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

项目总结 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，很少有研究 研究了用于止痛的阿片类药物对不良妊娠结局的影响。一些数据表明， 产前使用阿片类止痛药可能与某些出生缺陷的风险较高有关。然而，证据是 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 出于这些担忧，几乎没有关于阿片类药物后早产和小于胎龄儿出生风险的数据。 暴露于止痛剂和死产之间的关系尚未得到研究。安全使用产前阿片类止痛药的证据 因此没有定论。 这项研究的主要目标是确定与接触阿片类药物治疗疼痛相关的风险 与影响先前研究的偏见无关的怀孕。我们将研究几个重要的不利因素 可能与这种暴露有关的妊娠结局包括特定的出生缺陷、早产、 小于胎龄儿的出生和死产。母婴阿片类药物依赖的结局 产前阿片类止痛药的暴露也将进行评估。为了实现这一目标，我们组建了一个 2012年至2017年加拿大安大略省所有孕妇的基于人口的队列(N≈790,000例)，其中30,262例 在怀孕期间接触了阿片类镇痛剂。使用现代方法，如高维 替代参照物(包括未接触过的婴儿)的倾向性分数调整和敏感性分析 阿片类镇痛剂和未接触阿片类镇痛剂但产前接触其他镇痛剂的婴儿)，我们 将确定在病因学上相关的特定阿片类止痛剂暴露之间的相关性 妊娠期和这些母婴结局。这将是第一次研究 产前止痛剂阿片类药物的持续时间和剂量对这些不良结果的风险。我们以人口为基础 队列研究将提供对这些结果的绝对风险的估计，这不能从 现有的美国病例对照研究，需要这些研究为产妇的治疗选择提供信息。 在现有的美国数据中对产前药物安全性的研究，如医疗补助，排除了80%的怀孕 (即，具有受限福利、首肯护理、私人保险或未完全投保的妇女 怀孕)拥有完整的怀孕数据，这可能导致选择偏差或结果不能 泛化。对普适性的担忧也适用于美国私人保险受益人。要克服这些障碍 局限性我们建议使用现有的全民保健数据库进行一项基于人群的队列研究 加拿大人口最多的安大略省1300万人口的覆盖范围和完整的处方数据。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 与美国医疗服务提供者和孕妇有直接关系。更好地了解产前的风险 阿片类镇痛剂将指导妊娠疼痛的治疗和暴露婴儿的管理。

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.