Maternal use of prescribed opioid analgesics and risk of adverse offspring outcomes

处方阿片类镇痛药（POA）用于治疗疼痛在育龄妇女中很常见 和孕妇。然而，尽管其流行，但对POA使用的影响知之甚少， 怀孕对后代发育的影响。动物模型表明，产前阿片类药物暴露可以改变大脑 发育和行为，但这是否会转化为人类神经发育障碍的风险， 不知道。少数POA用于妊娠和分娩结局的观察性研究的结果如下： 混合并受到研究质量差的限制，包括对混杂因素的控制不足。现时的建议 通过对大量人口样本的综合分析，试图解决这些局限性。在 特别是，当前提案的目标是提高我们对POA使用和安全性的理解 在怀孕期间，重点关注不良出生结局（结构性出生缺陷，小于胎龄儿， 早产）和神经发育障碍（自闭症谱系和注意力缺陷/多动症 疾病）。我们建议分析一个无与伦比的，全国范围内的125万瑞典儿童出生的数据集。 2006-2017年，其中包括详细评估POA在妊娠、分娩结局和 神经发育障碍，以及可能影响两种治疗可能性的各种因素 和后代的结果。此外，我们建议使用和联合收割机多种先进的分析方法。 除了调整测量的因素，我们将使用几种类型的比较组来帮助 评估未测量的混杂因素的作用，包括兄弟姐妹，使用另一种疼痛的母亲的后代 药物（即，处方对乙酰氨基酚作为活性对照），以及使用POA的母亲的后代 但不是在怀孕期间。最后，我们还将评估与父亲POA使用的关联， 妊娠作为阴性对照。初步分析表明，妊娠期间使用POA 与不良的后代结果有关，但也与许多精神和社会经济因素有关， 与后代结果相关联，突出了我们建议的重要性。拟议的研究是 意义重大，因为它将提供影响POA使用的患者特征的更多描述 怀孕期间，以及更好地了解这种做法对后代结果的具体风险 与显著的发病率和死亡率相关。该建议是创新的，因为（a）使用无与伦比的 从许多国家登记册的链接中提取的数据，这些登记册为关键结构提供了精确的衡量标准; (b)使用多种先进方法并对其假设的有效性进行系统评估;以及 (c)一个独特的跨学科研究团队。这些结果将为医学研究提供重要信息。 妊娠期和育龄期妇女中POA疼痛管理的决策 年龄，告知随后的研究，以确定与POA使用相关的不良后果风险最大的后代，以及 指导后续的基础研究，以了解胎儿阿片类药物暴露影响背后的机制。

Prescribed opioid analgesic (POA) use for the treatment of pain is common among women of childbearing age and pregnant women. Despite its prevalence, however, little is known about the effects of POA use in pregnancy on offspring development. Animal models demonstrate that prenatal opioid exposure can alter brain development and behavior, but whether this translates to risks for neurodevelopmental disorders in humans is not known. Findings from the few observational studies of POA use in pregnancy and birth outcomes are mixed and limited by poor study quality, including inadequate control for confounding. The current proposal seeks to address these limitations through comprehensive analysis of a large population-based sample. In particular, the objective of the current proposal is to improve our understanding of the use and safety of POAs in pregnancy, focusing on adverse birth outcomes (structural birth defects, small size for gestational age, and preterm birth) and neurodevelopmental disorders (autism spectrum and attention-deficit/hyperactivity disorders). We propose to analyze an unparalleled, nation-wide dataset of 1.25 million Swedish children born 2006-2017, which includes detailed assessment of POA use in pregnancy, birth outcomes and neurodevelopmental disorders, and a wide range of factors that could influence the likelihood of both treatment and offspring outcomes. Furthermore we propose to use and combine multiple advanced methods of analysis. In addition to adjustment for measured factors, we will use several types of comparison groups to help evaluate the role of unmeasured confounding, including siblings, offspring of mothers using another pain medication (i.e., prescribed acetaminophen as an active comparator), and offspring of mothers using POAs before but not during pregnancy. Finally, we also will evaluate the associations with paternal POA use during pregnancy as a negative control. Preliminary analyses demonstrating that POA use during pregnancy is associated with adverse offspring outcomes, but also with many psychiatric and socioeconomic factors associated with the offspring outcomes, highlight the importance of our proposal. The proposed research is significant because it will provide a greater description of the patient characteristics that influence POA use during pregnancy, as well as a better understanding of the specific risks of the practice for offspring outcomes associated with significant morbidity and mortality. The proposal is innovative due to (a) the use of unparalleled data drawn from the linkage of numerous national registers that provide precise measures for key constructs; (b) the use of multiple advanced methods and systematic evaluation of the validity of their assumptions; and (c) a unique interdisciplinary team of researchers. The results will provide critical information for medical decision-making regarding the pain management with POAs in pregnancy and among women of childbearing age, inform ensuing research to identify offspring at greatest risk of adverse outcomes related to POA use, and guide subsequent basic research into mechanisms behind the effects of fetal opioid exposure.