- An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 23; 111(1):68-75.
The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants.The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs).This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml.Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia.Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.
- Effects of Essential Newborn Care Training on Fresh Stillbirths and Early Neonatal Deaths by Maternal Education. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 20; 111(1):61-67.
Infants of women with lower education levels are at higher risk for perinatal mortality.We explored the impact of training birth attendants and pregnant women in the Essential Newborn Care (ENC) Program on fresh stillbirths (FSBs) and early (7-day) neonatal deaths (END) by maternal education level in developing countries.A train-the-trainer model was used with local instructors in rural communities in six countries (Argentina, Democratic Republic of the Congo, Guatemala, India, Pakistan, and Zambia). Data were collected using a pre-/post-active baseline controlled study design.A total of 57,643 infants/mothers were enrolled. The follow-up rate at 7 days of age was 99.2%. The risk for FSB and END was higher for mothers with 0-7 years of education than for those with ≥8 years of education during both the pre- and post-ENC periods in unadjusted models and in models adjusted for confounding. The effect of ENC differed as a function of maternal education for FSB (interaction p = 0.041) without evidence that the effect of ENC differed as a function of maternal education for END. The model-based estimate of FSB risk was reduced among mothers with 0-7 years of education (19.7/1,000 live births pre-ENC, CI: 16.3, 23.0 vs. 12.2/1,000 live births post-ENC, CI: 16.3, 23.0, p < 0.001), but was not significantly different for mothers with ≥8 years of education, respectively.A low level of maternal education was associated with higher risk for FSB and END. ENC training was more effective in reducing FSB among mothers with low education levels.
- Temporal Patterns of Gene Expression Profiles in the Neonatal Mouse Lung after Hypoxia-Reoxygenation. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 17; 111(1):45-54.
One out of four children with neonatal asphyxia has lung involvement. Still, there has been little research on injury mechanisms of hypoxia-reoxygenation in the neonatal lung.To make a temporal profile of the gene expression changes of 44 a priori selected genes after hypoxia-reoxygenation in the newborn mouse lung, and to compare the changes after hyperoxic and normoxic reoxygenation.Postnatal day 7 mice were randomized to 2-hour hypoxia (8% O2) and 30-min reoxygenation in either 60% O2 or air. After 0-72 h of observation, gene expression changes and protein concentrations in whole lung homogenates were examined.Immediately after completed reoxygenation, 7 genes of mediators of inflammation were downregulated, and there was an antiapoptotic gene expression pattern. Three DNA glycosylases were downregulated, while genes involved in cell cycle renewal indicated both increased and decreased cell cycle arrest. Sod1 (T2.5h median H60: 1.01, H21: 0.88, p = 0.005; T5h median H60: 1.04, H21: 0.85, p = 0.038) and Il1b (T0h median H60: 0.86, H21: 1.08, p = 0.021) were significantly differentially expressed when comparing hyperoxic and normoxic reoxygenation.In this newborn mouse lung hypoxia-reoxygenation model, we found downregulation of genes of mediators of inflammation, an antiapoptotic gene expression pattern, and downregulation of DNA glycosylases. Sod1 and Il1b were significantly differentially expressed when comparing reoxygenation using 60% O2 with air.
- Haemodynamic Transition after Birth: A New Tool for Non-Invasive Cardiac Output Monitoring. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 17; 111(1):55-60.
Substantial haemodynamic changes occur during the first minutes after birth. Currently, only heart rate (HR) and arterial oxygen saturation are routinely used to monitor haemodynamic transition after birth.The aim of the present study was to continuously assess haemodynamic changes during transition in term infants for the first time by using electrical velocimetry (EV), a new method of non-invasive cardiac output monitoring (NICOM), based on impedance cardiography technology.In this prospective observational study, term neonates delivered by elective caesarean section underwent NICOM measurements within the first 15 min after birth. The beat-to-beat measurement over a 10-second period was used to calculate cardiac output (CO) for each minute after birth. The data of CO were only accepted when the signal quality index (SQI) remained >80% during the measurement period of 10 s.100 term neonates underwent 1,500 NICOM measurements. 1,143 (76.2%) measurements were excluded because of a SQI <80%. HR and CO showed a trend to increase within the first minutes, and decreased significantly from minute 3 (HR) and 4 (CO), until minute 12 and 10, respectively. Stroke volume remained stable during the observation period.The present study was the first using EV for NICOM during the transition period in a larger cohort of newborn infants. Results of NICOM were similar to available echocardiography data. The possibility of NICOM offers continuous CO measurement. The present study supports the idea that CO is closely related to HR in newborn infants.
- Evidence on Adrenaline Use in Resuscitation and Its Relevance to Newborn Infants: A Non-Systematic Review. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 13; 111(1):37-44.
Guidelines for newborn resuscitation state that if the heart rate does not increase despite adequate ventilation and chest compressions, adrenaline administration should be considered. However, controversy exists around the safety and effectiveness of adrenaline in newborn resuscitation. The aim of this review was to summarise a selection of the current knowledge about adrenaline during resuscitation and evaluate its relevance to newborn infants.A search in PubMed, Embase, and Google Scholar until September 1, 2015, using search terms including adrenaline/epinephrine, cardiopulmonary resuscitation, death, severe brain injury, necrotizing enterocolitis, bronchopulmonary dysplasia, and adrenaline versus vasopressin/placebo.Adult data indicate that adrenaline improves the return of spontaneous circulation (ROSC) but not survival to hospital discharge. Newborn animal studies reported that adrenaline might be needed to achieve ROSC. Intravenous administration (10-30 μg/kg) is recommended; however, if there is no intravenous access, a higher endotracheal dose (50-100 μg/kg) is needed. The safety and effectiveness of intraosseous adrenaline remain undetermined. Early and frequent dosing does not seem to be beneficial. In fact, negative hemodynamic effects have been observed, especially with doses ≥30 μg/kg intravenously. Little is known about adrenaline in birth asphyxia and in preterm infants, but observations indicate that hemodynamics and neurological outcomes may be impaired by adrenaline administration in these conditions. However, a causal relationship between adrenaline administration and outcomes cannot be established from the few available retrospective studies. Alternative vasoconstrictors have been investigated, but the evidence is scarce.More research is needed on the benefits and risks of adrenaline in asphyxia-induced bradycardia or cardiac arrest during perinatal transition.
- Glucocorticoid Receptor Gene Variants and Neonatal Outcome in Very-Low-Birth-Weight Preterm Infants. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 11; 111(1):22-29.
Induction of lung maturation by prenatal steroid treatment has become the standard of care for pregnant women at risk for preterm birth. In addition to the beneficial effects on lung maturation, prenatal steroids have been shown to reduce the incidence of neonatal death, necrotizing enterocolitis, sepsis, and intraventricular hemorrhage. However, little is known about the role of interindividual differences in corticoid sensitivity arising from polymorphisms in the glucocorticoid receptor (GR) gene.To assess the impact of GR polymorphisms N363S (rs56149945), R23K (rs6190), and BclI (rs41423247) on neonatal outcome.The GR polymorphisms N363S, R23K, and BclI were examined in 10,490 very-low-birth-weight (VLBW) preterm infants from 49 German tertiary level neonatal units (German Neonatal Network, GNN) with respect to neonatal outcome.Infants carrying the BclI genotype were at higher risk to develop bronchopulmonary dysplasia (BPD) (OR 1.12 per BclI allele, 95% CI: 1.02-1.23, p = 0.013) in a logistic regression model adjusted for gestational age, mechanical ventilation, and small for gestational age status. A similar relative risk was seen in the children (89.4%) who received antenatal betamethasone treatment (OR 1.16, 95% CI: 1.05-1.27, p = 0.003), whereas no such effect was detectable in infants without antenatal steroids. N363S and R23K did not show any stable association with neonatal outcome parameters.Except for a slightly higher risk of BPD in carriers of the GRBclI variant, the GR gene polymorphisms BclI, N363S, and R23K did not affect neonatal outcome parameters in this large multicenter cohort of VLBW preterm infants.
- Impact of Decreased Serum Insulin-Like Growth Factor-1 Levels on Central Aortic Compliance in Small-for-Gestational-Age Infants. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 11; 111(1):30-36.
Intrauterine growth restriction is associated with arterial hypertension in adulthood; however, the underlying mechanism is unclear.We hypothesized that serum insulin-like growth factor-1 (IGF-1) levels affect central aortic elastic properties and structure in small-for-gestational-age (SGA) infants.Eighteen SGA infants and 22 appropriate-for-gestational-age (AGA) infants were enrolled in this study. The serum IGF-1 level within 1 h of birth and abdominal aortic echo parameters at 1 week of age were retrospectively compared.In the SGA infants, IGF-1 levels (27.6 ± 17.7 vs. 42.6 ± 15 ng/ml, p = 0.006), aortic strain (10.2 ± 3.1 vs. 12.8 ± 3.1%, p = 0.01), and aortic distensibility (0.73 ± 0.19 vs. 0.92 ± 0.34 cm2/dyn × 10-4, p = 0.05) were significantly lower compared with AGA infants. By contrast, blood pressure, aortic intima-media thickness (aIMT) in relation to body weight (383 ± 163 vs. 256 ± 43 μm/kg, p < 0.001), aortic stiffness index in relation to body weight (2.0 ± 1.7 vs. 1.1 ± 0.4, p = 0.005), and arterial pressure-strain elastic modulus (293 ± 72 vs. 242 ± 78 mm Hg, p = 0.04) were higher compared with AGA infants. In the SGA infants, IGF-1 levels were significantly correlated with aortic strain (r = 0.49, p = 0.04), aIMT in relation to body weight (r = -0.61, p = 0.007), and aortic stiffness index in relation to body weight (r = -0.63, p = 0.005).Decreased serum IGF-1 levels in SGA infants may affect the vascular compliance and structure of the central aorta.
- N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 6; 111(1):12-21.
Perinatal asphyxia and ensuing reoxygenation change the antioxidant capacity of cells and organs.To analyze the neuroprotective effect of the antioxidant N-acetylcysteine amide (NACA) after perinatal hypoxia-reoxygenation with an emphasis on proinflammatory cytokines and the transcription factor NF-x03BA;B in the prefrontal cortex of neonatal pigs.Twenty-nine newborn pigs, aged 12-36 h, were subjected to global hypoxia and hypercapnia. One sham-operated group (n = 5) and 2 experimental groups (n = 12) were exposed to 8% oxygen, until the base excess was -20 mmol/l or the mean arterial blood pressure fell to <20 mm Hg (asphyxia with NACA or saline). The pigs were observed for 9.5 h after hypoxia. Samples of prefrontal cortex and plasma were analyzed.Cortex: there was no significant difference in mRNA expression between the intervention groups regarding IL-1β, IL6, TNFα, MMP2, MMP9 or IL18. Pigs exposed to hypoxia-reoxygenation and treatment with NACA (NACA-pigs) had a significantly lower protein concentration of IL-1β than pigs treated with saline (placebo controls), i.e. 8.8 ± 3.9 versus 16.8 ± 10.5 pg/mg protein (p = 0.02). The activation of the transcription factor NF-x03BA;B (measured as the fold-change of phosphorylated p65Ser 536), was reduced in the NACA-pigs when compared to the placebo controls (5.2 ± 4.3 vs. 16.0 ± 13.5; p = 0.02). No difference between the intervention groups regarding brain histopathology or in the levels of 8-oxoguanine measured in the prefrontal cortex were observed. Plasma: the NACA-pigs had a stronger reduction of TNFα in the first 30 min following asphyxia compared with the placebo controls, i.e. 36 (30-44) versus 24 (14-32)% (p = 0.01).The reduced levels of the pivotal inflammatory markers IL-1β and TNFα and the transcription factor NF-x03BA;B may indicate that NACA has possible neuroprotective effects after perinatal asphyxia.
- Diagnosis Accuracy of Transcutaneous Bilirubinometry in Very Preterm Newborns. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 5; 111(1):1-7.
Transcutaneous bilirubin (TcB) is a validated test for systematic screening of neonatal hyperbilirubinemia and monitoring term and near-term infants under phototherapy.To evaluate TcB diagnostic accuracy for very preterm neonates.Total serum bilirubin (TSB) and TcB measurements were performed prospectively in a multicenter sample of newborns <30 weeks of gestational age (GA). TcB sensitivity, specificity, predictive values, and likelihood ratios for the detection of neonates requiring phototherapy were calculated over the first 15 days of life, with or without phototherapy, with the expectation of achieving a detection rate of hyperbilirubinemia of over 95%. The potential influence of neonatal characteristics on the discordance between TcB and TSB in very preterm newborns was analyzed using multivariate multilevel logistic regression analyses.Altogether, 481 measurements were analyzed in 167 preterm patients. Mean GA was 27.6 ± 1.6 weeks. The rates of newborns requiring phototherapy were 52% in the first 3 days, 16% from the 4th to the 7th day, and 2% during the second week. Diagnostic performance was similar among babies with or without phototherapy. TcB sensitivity decreased over time from 100% (93.9-100.0) to 50% (1.3-98.7). Specificity showed an inverse evolution from 14.8% (7.0-26.2) to 80.7% (72.2-89.2). The best performance was that of negative predictive values which varied from 95.5 to 100.0. False negatives were rare throughout the study (0.8% of measurements). In a multivariate analysis, the only factor significantly influencing discordance between TcB and TSB was postnatal age. We did not find any impact of GA and skin color.Among very preterm babies, TcB measurements might be useful for screening for neonatal jaundice in the first 2 weeks of life. In case of a TcB value below the phototherapy threshold, invasive TSB quantification could be unnecessary, with potential avoidance of blood drawing.
- Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion. [JOURNAL ARTICLE]
- Neonatology 2016 Aug 5; 111(1):8-11.
Milrinone has been suggested as a possible first-line therapy for preterm neonates to prevent postligation cardiac syndrome (PLCS) through decreasing systemic vascular resistance and increasing cardiac contractility. The optimal dosing regimen, however, is not known.To model the dosing of milrinone in preterm infants for prevention of PLCS after surgical closure of patent ductus arteriosus (PDA).Milrinone time-concentration profiles were simulated for 1,000 subjects using the volume of distribution and clearance estimates based on one compartmental population pharmacokinetic model by Paradisis et al. [Arch Dis Child Fetal Neonatal Ed 2007;92:F204-F209]. Dose optimization was based on retrospectively collected demographic data from neonates undergoing PDA ligation in Estonian PICUs between 2012 and 2014 and existing pharmacodynamic data. The target plasma concentration was set at 150-200 ng/ml.The simulation study used demographic data from 31 neonates who underwent PDA ligation. The median postnatal age was 13 days (range: 3-29) and weight was 760 g (range: 500-2,351). With continuous infusion of milrinone 0.33 μg/kg/min, the proportion of subjects within the desired concentration range was 0% by 3 h, 36% by 6 h, and 61% by 8 h; 99% of subjects exceeded the range by 18 h. The maximum proportion of total simulated concentrations in the target range was attained with a bolus infusion of 0.73 μg/kg/min for 3 h followed by a 0.16-μg/kg/min maintenance infusion.Mathematical simulations suggest that in preterm neonates the plasma time-concentration profile of milrinone can be optimized with a slow loading dose followed by maintenance infusion.