Predicting Extubation Readiness in Preterm Infants Utilizing Machine Learning: A Diagnostic Utility Study.

OBJECTIVE: The objective of this study was to predict extubation readiness in preterm infants using machine learning analysis of bedside pulse oximeter and ventilator data. STUDY DESIGN: This is an observational study with prospective recordings of oxygen saturation (SpO2) and ventilator data from infants <30 weeks of gestation age. Research pulse oximeters collected SpO2 (1 Hz sampling rate) to quantify intermittent hypoxemia (IH). Continuous ventilator metrics were collected (4-5-minute sampling) from bedside ventilators. Data modeling was completed using unbiased machine learning algorithms. Three model sets were created using the following data source combinations: (1) IH and ventilator (IH + SIMV), (2) IH, and (3) ventilator (SIMV). Infants were also analyzed separated by postnatal age (infants <2 or ≥2 weeks of age). Models were compared by area under the receiver operating characteristic curve (AUC). RESULTS: A total of 110 extubation events from 110 preterm infants were analyzed. Infants had a median gestation age and birth weight of 26 weeks and 825 g, respectively. Of the 3 models presented, the IH + SIMV model achieved the highest AUC of 0.77 for all infants. Separating infants by postnatal age increased accuracy further achieving AUC of 0.94 for <2 weeks of age group and AUC of 0.83 for ≥2 weeks group. CONCLUSIONS: Machine learning analysis has the potential to enhance prediction accuracy of extubation readiness in preterm infants while utilizing readily available data streams from bedside pulse oximeters and ventilators.

The impact of intermittent hypoxemia on type 1 retinopathy of prematurity in preterm infants.

BACKGROUND: Intermittent hypoxemia (IH) may influence retinopathy of prematurity (ROP) development in preterm infants, however, previous studies had mixed results. This study tests the hypothesis that increased IH is associated with Type 1 ROP; a stage beyond which treatment is indicated. METHODS: IH was quantified by continuously monitoring oxygen saturation (SpO2) using high-resolution pulse oximeters during the first 10 weeks of life. Statistical analyses assessed the relationship and predictive ability of weekly and cumulative IH for Type 1 ROP development. RESULTS: Most analyses showed no association between IH and Type 1 ROP adjusting for gestational age (GA) and birth weight (BW). However, cumulative IH of longer duration during weeks 5-10, 6-10, and 7-10 were significantly associated with Type 1 ROP adjusting for GA and BW, e.g., the adjusted odds ratio of Type 1 ROP was 2.01 (p = 0.03) for every 3.8 seconds increase in IH duration from week 6-10. IH did not provide statistically significant added predictive ability above GA and BW. CONCLUSIONS: For most analyses there was no significant association between IH and Type 1 ROP adjusting for GA and BW. However, infants with longer IH duration during the second month of life had higher risk for Type 1 ROP. IMPACT: The relationship and predictive ability of intermittent hypoxemia (IH) on retinopathy of prematurity (ROP) is controversial. This study shows no significant association between IH events and Type 1 ROP after adjusting for gestational age (GA) and birth weight (BW), except for cumulative IH of longer duration in the second month of life. In this cohort, IH does not provide a statistically significant improvement in ROP prediction over GA and BW. This study is the first to assess the cumulative impact of IH measures on Type 1 ROP. Interventions for reducing IH duration during critical postnatal periods may improve ROP outcomes.

Wearable fiber-free optical sensor for continuous monitoring of neonatal cerebral blood flow and oxygenation.

BACKGROUND: Unstable cerebral hemodynamics places preterm infants at high risk of brain injury. We adapted an innovative, fiber-free, wearable diffuse speckle contrast flow-oximetry (DSCFO) device for continuous monitoring of both cerebral blood flow (CBF) and oxygenation in neonatal piglets and preterm infants. METHODS: DSCFO uses two small laser diodes as focused-point and a tiny CMOS camera as a high-density two-dimensional detector to detect spontaneous spatial fluctuation of diffuse laser speckles for CBF measurement, and light intensity attenuations for cerebral oxygenation measurement. The DSCFO was first validated against the established diffuse correlation spectroscopy (DCS) in neonatal piglets and then utilized for continuous CBF and oxygenation monitoring in preterm infants during intermittent hypoxemia (IH) events. RESULTS: Significant correlations between the DSCFO and DCS measurements of CBF variations in neonatal piglets were observed. IH events induced fluctuations in CBF, cerebral oxygenation, and peripheral cardiorespiratory vitals in preterm infants. However, no consistent correlation patterns were observed among peripheral and cerebral monitoring parameters. CONCLUSIONS: This pilot study demonstrated the feasibility of DSCFO technology to serve as a low-cost wearable sensor for continuous monitoring of multiple cerebral hemodynamic parameters. The results suggested the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations. IMPACT: The innovative DSCFO technology may serve as a low-cost wearable sensor for continuous bedside monitoring of multiple cerebral hemodynamic parameters in neonatal intensive care units. Concurrent DSCFO and DCS measurements of CBF variations in neonatal piglet models generated consistent results. No consistent correlation patterns were observed among peripheral and cerebral monitoring parameters in preterm neonates, suggesting the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations during IH events. Integrating and correlating multiple cerebral functional parameters with clinical outcomes may identify biomarkers for prediction and management of IH associated brain injury.

The Trend of Urinary N Terminal Probrain Natriuretic Peptide in Extremely Low Birth Weight Infants during the Neonatal Period.

OBJECTIVE: N-terminal probrain natriuretic peptide (NT-proBNP) is a biomarker of interest in many cardiopulmonary diseases in extremely low birth weight (ELBW) Infants. However, there is a gap in knowledge about the trend of ELBW infant's urinary NT-proBNP during the neonatal period. AIM: To determine the trend of urinary NT-proBNP during the first 4 weeks of life of an ELBW infant. STUDY DESIGN: We analyzed prospectively enrolled 87 ELBW infants. Urinary NT-proBNP to creatinine ratios were measured on days 1 to 7, 14, and 28 of life. We plotted each study point's means to determine the trend of urinary NT-proBNP over the entire neonatal period. Data were analyzed using the Friedman analysis of variance for comparative analysis of study points. RESULTS: Urinary NT-proBNP/creatinine ratios were significantly elevated on days 1 to 7 (mean 2,452, ± 1,518) than day 14 (mean 747, ± 176), and day 28 (mean 149, ± 54), p = 0.001. Overall, urinary NT-proBNP levels were highest during days 1 to 3 (mean 3,232, ± 1,255) and lowest on day 28 (mean 149, ± 54). CONCLUSION: Urinary NT-proBNP levels are higher during the first week in ELBW infants with a downward trend during the neonatal period, the lowest values at 4 weeks postnatal age. More studies are required to determine the clinical utility of this trend during and beyond the neonatal period. KEY POINTS: · NT-proBNP is a biomarker for monitoring cardiac disease in premature infants.. · The trend of urinary NT-proBNP is unknown in premature infants.. · A trend of urinary NT-proBNP was determined during the first 4 weeks in premature infants..

Noninvasive noncontact speckle contrast diffuse correlation tomography of cerebral blood flow in rats.

Continuous and longitudinal imaging of cerebral blood flow (CBF) variations provide vital information to investigate pathophysiology and interventions for a variety of neurological and cerebral diseases. An innovative noncontact speckle contrast diffuse correlation tomography (scDCT) system was downscaled and adapted for noninvasive imaging of CBF distributions in rat brain through intact scalp and skull. Algorithms for 2D mapping and 3D image reconstruction of CBF distributions were developed and optimized. The continuous imaging capability of the system was shown by imaging global CBF increases during CO2 inhalations and regional CBF decreases across two hemispheres during sequential unilateral and bilateral common carotid artery ligations. The longitudinal imaging capability was demonstrated by imaging CBF variations over a long recovery period of 14 days after an acute stroke. Compared to the 2D mapping method, the 3D imaging method reduces partial volume effects, but needs more computation time for image reconstruction. Results from this study generally agree with those reported in the literature using similar protocols to induce CBF changes in rats. The scDCT enables a relatively large penetration depth (up to ∼10 mm), which is sufficient for transcranial brain measurements in small animals and human neonates. Ultimately, we expect to provide a noninvasive noncontact cerebral imager for basic neuroscience research in small animal models and clinical applications in human neonates.

A Wearable Fiberless Optical Sensor for Continuous Monitoring of Cerebral Blood Flow in Mice.

Continuous and longitudinal monitoring of cerebral blood flow (CBF) in animal models provides information for studying the mechanisms and interventions of various cerebral diseases. Since anesthesia may affect brain hemodynamics, researchers have been seeking wearable devices for use in conscious animals. We present a wearable diffuse speckle contrast flowmeter (DSCF) probe for monitoring CBF variations in mice. The DSCF probe consists of a small low-power near-infrared laser diode as a point source and an ultra-small low-power CMOS camera as a 2D detector array, which can be affixed on a mouse head. The movement of red blood cells in brain cortex (i.e., CBF) produces spatial fluctuations of laser speckles, which are captured by the camera. The DSCF system was calibrated using tissue phantoms and validated in a human forearm and mouse brains for continuous monitoring of blood flow increases and decreases against the established technologies. Significant correlations were observed among these measurements (R2 ≥ 0.80, p < 10-5). This small fiberless probe has the potential to be worn by a freely moving conscious mouse. Moreover, the flexible source-detector configuration allows for varied probing depths up to ~8 mm, which is sufficient for transcranially detecting CBF in the cortices of rodents and newborn infants.

Blood transfusions in preterm infants: changes on perfusion index and intermittent hypoxemia.

BACKGROUND: Red blood cell (RBC) transfusion decreases intermittent hypoxemia (IH) events beyond the first week of life. This benefit may be related to improved perfusion to the respiratory control network. Perfusion index (PI) is a perfusion measure provided by the pulse oximeter. We hypothesized that the benefit in IH after RBC transfusion is associated with an increase in PI. In addition, we assessed the value of PI and clinical measures in predicting the effect of RBC transfusion on IH. STUDY DESIGN AND METHODS: We prospectively enrolled infants less than 30 weeks' gestation age. PI and oxygen saturation (SpO2 ) were monitored with high-resolution pulse oximeters 24 hours before and after RBC transfusion. Data were analyzed at three postnatal periods: Epoch 1, first week of life (1 to 7 days of life); Epoch 2, 2 to 4 weeks of life (8 to 28 days of life); and Epoch 3, 4 to 8 weeks of life. RESULTS: A total of 118 transfusions were analyzed. IH measures significantly decreased after transfusion in Epochs 2 and 3. PI significantly increased after transfusion, but it did not correlate with the decrease in IH measures. Mechanical ventilation, fraction of inspired oxygen (FiO2 ), and IH measures influenced the effects on oxygenation. CONCLUSIONS: RBC transfusion improved IH after the first week of life. The benefit in IH did not correlate with PI increase after transfusion. Pretransfusion respiratory support and IH measures predicted the effect of transfusion on oxygenation.

Vitamin E in the Preterm Infant: A Forgotten Cause of Hemolytic Anemia.

OBJECTIVE: Vitamin E deficiency in premature infants has been associated with hemolytic anemia. Its incidence decreased after the supplementation of preterm formulas and parenteral nutrition with vitamin E. Despite this, some infants still develop hemolytic anemia and receive vitamin E. STUDY DESIGN: Retrospective analysis of 70 infants admitted to a level IV intensive care unit and who developed hemolytic anemia and were treated with vitamin E. Infants were classified into two groups based on whether or not they responded to vitamin E therapy. Statistical methods included the use of descriptive statistics and marginal logistic regression models. RESULTS: Low hematocrit and reticulocytosis before vitamin E administration were associated with adequate response to treatment. Thrombocytosis, iron treatment (duration and dose), gestational age, birth weight, and type of feedings were not. Infants who received a short duration of parenteral nutrition and were on oxygen responded to vitamin E therapy. Infants with a hematocrit ≤ 26% and reticulocyte of 36.1% were more likely to respond to vitamin E. CONCLUSION: Although formulas and parenteral nutrition are supplemented with vitamin E; some preterm infants may still develop hemolytic anemia. Those with anemia, reticulocytosis, and oxygen requirement may benefit from additional vitamin E.

Relationship between perfusion index and patent ductus arteriosus in preterm infants.

BACKGROUND: Perfusion index (PI) is a noninvasive measure of perfusion. ΔPI (difference between pre- and postductal PI) may identify hemodynamically significant PDA. However, studies are limited to brief and intermittent ΔPI sampling. Our objective is to assess the value of continuous high resolution ΔPI monitoring in the diagnosis of PDA. METHODS: Continuous ΔPI monitoring in preterm infants was prospectively performed using two high-resolution pulse oximeters. Perfusion Index measures (ΔPI mean and variability, pre- and postductal PI) were analyzed over a 4-h period prior to echocardiography. A cardiologist blinded to the results evaluated for PDA on echocardiography. Linear mixed regression models were utilized for analyses. RESULTS: We obtained 31 echocardiography observations. Mean ΔPI (-0.23 vs. 0.16; P < 0.05), mean pre-PI (0.86 vs. 1.26; P < 0.05), and ΔPI variability (0.39 vs. 0.61; P = 0.05) were lower in infants with PDA compared to infants without PDA at the time of echocardiography. CONCLUSION: Mean ΔPI, ΔPI variability, and mean pre-PI measured 4 h prior to echocardiography detect PDA in preterm infants. PI is dynamic and should be assessed continuously. Perfusion index is a promising bedside measurement to identify PDA in preterm infants.

Effects of prenatal substance exposure on infant temperament vary by context.

This was a prospective longitudinal multisite study of the effects of prenatal cocaine and/or opiate exposure on temperament in 4-month-olds of the Maternal Lifestyle Study (N = 958: 366 cocaine exposed, 37 opiate exposed, 33 exposed to both drugs, 522 matched comparison). The study evaluated positivity and negativity during The Behavior Assessment of Infant Temperament (Garcia Coll et al., 1988). Parents rated temperament (Infant Behavior Questionnaire; Rothbart, 1981). Cocaine-exposed infants showed less positivity overall, mainly during activity and threshold items, more negativity during sociability items, and less negativity during irritability and threshold items. Latent profile analysis indicated individual temperament patterns were best described by three groups: low/moderate overall reactivity, high social negative reactivity, and high nonsocial negative reactivity. Infants with heavy cocaine exposure were more likely in high social negative reactivity profile, were less negative during threshold items, and required longer soothing intervention. Cocaine- and opiate-exposed infants scored lower on Infant Behavior Questionnaire smiling and laughter and duration of orienting scales. Opiate-exposed infants were rated as less respondent to soothing. By including a multitask measure of temperament we were able to show context-specific behavioral dysregulation in prenatally cocaine-exposed infants. The findings indicate flatter temperament may be specific to nonsocial contexts, whereas social interactions may be more distressing for cocaine-exposed infants.

Maternal race, demography, and health care disparities impact risk for intraventricular hemorrhage in preterm neonates.

OBJECTIVE: To determine whether risk factors associated with grade 2-4 intraventricular hemorrhage (IVH) differs between infants of African ancestry and white infants. STUDY DESIGN: Inborn, appropriate for gestational age infants with birth weight 500-1250 g and exposure to at least 1 dose of antenatal steroids were enrolled in 24 neonatal intensive care units. Cases had grade 2-4 IVH and controls matched for site, race, and birth weight range had 2 normal ultrasounds read centrally. Multivariate logistic regression modeling identified factors associated with IVH across African ancestry and white race. RESULTS: Subjects included 579 African ancestry or white race infants with grade 2-4 IVH and 532 controls. Mothers of African ancestry children were less educated, and white case mothers were more likely to have more than 1 prenatal visit and multiple gestation (P ≤ .01 for all). Increasing gestational age (P = .01), preeclampsia (P < .001), complete antenatal steroid exposure (P = .02), cesarean delivery (P < .001), and white race (P = .01) were associated with decreased risk for IVH. Chorioamnionitis (P = .01), 5-minute Apgar score <3 (P < .004), surfactant use (P < .001), and high-frequency ventilation (P < .001) were associated with increased risk for IVH. Among African ancestry infants, having more than 1 prenatal visit was associated with decreased risk (P = .02). Among white infants, multiple gestation was associated with increased risk (P < .001), and higher maternal education was associated with decreased risk (P < .05). CONCLUSION: The risk for IVH differs between infants of African ancestry and white infants, possibly attributable to both race and health care disparities.

Death or neurodevelopmental impairment at 18 to 22 months corrected age in a randomized trial of early dexamethasone to prevent death or chronic lung disease in extremely low birth weight infants.

OBJECTIVE: To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants. STUDY DESIGN: Evaluation of infants at 18-22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index and the Psychomotor Developmental Index. NDI was defined as moderate or severe cerebral palsy, Mental Developmental Index or Psychomotor Developmental Index <70, blindness, or hearing impairment. RESULTS: Death or NDI at 18-22 months corrected age was similar in the dexamethasone and placebo groups (65% vs 66%, P = .99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50% vs 41%, P = .42 for weight less than 10th percentile); 49% of infants in the placebo group received treatment with corticosteroid compared with 32% in the dexamethasone group (P = .02). CONCLUSION: The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.

Neonatal Abstinence Signs during Treatment: Trajectory, Resurgence and Heterogeneity.

Neonatal abstinence syndrome (NAS) presents with a varying severity of withdrawal signs and length of treatment (LOT). We examined the course and relevance of each of the NAS withdrawal signs during treatment in a sample of 182 infants with any prenatal opioid exposure, gestational age ≥ 35 weeks, without other medical conditions, and meeting the criteria for pharmacological treatment. Infants were monitored using the Finnegan Neonatal Abstinence Scoring Tool. Daily mean Finnegan scores were estimated using linear mixed models with random subject effects to account for repeated withdrawal scores from the same subject. Daily item prevalence was estimated using generalized estimating equations with a within-subject exchangeable correlation structure. The median LOT was 12.86 days. The prevalence of withdrawal signs decreased from day one to day three of treatment. However, certain central nervous system (CNS) and gastrointestinal (GI) signs showed sporadic increases in prevalence notable around two weeks of treatment, accounting for increases in Finnegan scores that guided pharmacotherapy. We question whether the resurgence of signs with a prolonged LOT is mainly a consequence of opioid tolerance or withdrawal. Monitoring CNS and GI signs throughout treatment is crucial. Future studies directed to better understand this clinical phenomenon may lead to the refining of NAS pharmacotherapy and perhaps the discovery of treatment alternatives.

A Wearable Fiber-Free Optical Sensor for Continuous Monitoring of Neonatal Cerebral Blood Flow and Oxygenation.

Impact: The innovative DSCFO technology may serve as a low-cost wearable sensor for continuous bedside monitoring of multiple cerebral hemodynamic parameters in neonatal intensive care units.Concurrent DSCFO and DCS measurements of CBF variations in neonatal piglet models generated consistent results.No consistent correlation patterns were observed among peripheral and cerebral monitoring parameters in preterm neonates, suggesting the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations during IH events.Integrating and correlating multiple cerebral functional parameters with clinical outcomes may identify biomarkers for prediction and management of IH associated brain injury. Background: Unstable cerebral hemodynamics places preterm infants at high risk of brain injury. We adapted an innovative, fiber-free, wearable diffuse speckle contrast flow-oximetry (DSCFO) device for continuous monitoring of both cerebral blood flow (CBF) and oxygenation in neonatal piglets and preterm infants. Methods: DSCFO uses two small laser diodes as focused-point and a tiny CMOS camera as a high-density two-dimensional detector to detect spontaneous spatial fluctuation of diffuse laser speckles for CBF measurement, and light intensity attenuations for cerebral oxygenation measurement. The DSCFO was first validated against the established diffuse correlation spectroscopy (DCS) in neonatal piglets and then utilized for continuous CBF and oxygenation monitoring in preterm infants during intermittent hypoxemia (IH) events. Results: Consistent results between the DSCFO and DCS measurements of CBF variations in neonatal piglets were observed. IH events induced fluctuations in CBF, cerebral oxygenation, and peripheral cardiorespiratory vitals in preterm infants. However, no consistent correlation patterns were observed among peripheral and cerebral monitoring parameters. Conclusions: This pilot study demonstrated the feasibility of DSCFO technology to serve as a low-cost wearable sensor for continuous monitoring of multiple cerebral hemodynamic parameters. The results suggested the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations.

The Impact of Intermittent Hypoxemia on Type 1 Retinopathy of Prematurity in Preterm Infants.

Background: Intermittent hypoxemia (IH) may influence retinopathy of prematurity (ROP) development in preterm infants, however, previous studies had mixed results. This study aims to assess the influence and evaluate the predictive ability of IH measures on Type 1 ROP, a stage beyond which ROP treatment is indicated. Methods: IH was quantified by continuously monitoring oxygen saturation (SpO2) using high-resolution pulse oximeters during the first 10 weeks of life. Statistical analyses assessed the relationship and predictive ability of weekly and cumulative IH variables for Type 1 ROP development. Results: Univariate analyses suggested that IH measures are greater in infants with Type 1 ROP and are predictive of Type 1 ROP development. Multivariable logistic regression analyses revealed that cumulative IH of longer duration during certain postnatal periods are associated with Type 1 ROP development after adjusting for gestational age (GA) or birth weight (BW). Although area under the curve (AUC) analyses revealed added predictivity of cumulative IH variables above GA or BW, these increments in AUC were not statistically significant. Conclusions: The duration of IH events was associated with Type 1 ROP development. Interventions for reducing the duration of IH events may potentially improve ROP outcomes.

Consequences of prenatal substance use.

BACKGROUND: Prenatal substance use is a major public health problem and a social morbidity, with consequences on the drug user and the offspring. OBJECTIVE: This review focuses on the child and adolescent outcomes following in utero drug exposure. METHODS: Studies on the effects of specific substances, legal and illegal; i.e., tobacco or nicotine, alcohol, marijuana, cocaine, opiates, and methamphetamine were evaluated and analyzed. RESULTS: In general, manifestations of prenatal exposure to legal and illegal substances include varying deficits in birth anthropometric measurements, mild-to-moderate transient neurobehavioral alterations in infancy and long-term behavioral problems noted from early childhood to adolescence. Severity of expression of behavioral problems is influenced by environmental factors. Further, behavioral alterations following in utero drug exposure often exist with mental health co-morbidities. CONCLUSION: Because of the long-term consequences of prenatal drug exposure on child and adolescent mental health, health providers need to promote substance use prevention, screen for exposure effects and provide or refer affected youths for intervention services. Preventive measures and treatment should consider other factors that may further increase the risk of psychopathology in the exposed children.

Assessment of the relative clinical utility of shortened Finnegan neonatal abstinence scoring tools.

OBJECTIVE: To assess the proposed shortened tools based on the Finnegan neonatal abstinence scoring tool (FNAS) for relative clinical utility. STUDY DESIGN: Retrospective study comparing shortened tools with FNAS on need for treatment, medication initiation cutoff score agreement, and length of treatment in 369 infants with prenatal opioid exposure using estimated areas under the receiver operating characteristic curves, Pearson and Spearman correlations, and proportion correctly classified, sensitivity, and specificity. RESULTS: The tools by Gomez et al. and Chervoneva et al. are most predictive of the FNAS cut-off values to initiate treatment, have cutoff values that best align with the FNAS cutoff values, and strongly correlate with the FNAS (r ≥ 0.88 corresponding to treatment initiation, r ≥ 0.83 during first 10 days of treatment). CONCLUSION: The tools of Gomez and Chervoneva demonstrated potential clinical usefulness by strongly associating with the need for treatment and monitoring the course of NAS therapy.

Understanding the effects of opioids vs non-opioids in the treatment of neonatal abstinence syndrome, an in vitro model.

Neonatal abstinence syndrome (NAS) refers to cadre of withdrawal manifestations in infants born to mothers who used illicit and licit substances during pregnancy. The increasing prevalence of NAS has been largely due to the maternal use of opioids during pregnancy. NAS contributes to increased morbidity and long-term disability in surviving infants. Clinically, oral opioid therapies for opioid exposure have been a standard treatment with morphine (MO) being the most commonly used medication. Recently, a non-opioid agent, clonidine (CD) has also been used with potentially favorable short- and long-term outcomes in infants. However, data regarding the cellular and molecular effects of these treatments on the developing brain is still lacking due to a lack of a reliable animal model that targets the neonatal brain. To address this gap in knowledge we determined the effects of MO or CD on the cell death of neonatal cortical explant cultures that were exposed to oxycodone (OXY) in utero. Sprague Dawley rats were randomized and implanted with programmable infusion pumps before mating to receive either the OXY (dose increasing from 1.21-1.90 mg/kg/day to a maximum dose of 2.86-3.49 mg/kg/day) or normal saline (NS) throughout pregnancy and until one week after delivery. Male and female rat pups were sacrificed on postnatal day 4, and the prefrontal cortex (PFC) and hippocampus (HC) were dissected and treated with MO (0.10-1.00 µM) or CD (1.20-120.00 µM) in culture media. After 5 days of treatment the explants were labeled with propidium iodide to detect cell death. Dead cells were analyzed and counted under fluorescence microscopy. In explants from the PFC, cell death was greater in those prenatally exposed to OXY and postnatally treated with MO (OXY/MO) (736.8 ± 76.5) compared to OXY/CD (620.9 ± 75.0; p = 0.005). In the HC explants, mean cell death counts were not significantly different between groups regardless of prenatal exposure or postnatal treatment (p = 0.19). The PFC is vital in controlling higher-order executive functions such as behavioral flexibility, learning and working memory. Therefore, our finding is consistent with executive function problems in children with prenatal opioid exposure.

Long-term impact of maternal substance use during pregnancy and extrauterine environmental adversity: stress hormone levels of preadolescent children.

Prenatal cocaine exposure (PCE) is associated with blunted stress responsivity within the extrauterine environment. This study investigated the association between PCE and diurnal salivary cortisol levels in preadolescent children characterized by high biological and/or social risk (n = 725). Saliva samples were collected at their home. Analyses revealed no group differences in basal evening or morning cortisol levels; however, children with higher degrees of PCE exhibited blunted overnight increases in cortisol, controlling for additional risk factors. Race and caregiver depression were also associated with diurnal cortisol patterns. Although repeated PCE may contribute to alterations in the normal or expected stress response later in life, sociodemographic and environmental factors are likewise important in understanding hormone physiology, especially as more time elapses from the PCE. Anticipating the potential long-term medical, developmental, or behavioral effects of an altered ability to mount a normal protective cortisol stress response is essential in optimizing the outcomes of children with PCE.

The combined effects of prenatal drug exposure and early adversity on neurobehavioral disinhibition in childhood and adolescence.

The negative effects of prenatal substance exposure on neurobiological and psychological development and of early adversity are clear, but little is known about their combined effects. In this study, multilevel analyses of the effects of prenatal substance exposure and early adversity on the emergence of neurobehavioral disinhibition in adolescence were conducted. Neurobehavioral disinhibition has previously been observed to occur frequently in multiproblem youth from high-risk backgrounds. In the present study, neurobehavioral disinhibition was assessed via behavioral dysregulation and poor executive function composite measures. Data were drawn from a prospective longitudinal investigation of prenatal substance exposure that included 1,073 participants followed from birth through adolescence. The results from latent growth modeling analyses showed mean stability but significant individual differences in behavioral dysregulation and mean decline with individual differences in executive function difficulties. Prior behavioral dysregulation predicted increased executive function difficulties. Prenatal drug use predicted the emergence and growth in neurobehavioral disinhibition across adolescence (directly for behavioral dysregulation and indirectly for executive function difficulties via early adversity and behavioral dysregulation). Prenatal drug use and early adversity exhibited unique effects on growth in behavioral dysregulation; early adversity uniquely predicted executive function difficulties. These results are discussed in terms of implications for theory development, social policy, and prevention science.