The Impact of Prescription Opioid Use on Pregnancy Outcomes

摘要 在美国，处方阿片类药物的使用和滥用迅速增加， 妇女我们小组最近的数据表明，22%的医疗补助受益人和14%的商业 保险受益人在怀孕期间暴露于阿片类药物，包括在头三个月期间暴露于阿片类药物的比例高达10%。 尽管暴露于处方阿片类药物的流行率很高，但对不良反应的影响知之甚少。 妊娠结局。流行病学和临床前数据表明，这种接触可能与 某些先天性畸形、早产、小于胎龄儿和缺血性心脏病的风险较高 胎盘并发症但数据很少，而且相互矛盾，可用的文献受到关注的限制 与回忆偏倚、剩余混杂偏倚和小样本量有关。 使用观察性数据评估处方阿片类药物的影响具有挑战性， 与非法使用和转移导致的潜在暴露错误分类相关，受适应症的混淆，以及 缺少其他相关混杂因素的信息。在这项研究中，我们将利用创新的，最先进的 流行病学方法，以克服这些挑战，产生无偏或最小偏差的估计， 在病因相关的妊娠期暴露于常用处方阿片类药物对妊娠结局的风险 妊娠期。我们打算采用的具体方法包括高维倾向评分 调整，倾向评分校准，替代参考（包括同胞和中断比较）， 活产敏感性分析、倾向评分精细分层和偏倚分析，以解释潜在的 暴露和结果的错误分类。 这项研究的主要目的是确定与处方阿片类药物相关的生物学效应 暴露，独立于混杂因素，因此与医疗和非医疗因素相关， 在怀孕期间使用处方阿片类药物。为了实现这一目标，我们将使用180万人的队列 医疗补助受益人的怀孕和170万商业保险怀孕的队列 受益人。我们将评估病因学期间处方阿片类药物暴露与 相关的窗口和各种重要的不良妊娠结局，以前假设是 与这种接触有关。我们还将评估与特定阿片类药物有关的结果，并将 评估暴露持续时间和剂量的影响。 研究结果将产生重要和直接的临床影响。了解安全性 怀孕期间的处方阿片类药物暴露将指导临床医生治疗疼痛的方法， 怀孕，将告知在怀孕期间滥用处方阿片类药物的妇女的咨询，并将 指导阿片类药物暴露妇女及其后代的临床管理。

ABSTRACT The rapid rise in the use and misuse of prescription opioids in the United States extends to pregnant women. Recent data from our group suggests that 22% of Medicaid beneficiaries and 14% of commercial insurance beneficiaries are exposed to opioids during pregnancy, including up to 10% during the first trimester. Despite the high prevalence of exposure to prescription opioids, little is known about the impact on adverse pregnancy outcomes. Epidemiological and pre-clinical data suggests that such exposure may be associated with higher risk of certain congenital malformations, preterm delivery, small for gestational age, and ischemic placental complications. But data are few and conflicting, and the available literature is limited by concerns related to recall bias, residual confounding bias, and small sample size. Evaluating the impact of prescription opioids using observational data is challenging due to concerns related to potential exposure misclassification due to illicit use and diversion, confounding by indication, and missing information on other relevant confounders. In this study we will utilize innovative, state of the art epidemiological methods to overcome these challenges, generating unbiased or minimally biased estimates of the risk to pregnancy outcomes of exposure to commonly used prescription opioids during etiologically relevant periods of gestation. Specific methods that we intend to employ include high-dimensional propensity score adjustment, propensity score calibration, alternative referents (including sibling and discontinuer comparisons), livebirths sensitivity analyses, propensity score fine stratification, and bias analyses to account for potential misclassification of exposure and outcome. The primary goal of the study is to define the biological effects associated with prescription opioid exposure, independent of confounding factors, which will therefore be relevant to both medical and non- medical use of prescription opioids during pregnancy. To accomplish this, we will use a cohort of 1.8 million pregnancies of Medicaid beneficiaries and a cohort of 1.7 million pregnancies of commercial insurance beneficiaries. We will evaluate the association between prescription opioid exposure during the etiologically relevant window and a variety of important adverse pregnancy outcomes previously hypothesized to be associated with such exposure. We will also assess for the outcomes in relation to specific opioids and will assess the impact of duration of exposure and dose. The results of the studies will have an important and direct clinical impact. Understanding the safety of prescription opioid exposure during pregnancy will guide clinicians' approach to the treatment of pain in pregnancy, will inform the counseling of women who misuse prescription opioids during pregnancy, and will guide the clinical management of opioid exposed women and their offspring.