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Background: Stress exposure in the neonatal intensive care unit (NICU) is associated with poor outcomes in preterm infants. However, factors predicting subsequent NICU stress exposure have not been identified. Purpose: To characterize NICU stressors experienced by preterm infants during the first 2 weeks of life and identify demographic, perinatal, and institutional variables associated with stress exposure. Methods: A secondary analysis of data from a nonexperimental, prospective study was conducted using data from 60 very preterm infants born 28 to 31 weeks gestational age. Stress exposures during the first 2 weeks of life, operationalized as number of invasive procedures, were characterized by type and quantity for each infant using data extracted from electronic health records. Associations between number of invasive procedures and demographic, perinatal, or institutional variables were analyzed using linear regressions with robust standard errors. Results: Preterm infants experienced, on average, 98 (SD = 41.8) invasive procedures. Of these invasive procedures, nasal and/or oral suctioning episodes (58.1%), followed by skin-breaking procedures (32.6%), were most frequent. Differences in the number of invasive procedures were found for maternal race; infants born to Black mothers experienced fewer total invasive procedures than infants born to White mothers. The number of invasive procedures also varied across NICUs. Implications for Practice and Research: Preterm infant stress exposure differed by maternal race and NICU, consistent with research findings of differential treatment of diverse infants. Further research is needed to understand the reasons for these differences and to identify best practices to standardize neonatal care. [ABSTRACT FROM AUTHOR]

Purpose: To characterize and quantify touch experienced by preterm infants in the NICU during essential nursing care, identify instances of skin-to-skin touch between infants and caregivers, and identify clinical/demographic variables associated with touch experiences. Design: Cross-sectional study. Sample: Preterm infants (N = 20) born 27–32 weeks post-menstrual age. Main Outcome Variable: Categories of touch during observations. Results: Touch experienced by infants during day and night shifts was primarily direct touch that was further categorized as general handling. During day shifts, 30 percent of direct touch was provided for comfort, but only 9.7 percent of touch was provided exclusively for comfort (i.e., without more intrusive touch). During night shifts, 10.6 percent of direct touch was provided for comfort, and 3 percent was categorized as exclusive comforting touch. Caregivers wore gloves for >89 percent of infant touch. Only the level of respiratory support was associated with touch categories during both shifts. [ABSTRACT FROM AUTHOR]

Objectives: Inflammation contributes to disparate neurodevelopmental outcomes between preterm and term-born infants. In this context, DNA methylation may contribute to inflammation by affecting gene expression. Brain-derived neurotrophic factor (BDNF) and nuclear factor-kappa-B-inhibitor alpha (NFKBIA) are important genes for targeted DNA methylation analysis. The aims of this study were to (1) identify associations between inflammatory factors and BDNF and NFKBIA methylation, and (2) identify associations between BDNF and NFKBIA methylation and early neurobehavior in preterm infants. Methods: In a longitudinal cohort study of preterm infants born 28–31 weeks gestational age, blood samples were collected weekly for the quantification of inflammatory factors. We extracted DNA from saliva samples and quantified methylation of six BDNF cytosine-phosphate-guanine (CpG) sites and five NFKBIA CpG sites. Neurobehavior was assessed using the Neurobehavioral Assessment of the Preterm Infant. Results: Sixty-five infants were included in the analysis. In females, inflammatory factors were positively associated with BDNF methylation of most CpG sites. Interleukin-1 receptor antagonist was negatively associated with NFKBIA methylation at two CpG sites. In males, interleukin-6 was negatively associated with BDNF and NFKBIA methylation at most CpG sites. In females, BDNF methylation at two sites was inversely associated with motor performance. In males, NFKBIA methylation at one site was inversely associated with motor performance. Conclusion: This study provides evidence for the relationship between inflammation and neurobehavior in preterm infants, working mechanistically through DNA methylation. The finding of a difference between males and females suggests that female infants are potentially more vulnerable to inflammation and warrants future study. [ABSTRACT FROM AUTHOR]

Background: Although the survival rate of very preterm infants has improved, rates of subsequent neurobehavioral disabilities remain high. One factor implicated in poor neurobehavioral and developmental outcomes is hospitalization and inconsistent caregiving patterns in the neonatal intensive care unit. Although much underlying brain damage occurs in utero or shortly after birth, neuroprotective strategies may stop progression of damage, particularly when these strategies are used during the most sensitive periods of neural plasticity 2-3 months before term age. Objective: The purpose of this analysis was to test the effect of a patterned feeding experience involving a tactile component (touch and/or holding) provided during feedings on preterm infants' clinical outcomes, measured by oral feeding progress, as an early indicator of neurodevelopment. Methods: We used an experimental, longitudinal, two-group random assignment design. Preterm infants (n = 120) were enrolled within the first week of life and randomized to an experimental group receiving a patterned feeding experience or to a control group receiving usual feeding care. Results: Analysis of data from 91 infants showed that infants receiving touch at more than 25% of early gavage feedings achieved full oral feeding more quickly; as touch exposure increased, time from first oral to full oral feeding decreased. There was no association between holding during early gavage feedings or touch during transition feedings and time to full oral feeding. Discussion: Neurological expectation during critical periods of development is important for infants. However, a preterm infant's environment is not predictable: Caregivers change regularly, medical procedures dictate touch and holding, and care provision based on infant cues is limited. Current knowledge supports caregiving that occurs with a naturally occurring sensation (i.e., hunger), is provided in a manner that is congruent with the expectation of the neurological system, and occurs with enough regularity to enhance neuronal and synaptic development. In this study, we modeled an experience infants would "expect" if they were not in the neonatal intensive care unit and demonstrated a shorter time from first oral feeding to full oral feeding, an important clinical outcome with neurodevelopmental implications. We recommend further research to determine the effect of patterned caregiving experiences on other areas of neurodevelopment, particularly those that may occur later in life. [ABSTRACT FROM AUTHOR]

Aims: (a) Determine relationships among stress exposure, inflammation, and neurodevelopment in very preterm infants and determine the mediated effect of inflammation on the relationship between stress exposure and neurodevelopment; (b) describe cytokine trajectories following birth and determine the effect of stress exposure on these trajectories; and (c) examine relationships between stress exposure and chronic stress responses in very preterm infants. Design: Non‐experimental, repeated measures. Methods: Very preterm infants born 28–31 weeks post menstrual age will be enrolled. Cumulative stress exposure over the first 14 days of life will be measured using the Neonatal Infant Stressor Scale. Blood will be collected weekly for the quantification of cytokines. Neurodevelopment will be assessed using the Neurobehavioral Assessment of the Preterm Infant and hair for quantification of hair cortisol will be collected at 35 weeks post menstrual age. Multiple linear regression and conditional process analysis will be used to analyse the relationships among stress exposure, inflammation and neurodevelopment. Linear mixed models will be used to determine inflammatory trajectories over time. IRB approval for the study was received May 2017, and funding from the National Institute of Nursing Research was awarded July 2017. Discussion: This study will determine the extent to which inflammation mediates the relationship between stress exposure and neurodevelopment. Interventions to attenuate inflammation in preterm infants may improve outcomes. Impact: Determining the potentially modifiable mediators of stress exposure and neurodevelopment in preterm infants is critical to improving long‐term outcomes. [ABSTRACT FROM AUTHOR]

Background: The use of functional connectivity magnetic resonance imaging (fcMRI) in research involving preterm infants is relatively new, and its feasibility in this population is not fully established. However, fcMRI images reveal functional neural connections that may be useful in establishing the mechanisms of neuroprotective interventions in preterm infants. Objective: The aim of this study was to determine the feasibility of using fcMRI to measure differences in functional neural connections in nursing intervention studies. Methods: A pilot study was conducted as part of a longitudinal, randomized controlled trial (RCT) testing the effect of a feeding intervention on neurodevelopmental and clinical outcomes of preterm infants randomly assigned to one of two groups: a patterned feeding experience (PFE) group and a usual feeding care (UFC) group. The fcMRIs were done at term-equivalent age. Visual, motor, and default mode networks were analyzed. Results: Seven infants were studied (four were in the PFE group, and three were in the UFC group). Participants were selected sequentially from the parent RCT. Clear images were obtained from all participants. Differences were noted among PFE and UFC infants: Infants receiving PFE were hyperconnective in the default mode (caudate, anterior cingulate cortex, and precuneus) and motor networks (middle temporal and middle occipital areas) and hypoconnective in others areas of the default mode (hippocampal and lingual regions) and motor networks (precentral and superior frontal cortices) relative to UFC infants. No differences were noted in visual networks. Discussion:The feasibility of using fcMRI at term-equivalent age in preterm infants who participated in an RCT on the effect of a nursing intervention was shown. Differences in connectivity among infants by group were detected. Further research is needed to show the benefit of fcMRI in studies of preterm infants given the costs of the procedure as well as the uncertain relationship of this early outcome measure to long-term neurodevelopment. [ABSTRACT FROM AUTHOR]

Preterm infants are at elevated risk for a host of neurodevelopmental problems, including disorders that appear later in life. Gene-environment interactions and prematurity may combine to increase the risk for poor neurodevelopmental outcomes. Increasing evidence supports a genetic link to risk for atypical development; however, no genomic risk profiles are currently used for infants without apparent genetic disorders. The purpose of this review was to synthesize recent evidence of genetic associations with atypical neurodevelopmental outcomes that may affect preterm infants who do not have a rare genetic disease. Electronic and hand-search strategies were used to find relevant articles that were English-language, peer-reviewed primary research or meta-analysis reports published between July 2009 and July 2014, involving human participants. Articles included in the analysis (N = 29) used a wide range of study designs and methodologies, complicating the analysis. An integrative-review design was used to synthesize the data. Numerous genes (n = 43) and additional large deletion copy number variants were associated with neurodevelopmental outcomes, including cognition, attention, perception, psychiatric disease, autism spectrum disorder, cerebral palsy, infant behavior, and alterations in brain architecture. The creation of genetic risk profiles for complex disorders of neurodevelopment is presently hindered by inconsistent genetic-association evidence, methodological considerations, reporting problems, and lack of replication. However, several avenues of investigation offer promise, including large (> 100 kb) copy number variants and the candidate genes MET, NRG3, and SLC6A4, each of which were reported to have associations with neurodevelopmental outcomes in multiple, high-quality studies. [ABSTRACT FROM AUTHOR]

Background: Neurobehavioral disabilities occur in 5-15% of preterm infants with an estimated 50-70% of very low birth weight preterm infants experiencing later dysfunction, including cognitive, behavioral, and social delays that often persist into adulthood. Factors implicated in poor neurobehavioral and developmental outcomes are hospitalization in the neonatal intensive care unit (NICU) and inconsistent caregiving patterns. Although much underlying brain damage occurs in utero or shortly after birth, neuroprotective strategies can stop lesions from progressing, particularly when these strategies are used during the most sensitive periods of neural plasticity occurring months before term age. The purpose of this randomized trial is to test the effect of a patterned feeding experience on preterm infants' neurobehavioral organization and development, cognitive function, and clinical outcomes. Methods: This trial uses an experimental, longitudinal, 2-group design with 120 preterm infants. Infants are enrolled within the first week of life and randomized to an experimental group receiving a patterned feeding experience from the first gavage feeding through discharge or to a control group receiving usual feeding care experience. The intervention involves a continuity of tactile experiences associated with feeding to train and build neuronal networks supportive of normal infant feeding experience. Primary outcomes are neurobehavioral organization as measured by Neurobehavioral Assessment of the Preterm Infant at 3 time points: the transition to oral feedings, NICU discharge, and 2 months corrected age. Secondary aims are cognitive function measured using the Bayley Scales of Infant and Toddler Development, Third Edition at 6 months corrected age, neurobehavioral development (sucking organization, feeding performance, and heart rate variability), and clinical outcomes (length of NICU stay and time to full oral feeding). The potential effects of demographic and biobehavioral factors (perinatal events and conditions of maternal or fetal/ newborn origin and immunologic and genetic biomarkers) on the outcome variables will also be considered. Discussion: Theoretically, the intervention provided at a critical time in neurologic system development and associated with a recurring event (feeding) should enhance neural connections that may be important for later development, particularly language and other cognitive and neurobehavioral organization skills. Trial registration: NCT01577615 11 April 2012. [ABSTRACT FROM AUTHOR]

Background: Preterm infants are at risk for impaired neurodevelopment. Inflammation may be an important modifiable mediator of preterm birth and neurodevelopmental impairment, but few studies have examined longitudinal measures of inflammation.Objective: To determine the relationship between longitudinal measures of inflammation and neurobehavior in very preterm infants.Study Design: Non-experimental, repeated measures cohort study.Methods: Very preterm infants were enrolled between October 2017 and December 2018. Blood was collected weekly until 35 weeks post-menstrual age for the quantification of plasma cytokines. Neurobehavior was assessed at 35 weeks post-menstrual age using the cluster scores for motor development and vigor and alertness/orientation from the Neurobehavioral Assessment of the Preterm Infant. Multiple linear regression models with robust standard errors were used to analyze the data. Average levels of individual cytokines, cytokine trends, and composite scores were used as measures of inflammation.Results: Seventy-three infants were enrolled in the study. Interleukin-1 receptor antagonist was associated with motor development and vigor scores. Interleukin-6 was associated with alertness/orientation scores. Tumor necrosis factor-alpha and composite scores of inflammation were associated with motor development and vigor and alertness/orientation scores. There were interactions with post-menstrual age at birth and infant sex.Conclusion: Inflammation may be an important predictor of short-term neurobehavior in preterm infants. Interleukin-1 receptor antagonist, interleukin-6, and tumor necrosis factor-alpha are key cytokines for studies of preterm infants, but composite scores may be a better measure of inflammation than individual cytokines. Inflammation can be damaging to the immature brain and may be a specific target for future interventions to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: Extended hospitalization in neonatal intensive care units subjects preterm infants to multiple stress exposures that affect long-term cognitive functioning, motor development, and stress reactivity. Measurement of stress exposure is challenging with multiple measures of stress exposure in use, including counts of skin-breaking or invasive procedures or counts of noxious sensory exposures. Objectives: The purpose of this analysis was to compare measures of stress exposure commonly used by researchers and to determine the predictive validity of these measures for early neurobehavior. We accomplished this objective through the following specific aims: (a) describe the stress exposures of preterm infants in the first 2 weeks of life, (b) determine the correlations among measures of stress exposure, and (c) compare the predictive validity of measures of stress exposure for early neurobehavior. Methods: Very preterm infants born between 28 and 31 weeks postmenstrual age were enrolled from four neonatal intensive care units in a large Midwest city. We measured stress exposure over the first 14 days of life for each infant as a count of skin-breaking procedures, a count of invasive procedures, and cumulative scores derived from the Neonatal Infant Stressor Scale. Neurobehavior was assessed at 35 weeks postmenstrual age using the motor development and vigor and alertness/orientation subscales from the Neurobehavioral Assessment of the Preterm Infant. We used Spearman's rho to determine correlations among the measures of stress exposure and multiple linear regression to determine the predictive validity of each stress exposure measure for neurobehavioral outcomes. Results: Seventy-one preterm infants were included in the analysis. We found marked variance across individuals in all measures of stress exposure. There were moderate-high correlations among the measures of stress exposure. No measure of stress exposure was associated with early neurobehavior. Discussion: The stress experiences of hospitalized preterm infants vary. This variance is reflected in all measures of stress exposure. Because measures of stress exposure are highly correlated, the most objective measure requiring the least interpretation should be used. However, the currently available measures of stress exposure used in this analysis may not reflect the infant's physiological stress responses and fail to associate with early neurobehavior. [ABSTRACT FROM AUTHOR]

Background: Inflammation may be an important predictor of long-term neurodevelopment in preterm infants. The identification of specific inflammatory biomarkers that predict outcomes is an important research goal. Objectives: The purpose of this analysis was to identify associations between an early measure of inflammation and neurodevelopment in very preterm infants and to identify differences in the relationship between inflammation and neurodevelopment based on infant gender and race. Methods: We conducted a secondary analysis of data from a randomized controlled trial of a caregiving intervention for preterm infants born less than 33 weeks postmenstrual age. Plasma was collected with a clinically indicated laboratory draw by neonatal intensive care unit nurses and analyzed by multiplex assay for cytokines, chemokines, and growth factors. Neurobehavior was assessed by research nurses at the time of discharge from the neonatal intensive care unit using the motor development and vigor and alertness/orientation clusters from the Neurobehavioral Assessment of the Preterm Infant. Neurodevelopment was assessed at 6 months corrected age by the developmental specialist in the hospital's neonatal follow-up clinic using the Bayley Scales of Infant Development, Third Edition. We used linear regressions to estimate the effect of cytokine levels on neurodevelopment and allowed the effects to differ by infant gender and race. Results: In a sample of 62 preterm infants with discharge neurobehavioral assessments and a sample of 40 preterm infants with 6-month neurodevelopmental assessments, we found inconsistent associations between single-time point inflammatory measures and neurobehavior or neurodevelopment in analyses of the total sample. However, regressions with interactions revealed effects for multiple inflammatory measures on early neurobehavior and neurodevelopment that differed by infant gender and race. Discussion: Although early single-time point measures of inflammation may be insufficient to predict neurodevelopment for all preterm infants, the effect of inflammation appears to differ by infant gender and race. These demographic factors may be important considerations for future studies of inflammation and neurodevelopment as well was the development of future interventions to optimize outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this study was to test a coding system, the Maternal–Infant Synchrony Scale (MISS), for assessing synchrony of feeding interaction between a mother and her preterm infant. The secondary aim was to describe mother and preterm infant synchrony during feeding and the change over time. Methods: A descriptive, longitudinal design using data collected during an earlier study was employed, using a sample dataset from 10 mother–infant dyads that completed three data collection points. The Noldus Observer XT 8.0 (Noldus Information Technology b.v., 2006) was used for data review and coding. The MISS was created from pilot data and definitions further refined. The frequency of occurrence for select behaviors and the percentage of time behaviors occurred during the feeding and the changes in behaviors over the three observations periods were calculated. Results: The synchrony tool developed in this study demonstrates that changes occur in mother and infant behavior over time. Mothers were attentive and focused during feedings and monitored their infants’ sucking intently but there was little interaction between the dyad. Infant attempts at interaction were greater than the mother attempts to engage her infant. The influence of infant maturation on feeding behaviors was evident across observations. Conclusion: This study revealed behaviors that are descriptive of the interaction and can be used to develop interventions that would support the developing relationship. Use of the MISS with a larger sample size and a cohort of healthy, term newborns is needed to establish the MISS as a valid and reliable measure of synchrony. [Copyright &y& Elsevier]

Background: Hair cortisol is a measure of chronic or repeated hypothalamic--pituitary--adrenal axis activation in response to physical or psychological stressors. Hair cortisol has been successfully used as a measure of chronic stress in adults and children; however, its use as a valid measure in preterm infants has been limited by challenges in measuring cortisol in the low mass samples collectable from these infants. Objectives: The purpose of this report is to present a novel protocol for the measurement of hair cortisol in very low mass hair samples. Methods: Small changes were made to previously published protocols. After washing and pulverizing the hair samples, a double methanol cortisol extraction was performed. Samples were spiked with a known quantity of cortisol and analyzed in duplicate using an enzyme-linked immunosorbent assay. Results: Hair cortisol was detectable in samples weighing between 0.4 and 10.9 mg. The mean cortisol level was 23.74 pg/mg hair (SD = 26.38). Discussion: With small changes to previously published laboratory protocols, cortisol is quantifiable in low mass hair samples from preterm infants. This technical advance is an important step toward quantifying the stress experiences of hospitalized preterm infants. [ABSTRACT FROM AUTHOR]