Preterm-born Neonates Research Articles

Neonatal Exhaled Breath Sampling for Infrared Spectroscopy: Biomarker Analysis.

Monitoring health conditions in neonates for early therapeutic intervention in case deviations from physiological conditions is crucial for their long-term development. Due to their immaturity preterm born neonates are dependent on particularly careful physical and neurological diagnostic methods. Ideally, these should be noninvasive, noncontact, and radiation free. Infrared spectroscopy was used to analyze exhaled breath from 71 neonates with a special emphasis on preterm infants, as a noninvasive, noncontact, and radiation-free diagnostic tool. Passive sample collection was performed by skilled clinicians. Depending on the mode of respiratory support of infants, four different sampling procedures were adapted to collect exhaled breath. With the aid of appropriate reference samples, infrared spectroscopy has successfully demonstrated its effectiveness in the analysis of breath samples of neonates. The discernible increase in concentrations of carbon dioxide, carbon monoxide, and methane in collected samples compared to reference samples served as compelling evidence of the presence of exhaled breath. With regard to technical hurdles and sample analysis, samples collected from neonates without respiratory support proved to be more advantageous compared to those obtained from intubated infants and those with CPAP (continuous positive airway pressure). The main obstacle lies in the significant dilution of exhaled breath in the case of neonates receiving respiratory support. Metabolic analysis of breath samples holds promise for the development of noninvasive biomarker-based diagnostics for both preterm and sick neonates provided an adequate amount of breath is collected.

Developmental pattern of individual morphometric similarity network in the human fetal brain

The development of the cerebral cortex during the fetal period is a complex yet well-coordinated process. MRI-based morphological brain network provides a powerful tool for describing this process at a network level. Due to the challenges of in-utero MRI acquisition and image processing, the fetal morphological brain network has not been established. In this study, utilizing high-resolution in-utero MRI data, we constructed an individual morphometric similarity network for each fetus based on multiple cortical features. The spatiotemporal development of morphological connections was described at the level of edge, node, and lobe, respectively. Based on graph theoretical method, the topology structure of fetal morphological network was characterized. Edge analysis demonstrated an increase of morphological dissimilarity between hemispheres with gestational age, especially for the parietal cortex. The limbic and parieto-occipital regions exhibited the most drastic changes of morphological connections at both the edge and node levels. Between- and within-lobe analysis illustrated that the limbic lobe became more similar to other lobes, while the parietal and occipital lobes became more dissimilar to other lobes. Graph theoretical analysis indicated that the small-world structure of the fetal morphological network appeared as early as 22 weeks and that the network topology exhibited an enhanced integration and reduced segregation during prenatal development. The findings obtained from the preterm-born neonates agreed well with those of the fetuses. In summary, this study fills a gap in prenatal morphological brain network research and provides a piece of important evidence for understanding the normal development of fetal brain connectome during the second-third trimester.

Preterm-birth alters the development of nodal clustering and neural connection pattern in brain structural network at term-equivalent age.

Preterm-born neonates are prone to impaired neurodevelopment that may be associated with disrupted whole-brain structural connectivity. The present study aimed to investigate the longitudinal developmental pattern of the structural network from preterm birth to term-equivalent age (TEA), and identify how prematurity influences the network topological organization and properties of local brain regions. Multi-shell diffusion-weighted MRI of 28 preterm-born scanned a short time after birth (PB-AB) and at TEA (PB-TEA), and 28 matched term-born (TB) neonates in the Developing Human Connectome Project (dHCP) were used to construct structural networks through constrained spherical deconvolution tractography. Structural network development from preterm birth to TEA showed reduced shortest path length, clustering coefficient, and modularity, and more "connector" hubs linking disparate communities. Furthermore, compared with TB newborns, premature birth significantly altered the nodal properties (i.e., clustering coefficient, within-module degree, and participation coefficient) in the limbic/paralimbic, default-mode, and subcortical systems but not global topology at TEA, and we were able to distinguish the PB from TB neonates at TEA based on the nodal properties with 96.43% accuracy. Our findings demonstrated a topological reorganization of the structural network occurs during the perinatal period that may prioritize the optimization of global network organization to form a more efficient architecture; and local topology was more vulnerable to premature birth-related factors than global organization of the structural network, which may underlie the impaired cognition and behavior in PB infants.

Ideal Mode of Auditory Stimulation in Preterm Neonates in Neonatal Intensive Care Unit: A Systematic Review.

The objective of this review was to find out the best mode of auditory stimulation for preterm neonates admitted to the neonatal intensive care unit. We also aimed to find out the different effects of different types of auditory stimulation in these neonates. Advanced neonatal care and technological advances in neonatal intensive care units have led to increased survival of preterm-born neonates, but this in turn leads to increased incidences of disabilities like cerebral palsy, visual impairment, delayed social development, etc. Early intervention is provided to facilitate further development and prevent delays in all domains. Auditory stimulation is proven to benefit these neonates to stabilize their vitals and improve their auditory performance in later life.Different modes of auditory stimulation have been studied worldwide, but none of the studies has presented the ideal mode of auditory stimulation for these preterm neonates. In this review, we have discussed the effects produced by different types of auditory stimulation and compared their pros and cons. For conducting a systematic review, a search strategy adopted by MEDLINE is used. A total of 78 articles published between 2012 and 2017, on the effects of auditory stimulation on preterm infants' performance were reviewed.Out of that, eight studies that met the inclusion criteria and focused on short-term and long-term effects were included in this systematic review. Search terms included preterm neonates, auditory stimulation, and early intervention. Randomized controlled trials and cohort studies were included. Auditory stimulation by maternal sound provides physiological and autonomic stability, but the behavioral states of preterm neonates improved with auditory stimulation by music therapy with lullabies. Maternal singing during kangaroo care may be recommended for providing physiological stability.

The Endothelial Glycocalyx and Neonatal Sepsis.

Sepsis carries a substantial risk of morbidity and mortality in newborns, especially preterm-born neonates. Endothelial glycocalyx (eGC) is a carbohydrate-rich layer lining the vascular endothelium, with important vascular barrier function and cell adhesion properties, serving also as a mechano-sensor for blood flow. eGC shedding is recognized as a fundamental pathophysiological process generating microvascular dysfunction, which in turn contributes to multiple organ failure and death in sepsis. Although the disruption of eGC and its consequences have been investigated intensively in the adult population, its composition, development, and potential mechanisms of action are still poorly studied during the neonatal period, and more specifically, in neonatal sepsis. Further knowledge on this topic may provide a better understanding of the molecular mechanisms that guide the sepsis pathology during the neonatal period, and would increase the usefulness of endothelial glycocalyx dysfunction as a diagnostic and prognostic biomarker. We reviewed several components of the eGC that help to deeply understand the mechanisms involved in the eGC disruption during the neonatal period. In addition, we evaluated the potential of eGC components as biomarkers and future targets to develop therapeutic strategies for neonatal sepsis.

Aberrant claustrum structure in preterm-born neonates: an MRI study

The human claustrum is a gray matter structure in the white matter between insula and striatum. Previous analysis found altered claustrum microstructure in very preterm-born adults associated with lower cognitive performance. As the claustrum development is related to hypoxia–ischemia sensitive transient cell populations being at-risk in premature birth, we hypothesized that claustrum structure is already altered in preterm-born neonates.We studied anatomical and diffusion-weighted MRIs of 83 preterm- and 83 term-born neonates at term-equivalent age. Additionally, claustrum development was analyzed both in a spectrum of 377 term-born neonates and longitudinally in 53 preterm-born subjects. Data was provided by the developing Human Connectome Project.Claustrum development showed increasing volume, increasing fractional anisotropy (FA), and decreasing mean diffusivity (MD) around term both across term- and preterm-born neonates. Relative to term-born ones, preterm-born neonates had (i) increased absolute and relative claustrum volumes, both indicating increased cellular and/or extracellular matter and being in contrast to other subcortical gray matter regions of decreased volumes such as thalamus; (ii) lower claustrum FA and higher claustrum MD, pointing at increased extracellular matrix and impaired axonal integrity; and (iii) aberrant covariance between claustrum FA and MD, respectively, and that of distributed gray matter regions, hinting at relatively altered claustrum microstructure.Results together demonstrate specifically aberrant claustrum structure in preterm-born neonates, suggesting altered claustrum development in prematurity, potentially relevant for later cognitive performance.

Reduced Cerebellar Volume in Term Infants with Complex Congenital Heart Disease: Correlation with Postnatal Growth Measurements.

: ObjectivesAberrant cerebellar development and the associated neurocognitive deficits has been postulated in infants with congenital heart disease (CHD). Our objective is to investigate the effect of postnatal head and somatic growth on cerebellar development in neonates with CHD. We compared term-born neonates with a history of CHD with a cohort of preterm-born neonates, two cohorts at similar risk for neurodevelopment impairment, in order to determine if they are similarly affected in the early developmental period. Study Design: 51 preterms-born healthy neonates, 62 term-born CHD neonates, and 54 term-born healthy neonates underwent a brain MRI with volumetric imaging. Cerebellar volumes were extracted through an automated segmentation pipeline that was developed in-house. Volumes were correlated with clinical growth parameters at both the birth and time of MRI. Results: The CHD cohort showed significantly lower cerebellar volumes when compared with both the control (p < 0.015) and preterm (p < 0.004) groups. Change in weight from birth to time of MRI showed a moderately strong correlation with cerebellar volume at time of MRI (r = 0.437, p < 0.002) in the preterms, but not in the CHD neonates (r = 0.205, p < 0.116). Changes in birth length and head circumference showed no significant correlation with cerebellar volume at time of MRI in either cohort. Conclusions: Cerebellar development in premature-born infants is associated with change in birth weight in the early post-natal period. This association is not observed in term-born neonates with CHD, suggesting differential mechanisms of aberrant cerebellar development in these perinatal at-risk populations.

Harmonized Segmentation of Neonatal Brain MRI.

Deep learning based medical image segmentation has shown great potential in becoming a key part of the clinical analysis pipeline. However, many of these models rely on the assumption that the train and test data come from the same distribution. This means that such methods cannot guarantee high quality predictions when the source and target domains are dissimilar due to different acquisition protocols, or biases in patient cohorts. Recently, unsupervised domain adaptation techniques have shown great potential in alleviating this problem by minimizing the shift between the source and target distributions, without requiring the use of labeled data in the target domain. In this work, we aim to predict tissue segmentation maps on T2-weighted magnetic resonance imaging data of an unseen preterm-born neonatal population, which has both different acquisition parameters and population bias when compared to our training data. We achieve this by investigating two unsupervised domain adaptation techniques with the objective of finding the best solution for our problem. We compare the two methods with a baseline fully-supervised segmentation network and report our results in terms of Dice scores obtained on our source test dataset. Moreover, we analyse tissue volumes and cortical thickness measures of the harmonized data on a subset of the population matched for gestational age at birth and postmenstrual age at scan. Finally, we demonstrate the applicability of the harmonized cortical gray matter maps with an analysis comparing term and preterm-born neonates and a proof-of-principle investigation of the association between cortical thickness and a language outcome measure.

Post-Exchange Transfusion Sodium Change Within a Laboratory Reference Range of Serum in Hospitalized Severe Neonatal Jaundice Cases

Background: Blood exchange transfusion (ECT) therapy is an essential part of the modern health care for high-risk icteric neonates. Objectives: Therefore, this study sought to examine the effectiveness of monitoring sodium disorders and the required interventions indicating the overall state of health of hospitalized jaundiced neonates. Methods: This prospective analytic study was performed on 49 neonates diagnosed with severe jaundice undergoing screened exchange blood transfusion from November 2018 to May 2019. Serum sodium ion concentrations testing was performed before the exchange, then 1 - 3 hours later, and again 24 hours after receiving ECT, using a sensitive ELISA kit in a laboratory. Using the newest version of SPSS 24 software program, the association between different numerical variables was calculated by a repeated-measure ANOVA test. P &lt; 0.05 criterion was set as the threshold of significance. Results: Out of the total 49 neonates, 24 (48.5%) were girls and 25 (51.5%) were boys, of which 93.9% and 6.1% were term and preterm-born neonates, respectively. The average birth weight was 2843 ± 267/510 g and the mean period of hospital stay was 4.55 ± 2.399 days. The various causes of severe neonatal jaundice of all the hospitalized cases were 45% unknown, 43% combined ABO and Rh incompatibility, 10% breastfeeding pattern, and 2% G6PD deficiency. A continual fall in serum sodium was observed following banked blood exchange (P &lt; 0.05). However, these reversible changes were outside the expected normal range. Despite a diminished sodium concentration, the mean sodium levels were within the laboratory reference range of serum (137 - 142 mEq/L) in all the three measured duration times. Moreover, variation in the amount of serum sodium was associated with an unknown underlying cause that led to neonatal jaundice (P = 0.04) and this difference did not reach statistical significance in terms of birth weight, gestational age, and other causes accounting for high bilirubin (P &gt; 0.05). Conclusions: Given these facts, it was concluded that neonatal jaundice was significantly associated with post-exchange serum sodium changes within the laboratory reference range of serum.

Can you see what I see? Assessing brain maturation and injury in preterm and term neonates.

This scientific commentary refers to ‘Modelling brain development to detect white matter injury in term and preterm born neonates’ by O’Muircheartaigh et al. (doi: 10.1093/brain/awz412).

Modelling brain development to detect white matter injury in term and preterm born neonates.

Premature birth occurs during a period of rapid brain growth. In this context, interpreting clinical neuroimaging can be complicated by the typical changes in brain contrast, size and gyrification occurring in the background to any pathology. To model and describe this evolving background in brain shape and contrast, we used a Bayesian regression technique, Gaussian process regression, adapted to multiple correlated outputs. Using MRI, we simultaneously estimated brain tissue intensity on T1- and T2-weighted scans as well as local tissue shape in a large cohort of 408 neonates scanned cross-sectionally across the perinatal period. The resulting model provided a continuous estimate of brain shape and intensity, appropriate to age at scan, degree of prematurity and sex. Next, we investigated the clinical utility of this model to detect focal white matter injury. In individual neonates, we calculated deviations of a neonate's observed MRI from that predicted by the model to detect punctate white matter lesions with very good accuracy (area under the curve > 0.95). To investigate longitudinal consistency of the model, we calculated model deviations in 46 neonates who were scanned on a second occasion. These infants' voxelwise deviations from the model could be used to identify them from the other 408 images in 83% (T2-weighted) and 76% (T1-weighted) of cases, indicating an anatomical fingerprint. Our approach provides accurate estimates of non-linear changes in brain tissue intensity and shape with clear potential for radiological use.

Cerebral hemodynamic responses in preterm-born neonates to visual stimulation: classification according to subgroups and analysis of frontotemporal-occipital functional connectivity.

.How neurovascular coupling develops in preterm-born neonates has been largely neglected in scientific research. We measured visually evoked (flicker light) hemodynamic responses (HRs) in preterm-born neonates (, gestational age: weeks, postnatal age: days) at the visual cortex (VC) and left frontotemporal lobe (FTL) using functional near-infrared spectroscopy (fNIRS) neuroimaging. We found that the HR characteristics show a large intersubject variability but could be classified into three groups according to the changes of oxyhemoglobin concentration at the VC [(A) increase, (B) decrease, or (C) inconclusive]. In groups A and B, the HRs at the left FTL were correlated with those at the VC, indicating the presence of a frontotemporal–occipital functional connectivity. Neonates in group A had a higher weight at measurement compared to those in group B, and had the lowest baseline total hemoglobin concentration and hematocrit compared to group C. To the best of our knowledge, this is the first fNIRS study showing (1) that the HRs of preterm-born neonates need to be classified into subgroups, (2) that the subgroups differed in terms of weight at measurement, and (3) that HRs can be observed also at the FTL during visual stimulation. These findings add insights into how neurovascular coupling develops in preterm-born neonates.

Drug utilization pattern in a neonatal intensive care unit at tertiary care hospital attached to a medical college in Southern Karnataka, India

Background: Neonates and in particular preterm neonates belongs to the most vulnerable population. A neonatal intensive Care Unit (NICU) is a highly specialized unit that provides high quality skilled care to critically ill new newborn, premature or low birth weight babies. Apart from facilities for continuous clinical and biochemical monitoring, NICU management involves the use of wide range of medications. Irrational prescription of drug is common in clinical practice, important reason being lack of knowledge about drug prescription. Developing countries have limited funds available for health care and drugs so it becomes very important to prescribe drugs rationally. The present study was done to find out the drug utilization pattern and improve the rational use which aids in the improvement of neonatal care. Methods: The study was retrospective study in NICU of tertiary care hospital attached to MIMS, Mandya for a duration of 6 months. Data extraction sheet were used to collect the information regarding demographic details, maternal and delivery details, indication for admission, final diagnosis and medications administered. Data collected were evaluated for the category of prescribed, based on World Health Organization Anatomical Therapeutic Committee (WHO classification system and were analyzed using SPSS. WHO drug utilization core indicators were also evaluated.Results: Among 400 neonates admitted in NICU during the study period, 53.7% were males and 46.2% were females. There were 29.7% preterm born neonates. The maximum number of neonates were admitted in early neonatal period (87.25%). Neonatal sepsis (37.9%) and Birth asphyxia (11.6%) were the most common indications for admission. The total number of drugs prescribed was 1428 and the average number of drugs per neonate was 3.57. Preterm (&lt;37weeks) and low birth weight (&lt;2.5Kg) were exposed to significantly higher number of drugs. The most frequently prescribed therapeutic class of drugs was anti-infectives (60.36%), followed by drugs of central nervous system (7. 84%). Among the anti-infectives, the most commonly prescribed drugs were Ampicillin (59%), followed by gentamycin (42.5%). High end antibiotics like carbapenems, colistin’s and linezolid were used in less than 5% of cases.Conclusions: Drug use in neonates should be minimal and focus on the importance of therapeutic treatment guidelines establishment in hospital to control the over usage of antibiotics.

Adverse neuropsychiatric development following perinatal brain injury: from a preclinical perspective.

Perinatal brain injury is a leading cause of death and disability in young children. Recent advances in obstetrics, reproductive medicine and neonatal intensive care have resulted in significantly higher survival rates of preterm or sick born neonates, at the price of increased prevalence of neurological, behavioural and psychiatric problems in later life. Therefore, the current focus of experimental research shifts from immediate injury processes to the consequences for brain function in later life. The aetiology of perinatal brain injury is multi-factorial involving maternal and also labour-associated factors, including not only placental insufficiency and hypoxia-ischaemia but also exposure to high oxygen concentrations, maternal infection yielding excess inflammation, genetic factors and stress as important players, all of them associated with adverse long-term neurological outcome. Several animal models addressing these noxious stimuli have been established in the past to unravel the underlying molecular and cellular mechanisms of altered brain development. In spite of substantial efforts to investigate short-term consequences, preclinical evaluation of the long-term sequelae for the development of cognitive and neuropsychiatric disorders have rarely been addressed. This review will summarise and discuss not only current evidence but also requirements for experimental research providing a causal link between insults to the developing brain and long-lasting neurodevelopmental disorders.

P01.04: Longitudinal assessments of the fetal adrenal gland indicates preterm birth

Fetal adrenal gland receives rising awareness as a predictor of spontaneous preterm birth. Previous studies focused on cross-sectional assessments. We first aimed for longitudinally analysis and evaluated trajectories for term and preterm born neonates separately. Analyses were based on data from a population-based low-risk prospective pregnancy cohort. For this analyses, complete adrenal gland measurements had to be available, which we assessed at 24, 29 and 36 wks (n= 298 for analyses regarding total adrenal gland, n= 227 for adrenal mark). Median (25th, 75th percentile) values were calculated for adrenal gland volume corrected for estimated fetal weight and the ratio of adrenal mark width/total adrenal width (w/W). Continuous Friedman test was used for differences across pregnancy, Mann-Whitney-U test for comparisons between term and preterm. Absolute adrenal volume increased with gestational age (p<0.0001). Regarding the ratio w/W, we observed a decrease over the course of pregnancy (p<0.0001). When stratifying our study sample into term and preterm born neonates, we only considered those neonates with complete data at all three time points. Hence, for those preterm neonates an ultrasound measurement was available at 36 wks and birth occurred shortly afterwards. While we observed similar trajectories regarding total adrenal gland volume (pfor difference ≥0.2), ratio w/W trajectories for term and preterm neonates differed particularly at 29 wks (pfor difference =0.3, 0.007, and 0.08 at 24, 29, and 36 wks, respectively). Compared to term born neonates, preterm ones had a lower ratio at 24, 29 and a higher at 36 wks, with a median increase from 0.43 to 0.49. Our study adds important longitudinal data on the fetal adrenal gland and supports the hypothesis that the adrenal mark enlarges prior to preterm birth and that this occurs already in the second trimester.

Antenatal exposure to antidepressants is associated with altered brain development in very preterm-born neonates

BackgroundAntenatal exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with an enhanced risk of preterm birth. Very preterm-born neonates (<32weeks’ gestation) antenatally-exposed to SSRIs may show altered brain development. ObjectiveTo examine whether antenatal-SSRI exposure was associated with adverse neonatal brain microstructural and metabolic development using diffusion tensor and magnetic resonance spectroscopic imaging. Design/MethodsOf 177 neonates enrolled, 14 (8%) were antenatally exposed to SSRIs. Neonates were scanned twice (median week 32; interquartile range [IQR]: 30.4–33.6) and again at term-equivalent age (40.1, IQR: 38.6–42.1). Using a region-of-interest approach, N-acetylaspartate to choline ratios (NAA/Cho), lactate to choline ratios, white and gray matter fractional anisotropy (FA), mean, axial, radial diffusivity (MD, AD, RD) values were extracted from white and gray matter subcortical regions. Neurodevelopment was assessed at 18 months, corrected age. ResultsSSRI-exposed neonates exhibited increased FA and decreased MD, AD and RD values in the superior white matter (p<0.05). FA values in the basal ganglia and thalamus were significantly lower in neonates antenatally exposed to SSRIs, compared to non-exposed (p=0.004). Lower NAA/Cho values (p=0.04) and higher Lactate/Cho values (p=0.004) in posterior gray matter were evident in neonates exposed to SSRIs. No association with antenatal-SSRI exposure and neurodevelopment was evident. ConclusionsGiven the importance of treating depression in mothers at risk for preterm delivery, the impact of antenatal-SSRIs on early brain development requires further attention. Future research is directed at determining the mechanism of this relationship and the contribution of maternal mood.

NEOCIVET: Towards accurate morphometry of neonatal gyrification and clinical applications in preterm newborns

Cerebral cortical folding becomes dramatically more complex in the fetal brain during the 3rd trimester of gestation; the process continues in a similar fashion in children who are born prematurely. To quantify this morphological development, it is necessary to extract the interface between gray matter and white matter, which is particularly challenging due to changing tissue contrast during brain maturation. We employed the well-established CIVET pipeline to extract this cortical surface, with point correspondence across subjects, using a surface-based spherical registration. We then developed a variant of the pipeline, called NEOCIVET, that quantified cortical folding using mean curvature and sulcal depth while addressing the well-known problems of poor and temporally-varying gray/white contrast as well as motion artifact in neonatal MRI. NEOCIVET includes: i) a tissue classification technique that analyzed multi-atlas texture patches using the nonlocal mean estimator and subsequently applied a label fusion approach based on a joint probability between templates, ii) neonatal template construction based on age-specific sub-groups, and iii) masking of non-interesting structures using label-fusion approaches. These techniques replaced modules that might be suboptimal for regional analysis of poor-contrast neonatal cortex. The proposed segmentation method showed more accurate results in subjects with various ages and with various degrees of motion compared to state-of-the-art methods. In the analysis of 158 preterm-born neonates, many with multiple scans (n=231; 26–40weeks postmenstrual age at scan), NEOCIVET identified increases in cortical folding over time in numerous cortical regions (mean curvature: +0.003/week; sulcal depth: +0.04mm/week) while folding did not change in major sulci that are known to develop early (corrected p<0.05). The proposed pipeline successfully mapped cortical structural development, supporting current models of cerebral morphogenesis, and furthermore, revealed impairment of cortical folding in extremely preterm newborns relative to relatively late preterm newborns, demonstrating its potential to provide biomarkers of prematurity-related developmental outcome.

Mathematical Modeling of the Biomarker Milieu to Characterize Preterm Birth and Predict Adverse Neonatal Outcomes.

To identify preterm neonates at risk for adverse neonatal outcomes. A nested case-control study from the prospectively followed Boston Birth Cohort of mother-neonate pairs was performed. A classification model for preterm-born neonates was derived from 27 cord blood biomarkers using orthogonal projections to latent structures discriminant analysis. Predictive relationships were made between biomarkers and adverse outcomes using logistic regression. From 926 births (53% of which were preterm), using weighted values for 27 biomarkers, a score was created that classified 73% of preterm deliveries. Soluble TNF-R1, NT-3, MCP-1, BDNF, IL-4, MMP-9, TREM-1, TNF-α, IL-5 and IL-10 were most influential. Our model was more sensitive for birth <34 weeks (sensitivity 89.5%, specificity 76.9%). IL-10, TNF-α, BDNF, NT-3, MMP-9, sTNF-R1 and MCP-1 were significantly predictive of NEC, IVH, sepsis and infections. We developed a novel mathematical model of 27 biomarkers associated with adverse neonatal outcomes in neonates born preterm.

Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants.

Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome. A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development-III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries. Total midazolam dose predicted decreased hippocampal volumes (β = -1.8, p < 0.001) and increased MD (β = 0.002, p = 0.02), whereas invasive procedures did not (β = 0, p > 0.5 each). Lower cognitive scores were associated with hippocampal growth (β = -0.31, p = 0.003), midazolam dose (β = -0.27, p = 0.03), and surgery (β = -8.32, p = 0.04). Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned.

Tract-Based Spatial Statistics in Preterm-Born Neonates Predicts Cognitive and Motor Outcomes at 18 Months.

Adverse neurodevelopmental outcome is common in children born preterm. Early sensitive predictors of neurodevelopmental outcome such as MR imaging are needed. Tract-based spatial statistics, a diffusion MR imaging analysis method, performed at term-equivalent age (40 weeks) is a promising predictor of neurodevelopmental outcomes in children born very preterm. We sought to determine the association of tract-based spatial statistics findings before term-equivalent age with neurodevelopmental outcome at 18-months corrected age. Of 180 neonates (born at 24-32-weeks' gestation) enrolled, 153 had DTI acquired early at 32 weeks' postmenstrual age and 105 had DTI acquired later at 39.6 weeks' postmenstrual age. Voxelwise statistics were calculated by performing tract-based spatial statistics on DTI that was aligned to age-appropriate templates. At 18-month corrected age, 166 neonates underwent neurodevelopmental assessment by using the Bayley Scales of Infant Development, 3rd ed, and the Peabody Developmental Motor Scales, 2nd ed. Tract-based spatial statistics analysis applied to early-acquired scans (postmenstrual age of 30-33 weeks) indicated a limited significant positive association between motor skills and axial diffusivity and radial diffusivity values in the corpus callosum, internal and external/extreme capsules, and midbrain (P < .05, corrected). In contrast, for term scans (postmenstrual age of 37-41 weeks), tract-based spatial statistics analysis showed a significant relationship between both motor and cognitive scores with fractional anisotropy in the corpus callosum and corticospinal tracts (P < .05, corrected). Tract-based spatial statistics in a limited subset of neonates (n = 22) scanned at <30 weeks did not significantly predict neurodevelopmental outcomes. The strength of the association between fractional anisotropy values and neurodevelopmental outcome scores increased from early-to-late-acquired scans in preterm-born neonates, consistent with brain dysmaturation in this population.