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Opioid use disorder during pregnancy significantly increases the likelihood of adverse developmental outcomes in the offspring. Texture analysis serves as a quantitative technique that could be vital in identifying microstructural variations in placentas that have been exposed to opioids and other substances. This is a prospective, multisite cross-sectional study that recruited pregnant women that were greater than 16 weeks of gestation. We manually segmented placenta tissue from half-Fourier single-shot turbo spin-echo (HASTE) sequence MR images. We then assessed placental surface area and texture features using a radiomics pipeline. Using linear models, we assessed the association of substance use on placental surface area and texture features, accounting for demographic characteristics. There were 33 pregnant women with opioid use and 29 controls. Based on regression analysis, opioid exposure was associated with alterations in two texture features while tobacco exposure was associated with alterations in five texture features prior to multiple comparison correction. These were no longer significant after correcting for multiple comparisons. Additionally, tobacco exposure was significantly associated with greater placenta surface area.

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. Methadone accumulated in the placenta and fetal brain, but methadone levels in offspring dropped rapidly at birth which was associated with symptoms and behaviors consistent with neonatal opioid withdrawal. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition. Furthermore, these behavioral alterations were associated with reduced neuronal density in the motor cortex and a disruption in motor neuron intrinsic properties and local circuit connectivity. The present study adds to the limited body of work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring physical and neurobehavioral development. The far-reaching opioid crisis extends to babies born to mothers who take prescription or illicit opioids during pregnancy. Opioids such as oxycodone and methadone can freely cross the placenta from mother to baby. With the rising misuse of and addiction to opioids, the number of babies born physically dependent on opioids has risen sharply over the last decade. Although these infants are only passively exposed to opioids in the womb, they can still experience withdrawal symptoms at birth. This withdrawal is characterized by irritability, excessive crying, body shakes, problems with feeding, fevers and diarrhea. While considerable attention has been given to treating opioid withdrawal in newborn babies, little is known about how these children develop in their first years of life. This is, in part, because it is difficult for researchers to separate drug-related effects from other factors in a child’s home environment that can also disrupt their development. In addition, the biological mechanisms underpinning opioid-related impairments to infant development also remain unclear. Animal models have been used to study the effects of opioid exposure during pregnancy (termed prenatal exposure) on infants. These models, however, could be improved to better replicate the typical pattern of opioid use among pregnant women. Recognizing this gap, Grecco et al. have developed a mouse model of prenatal methadone exposure where female mice that were previously dependent on oxycodone were treated with methadone throughout their pregnancy. Methadone is an opioid drug commonly prescribed for treating opioid use disorder in pregnant women and was found to accumulate at high levels in the fetal brain of mice, which fell quickly after birth. The offspring also experienced withdrawal symptoms. Grecco et al. then examined the physical, behavioral and brain development of mice born to opioid-treated mothers. These included assessments of the animals’ motor skills, sensory reflexes and behavior in their first four weeks of life. Additional experiments tested the properties of nerve cells in the brain to examine cell-level changes. The assessments showed that methadone exposure in the womb impaired the physical growth of offspring and this persisted into ‘adolescence’. Prenatal methadone exposure also delayed progress towards key developmental milestones and led to hyperactivity in three-week-old mice. Moreover, Grecco et al. found that these mice had reduced neuron density and cell-to-cell connectivity in the part of the brain which controls movement. These findings shed light on the potential consequences of prenatal methadone exposure on physical, behavioral and brain development in infants. This model could also be used to study new potential treatments or intervention strategies for offspring exposed to opioids during pregnancy.

There is growing interest in understanding the effects of opioid use on the brain, yet the effects of opioid use on the pregnant maternal brain are still relatively unknown. Pregnant women with opioid exposure during pregnancy are at high risk for adverse neurological and neuropsychiatric outcomes. Much of what is currently known about the impact of opioids on the maternal brain is mainly derived from studies in animal models; however, species-specific opioid pathways and other socio-environmental factors complicate the interpretation of results. A few studies in non-pregnant adults have shown the utility of magnetic resonance spectroscopy (MRS) in risk prediction in substance exposure. We know that pregnancy alters the pharmacodynamics and pharmacokinetics of opioid metabolism, and the impact of opioids on synapses may differ during pregnancy compared to the non-pregnant state. We, therefore, aimed to understand the neurometabolic alterations in pregnant women on medications for opioid use disorder (MOUD). In our multicenter study, we utilized 1H MRS to analyze metabolic alterations in the dorsal anterior cingulate cortex (dACC) in pregnant women on MOUD (12 subjects) vs. pregnant control women (21 subjects) without substance exposure. Using multivariable linear regression, we identified a positive association between opioid exposure and choline-to-creatine (Cho/Cr) ratios after correcting for gestational age and scanner site. We also identified a significant elevation in the Cho/Cr ratio in pregnant women on MOUD and concomitant polysubstance exposure when compared to pregnant women on MOUD without exposure to other substances and control pregnant women. These altered metabolite concentrations that we identified in the dACC may provide a mechanistic understanding of the neurobiology of MOUD and insights for better management and outcomes.

Introduction Prenatal opioid exposure (POE) is a major public health consequence of the opioid epidemic. Long‐term health outcomes associated with POE remain unclear, especially for children with POE without a diagnosis of neonatal abstinence syndrome (NAS). Here, we aimed to describe the health outcomes of children with POE and with POE and NAS compared to unexposed children during the first 7 years of life. Design In this retrospective observational cohort study, children born between 2015 and 2022 were identified from the Maternal and Infant Data Hub (MIDH), a data repository that continuously integrates maternal, neonatal, and pediatric records from two academic medical centers and one pediatric hospital system in the Midwest, USA. Methods International Classification of Diseases, 10th Revision, Clinical Modification (ICD‐10 CM) chapters A00‐N99 served as outcomes of interest. Annual incidence and crude incidence rate ratios were calculated to explore descriptive differences between the exposed and unexposed groups. Results The study included 22,002 children, 20,130 (91.5%) of whom were unexposed and 1872 (8.5%) were exposed. Of the 1872 exposed children, 371 (19.8%) received a diagnosis of NAS (POE + NAS) and 1501 were in the POE‐NAS group. Across all 7 years, exposed children had a higher incidence of diagnoses in most ICD‐10 CM chapters compared to unexposed children. A consistently higher incidence rate ratio of diagnosis was observed in both POE‐NAS and POE + NAS groups (vs. unexposed) related to mental and behavioral disorders, eye diagnoses, and diseases of the musculoskeletal system and gastrointestinal systems. Conclusions POE is associated with an increased risk of diagnoses in a number of ICD‐10 CM chapters throughout childhood. These findings underscore the need for early screening and targeted interventions to support exposed children and improve their well‐being. Further research is required to explore underlying mechanisms and develop preventive measures for at‐risk populations. Clinical Relevance Understanding the conditions more often diagnosed in children with prenatal opioid exposure will help to improve care provided to this population. As a result of study findings, nurses who provide care to children with prenatal opioid exposure can prioritize their assessments and allocate time, resources, and education toward areas more likely to be affected.

Background Growing research points to potential long-term developmental implications of prenatal opioid exposure for children. Yet, polysubstance use and adverse childhood experiences are raised as potential confounders. Further, there is a lack of data on school-age children and the children’s strengths. Methods Parents and caregivers of children with prenatal opioid exposure worked with the study team to design, collect, and descriptively analyze mixed method data. Data were collected through survey ( n  = 148) and two focus groups ( n  = 15) from a convenience sample in mostly West Virginia and Massachusetts. Results Nearly half of the children in the sample were diagnosed with multiple developmental delays, behavioral health conditions, and specific learning disorders. Roughly 85% of children have behavioral challenges. Associations between prenatal opioid exposure and negative developmental outcomes did not vary by type of opioid nor by polysubstance use, while controlling for adverse childhood experiences. Importantly, over 80% of families also reported their child’s strengths, including empathy, social magnetism, and their resilience. Conclusions The challenges for children born with prenatal opioid exposure may extend into school-age. The results are consistent with prior research on younger children, suggesting a need for best practices for caring for these children beyond the neonatal stage.

Over the past two decades, Opioid Use Disorder (OUD) among pregnant women has become a major global public health concern. OUD has been characterized as a problematic pattern of opioid use despite adverse physical, psychological, behavioral, and or social consequences. Due to the relapsing–remitting nature of this disorder, pregnant mothers are chronically exposed to exogenous opioids, resulting in adverse neurological and neuropsychiatric outcomes. Collateral fetal exposure to opioids also precipitates severe neurodevelopmental and neurocognitive sequelae. At present, much of what is known regarding the neurobiological consequences of OUD and prenatal opioid exposure (POE) has been derived from preclinical studies in animal models and postnatal or postmortem investigations in humans. However, species-specific differences in brain development, variations in subject age/health/background, and disparities in sample collection or storage have complicated the interpretation of findings produced by these explorations. The ethical or logistical inaccessibility of human fetal brain tissue has also limited direct examinations of prenatal drug effects. To circumvent these confounding factors, recent groups have begun employing induced pluripotent stem cell (iPSC)-derived brain organoid technology, which provides access to key aspects of cellular and molecular brain development, structure, and function in vitro . In this review, we endeavor to encapsulate the advancements in brain organoid culture that have enabled scientists to model and dissect the neural underpinnings and effects of OUD and POE. We hope not only to emphasize the utility of brain organoids for investigating these conditions, but also to highlight opportunities for further technical and conceptual progress. Although the application of brain organoids to this critical field of research is still in its nascent stages, understanding the neurobiology of OUD and POE via this modality will provide critical insights for improving maternal and fetal outcomes.

In recent decades, there has been a dramatic rise in the rates of children being born after in utero exposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a powerful influence on synaptic development, secreting factors to either promote or inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist buprenorphine on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on the excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, indicating a complex neuroadaptive response in the event of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LDs), suggestive of a maladaptive stress response in the developing CNS.

Purpose Prenatal opioid exposure (POE) is a growing public health concern due to its associated adverse outcomes including neonatal opioid withdrawal syndrome (NOWS). The aim of this study was to assess alterations in thalamic functional connectivity in neonates with POE using resting-state functional magnetic resonance imaging (rs-fMRI) and identify whether these altered connectivity measures were associated with NOWS severity. Methods In this prospective, IRB-approved study, we performed rs-fMRI in 19 infants with POE and 20 healthy control infants without POE. Following standard pre-processing, we performed seed-based functional connectivity analysis with the right and left thalamus as the regions of interest. We performed post hoc analysis in the prenatal opioid exposure group to identify associations of altered thalamocortical connectivity with severity of NOWS. P value of < .05 was considered statistically significant. Results There were several regions of significantly altered thalamic to cortical functional connectivity in infants with POE compared to the healthy infants. Distinct regions of thalamocortical functional connectivity correlated with maximum modified Finnegan score. Association between thalamocortical connectivity and severity of NOWS was nominally modified by maternal psychological conditions and polysubstance use. Conclusion Our findings reveal prenatal opioid exposure-related alterations in thalamic functional connectivity in the infant brain that are correlated with severity of NOWS. Future studies may benefit from evaluation of thalamocortical resting state functional connectivity in infants with POE to help  stratify risk of long term neurodevelopmental outcomes.

Abstract The increasing incidence of opioid use during pregnancy has led to a rise in the number of infants exposed to opioids in utero. Prenatal opioid exposure may have consequences for health and (neuro)development, including neonatal opioid withdrawal syndrome (NOWS). It is unknown which infants are at greatest risk for NOWS. DNA methylation (DNAm) is an epigenetic mark reflecting both allelic variation and environmental exposures, which may provide biomarkers for prenatal opioid exposure and infant NOWS. The placenta is an accessible, biologically relevant tissue in which to directly investigate the epigenetic effects of prenatal opioid exposure. Therefore, the aims of this study were to examine whether prenatal opioid exposure is associated with differential DNAm, including epigenetic age acceleration (EAA) in the placenta. We performed an epigenome-wide association study based on co-methylated regions and single CpG sites in placental samples from in utero opioid-exposed (n = 19) and nonexposed infants (n = 143), correcting for potential confounders. We did not identify statistically significant differential DNAm profiles, but the strongest associations were found for cg06621211; cg18688392 (ZMIZ1, adjusted P = .068) and cg04460738 (KCNMA1, adjusted P = .068), although effect sizes were very small. One of these DNAm patterns (cg06621211) was in part under control of genetic variants through methylation quantitative trait loci. The involved single nucleotide polymorphism did not show significant associations in recent genome-wide association studies for phenotypes related to substance use, and the finding was not driven by potential co-occurring substance use based on sensitivity analyses. There was also no association between placental EAA and in utero opioid exposure. In conclusion, placental DNAm showed limited associations with in utero opioid exposure and NOWS diagnosis.

Prenatal substance exposure (PSE) can lead to various harmful outcomes for the developing fetus and is linked to many emotional, behavioral, and cognitive difficulties later in life. Therefore, examination of the relationship between the development of associated brain structures and PSE is important for the development of more specific or new preventative methods. Our study's primary objective was to examine the relationship between the physical development of the amygdala, hippocampus, and parahippocampus following prenatal alcohol, tobacco, and prescription opioid exposure. We conducted a cross-sectional analysis of the Adolescent Brain and Cognitive Development (ABCD) Study, a longitudinal neuroimaging study that measures brain morphometry from childhood throughout adolescence. Data were collected from approximately 12,000 children (ages 9 and 10) and parents across 22 sites within the United States. Prenatal opioid, tobacco, and alcohol use was determined through parent self-report of use during pregnancy. We extracted variables assessing the volumetric size (mm ) of the amygdala, hippocampus, and parahippocampal gyrus as well as brain volume, poverty level, age, sex, and race/ethnicity for controls within our adjusted models. We reported sociodemographic characteristics of the sample overall and by children who had PSE. We calculated and reported the means of each of the specific brain regions by substance exposure. Finally, we constructed multivariable regression models to measure the associations between different PSE and the demographic characteristics, total brain volume, and volume of each brain structure. Among the total sample, 24.6% had prenatal alcohol exposure, 13.6% had prenatal tobacco exposure, and 1.2% had prenatal opioid exposure. On average, those with prenatal tobacco exposure were found to have a statistically significant smaller parahippocampus. We found a significant association between prenatal tobacco exposure and smaller parahippocampal volume, which may have profound impacts on the livelihood of individuals including motor delays, poor cognitive and behavioral outcomes, and long-term health consequences. Given the cumulative neurodevelopmental effects associated with PSE, we recommend that healthcare providers increase screening rates, detection, and referrals for cessation. Additionally, we recommend that medical associations lobby policymakers to address upstream barriers to the effective identification of at-risk pregnant individuals, specifically, eliminating or significantly reducing punitive legal consequences stemming from state laws concerning prenatal substance use.