镇痛药暴露在病因相关的 妊娠窗口和这些母婴结果。这将是第一项研究， 产前镇痛阿片类药物的持续时间和剂量对这些不良后果的风险。我们的人口为基础 队列研究将提供这些结局的绝对风险估计值，这无法从 现有的美国病例对照研究，这是必要的，以告知产妇的治疗选择。 在美国现存的数据中，产前药物的安全性研究排除了80%的妊娠， (i.e.,妇女有限制的福利，资本化的照顾，私人保险，或不完整的登记期间， 妊娠）获得完整的妊娠数据，这可能导致选择偏倚或无法 一般化。对普遍性的担忧也适用于美国私人保险受益人。克服这些 局限性，我们提出了一个基于人群的队列研究，使用现有的数据库，全民医疗保健 安大略是加拿大人口最多的省份，拥有1300万人口。临床 美国和加拿大孕妇的护理和特征相似，因此这项研究的结果将 与美国供应商和孕妇直接相关。更好地了解产前风险 阿片类镇痛剂将指导妊娠期疼痛的治疗和接触药物的婴儿的管理。

PROJECT SUMMARY Prescription opioid use in pregnancy has increased dramatically over the past two decades. Yet, few studies have examined the impact of opioids used for pain on adverse pregnancy outcomes. Some data suggest that prenatal opioid analgesics may be associated with a higher risk of certain birth defects. However, evidence is limited by discrepant study results, poor maternal recall of medication use, and small sample sizes. In addition to these concerns, there are little data on the risk of preterm and small for gestational age birth following opioid analgesic exposure, and stillbirth has not been studied. Evidence of the safe use of prenatal opioid analgesics is thus inconclusive. The primary goal of this study is to determine the risks associated with exposure to opioids for pain in pregnancy independent of biases that have affected prior studies. We will examine several important adverse pregnancy outcomes possibly associated with such exposure including specific birth defects, preterm birth, small for gestational age birth, and stillbirth. The outcomes of maternal and infant opioid dependence following prenatal opioid analgesic exposure also will be evaluated. To achieve this goal we have assembled a population-based cohort of all pregnancies in Ontario, Canada (N≈790,000) from 2012-2017, 30,262 of which were exposed to opioid analgesics during pregnancy. Using modern methods such as high-dimensional propensity score adjustment and sensitivity analyses of alternative referents (including infants unexposed to opioid analgesics and infants unexposed to opioid analgesics but prenatally exposed to other analgesics), we will determine the associations between particular opioid analgesic exposures during the etiologically relevant windows of gestation and these maternal and infant outcomes. This will be the first study to examine the duration and dose of prenatal analgesic opioids on the risk of these adverse outcomes. Our population-based cohort study will provide estimates of the absolute risk of these outcomes, which cannot be estimated from existing US case-control studies, and which are needed to inform maternal treatment choices. Studies of the safety of prenatal medications in extant US data such as Medicaid exclude 80% of pregnancies (i.e., women with restricted benefits, capitated care, private insurance, or incomplete enrollment during pregnancy) to have complete pregnancy data, which may result in selection bias or results that cannot be generalized. Concerns of generalizability also apply to US private insurance beneficiaries. To overcome these limitations we propose a population-based cohort study using an extant database of universal healthcare coverage and complete prescription data for Ontario, Canada’s most populous province of 13 million. Clinical care and characteristics of pregnant women in the US and Canada are similar, thus the results of this study will have direct relevance for US providers and pregnant women. Better understanding of the risks of prenatal opioid analgesics will direct treatment of pain in pregnancy and management of exposed infants.