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阿片类药物。这重新 反映出过去 12 年来妊娠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 阿德。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。 选择社会因素。与此同时，新生儿戒断综合症 (NAS) 发生率增加了 3 至 20 倍以上 自 2000 年以来。在美国，每 25 分钟就有一名依赖阿片类药物的婴儿出生。儿童预先接触阿片类药物 出生时和新生儿期的人在以后的生活中面临阿片类药物滥用的风险，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赋予了重大的社会意义 和经济负担，并导致生产性生活的丧失。尽管阿片类药物的暴露率很高，但很少有 了解导致不良产妇结局和儿童神经发育结局的因素 德伦与母亲 OUD。此外，宫内阿片类药物暴露对胎盘功能、胎儿成熟的影响 新生儿大脑活动尚不清楚。解决孕产妇阿片类药物滥用和 NAS 问题需要采取全面的措施 了解多种母婴因素。迫切需要及早、有针对性地识别 患有 OUD 的孕妇有复发的风险以及长期孕产妇和儿童结局不佳的风险。我们的长期 长期目标是减少未来产妇 OUD 和阿片类药物维持治疗的复发，降低严重程度 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。 该提案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 使用严格的前瞻性纵向设计、创新的组合药物来评估孕产妇和婴儿的结局 宏观遗传学方法、胎儿 MRI 和新生儿大脑静息态功能 MRI 分析。我们早期的工作 研究表明，母体/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不良反应。我们的初步数据显示，接受 NAS 治疗的儿童有显着的 两年后认知功能较差。根据我们之前的结果，我们假设组合 母婴遗传特征、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 治疗将影响孕产妇和儿童结局 阿片类药物暴露。具体目标是： 1) 识别孕妇的高风险遗传特征和心理社会因素 患有阿片类药物使用障碍的女性，并且容易导致产妇阿片类药物维持治疗效果不佳 来了； 2) 确定母婴遗传谱和母体阿片类药物治疗不良预测因素 胎儿发育、NAS 严重程度和新生儿脑功能； 3) 开发孕产妇预测模型 宫内阿片类药物暴露儿童的阿片类药物复发和长期神经发育结果不佳。 这项研究的关键新知识将使母婴阿片类药物暴露的安全、有效治疗成为可能。 通过主动的风险预测和个性化干预来实现确定的神经发育结果。

项目成果

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

产前阿片类药物暴露婴儿的全球大脑功能网络连接。

• 发表时间: 2022
• 作者: Radhakrishnan, Rupa;Vishnubhotla, Ramana V;Zhao, Yi;Yan, Jingwen;He, Bing;Steinhardt, Nicole;Haas, David M;Sokol, Gregory M;Sadhasivam, Senthilkumar
• 通讯作者: Sadhasivam, Senthilkumar

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。

• 发表时间: 2022-08
• 影响因子: 2.8
• 作者: Radhakrishnan, Rupa;Vishnubhotla, Ramana V;Guckien, Zoe;Zhao, Yi;Sokol, Gregory M;Haas, David M;Sadhasivam, Senthilkumar
• 通讯作者: Sadhasivam, Senthilkumar

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

产前阿片类药物暴露婴儿的静息态功能 MRI——一项试点研究。

• 发表时间: 2021-04
• 影响因子: 2.8
• 作者: Radhakrishnan, Rupa;Elsaid, Nahla M H;Sadhasivam, Senthilkumar;Reher, Thomas A;Hines, Abbey C;Yoder, Karmen K;Saykin, Andrew J;Wu, Yu
• 通讯作者: Wu, Yu

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

胎儿 MRI 上胎儿大脑发育和产前阿片类药物暴露和吸烟的形态测定的初步研究。

• 发表时间: 2022-01
• 作者: Radhakrishnan, Rupa;Brown, Brandon P;Haas, David M;Zang, Yong;Sparks, Christina;Sadhasivam, Senthilkumar
• 通讯作者: Sadhasivam, Senthilkumar

Placental volume in pregnant women with opioid use: prenatal MRI assessment.

使用阿片类药物的孕妇的胎盘体积：产前 MRI 评估。

• 发表时间: 2023-12
• 作者: Wise, Rachel L;Brown, Brandon P;Haas, David M;Sparks, Christina;Sadhasivam, Senthilkumar;Zhao, Yi;Radhakrishnan, Rupa
• 通讯作者: Radhakrishnan, Rupa