Novel biomarkers to assess in utero effects of maternal opioid use: First steps toward understanding short‐ and long‐term neurodevelopmental sequelae

Abstract

Maternal opioid use disorder is common, resulting in significant neonatal morbidity and cost. Currently, it is not possible to predict which opioid‐exposed newborns will require pharmacotherapy for neonatal abstinence syndrome. Further, little is known regarding the effects of maternal opioid use disorder on the developing human brain. We hypothesized that novel methodologies utilizing fetal central nervous system‐derived extracellular vesicles isolated from maternal blood can address these gaps in knowledge. Plasma from opioid users and controls between 9 and 21 weeks was precipitated and extracellular vesicles were isolated. Mu opioid and cannabinoid receptor levels were quantified. Label‐free proteomics studies and unbiased small RNA next generation sequencing was performed in paired fetal brain tissue. Maternal opioid use disorder increased mu opioid receptor protein levels in extracellular vesicles independent of opioid equivalent dose. Moreover, cannabinoid receptor levels in extracellular vesicles were upregulated with opioid exposure indicating cross talk with endocannabinoids. Maternal opioid use disorder was associated with significant changes in extracellular vesicle protein cargo and fetal brain micro RNA expression, especially in male fetuses. Many of the altered cargo molecules and micro RNAs identified are associated with adverse clinical neurodevelopmental outcomes. Our data suggest that assays relying on extracellular vesicles isolated from maternal blood extracellular vesicles may provide information regarding fetal response to opioids in the setting of maternal opioid use disorder. Prospective clinical studies are needed to evaluate the association between extracellular vesicle biomarkers, risk of neonatal abstinence syndrome and neurodevelopmental outcomes.

Developmental opioid exposures: Neurobiological underpinnings, behavioral impacts, and policy implications

“…Related to these complexities, a recent study isolated extracellular vesicles and synaptosomes from fetal neural samples in humans and observed complex changes in endogenous opioid and endocannabinoid receptor levels. 55,56 The study identified distinct effects between the two membrane preparations that were analyzed, and between the two opioids that participants in this study were using—buprenorphine and methadone. Moreover, microRNA sequencing revealed sex-dependent effects on expression pattern.…”

Prenatal Morphine Exposure Increases Cardiovascular Disease Risk and Programs Neurogenic Hypertension in the Adult Offspring

“…OUD during pregnancy has been linked to low-birth weight, preterm birth, birth defects and NOWS. [2][3][4][5]18 Several factors associated with pregnancy outcomes have been shown to increase the risk of developing cardiovascular and metabolic diseases. [47][48][49] Low-birth weight and catch-up growth are established predictor of CVD risk, catch-up growth, a compensatory weight gain leading to rapid growth in infants or young children who are smaller for their age or adjusted age.…”

“…1 However, a third concerning wave caused by synthetic opioids, specifically illicit fentanyl and fentanyl-like analogs, has been on an alarming rise since 2013. 1 Nevertheless, an understudied area related to the opioid epidemic is OUD during pregnancy, which results in a 5-fold increase in neonatal opioid withdrawal syndrome (NOWS) incidence, [2][3][4] affecting different body systems (eg, cardiovascular, gastrointestinal). NOWS severity is influenced by the length of exposure, type of opioid, and other licit and illicit substances that the mother uses.…”

Anesthetic management of the parturient with opioid addiction

“…Medically supervised opioid withdrawal or detoxification in pregnant women with OUD is possible and has been suggested as an important strategy to decrease fetal exposure and opioidassociated fetal brain stress, [31][32][33][34][35][36][37][38] but needs to account for the possibility of maternal relapse and fetal withdrawals, which may result in fetal demise. 39 Rather, because it significantly reduces the risk of both relapse and withdrawal, MAT is the preferred treatment modality for pregnant women with OUD.…”