A Deep Intronic PKHD1 Variant Identified by SpliceAI in a Deceased Neonate With Autosomal Recessive Polycystic Kidney Disease.

The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.

Renal injury in neonates: use of "omics" for developing precision medicine in neonatology.

Preterm birth is associated with increased risks of morbidity and mortality along with increased healthcare costs. Advances in medicine have enhanced survival for preterm infants but the overall incidence of major morbidities has changed very little. Abnormal renal development is an important consequence of premature birth. Acute kidney injury (AKI) in the neonatal period is multifactorial and may increase lifetime risk of chronic kidney disease.Traditional biomarkers in newborns suffer from considerable confounders, limiting their use for early identification of AKI. There is a need to develop novel biomarkers that can identify, in real time, the evolution of renal dysfunction in an early diagnostic, monitoring and prognostic fashion. Use of "omics", particularly metabolomics, may provide valuable information regarding functional pathways underlying AKI and prediction of clinical outcomes.The emerging knowledge generated by the application of "omics" (genomics, proteomics, metabolomics) in neonatology provides new insights that can help to identify markers of early diagnosis, disease progression, and identify new therapeutic targets. Additionally, omics will have major implications in the field of personalized healthcare in the future. Here, we will review the current knowledge of different omics technologies in neonatal-perinatal medicine including biomarker discovery, defining as yet unrecognized biologic therapeutic targets, and linking of omics to relevant standard indices and long-term outcomes.

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.

Quantifying Neonatal Sucking Performance: Promise of New Methods.

Neonatal feeding has been traditionally understudied so guidelines and evidence-based support for common feeding practices are limited. A major contributing factor to the paucity of evidence-based practice in this area has been the lack of simple-to-use, low-cost tools for monitoring sucking performance. We describe new methods for quantifying neonatal sucking performance that hold significant clinical and research promise. We present early results from an ongoing study investigating neonatal sucking as a marker of risk for adverse neurodevelopmental outcomes. We include quantitative measures of sucking performance to better understand how movement variability evolves during skill acquisition. Results showed the coefficient of variation of suck duration was significantly different between preterm neonates at high risk for developmental concerns (HRPT) and preterm neonates at low risk for developmental concerns (LRPT). For HRPT, results indicated the coefficient of variation of suck smoothness increased from initial feeding to discharge and remained significantly greater than healthy full-term newborns (FT) at discharge. There was no significant difference in our measures between FT and LRPT at discharge. Our findings highlight the need to include neonatal sucking assessment as part of routine clinical care in order to capture the relative risk of adverse neurodevelopmental outcomes at discharge.

Early urinary biomarkers of acute kidney injury in preterm infants.

BACKGROUND: Acute kidney injury (AKI) in the neonatal intensive care setting is multifactorial and is associated with significant morbidity and mortality. This study evaluates the utility of novel urinary biomarkers to predict the development and/or severity AKI in preterm infants. METHODS: We performed a case-control study on a prospective cohort of preterm infants (<32 wk), to compare seven urine biomarkers between 25 infants with AKI and 20 infants without AKI. RESULTS: Infants with AKI had significantly higher neutrophil gelatinase-associated lipocalin (NGAL) (median, control (CTRL) vs. AKI; 0.598 vs. 4.24 µg/ml; P < 0.0001). In contrast, urinary epidermal growth factor (EGF) levels were significantly lower in infants who developed AKI compared to controls (median, CTRL vs. AKI; 0.016 vs. 0.006 µg/ml; P < 0.001). The area under the curve (AUC) for NGAL for prediction of stage I AKI on the day prior to AKI diagnosis (day-1) was 0.91, and for the prediction of stage II/III, AKI was 0.92. Similarly, urine EGF was a predictor of renal injury on day -1 (AUC: 0.97 for stage I and 0.86 for stage II/III AKI). CONCLUSION: Urinary biomarkers may be useful to predict AKI development prior to changes in serum creatinine (SCr) in preterm infants.

Cellular strain amplifies LPS-induced stress signaling in immature enterocytes: potential implications for preterm infant NCPAP.

BACKGROUND: Recent clinical observations of increased necrotizing enterocolitis (NEC) incidence in some nasal continuous positive airway pressure (NCPAP) patients raise concerns about whether the related abdominal distension is benign or contributes to NEC. We tested the hypothesis that mechanical strain causes an exaggerated enterocyte inflammatory response and decreased enterocyte growth and proliferation in the absence and presence of lipopolysaccharide (LPS). METHODS: First we used a confluent enterocyte (IEC-6) monolayer to investigate effects of strain on inflammatory cytokine production and Toll-like receptor 4 (TLR-4) gene expression. Then we used a low seeding density to measure cell growth and proliferation. Ten percent mechanical strain was applied. RESULTS: Significant increases in interleukin (IL)-8 and in IL-6 were observed after 8 and 24 h of cellular strain, respectively, and maintained throughout the study. TLR-4 expression was increased at 48 h. Mechanical strain led to slower proliferation and division whereas LPS alone had minimal effects. The responses of LPS and strain were supra-additive, suggesting synergistic cellular effects. CONCLUSION: We speculate intestinal distension associated with the use of NCPAP, especially in the presence of abnormal gut colonization, may result in increased inflammatory cytokine production and be a contributing factor to neonatal intestinal morbidities.

LPS-binding protein enables intestinal epithelial restitution despite LPS exposure.

OBJECTIVES: Intestinal epithelial restitution is the first part in the process of mucosal repair after injury in the intestine. Integrity of the intestinal mucosal barrier is important as a first line of defense against bacteria and endotoxin. Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely-low-birth-weight infants, but its mechanisms are not well defined. Abnormal bacterial colonization, immature barrier function, innate immunity activation, and inflammation likely play a role. Lipopolysaccharide (LPS)-binding protein (LBP) is secreted by enterocytes in response to inflammatory stimuli and has concentration-dependent effects. At basal concentrations, LBP stimulates the inflammatory response by presenting LPS to its receptor; however, at high concentrations, LBP is able to neutralize LPS and prevent an exaggerated inflammatory response. We sought to determine how LBP would affect wound healing in an in vitro model of intestinal cell restitution and protect against intestinal injury in a rodent model of NEC. METHODS: Immature intestinal epithelial cells (IEC-6) were seeded in poly-L-lysine-coated 8-chamber slides and grown to confluence. A 500-µm wound was created using a cell scraper mounted on the microscope to achieve uniform wounding. Media was replaced with media containing LPS ± LBP. Slide wells were imaged after 0, 8, and 24 hours and then fixed. Cellular restitution was evaluated via digital images captured on an inverted microscope and wound closure was determined by automated analysis. Toll-like receptor 4 (TLR4) was determined by reverse transcriptase-polymerase chain reaction after RNA isolation from wounded cells 24 hours after treatment. RESULTS: LPS alone attenuated wound healing in immature intestinal epithelium. This attenuation is reversed by 24 hours with increasing concentrations of LBP so that wound healing is equivalent to control (P < 0.001). TLR4 was increased with LPS alone but levels returned to that of control after addition of LBP in the higher concentrations. LBP had no effect on the development of intestinal injury when given during our rodent model of NEC. Abnormal bacterial colonization and activation of innate immunity by LPS are likely involved in the pathogenesis of NEC.The attenuation of wound healing was reversed when LBP was added to LPS but only in the higher concentrations. At these same concentrations of LBP, TLR4 was decreased to that of control. CONCLUSIONS: These results indicate that LBP may be a novel therapeutic strategy to facilitate wound healing after the acute phase of NEC and other forms of intestinal injury.

Poly(ADP-ribose) polymerase-1: a novel therapeutic target in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of infancy, afflicting 11% of infants born 22-28 wk GA. Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production, protein oxidation, and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide (NAD+) as a substrate. However, in the presence of severe oxidative stress and DNA damage, PARP-1 overactivation may ensue, depleting cells of NAD+ and ATP, killing them by metabolic catastrophe. Here, we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked PARP-1 expression and that administration of a PARP-1 inhibitor (nicotinamide) attenuates intestinal injury in a newborn rat model of NEC. In this model, 56% of control pups developed NEC (any stage) versus 14% of pups receiving nicotinamide. Forty-four percent of control pups developed high-grade NEC (grades 3-4), whereas only 7% of pups receiving nicotinamide developed high-grade NEC. Nicotinamide treatment protects pups against intestinal injury incurred in the newborn rat NEC model. We speculate that PARP-1 overactivation in NEC may drive mucosal cell death in this disease and that PARP-1 may be a novel therapeutic target in NEC.

Probiotics and prebiotics for the prevention of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) continues to be a major cause of morbidity and mortality in premature infants. Although the pathogenesis of NEC remains unclear, abnormal bacterial colonization has been postulated as playing a central role. Various factors impact bacterial colonization following delivery. Compared to term infants, the bacterial colonization pattern in prematurely born infants is markedly different, with a greater predilection for colonization with pathogenic bacteria. Probiotic and prebiotic administration offers the opportunity to manipulate the intestinal bacterial environment, favoring the growth of commensal bacteria. Experimental data from animal studies and data from human trials suggest that probiotics decrease the incidence of NEC. These preliminary studies support the need for a large, randomized, controlled trial to further investigate the role of probiotics in the prevention of NEC.

Necrotizing enterocolitis in neonates undergoing the hybrid approach to complex congenital heart disease.

OBJECTIVE: To investigate the prevalence of necrotizing enterocolitis (NEC) in neonates undergoing the Stage I hybrid procedure for palliation of complex congenital heart disease (CHD). Neonates undergoing the Norwood surgery for hypoplastic left-heart syndrome have the highest risk for NEC of all CHD patients. The hybrid procedure is another palliative option for hypoplastic left-heart syndrome, but NEC in neonates undergoing this procedure has not been reported. DESIGN: Retrospective chart review of 73 neonates who underwent the hybrid procedure for palliation of complex CHD. Demographic, perinatal, perioperative, clinical, and procedural data were collected. NEC was defined as modified Bell's Stage II and above. SETTING: The cardiothoracic and neonatal intensive care units in a large free-standing children's hospital. PATIENTS: All neonates who underwent the hybrid Stage I procedure for the palliation of complex CHD from April 2002 through April 2008. MEASUREMENTS AND MAIN RESULTS: Seventy-three neonates were reviewed and 11.0% (eight of 73) developed NEC. Of the patients with NEC, 37.5% (three of eight) died and two patients required abdominal surgery. Earlier gestational age (< 37 wks), lower maximum dose of prostaglandin infusion, and unexpected readmission to the intensive care unit were statistically associated with NEC (p = .009, 0.02, and 0.04, respectively). No other demographic, perinatal, perioperative, clinical, or procedural variables were associated with the development of NEC in this patient population, including enteral feeding regimens, umbilical artery catheters, inotrope use, and average oxygen saturation and diastolic blood pressure. CONCLUSIONS: The prevalence of NEC in patients undergoing the hybrid procedure is comparable to that reported for neonates undergoing the Norwood procedure. Earlier gestational age is a significant risk factor for NEC in patients who undergo the hybrid Stage I procedure. Multidisciplinary approaches to better understand abdominal complications and to develop feeding regimens in neonates undergoing the hybrid approach to complex CHD are needed to improve outcomes and decrease morbidities.

Response to first dose of inhaled albuterol in mechanically ventilated preterm infants.

BACKGROUND: Bronchodilator responses among preterm infants are heterogeneous. Bedside measurements may identify responders. STUDY DESIGN: Respiratory measurements (Resistance, Compliance, FiO2) and pulse oximetry (SpO2) patterns were downloaded from infants <30 weeks gestational age during the first 2 months of life. Mechanically ventilated infants who received albuterol were included (n = 33). Measurements were compared before and after first albuterol. Secondary analyses assessed subsequent doses. RESULTS: Median gestation and birthweight were 25 3/7 weeks and 730 g, respectively. Mean Resistance decreased post-albuterol (p = 0.007). Sixty-eight percent of infants were responders based on decreased Resistance. Compliance and FiO2 did not significantly differ. Percent time in hypoxemia (SpO2 < 85%) decreased post albuterol (p < 0.02). In responders, Resistance changes diminished with subsequent administration (all p = 0.01). CONCLUSIONS: Ventilator resistance decreased in two-thirds of preterm infants, consistent with studies that utilized formal pulmonary function testing. Albuterol had a variable effect on delivered FiO2; however, hypoxemia may be useful in evaluating albuterol response.

Use of polyethylene bags in extremely low birth weight infant resuscitation for the prevention of hypothermia.

OBJECTIVE: To compare the clinical responses of extremely low birth weight (ELBW) infants resuscitated in polyethylene bags with ELBW infants who were resuscitated using traditional temperature control measures. STUDY DESIGN: Retrospective cohort investigation of 70 ELBW infants who were resuscitated using polyethylene bags (study) and 70 ELBW infants (control) resuscitated without polyethylene bags matched by birth weight, gestational age and gender. RESULTS: Infants in the study and control groups were comparable demographically and in obstetric risk factors. Study and control infants were similar in birth weight, gestational age and low 5-minute Apgar score. Axillary temperature on admission to the neonatal intensive care unit (NICU) and at 1 hour was greater in the study group as compared with controls. The incidence of grade III-IV intraventricular hemorrhage and periventricular leukomalacia (PVL) combined was decreased in the study group as compared with controls. Other neonatal comorbidities were not different. CONCLUSION: Resuscitation of ELBW infants in polyethylene bags led to higher skin temperature on admission to the NICU and at 1 hour of life. These infants were less likely to develop grade 3-4 PVL than infants resuscitated using traditional temperature control measures. No deleterious clinical effects were observed in infants resuscitated using polyethylene bags.

Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy.

Type 1 diabetes is associated with a unique form of cardiomyopathy that is present without atherosclerosis. Redox imbalance and/or changes in vascular endothelial growth factor (VEGF) expression have been associated with diabetes-related cardiomyopathy. However, the mechanisms of these changes and their interrelationships remain unclear. Using a murine type 1 diabetes model, we tested the hypothesis that alterations in cardiac performance are associated with decreased cardiac microvascular prevalence, as well as downregulation of VEGF isoforms. We also investigated oxidative stress as a contributor to regulate individual VEGF isoforms and microvascular rarefaction. Significant and rapid hyperglycemia was observed at 1 wk post-streptozotocin (STZ) and persisted throughout the 5-wk study. Left ventricular (LV) fractional shortening was reduced at week 1 and 5 post-STZ insult relative to age-matched controls. We also observed the early reduction in E/A ratio at 1 wk. Immunostaining for CD31 and digital image analysis demonstrated a 35% reduction in microvessels/myocardial area, indicative of rarefaction, which was highly correlated with fractional shortening. Furthermore, a significant increase in the prevalence of protein 3-nitrotyrosine was observed in the diabetic cardiac tissue, which was inversely associated with microvascular rarefaction. The expressions of three VEGF isoforms were significantly reduced to different extents. The reduction of VEGF(164) was associated with GSSG accumulation. These data demonstrate that the mouse model of STZ-induced diabetes has hallmark features observed in humans with respect to nonischemic systolic and diastolic performance and microvascular rarefaction, which are associated with changes in VEGF isoform expression and redox imbalance in the myocardium.

Prenatal lipopolysaccharide increases postnatal intestinal injury in a rat model of necrotizing enterocolitis.

BACKGROUND: An increased incidence of necrotizing enterocolitis (NEC) has been noted in infants who are born to mothers with chorioamnionitis. HYPOTHESIS: Our objective was to test the hypothesis that newborn rat pups born to mothers exposed to prenatal lipopolysaccharide during pregnancy would be more susceptible to intestinal injury in a rat model of NEC and that the increased intestinal injury is mediated by dysregulation of inducible nitric oxide synthase. METHODS: Time-dated pregnant Sprague-Dawley dams were given an intraperitoneal injection of either 2 mg/kg of lipopolysaccharide or vehicle. Rat pups from each group of dams were delivered at term and placed in a rat NEC model. A subset of pups was given either vehicle or aminoguanidine. Intestines were harvested and graded for degree of intestinal injury. RESULTS: Maternal prenatal lipopolysaccharide exposure increased the frequency and severity of intestinal injury in the neonatal rat NEC model. Treatment with aminoguanidine significantly decreased plasma nitric oxide levels. Additionally, aminoguanidine significantly decreased intestinal injury. CONCLUSIONS: Intestinal injury observed may be mediated via nitric oxide synthase dysregulation.

A comparison of the nutritive sucking performance of full term and preterm neonates at hospital discharge: A prospective study.

BACKGROUND: Studies show that 40% to 70% of premature infants exhibit both immature and atypical feeding ability. To establish thresholds of performance and develop efficacious treatments for initiating and advancing oral feedings, we must first identify the nutritive sucking performance measures impacted by preterm birth. AIMS: To compare objective measures of neonatal nutritive sucking between full term and preterm infants at hospital discharge. STUDY DESIGN AND METHODS: This was a prospective observational study including full term (FT; N = 32) and preterm (PT; N = 44) infants. Nutritive sucking performance at discharge was assessed. The outcome measures of interest were means and coefficients of variability of nutritive sucking peak amplitude, frequency, duration, and smoothness, and feeding-related length of stay. RESULTS: There was a significant difference in sucking performance between groups; FT infants demonstrated significantly lower mean suck frequency, with longer suck duration and greater suck smoothness as compared to PT. PT infants had significantly less variability in suck amplitude and frequency as compared to FT, while FT infants had significantly less variability in suck smoothness as compared to PT. Post hoc regression analyses found suck frequency alone accounted for 28% of the variance in feeding length of stay for PT; suck smoothness alone accounted for 34% of the variance in feeding length of stay for FT. CONCLUSIONS: Suck frequency may be an important intervention target for PT infants having difficulty transitioning to oral feeding. Suck smoothness may be a sensitive marker for identifying infants at high risk for feeding challenges.

The neonatal intestinal vasculature: contributing factors to necrotizing enterocolitis.

Based on the demonstration of coagulation necrosis, it is clear that intestinal ischemia plays a role in the pathogenesis of necrotizing enterocolitis (NEC). Intestinal vascular resistance is determined by a dynamic balance between vasoconstrictive and vasodilatory inputs. In the newborn, this balance heavily favors vasodilation secondary to the copious production of endothelium-derived nitric oxide (NO), a circumstance which serves to ensure adequate blood flow and thus oxygen delivery to the rapidly growing intestine. Endothelial cell injury could shift this balance in favor of endothelin (ET)-1-mediated vasoconstriction, leading to intestinal ischemia and tissue injury. Evidence obtained from animal models and from human tissue collected from infants with NEC implicates NO and ET-1 dysregulation in the pathogenesis of NEC. Strategies focused on maintaining the delicate balance favoring vasodilation in the newborn intestinal circulation may prove to be useful in the prevention and treatment of NEC.

Necrotizing enterocolitis in neonates with congenital heart disease.

Both necrotizing enterocolitis (NEC) and congenital heart disease (CHD) are causes of significant morbidity and mortality in the neonatal population. While two distinct disease processes, NEC and CHD are inter-related as the incidence of NEC is greater in neonates with CHD than the normal newborn population. It is likely that circulatory perturbations, especially those seen in infants with left ventricular outflow tract lesions and single ventricle physiology, the stress of cardiac surgery and cardiopulmonary bypass, and the underlying baseline elevation of circulating endotoxin and proinflammatory cytokines all play a role in the pathogenesis of NEC in this uniquely susceptible population. The neurodevelopmental impairment in infants requiring surgery for NEC and in infants with complex congenital heart disease is alarming and requires further investigation. As medical and surgical advances allow for the palliation and correction of complex lesions at an earlier gestational age and lower birth weight, the already high risk of NEC in this population is likely to increase. This will require more aggressive study of the etiology of NEC in patients with CHD and the development of preventative therapies in order to decrease the impressive morbidity and mortality associated with the combination of these disease processes. In this article, we review the pathogenesis of NEC and CHD including associated mortality and morbidities and discuss possible mechanisms linking these two disease states.

Endothelial nitric oxide synthase in human intestine resected for necrotizing enterocolitis.

OBJECTIVE: To determine the expression and function of endothelial nitric oxide synthase (eNOS) in submucosal arterioles harvested from human intestine resected for necrotizing enterocolitis (NEC) or congenital bowel disease. STUDY DESIGN: eNOS expression was determined by using immunohistochemistry. The arteriolar diameter was measured in vitro at pressures of 10 to 40 mm Hg and also in response to the eNOS agonist acetylcholine (ACh), the exogenous nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine, and the smooth muscle relaxant papaverine. Arteriolar release of NO in response to ACh was determined with a Sievers NOAnalyzer. Hemodynamics were also determined at flow rates of 50 and 100 microL/min. RESULTS: eNOS was present in microvessels from both groups, but NEC arterioles failed to demonstrate physiological evidence of eNOS function: they constricted in response to pressure, failed to dilate or generate NO in response to ACh, and failed to dilate in response to flow. However, they dilated in response to exogenous NO and papaverine, indicating functional vascular smooth muscle and vasodilator reserve. CONCLUSION: eNOS-derived NO, a vasodilator in the newborn intestine, did not contribute to vasoregulation in arterioles harvested from intestine resected for NEC. These vessels were constricted; lack of eNOS-derived NO may contribute to this vasoconstriction.

Neurological consequences of systemic inflammation in the premature neonate.

Despite substantial progress in neonatal care over the past two decades leading to improved survival of extremely premature infants, extreme prematurity continues to be associated with long term neurodevelopmental impairments. Cerebral white matter injury is the predominant form of insult in preterm brain leading to adverse neurological consequences. Such brain injury pattern and unfavorable neurologic sequelae is commonly encountered in premature infants exposed to systemic inflammatory states such as clinical or culture proven sepsis with or without evidence of meningitis, prolonged mechanical ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis and chorioamnionitis. Underlying mechanisms may include cytokine mediated processes without direct entry of pathogens into the brain, developmental differences in immune response and complex neurovascular barrier system that play a critical role in regulating the cerebral response to various systemic inflammatory insults in premature infants. Understanding of these pathologic mechanisms and clinical correlates of such injury based on serum biomarkers or brain imaging findings on magnetic resonance imaging will pave way for future research and translational therapeutic opportunities for the developing brain.

Plasma Brain-Derived Neurotrophic Factor Levels in Newborn Infants with Neonatal Abstinence Syndrome.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a type of growth factor that promotes growth and survival of neurons. Fetal exposure to opiates can lead to postnatal withdrawal syndrome, which is referred as neonatal abstinence syndrome (NAS). Preclinical and clinical studies have shown an association between opiates exposure and alteration in BDNF expression in the brain and serum levels in adult. However, to date, there are no data available on the effects of opiate exposure on BDNF levels in infant who are exposed to opiates in utero and whether BDNF level may correlate with the severity of NAS. OBJECTIVE: To compare plasma BDNF levels among NAS and non-NAS infants and to determine the correlation of BDNF levels and the severity of NAS. METHODS: This is a prospective cohort study with no intervention involved. Infants ≥35 weeks of gestation were enrolled. BDNF level was measured using enzyme-linked immunosorbent assay technique from blood samples drawn within 48 h of life. The severity of NAS was determined by the length of hospital stay, number of medications required to treat NAS. RESULTS: 67 infants were enrolled, 34 NAS and 33 non-NAS. Mean gestational age did not differ between the two groups. Mean birth weight of NAS infants was significantly lower than the non-NAS infants (3,070 ± 523 vs. 3,340 ± 459 g, p = 0.028). Mean BDNF level in NAS group was 252.2 ± 91.6 ng/ml, significantly higher than 211.3 ± 66.3 ng/ml in the non-NAS group (p = 0.04). There were no differences in BDNF levels between NAS infants that required one medication vs. more than one medication (254 ± 91 vs. 218 ± 106 ng/ml, p = 0.47). There was no correlation between the BDNF levels and length of hospital stay (p = 0.68) among NAS infants. Overall, there were no significant correlations between BDNF levels and NAS scores except at around 15 h after admission (correlation 0.35, p = 0.045). CONCLUSION: Plasma BDNF level was significantly increased in NAS infants during the first 48 h when compared to non-NAS infants. The correlations between plasma BDNF levels and the severity of NAS warrant further study. These results suggest that BDNF may play a neuromodulatory role during withdrawal after in utero opiate exposure.