Grants and Contracts Details

Description

Maternal opioid use disorder (OUD) during pregnancy has risen at an alarming rate over the past decade from 3.5 to 8.2 per 1,000 deliveries in the United States. Subjects with experience increased incidence of adverse perinatal outcomes, notably preterm birth, miscarriage, delivery complications. Moreover, 50% of infants with exposure to opioids, with or without other substances will develop a constellation of withdrawal manifestations, referred to as Neonatal Opioid Withdrawal Syndrome (NOWS). The sharp increase in NOWS from 7 cases per 1,000 NICU admissions to 27 cases per 1,000 admissions between 2004 and 2013 means a NOWS diagnosis approximately every 20 minutes and one hospitalization every hour in the United States in the past decade. These hospitalizations are characterized by longer NICU stays and more infants receiving pharmacotherapy. Moreover, in utero exposure to opioids results in myelination deficits and smaller head circumference leading to increased risk of neurodevelopment impairment, lower Mental Development Index, and Psychomotor Development Index scores compared to non-exposed infants. Although it is well established that opioids can cross the placenta and can act directly on endogenous opioid receptors in the fetal brain, the detailed impact of MOUD on placental function, as well as on neonate brain development and neurodevelopmental outcomes remain poorly understood. In this application, we will test the central hypothesis that MOUD-driven inflammation and dysregulation of the placental landscape are linked to adverse neurocognitive outcomes in the offspring. We are uniquely positioned to address this hypothesis by leveraging the infrastructure of the Perinatal Assistance and Treatment Home (PATHways) program, a unique resource at the University of Kentucky that serves pregnant women with substance use disorder. We will collect longitudinal placenta imaging data, paired placenta and umbilical cord blood samples at delivery, followed by battery of neurodevelopmental tests on the infants throughout the first year to complete the following specific aims: Aim 1: Determine the impact of maternal OUD on placenta inflammation and health. Previous studies have indicated that MOUD Previous studies have indicated that MOUD is associated with fetal growth restriction and preterm birth which may be mediated by delayed villous maturation and reduced fetal-to-placental ratio. A higher inflammatory burden in patients with maternal OUD potentially mediates placental dysfunction and dysmaturation. Therefore, this aim will test the hypothesis that placental inflammation and altered placental growth/function. We will determine the impact of maternal OUD on biophysical and biochemical markers of placental growth obtained by Doppler ultrasound examination of fetal and maternal circulations in addition to circulating levels of placental growth and vascular factor. These findings will be correlated with detailed placental histological variation observed post-delivery and fetal/neonatal biometry. Decidua and trophoblast organoids will be generated from placenta tissue to elucidate structural and inflammatory changes. In addition, exacerbated placental inflammation will be defined at delivery by measuring tissue levels inflammatory mediators and spatial transcriptomics analysis which will be correlated with biomarkers of placental growth/function and fetal growth. Aim 2: Determine the impact of maternal opioid use on microglia phenotype and function in the neonate. Rodent models of MOUD reported increased neuroinflammation in the offspring and alteration in microglia, the brain-tissue resident phagocytes with a critical role in maintenance of brain homeostasis. Therefore, this aim will test the hypothesis that MOUD leads to rewiring of microglia resulting in adverse neurocognitive outcomes. The impact of MOUD on neonatal neurotropic factor production including BDNF and GFAP will be assessed in cord blood plasma at delivery. Furthermore, we will measure brain cell-derived exosomes in plasma as biomarkers of brain health and inflammation. Finally, to assess the effect of MOUD on microglia, we will use umbilical cord blood monocyte-derived microglia-like and Hofbauer cells to assess MOUD-driven changes in the transcriptional, epigenetic, and functional landscapes using single cell and bulk genomics. Aim 3: Determine the impact of maternal opioid use on neurobehavioral outcomes. Prenatal opioid exposure is associated with a decreased birth head circumference, development of NOWS, in addition to early childhood and long term neurobehavioral and cognitive deficits. In this aim, we will test the hypothesis that Maternal OUD-associated changes in perinatal immunologic processes will be predictive of infant neurodevelopmental outcomes. We will perform clinical measurements and neurobehavioral assessment in the newborn period, followed by neurodevelopmental testing at 3, 6 and 12 months. These measurements will be correlated to inflammatory mediators and neurotropic factors measured in cord blood and neonatal samples collected during hospitalization. Findings from these three aims will be integrated to generate a comprehensive model of the impact of MOUD on placental dysregulation and the link to adverse neurodevelopmental outcomes in the offspring. The success of this application is bolstered by access to PATHways, a unique clinic dedicated to caring for pregnant women with substance use disorder, the innovative and multi-modal experimental approach, the longitudinal study design, and the multidisciplinary team with expertise in MFM, neonatology, pathology, immunologists, neuroinflammation, and biostatistics .
StatusActive
Effective start/end date8/1/237/31/26

Funding

  • National Institute on Drug Abuse: $1,032,655.00

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