Effects of Opioid Use Disorder in Pregnancy on Long-Term Maternal and Child Outcomes

项目摘要：在美国，14-21%的孕妇在怀孕期间接触阿片类药物。这一次重新- 反映了过去12月怀孕期间处方阿片类药物使用和阿片类药物使用障碍(OUD)增加了一倍- 艾德。由于产后抑郁症和其他精神疾病，怀孕期间和分娩后阿片类药物的复发率很高。 选择的社会因素。与此同时，新生儿禁欲综合症(NAS)的发生率增加了3到20倍以上 从2000年开始。在美国，每25分钟就有一个婴儿出生时依赖阿片类药物。儿童接触阿片类药物前- 出生时和新生儿期有在以后的生活中滥用阿片类药物的风险，并可能发展出认知、行为- 精神障碍和神经发育问题。所有这些可预防的公共卫生危机赋予了重大的社会 和经济负担，以及生产生活的损失。尽管接触阿片类药物的比例很高，但几乎没有 已知婴幼儿不良母体结局和神经发育结局的易感因素 有母性的孩子。此外，宫内阿片类药物暴露对胎盘功能、胎儿成熟的影响 和新生儿的大脑活动是未知的。解决母亲阿片类药物滥用和NAS需要全面的 对多种母婴因素的理解。迫切需要及早和有针对性地识别 有反复发作风险和不良的长期孕产妇和儿童结局的孕妇。我们的长- 学期目标是减少未来母亲对阿片类药物维持治疗的依赖和复发，降低严重程度 对于NAS，个性化NAS治疗，并改善宫内阿片类药物暴露儿童的神经发育。 这项建议的目的是确定阿片类药物相关的多因素遗传、心理社会预测因素。 母婴结局使用严格的前瞻性纵向设计，创新的组合药物- 胚胎发育途径、胎儿MRI和新生儿脑静息状态功能MRI分析。我们早期的工作 提示母亲/新生儿遗传变异和阿片类药物遗传学与NAS-Se相关。 阿片类药物的真实性和不良反应。我们的初步数据显示，接受NAS治疗的儿童 在生命的两年里认知功能更差。根据我们之前的结果，我们假设一个组合 母婴遗传概况、母亲心理社会因素、母亲阿片类药物治疗反应、胎儿 新生儿神经发育和NAS治疗将影响产前母婴结局 阿片类药物暴露。具体目的是：1)确定妊娠高血压综合征的高危遗传特征和心理社会因素。 患有阿片类药物使用障碍和易患不良母亲阿片类药物维持治疗的妇女-- 2)确定母婴遗传图谱和母体阿片类药物治疗预测不良反应的因素 胎儿发育、NAS的严重程度和新生儿的脑功能；以及3)开发预测模型。 在宫内阿片类药物暴露的儿童中，阿片类药物复发和不良的长期神经发育结果。 这项研究的关键新知识将使母婴阿片类药物博览会能够安全、有效地治疗- 通过实现主动的风险预测和个性化干预，确保和神经发育结果。

Project Summary: In the US, 14-21% of pregnant women are exposed to opioids during pregnancy. This re- flects a doubling of prescribed opioid use and opioid use disorder (OUD) in pregnancy in the past dec- ade. Opioid relapse during pregnancy and after delivery is high due to post-partum depression and other psy- chosocial factors. In parallel, neonatal abstinence syndrome (NAS) rates have increased more than 3 to 20 fold since 2000. Every 25 minutes, a baby is born dependent to opioids in the US. Children exposed to opioids pre- natally and in the neonatal period are at risk of opioid misuse later in life, and may develop cognitive, behavior- al and neurodevelopmental problems. All these preventable public health crises confer a significant societal and economic burden, with loss of productive life. Despite the high prevalence of exposure to opioids, little is known about the factors predisposing to poor maternal outcomes, and neurodevelopmental outcomes in chil- dren with maternal OUD. Further, the effect of in-utero opioid exposure on placental function, fetal maturation and neonatal brain activity are unknown. Tackling maternal opioid misuse and NAS requires a comprehensive understanding of multiple maternal-infant factors. There is a critical need for early and targeted identification of pregnant women with OUD at risk for relapse and poor long term maternal and childhood outcomes. Our long- term goals are to reduce future maternal OUD and relapse on opioid maintenance therapy, decrease severity of NAS, personalize NAS treatment, and improve neurodevelopment in children with in-utero opioid exposure. The objective of this proposal is to determine multi-factorial genetic, psychosocial predictors of opioid related maternal and infant outcomes using rigorous prospective longitudinal design, innovative combinatorial phar- macogenetic approach, fetal MRI and neonatal brain resting state functional MRI analysis. Our earlier work showed that maternal/neonatal genetic variations and opioid-pharmacogenetics were associated with NAS se- verity and adverse effects of opioids. Our preliminary data show that children treated for NAS had significantly worse cognitive function at two years of life. Based on our previous results, we hypothesize that a combination of maternal and infant genetic profile, maternal psychosocial factors, maternal opioid treatment response, fetal and neonatal neurodevelopment and NAS treatment will affect maternal and childhood outcomes with prenatal opioid exposure.The specific aims are to: 1) Identify high-risk genetic profiles and psychosocial factors in preg- nant women with opioid use disorder, and predisposing to poor maternal opioid maintenance treatment out- comes; 2) Determine maternal-infant genetic profiles and maternal opioid treatment factors predicting adverse fetal development, severity of NAS, and neonatal brain function; and 3) Develop predictive models for maternal opioid relapse, and poor long-term neuro-developmental outcomes in children with in-utero opioid exposure. Critical new knowledge from this research will enable safe, effective treatment of maternal-infant opioid expo- sure and neurodevelopmental outcomes by enabling proactive risk predictions and personalized interventions.