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

妊娠期阿片类药物使用障碍对母婴长期结局的影响

• 批准号: 10430172
• 负责人: Senthilkumar Sadhasivam
• 金额: $ 45.91万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430172
• 关键词: 2 year old; ABCB1 gene; Adverse effects; Affect; American; Behavior; Brain; Brain imaging; Buprenorphine; Child; Childhood; Clinical; Cognitive; Consensus; DRD2 gene; Data; Drug Kinetics; Economic Burden; Environmental Risk Factor; Epigenetic Process; Exposure to; Fetal Development; Fetus; Functional Magnetic Resonance Imaging; Future; Genes; Genetic; Genetic Risk; Genetic Variation; Genotype; Goals; High Prevalence; High Risk Woman; Hospitalization; Image; Imaging Device; Infant; Infant Care; Infant Development; Injury; Knowledge; Length of Stay; Life; Magnetic Resonance Imaging; Modeling; Morphine; Mothers; Neonatal; Neonatal Abstinence Syndrome; Neurodevelopmental Problem; Opioid; Opioid replacement therapy; Oral; Outcome; Overdose; Pattern; Pharmacogenetics; Placenta; Postpartum Depression; Predictive Factor; Predisposing Factor; Pregnancy; Pregnancy Outcome; Pregnant Women; Problem behavior; Psychological Factors; Psychosocial Factor; Public Health; Relapse; Research; Rest; Risk; Risk Factors; Severities; Treatment Factor; Treatment outcome; Variant; Work; adverse pregnancy outcome; base; buprenorphine treatment; cognitive function; combinatorial; cost efficient; design; effective therapy; fetal; fetal opioid exposure; genetic signature; genetic variant; high risk; illicit opioid; imaging approach; imaging biomarker; improved; in utero; infant outcome; innovation; insight; inter-individual variation; longitudinal design; maternal opioid use; maternal outcome; medication-assisted treatment; multidisciplinary; neonatal brain; neonatal outcome; neonatal period; neurodevelopment; novel; opioid exposure; opioid misuse; opioid use; opioid use disorder; opioid use in pregnancy; opioid withdrawal; personalized intervention; predictive modeling; prenatal; prescription opioid; prospective; psychologic; psychosocial; public health relevance; relapse risk; response; risk prediction; socioeconomics; socioenvironmental factor; tool; treatment response; treatment strategy

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.

项目摘要：在美国，14-21%的孕妇在怀孕期间接触过阿片类药物。这是- 反映了在过去的12月里，怀孕期间处方阿片类药物的使用和阿片类药物使用障碍（OUD）增加了一倍， 阿德。由于产后抑郁症和其他精神疾病，怀孕期间和分娩后的阿片类药物复发率很高。 非社会因素与此同时，新生儿戒断综合征（NAS）的发病率增加了3至20倍以上 自2000年以来在美国，每25分钟就有一个婴儿出生依赖阿片类药物。暴露于阿片类药物的儿童 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，并可能发展认知，行为， al和神经发育问题。所有这些可预防的公共卫生危机都给社会带来了重大影响。 和经济负担，以及生产生活的损失。尽管阿片类药物的暴露率很高， 了解导致母亲不良结局的因素，以及儿童的神经发育结局， 与母亲OUD。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都是未知的解决母体阿片类药物滥用和NAS需要一个全面的 了解多种母婴因素。迫切需要及早和有针对性地查明 患有OUD的孕妇有复发的风险，长期母婴结局较差。我们长久以来- 长期目标是减少未来母体OUD和阿片类药物维持治疗的复发， 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，心理社会预测因子 采用严格的前瞻性纵向设计，创新的组合phar， 磁共振成像的方法，胎儿和新生儿脑静息态功能磁共振成像分析。我们前面的工作 表明母亲/新生儿遗传变异和阿片类药物遗传学与NAS相关。 阿片类药物的真实性和副作用。我们的初步数据显示，接受NAS治疗的儿童 认知功能在2岁时会变差基于我们之前的研究结果，我们假设 母亲和婴儿的遗传特征，母亲的心理社会因素，母亲的阿片类药物治疗反应，胎儿 新生儿神经发育和NAS治疗将影响产前检查的母婴结局， 阿片类药物暴露。具体目标是：1）确定高风险的遗传概况和心理社会因素，在孕妇， 患有阿片类药物使用障碍的女性，以及易于接受不良母体阿片类药物维持治疗的女性， 2）确定母婴遗传谱和母体阿片类药物治疗因素，预测不良反应。 胎儿发育，NAS的严重程度和新生儿脑功能;和3）开发母亲的预测模型 阿片类药物复发，以及宫内阿片类药物暴露儿童的长期神经发育结局不良。 这项研究的关键新知识将使母婴阿片类药物暴露的安全，有效的治疗成为可能。 通过积极主动的风险预测和个性化干预，确保神经发育的结果。

项目成果

Resting state functional MRI in infants with prenatal opioid exposure-a pilot study.

• DOI: 10.1007/s00234-020-02552-3
• 发表时间: 2021-04
• 期刊: Neuroradiology
• 影响因子: 2.8

Pilot study of fetal brain development and morphometry in prenatal opioid exposure and smoking on fetal MRI.

• DOI: 10.1016/j.neurad.2020.12.004
• 发表时间: 2022-01
• 期刊: Journal of neuroradiology = Journal de neuroradiologie
• 作者: Radhakrishnan R;Brown BP;Haas DM;Zang Y;Sparks C;Sadhasivam S
• 通讯作者: Sadhasivam S

Thalamocortical functional connectivity in infants with prenatal opioid exposure correlates with severity of neonatal opioid withdrawal syndrome.

产前阿片类药物暴露婴儿的丘脑皮质功能连接与新生儿阿片类药物戒断综合征的严重程度相关。

• DOI: 10.1007/s00234-022-02939-4
• 发表时间: 2022
• 期刊: Neuroradiology
• 影响因子: 2.8
• 作者: Radhakrishnan,Rupa;Vishnubhotla,RamanaV;Guckien,Zoe;Zhao,Yi;Sokol,GregoryM;Haas,DavidM;Sadhasivam,Senthilkumar
• 通讯作者: Sadhasivam,Senthilkumar

Global Brain Functional Network Connectivity in Infants With Prenatal Opioid Exposure.

• DOI: 10.3389/fped.2022.847037
• 发表时间: 2022
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6
• 作者: Radhakrishnan R;Vishnubhotla RV;Zhao Y;Yan J;He B;Steinhardt N;Haas DM;Sokol GM;Sadhasivam S
• 通讯作者: Sadhasivam S