Influence of Eat, Sleep, and Console on Infants Pharmacologically Treated for Opioid Withdrawal: A Post Hoc Subgroup Analysis of the ESC-NOW Randomized Clinical Trial.

Importance: The function-based eat, sleep, console (ESC) care approach substantially reduces the proportion of infants who receive pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS). This reduction has led to concerns for increased postnatal opioid exposure in infants who receive pharmacologic treatment. However, the effect of the ESC care approach on hospital outcomes for infants pharmacologically treated for NOWS is currently unknown. Objective: To evaluate differences in opioid exposure and total length of hospital stay (LOS) for pharmacologically treated infants managed with the ESC care approach vs usual care with the Finnegan tool. Design, Setting, and Participants: This post hoc subgroup analysis involved infants pharmacologically treated in ESC-NOW, a stepped-wedge cluster randomized clinical trial conducted at 26 US hospitals. Hospitals maintained pretrial practices for pharmacologic treatment, including opioid type, scheduled opioid dosing, and use of adjuvant medications. Infants were born at 36 weeks' gestation or later, had evidence of antenatal opioid exposure, and received opioid treatment for NOWS between September 2020 and March 2022. Data were analyzed from November 2022 to January 2024. Exposure: Opioid treatment for NOWS and the ESC care approach. Main Outcomes and Measures: For each outcome (total opioid exposure, peak opioid dose, time from birth to initiation of first opioid dose, length of opioid treatment, and LOS), we used generalized linear mixed models to adjust for the stepped-wedge design and maternal and infant characteristics. Results: In the ESC-NOW trial, 463 of 1305 infants were pharmacologically treated (143/603 [23.7%] in the ESC care approach group and 320/702 [45.6%] in the usual care group). Mean total opioid exposure was lower in the ESC care approach group with an absolute difference of 4.1 morphine milligram equivalents per kilogram (MME/kg) (95% CI, 1.3-7.0) when compared with usual care (4.8 MME/kg vs 8.9 MME/kg, respectively; P = .001). Mean time from birth to initiation of pharmacologic treatment was 22.4 hours (95% CI, 7.1-37.7) longer with the ESC care approach vs usual care (75.4 vs 53.0 hours, respectively; P = .002). No significant difference in mean peak opioid dose was observed between groups (ESC care approach, 0.147 MME/kg, vs usual care, 0.126 MME/kg). The mean length of treatment was 6.3 days shorter (95% CI, 3.0-9.6) in the ESC care approach group vs usual care group (11.8 vs 18.1 days, respectively; P < .001), and mean LOS was 6.2 days shorter (95% CI, 3.0-9.4) with the ESC care approach than with usual care (16.7 vs 22.9 days, respectively; P < .001). Conclusion and Relevance: When compared with usual care, the ESC care approach was associated with less opioid exposure and shorter LOS for infants pharmacologically treated for NOWS. The ESC care approach was not associated with a higher peak opioid dose, although pharmacologic treatment was typically initiated later. Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

The impact of recreational cannabinoid legalization on utilization in a pregnant population.

Background: Marijuana potency and utilization both continue to increase across the United States. While the overall prevalence of cannabinoid utilization during pregnancy has been surveyed in various studies, the direct impact of changing governmental policies on pregnancy use is less characterized. Thus, we aimed to investigate how the legalization of recreational cannabinoid products impacted use during pregnancy in the state of New Mexico. Methods: Participants who had a live birth during two study epochs were included: pre-legalization (Epoch 1: 1 January 2019-31 March 2021) and post-legalization (Epoch 2: 1 November 2021-30 November 2022). Participants were further divided into case group [prenatal cannabinoid exposure (PCE)] vs. control (no PCE), with cases being identified by documented self-report or a positive laboratory toxicology test for cannabinoid use during pregnancy. Results: A total of 1,191 maternal/infant dyads were included in Epoch 1, and 378 maternal/infant dyads were included in Epoch 2. In Epoch 1, 788 dyads were controls with 403 cases, while Epoch 2 had 292 controls and 86 cases. Interestingly there was a significant decrease in self-report or positive laboratory toxicology tests in Epoch 2 compared to Epoch 1. Infants born following PCE in both Epoch groups were more commonly born via Cesarean section, had significantly smaller birth weight, length, and head circumference as well as significantly lower Apgar scores at 1 and 5 min. Conclusion: The finding of decreased reported cannabinoid use in the post-legalization group is contradictory to previous studies which have shown increased rates of cannabinoid use after legalization. This could be due to multiple factors including changes in screening practices, the COVID-19 pandemic, and lack of commercialization of THC products. Additional studies are needed to further characterize how changing governmental policies impacts utilization during pregnancy.

Sex-specific alterations in cognitive control following moderate prenatal alcohol exposure and transient systemic hypoxia ischemia in the rat.

BACKGROUND: Prenatal alcohol exposure (PAE) continues to be a worldwide problem. Affected offspring display impaired neurodevelopment, including difficulties with executive control. Although PAE has also been associated with decreased blood flow to fetuses, the relationship between PAE and altered blood flow is not well understood. METHODS: We used preclinical models of PAE, transient systemic hypoxia ischemia (TSHI), and PAE + TSHI combined to assess the effects on neurodevelopmental outcomes using translationally relevant touchscreen operant platform testing. Twenty-eight Long-Evans (Blue Spruce, Strain HsdBlu:LE) dams were randomly assigned to one of four experimental groups: Saccharin Control (Sham), 5% Ethanol (PAE), TSHI, or 5% Ethanol and TSHI (PAE + TSHI). Dams consumed either saccharin or 5% ethanol during gestation. TSHI was induced on Embryonic Day 19 (E19) during an open laparotomy where the uterine arteries were transiently occluded for 1 h. Pups were born normally and, after weaning, were separated by sex. A total of 80 offspring, 40 males and 40 females, were tested on the 5-Choice Continuous Performance paradigm (5C-CPT). RESULTS: Female offspring were significantly impacted by TSHI, but not PAE, with an increase in false alarms and a decrease in hit rates, omissions, accuracy, and correct choice latencies. In contrast, male offspring were mildly affected by PAE, but not TSHI, showing decreases in premature responses and increases in accuracy. No significant interactions between PAE and TSHI were detected on any measure. CONCLUSION: Transient systemic hypoxia ischemia impaired performance on the 5C-CPT in females, leading to a bias toward stimulus responsivity regardless of stimulus type. In contrast, TSHI did not affect male offspring, and only slight effects of PAE were seen. Together, these data suggest that TSHI in females may cause alterations in cortical structures that override alterations caused by moderate PAE.

Impact of low-level prenatal alcohol exposure and maternal stress on autonomic regulation.

BACKGROUND: Prenatal alcohol exposure (PAE) impacts the neurodevelopment of the fetus, including the infant's ability to self-regulate. Heart rate variability (HRV), that is, the beat-to-beat variability in heart rate, is a non-invasive measurement that can indicate autonomic nervous system (ANS) function/dysfunction. METHODS: The study consisted of a subset of our ENRICH-2 cohort: 80 participants (32 PAE and 48 Controls) who had completed three visits during pregnancy. The participants completed a comprehensive assessment of PAE and other substances throughout pregnancy and assessments for stress, anxiety, and depression in the third trimester. At 24 h of age, infant HRV was assessed in the hospital during the clinically indicated heel lance; 3- to 5-min HRV epochs were obtained during baseline, heel lancing, and recovery episodes. RESULTS: Parameters of HRV differed in infants with PAE compared to Controls during the recovery phase of the heel lance (respiratory sinus arrhythmia (RSA) and high-frequency (HF), p < 0.05). Increased maternal stress was also strongly associated with abnormalities in RSA, HF, and low-frequency / high-frequency (LF/HF, p's < 0.05). CONCLUSIONS: Alterations in ANS regulation associated with PAE and maternal stress may reflect abnormal development of the hypothalamic-pituitary-adrenal axis and have long term implications for infant responsiveness and self-regulation. IMPACT: Previous studies have focused on effects of moderate to heavy prenatal alcohol exposure (PAE) on autonomic dysregulation, but little is known about the effects of lower levels of PAE on infant self-regulation and heart rate variability (HRV). Prenatal stress is another risk factor for autonomic dysregulation. Mild PAE impacts infant self-regulation, which can be assessed using HRV. However, the effect of prenatal stress is stronger than that of mild PAE or other mental health variables on autonomic dysregulation.

Pilot study shows skin-to-skin care with parents improves heart rate variability in preterm infants in the neonatal intensive care unit.

Background: Skin-to-skin care in the newborn intensive care unit typically lasts for short periods of time and enhances breastfeeding, attachment, and parental self-esteem. Heart rate variability (HRV) increases with gestational age and is a measure of maturation of parasympathetic vs. sympathetic autonomic nervous system activity. HRV measurements may be useful in capturing changes in autonomic regulation in response to skin-to-skin care. Objective: To analyze the effects of skin-to-skin care on HRV in preterm infants receiving respiratory support. We hypothesized that skin-to-skin care would result in a more mature pattern of parasympathetic activity. Methods: In this prospective crossover study, infants <30 weeks' gestation and 1-6 weeks postnatal age had HRV recorded for 30 min before, during, and after skin-to-skin care sessions. HRV characteristics analyzed included the standard deviation of the normal-to-normal interval (SDNN), the root mean squared of successive differences of normal-to-normal intervals (RMSSD), and the standard deviation of decelerations (SDDec). Results: 10 infants between 25 5/7-29 6/7 weeks gestational age and 7-41 days postnatal age completed 22 sessions while receiving respiratory support (positive pressure ventilation or nasal cannula oxygen). Two measures of HRV (SDNN and RMSSD) were significantly decreased by the end of the skin-to-skin sessions, compared to pre-session values. SDNN decreased from a median of 10.44 ms before the session to 6.70 ms after being placed back in bed (p < 0.05), with RMSSD decreasing from a median of 6.80 ms before the session to 4.32 ms while being held at the end of 30 min (p < 0.05). Discussion: Skin-to-skin care with a parent resulted in a more mature autonomic nervous system pattern in preterm infants receiving respiratory support, suggesting physiologic benefit for the infant. No adverse events were seen during any session.

Prenatal cannabinoid exposure: why expecting individuals should take a pregnancy pause from using cannabinoid products.

Cannabinoid use in all populations is increasing as legalization across the United States continues. Concerningly, there is a lack of caution provided by medical providers to pregnant individuals as to the impact the use of cannabinoids could have on the developing fetus. Research continues in both the preclinical and clinical areas, and is severely needed, as the potency of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, has increased dramatically since the initial studies were completed. Thus far, clinical studies raise compelling evidence for short term memory deficits, impulse control issues, and attention deficiencies following prenatal cannabinoid exposure (PCE). These changes may be mediated through epigenetic modifications that not only impact the current offspring but could carry forward to future generations. While additional studies are needed, a pregnancy pause from cannabinoid products should be strongly recommended by providers to ensure the optimal health and well-being of our future generations.

Medication for Opioid Use Disorder During Pregnancy - Maternal and Infant Network to Understand Outcomes Associated with Use of Medication for Opioid Use Disorder During Pregnancy (MAT-LINK), 2014-2021.

Problem: Medication for opioid use disorder (MOUD) is recommended for persons with opioid use disorder (OUD) during pregnancy. However, knowledge gaps exist about best practices for management of OUD during pregnancy and these data are needed to guide clinical care. Period Covered: 2014-2021. Description of the System: Established in 2019, the Maternal and Infant Network to Understand Outcomes Associated with Medication for Opioid Use Disorder During Pregnancy (MAT-LINK) is a surveillance network of seven clinical sites in the United States. Boston Medical Center, Kaiser Permanente Northwest, The Ohio State University, and the University of Utah were the initial clinical sites in 2019. In 2021, three clinical sites were added to the network (the University of New Mexico, the University of Rochester, and the University of South Florida). Persons receiving care at the seven clinical sites are diverse in terms of geography, urbanicity, race and ethnicity, insurance coverage, and type of MOUD received. The goal of MAT-LINK is to capture demographic and clinical information about persons with OUD during pregnancy to better understand the effect of MOUD on outcomes and, ultimately, provide information for clinical care and public health interventions for this population. MAT-LINK maintains strict confidentiality through robust information technology architecture. MAT-LINK surveillance methods, population characteristics, and evaluation findings are described in this inaugural surveillance report. This report is the first to describe the system, presenting detailed information on funding, structure, data elements, and methods as well as findings from a surveillance evaluation. The findings presented in this report are limited to selected demographic characteristics of pregnant persons overall and by MOUD treatment status. Clinical and outcome data are not included because data collection and cleaning have not been completed; initial analyses of clinical and outcome data will begin in 2023. Results: The MAT-LINK surveillance network gathered data on 5,541 reported pregnancies with a known pregnancy outcome during 2014-2021 among persons with OUD from seven clinical sites. The mean maternal age was 29.7 (SD = ±5.1) years. By race and ethnicity, 86.3% of pregnant persons were identified as White, 25.4% as Hispanic or Latino, and 5.8% as Black or African American. Among pregnant persons, 81.6% had public insurance, and 84.4% lived in urban areas. Compared with persons not receiving MOUD during pregnancy, those receiving MOUD during pregnancy were more likely to be older and White and to have public insurance. The evaluation of the surveillance system found that the initial four clinical sites were not representative of demographics of the South or Southwest regions of the United States and had low representation from certain racial and ethnic groups compared with the overall U.S. population; however, the addition of three clinical sites in 2021 made the surveillance network more representative. Automated extraction and processing improved the speed of data collection and analysis. The ability to add new clinical sites and variables demonstrated the flexibility of MAT-LINK. Interpretation: MAT-LINK is the first surveillance system to collect comprehensive, longitudinal data on pregnant person-infant dyads with perinatal outcomes associated with MOUD during pregnancy from multiple clinical sites. Analyses of clinical site data demonstrated different sociodemographic characteristics between the MOUD and non-MOUD treatment groups. Public Health Actions: MAT-LINK is a timely and flexible surveillance system with data on approximately 5,500 pregnancies. Ongoing data collection and analyses of these data will provide information to support clinical and public health guidance to improve health outcomes among pregnant persons with OUD and their children.

Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

The Impact of Coronavirus Disease 2019 on Maternal and Fetal Wellbeing in New Mexico.

Coronavirus disease 2019 (COVID-19) has been shown to affect the vasculature, including placental changes. Insults to the placenta, especially in the first and second trimester, can affect placental functionality with a resultant impact on fetal growth and wellbeing. Thus, we explored the relationship between antenatally acquired maternal COVID-19 infection and neonatal birth characteristics. A retrospective chart review was completed using the University of New Mexico electronic medical record system. ICD-10 codes were used to identify individuals that had a positive pregnancy test and positive COVID-19 screening test between 1 March 2020 to 24 March 2021. Chi-square and nonparametric Wilcoxon analyses were used, with p < 0.05 considered significant. A total of 487 dyad charts was analyzed, with 76 (16%) individuals identified as being COVID-19-positive (CovPos) during pregnancy. CovPos mothers were significantly more likely to deliver via a cesarean section compared to CovNeg mothers (33% vs. 20%, p < 0.01). There was a significant difference in gestational age at delivery, with infants born to CovPos individuals born at an earlier gestational age than those born to CovNeg individuals (37.6 vs. 38.5 weeks; p < 0.01). Our findings showed differences in maternal and infant characteristics following COVID-19 infection during pregnancy. Additional investigations are required to further delineate these relationships with a focus on potential long-term impacts on the neonate.

Post-discharge healthcare utilization in infants with neonatal opioid withdrawal syndrome.

The opioid epidemic in the United States has led to a significant increase in the incidence of neonatal opioid withdrawal syndrome (NOWS); however, the understanding of long-term consequences of NOWS is limited. The objective of this study was to evaluate post-discharge healthcare utilization in infants with NOWS and examine the association between NOWS severity and healthcare utilization. A retrospective cohort design was used to ascertain healthcare utilization in the first year after birth-related discharge using the CERNER Health Facts® database. ICD-9/ICD-10 diagnostic codes were used to identify live births and to classify infants into two study groups: NOWS and uncomplicated births (a 25% random sample). Evaluated outcomes included rehospitalization, emergency department (ED) visits within 30-days and one-year after discharge, and a composite one-year utilization event (either hospitalization or emergency department visit during that year). NOWS severity was operationalized as pharmacologic treatment, length of hospitalization, and medical conditions often associated with NOWS. In 3,526 infants with NOWS (restricted to gestational age ≥ 33 weeks), NOWS severity was associated with an increase in composite one-year utilization (OR: 1.1; 95% CI: 1.04-1.2) after adjusting for prematurity, sepsis, jaundice, use of antibiotics, infant sex, insurance status, race, hospital bed size, year of birth, and census division. In a subset of full-term infants (3008 with NOWS and 88,452 uncomplicated births), having a NOWS diagnosis was associated with higher odds of a 30-day (OR: 1.6; 95% CI: 1.03-2.4) and one-year rehospitalization (OR: 1.6; 95% CI: 1.1-2.4) after adjusting for infant sex, race, type of medical insurance, hospital location, census division, year of primary encounter, hospital bed size, and medical conditions. This study found higher healthcare utilization during the first year of life in infants diagnosed with NOWS, especially those with severe NOWS. Findings suggest a need for closer post-discharge follow-up and management of infants with NOWS.

Prenatal Alcohol Exposure and Chorioamnionitis Results in Microstructural Brain Injury in a Preclinical Investigation.

BACKGROUND: Prenatal Alcohol Exposure (PAE) impacts 2% to 5% of infants born in the United States yearly. Women who consume alcohol during pregnancy have a five-fold increased rate of Chorioamnionitis (CHORIO). Both PAE and CHORIO cause microstructural injury to multiple brain regions including major white matter tracts. OBJECTIVE: Utilizing two previously established animal models, we hypothesized that the combination of PAE+CHORIO would result in greater deficits in myelination and structural integrity than PAE alone. MATERIAL AND METHODS: Pregnant Long-Evans rats voluntarily drank 5% ethanol or saccharin until Gestational Day 19 (GD). On GD19, CHORIO was induced in one group of PAE dams by a 30 min uterine artery occlusion and injection of Lipopolysaccharide (LPS) into each amniotic sac. The remaining PAE dams and saccharin controls underwent sham surgery. Pups were born on GD22 and weaned on Postnatal Day 24 (PD). On PD28, offspring were sacrificed, and their brains examined using ex-vivo Diffusion Tensor Imaging (DTI). RESULTS: Compared to control, PAE alone did not affect offspring birth weights, mortality or any DTI measures. In contrast, PAE+CHORIO significantly reduced offspring survival and, in surviving pups, increased Radial Diffusivity (RD) in medial frontal cortex and decreased Fractional Anisotropy (FA) in medial and ventral frontal cortex and within capsular regions. CONCLUSION: The combination of moderate PAE+CHORIO results in an increased mortality, concomitant with diffuse microstructural brain injury noted in young adolescent offspring at PD28. Future studies should examine the extent to which PAE exacerbates the damage caused by CHORIO alone and whether these deficits persist into adulthood.

Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity.

The increased incidence of opioid use during pregnancy warrants investigation to reveal the impact of opioid exposure on the developing fetus. Exposure during critical periods of development could have enduring consequences for affected individuals. Particularly, evidence is mounting that developmental injury can result in immune priming, whereby subsequent immune activation elicits an exaggerated immune response. This maladaptive hypersensitivity to immune challenge perpetuates dysregulated inflammatory signaling and poor health outcomes. Utilizing an established preclinical rat model of perinatal methadone exposure, we sought to investigate the consequences of developmental opioid exposure on in vitro activation of peripheral blood mononuclear cells (PBMCs). We hypothesize that PBMCs from methadone-exposed rats would exhibit abnormal chemokine and cytokine expression at baseline, with exaggerated chemokine and cytokine production following immune stimulation compared to saline-exposed controls. On postnatal day (P) 7, pup PMBCs were isolated and cultured, pooling three pups per n. Following 3 and 24 h, the supernatant from cultured PMBCs was collected and assessed for inflammatory cytokine and chemokine expression at baseline or lipopolysaccharide (LPS) stimulation using multiplex electrochemiluminescence. Following 3 and 24 h, baseline production of proinflammatory chemokine and cytokine levels were significantly increased in methadone PBMCs (p < 0.0001). Stimulation with LPS for 3 h resulted in increased tumor necrosis factor (TNF-α) and C-X-C motif chemokine ligand 1 (CXCL1) expression by 3.5-fold in PBMCs from methadone-exposed PBMCs compared to PBMCs from saline-exposed controls (p < 0.0001). Peripheral blood mononuclear cell hyperreactivity was still apparent at 24 h of LPS stimulation, evidenced by significantly increased TNF-α, CXCL1, interleukin 6 (IL-6), and IL-10 production by methadone PMBCs compared to saline control PBMCs (p < 0.0001). Together, we provide evidence of increased production of proinflammatory molecules from methadone PBMCs at baseline, in addition to sustained hyperreactivity relative to saline-exposed controls. Exaggerated peripheral immune responses exacerbate inflammatory signaling, with subsequent consequences on many organ systems throughout the body, such as the developing nervous system. Enhanced understanding of these inflammatory mechanisms will allow for appropriate therapeutic development for infants who were exposed to opioids during development. Furthermore, these data highlight the utility of this in vitro PBMC assay technique for future biomarker development to guide specific treatment for patients exposed to opioids during gestation.

Neonatal Hypoxic-Ischemic Encephalopathy Yields Permanent Deficits in Learning Acquisition: A Preclinical Touchscreen Assessment.

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a common problem world-wide for infants born at term. The impact of HIE on long-term outcomes, especially into adulthood, is not well-described. To facilitate identification of biobehavioral biomarkers utilizing a translational platform, we sought to investigate the impact of HIE on executive function and cognitive outcomes into adulthood utilizing a murine model of HIE. HIE mice (unilateral common carotid artery occlusion to induce ischemia, followed by hypoxia with a FiO2 of 0.08 for 45 min) and control mice were tested on discrimination and reversal touchscreen tasks (using their noses) shown to be sensitive to loss of basal ganglia or cortical function, respectively. We hypothesized that the HIE injury would result in deficits in reversal learning, revealing complex cognitive and executive functioning impairments. Following HIE, mice had a mild discrimination impairment as measured by incorrect responses but were able to learn the paradigm to similar levels as controls. During reversal, HIE mice required significantly more total trials, errors and correction trials across the paradigm. Analysis of specific stages showed that reversal impairments in HIE were driven by significant increases in all measured parameters during the late learning, striatal-mediated portion of the task. Together, these results support the concept that HIE occurring during the neonatal period results in abnormal neurodevelopment that persists into adulthood, which can impact efficient associated learning. Further, these data show that utilization of an established model of HIE coupled with touchscreen learning provides valuable information for screening therapeutic interventions that could mitigate these deficits to improve the long-term outcomes of this vulnerable population.

Prenatal opioid exposure: The next neonatal neuroinflammatory disease.

The rates of opioid use disorder during pregnancy have more than quadrupled in the last decade, resulting in numerous infants suffering exposure to opioids during the perinatal period, a critical period of central nervous system (CNS) development. Despite increasing use, the characterization and definition of the molecular and cellular mechanisms of the long-term neurodevelopmental impacts of opioid exposure commencing in utero remains incomplete. Thus, in consideration of the looming public health crisis stemming from the multitude of infants with prenatal opioid exposure entering school age, we undertook an investigation of the effects of perinatal methadone exposure in a novel preclinical model. Specifically, we examined the effects of opioids on the developing brain to elucidate mechanisms of putative neural cell injury, to identify diagnostic biomarkers and to guide clinical studies of outcome and follow-up. We hypothesized that methadone would induce a pronounced inflammatory profile in both dams and their pups, and be associated with immune system dysfunction, sustained CNS injury, and altered cognition and executive function into adulthood. This investigation was conducted using a combination of cellular, molecular, biochemical, and clinically translatable biomarker, imaging and cognitive assessment platforms. Data reveal that perinatal methadone exposure increases inflammatory cytokines in the neonatal peripheral circulation, and reprograms and primes the immune system through sustained peripheral immune hyperreactivity. In the brain, perinatal methadone exposure not only increases chemokines and cytokines throughout a crucial developmental period, but also alters microglia morphology consistent with activation, and upregulates TLR4 and MyD88 mRNA. This increase in neuroinflammation coincides with reduced myelin basic protein and altered neurofilament expression, as well as reduced structural coherence and significantly decreased fractional anisotropy on diffusion tensor imaging. In addition to this microstructural brain injury, adult rats exposed to methadone in the perinatal period have significant impairment in associative learning and executive control as assessed using touchscreen technology. Collectively, these data reveal a distinct systemic and neuroinflammatory signature associated with prenatal methadone exposure, suggestive of an altered CNS microenvironment, dysregulated developmental homeostasis, complex concurrent neural injury, and imaging and cognitive findings consistent with clinical literature. Further investigation is required to define appropriate therapies targeted at the neural injury and improve the long-term outcomes for this exceedingly vulnerable patient population.

Update on Erythropoiesis-Stimulating Agents Administered to Neonates for Neuroprotection.

Erythropoiesis-stimulating agents (ESAs) such as erythropoietin and darbepoetin have been studied as red blood cell growth factors in preterm and term infants for more than 30 years. Recently, studies have focused on the potential neuroprotective effects of ESAs. In this review, we summarize preclinical animal models and recent clinical trials that provide evidence for ESAs as potential treatments to improve neurodevelopmental outcomes in preterm and term infants.

Postnatal diagnosis of de novo complex der(8) in a boy with prenatal diagnosis of recombinant chromosome 8 syndrome.

Recombinant chromosome 8 syndrome is caused by duplication of 8q and deletion of 8p. A fetus with anomalies was misdiagnosed with this syndrome based on an amniocyte karyotype. Postnatal chromosomal microarray and other studies identified a de novo derivative chromosome 8. For fetal anomalies, detailed genetic studies may be required.

CXCR2 Blockade Mitigates Neural Cell Injury Following Preclinical Chorioamnionitis.

Minimizing central nervous system (CNS) injury from preterm birth depends upon identification of the critical pathways that underlie essential neurodevelopmental and CNS pathophysiology. While chorioamnionitis (CHORIO), is a leading cause of preterm birth, the precise mechanism linking prenatal brain injury and long-term CNS injury is unknown. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its cognate receptor, CXCR2, are implicated in a variety of uterine and neuropathologies, however, their role in CNS injury associated with preterm birth is poorly defined. To evaluate the putative efficacy of CXCR2 blockade in neural repair secondary to CHORIO, we tested the hypothesis that transient postnatal CXCR2 antagonism would reduce neutrophil activation and mitigate cerebral microstructural injury in rats. To this end, a laparotomy was performed on embryonic day 18 (E18) in Sprague Dawley rats, with uterine arteries transiently occluded for 60 min, and lipopolysaccharide (LPS, 4 µg/sac) injected into each amniotic sac. SB225002, a CXCR2 antagonist (3 mg/kg), was administered intraperitoneally from postnatal day 1 (P1)-P5. Brains were collected on P7 and P21 and analyzed with western blot, immunohistochemistry and ex vivo diffusion tensor imaging (DTI). Results demonstrate that transient CXCR2 blockade reduced cerebral neutrophil activation (myeloperoxidase expression/MPO) and mitigated connexin43 expression, indicative of reduced neuroinflammation at P7 (p < 0.05 for all). CXCR2 blockade also reduced alpha II-spectrin calpain-mediated cleavage, improved pNF/NF ratio, and minimized Iba1 and GFAP expression consistent with improved neuronal and axonal health and reduced gliosis at P21. Importantly, DTI revealed diffuse white matter injury and decreased microstructural integrity following CHORIO as indicated by lower fractional anisotropy (FA) and elevated radial diffusivity (RD) in major white matter tracts (p < 0.05). Early postnatal CXCR2 blockade also reduced microstructural abnormalities in white matter and hippocampus at P21 (p < 0.05). Together, these data indicate that transient postnatal blockade of CXCR2 ameliorates perinatal abnormalities in inflammatory signaling, and facilitates neural repair following CHORIO. Further characterization of neuroinflammatory signaling, specifically via CXCL1/CXCR2 through the placental-fetal-brain axis, may clarify stratification of brain injury following preterm birth, and improve use of targeted interventions in this highly vulnerable patient population.

Chorioamnionitis in Rats Precipitates Extended Postnatal Inflammatory Lymphocyte Hyperreactivity.

Preterm birth is an important cause of perinatal brain injury (PBI). Neurological injury in extremely preterm infants often begins in utero with chorioamnionitis (CHORIO) or inflammation/infection of the placenta and concomitant placental insufficiency. Studies in humans have shown dysregulated inflammatory signaling throughout the placental-fetal brain axis and altered peripheral immune responses in children born preterm with cerebral palsy (CP). We hypothesized that peripheral immune responses would be altered in our well-established rat model of CP. Specifically, we proposed that isolated peripheral blood mononuclear cells (PBMCs) would be hyperresponsive to a second hit of inflammation throughout an extended postnatal time course. Pregnant Sprague-Dawley dams underwent a laparotomy on embryonic day 18 (E18) with occlusion of the uterine arteries (for 60 min) followed by intra-amniotic injection of lipopolysaccharide (LPS, 4 µg/sac) to induce injury in utero. Shams underwent laparotomy only, with equivalent duration of anesthesia. Laparotomies were then closed, and the rat pups were born at E22. PBMCs were isolated from pups on postnatal day 7 (P7) and P21, and subsequently stimulated in vitro with LPS for 3 or 24 h. A secreted inflammatory profile analysis of conditioned media was performed using multiplex electrochemiluminescent immunoassays, and the composition of inflammatory cells was assayed with flow cytometry (FC). Results indicate that CHORIO PBMCs challenged with LPS are hyperreactive and secrete significantly more tumor necrosis factor α (TNFα) and C-X-C chemokine ligand 1 at P7. FC confirmed increased intracellular TNFα in CHORIO pups at P7 following LPS stimulation, in addition to increased numbers of CD11b/c immunopositive myeloid cells. Notably, TNFα secretion was sustained until P21, with increased interleukin 6, concomitant with increased expression of integrin ß1, suggesting both sustained peripheral immune hyperreactivity and a heightened activation state. Taken together, these data indicate that in utero injury primes the immune system and augments enhanced inflammatory signaling. The insidious effects of primed peripheral immune cells may compound PBI secondary to CHORIO and/or placental insufficiency, and thereby render the brain susceptible to future chronic neurological disease. Further understanding of inflammatory mechanisms in PBI may yield clinically important biomarkers and facilitate individualized repair strategies and treatments.

A Congenital Case of Ependymoblastoma: A Rare and Aggressive Brain Tumor.

Congenital brain tumors are rare, representing <2% of all childhood brain tumors. Of these, ependymoblastoma is a profoundly aggressive embryonal brain tumor that is included in the diagnostic entity known as an embryonal tumor with multilayered rosettes. This report of a congenital ependymoblastoma diagnosed at birth aims to highlight how much remains unknown about embryonal tumor with multilayered rosettes and the devastating prognosis of this condition. Despite recent advancements made in identifying molecular targets for therapy, this tumor continues to have a high rate of recurrence with few successful treatment options, especially when diagnosed in the newborn period.