Vitamin K insufficiency and the prophylaxis strategy in term healthy infants: A multicentre study.

BACKGROUND/AIM: Late vitamin K deficiency bleeding (VKDB) during early infancy is a serious problem worldwide. Vitamin K (VK) deficiency commonly occurs in newborns who are exclusively breastfed. Protein Induced by VK Absence (PIVKA-II) has been identified as an early indicator of subclinical VK deficiency in neonates, surpassing prothrombin time. To assess PIVKA-II levels at 48 h, 1 and 3 months of age in full-term newborns who were exclusively breastfed and received varying VKDB prophylaxis regimens. METHODS: A prospective observational study was conducted in four hospitals, enrolling 105 newborns. PIVKA-II levels were measured using a sandwich-type enzyme-linked immunosorbent assay. RESULTS: At 48 h of age, there was no significant difference in PIVKA-II concentrations between newborns who received intramuscular administration of 1 mg of phylloquinone (VK1) and those who received oral administration of 2 mg of VK1 at birth. At 1 and 3 months of life, infants who received any supplementation regimen between 2 and 14 weeks exhibited significantly lower PIVKA-II concentrations compared to infants who received only 1 mg of intramuscular VK1 at birth. The prophylaxis involving a dose of 1 mg of intramuscular VK1 at birth followed by oral administration of 150 µg/day of VK1 from the 2nd to the 14th week of life showed the lowest PIVKA-II blood concentrations. CONCLUSIONS: Oral supplementation of VK1 after discharge significantly reduced PIVKA-II concentrations in exclusively breastfed term infants. These findings suggest the importance of oral VK1 supplementation in exclusively breastfed infants during their first 3 months of life to avoid the risk of VK insufficiency.

Melatonin in Newborn Infants Undergoing Surgery: A Pilot Study on Its Effects on Postoperative Oxidative Stress.

Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal surgical patients. This randomized, blinded, prospective pilot study tested the hypothesis that oral melatonin supplementation in newborn infants undergoing surgery is effective in reducing perioperative oxidative stress. A total of twenty-three newborn infants requiring surgery were enrolled: 10 received a single dose of oral melatonin 0.5 mg/kg in the morning, before surgery (MEL group), and 13 newborns served as the control group (untreated group). Plasma concentrations of melatonin, Non-Protein-Bound Iron (NPBI), Advanced Oxidation Protein Products (AOPP), and F2-Isoprostanes (F2-IsoPs) were measured. Both in the pre- and postoperative period, melatonin concentrations were significantly higher in the MEL group than in the untreated group (preoperative: 1265.50 ± 717.03 vs. 23.23 ± 17.71 pg/mL, p < 0.0001; postoperative: 1465.20 ± 538.38 vs. 56.47 ± 37.18 pg/mL, p < 0.0001). Melatonin significantly increased from the pre- to postoperative period in the untreated group (23.23 ± 17.71 vs. 56.47 ± 37.18 pg/mL; pg/mL p = 0.006). In the MEL group, the mean blood concentrations of NPBI, F2-IsoPs, and AOPP significantly decreased from the pre- to the postoperative period (4.69 ± 3.85 vs. 1.65 ± 1.18 micromol/dL, p = 0.049; 128.40 ± 92.30 vs. 50.25 ± 47.47 pg/mL, p = 0.037 and 65.18 ± 15.50 vs. 43.98 ± 17.92 micromol/dL, p = 0.022, respectively). Melatonin concentration increases physiologically from the pre- to the postoperative period, suggesting a defensive physiologic response to counteract oxidative stress. The administration of exogenous melatonin in newborn infants undergoing surgery reduces lipid and protein peroxidation in the postoperative period, showing a potential role in protecting babies from the deleterious consequences of oxidative stress.

Antioxidant Effect of Melatonin in Preterm Newborns.

INTRODUCTION: Preterm infants are at risk of free radical-mediated diseases from oxidative stress (OS) injury. Increased free radical generation has been demonstrated in preterm infants during the first seven days of life. Melatonin (MEL) is a powerful antioxidant and scavenger of free radicals. In preterm neonates, melatonin deficiency has been reported. Exogenous melatonin administration appears a promising strategy in the treatment of neonatal morbidities in which OS has a leading role. OBJECTIVE: The aim was to evaluate plasma MEL concentrations and OS biomarkers in preterm newborns after early administration of melatonin. METHODS: A prospective, randomized double-blind placebo-controlled pilot study was conducted from January 2019 to September 2020. Thirty-six preterm newborns were enrolled. Starting from the first day of life, 21 received a single dose of oral melatonin 0.5 mg/kg once a day, in the morning (MEL group); 15 newborns received an equivalent dose of placebo (placebo group). Samples of 0.2 mL of plasma were collected at 24 and 48 hours after MEL administration. Plasma concentrations of melatonin, non-protein-bound iron (NPBI), advanced oxidation protein products (AOPP), and F2-isoprostanes (F2-Isopr) were measured. Babies were clinically followed until discharge. RESULTS: At 24 and 48 hours after MEL administration, the MEL concentrations were significantly higher in the MEL group than in the placebo group (52759.30 ± 63529.09 vs. 28.57 ± 46.24 pg/mL and 279397.6 ± 516344.2 vs. 38.50 ± 44.01 pg/mL, respectively). NPBI and AOPP did not show any statistically significant differences between the groups both at 24 and 48 hours. At 48 hours, the mean blood concentrations of F2-Isopr were significantly lower in the MEL group than in the placebo group (36.48 ± 33.85 pg/mL vs.89.97 ± 52.01 pg/mL). CONCLUSIONS: Early melatonin administration in preterm newborns reduces lipid peroxidation in the first days of life showing a potential role to protect high-risk newborns. Trial Registration. This trial is registered with NCT04785183, Early Supplementation of Melatonin in Preterm Newborns: the Effects on Oxidative Stress.

A randomized controlled study of immediate versus delayed umbilical cord clamping in infants born by elective caesarean section.

BACKGROUND: Delayed umbilical cord clamping is associated with greater haemoglobin concentration and iron storage between 3 and 6 months of life and with less need of blood transfusion and lower incidence of neonatal hypotension compared to early umbilical cord clamping. METHODS: The aim was to test the hypothesis that delayed cord clamping is better than early cord clamping in term infants born by elective caesarean section. Group A was subjected to immediate cord clamping while in the Group B, the umbilical cord was clamped 1 min after birth. Primary aim was revealed the difference in pre-ductal saturation between two groups while secondary aim was investigating the difference in HR, Ht, bilirubin and glycaemia. Pre-ductal SpO2 and HR were recorded at 5 and 10 min after birth, T was analysed 10 min after birth, glycaemia was revealed at 120 min while Ht and bilirubin were collected at 72 h. RESULTS: 132 newborns were enrolled in the study and allocated in ratio 1:1 to group A or B. Delayed cord clamping did not improve SpO2, HR and T values compared to immediate cord clamping (p > 0,05). However, Group B showed greater haematocrit and bilirubin values at 72 h compared to Group A (56,71 ± 6663 vs 51,56 ± 6929; p < 0,05 and 8,54 ± 2,90 vs 7,06 ± 2,76; p < 0,05). Glycaemia value did not differ between two groups (p > 0,05). CONCLUSIONS: Group B did not reveal any differences in SpO2, HR, T and glycaemia compared to Group A. Group B showed greater values of haematocrit and bilirubin but without need of phototherapy. TRIAL REGISTRATION: Umbilical Cord Clamping: What Are the Benefits; NCT03878602. Registered 18 March 2019 retrospectively registered.

Effects of early nutrition and growth on brain volumes, white matter microstructure, and neurodevelopmental outcome in preterm newborns.

BackgroundThis study aimed to investigate the effect of nutrition and growth during the first 4 weeks after birth on cerebral volumes and white matter maturation at term equivalent age (TEA) and on neurodevelopmental outcome at 2 years' corrected age (CA), in preterm infants.MethodsOne hundred thirty-one infants born at a gestational age (GA) <31 weeks with magnetic resonance imaging (MRI) at TEA were studied. Cortical gray matter (CGM) volumes, basal ganglia and thalami (BGT) volumes, cerebellar volumes, and total brain volume (TBV) were computed. Fractional anisotropy (FA) in the posterior limb of internal capsule (PLIC) was obtained. Cognitive and motor scores were assessed at 2 years' CA.ResultsCumulative fat and enteral intakes were positively related to larger cerebellar and BGT volumes. Weight gain was associated with larger cerebellar, BGT, and CGM volume. Cumulative fat and caloric intake, and enteral intakes were positively associated with FA in the PLIC. Cumulative protein intake was positively associated with higher cognitive and motor scores (all P<0.05).ConclusionOur study demonstrated a positive association between nutrition, weight gain, and brain volumes. Moreover, we found a positive relationship between nutrition, white matter maturation at TEA, and neurodevelopment in infancy. These findings emphasize the importance of growth and nutrition with a balanced protein, fat, and caloric content for brain development.

Oxygen Use in Neonatal Care: A Two-edged Sword.

In the neonatal period, the clinical use of oxygen should be taken into consideration for its beneficial and toxicity effects. Oxygen toxicity is due to the development of reactive oxygen species (ROS) such as OH• that is one of the strongest oxidants in nature. Of note, generation of ROS is a normal occurrence in human and it is involved in a myriad of physiological reactions. Anyway an imbalance between production of oxidant species and antioxidant defenses, called oxidative stress, could affect various aspect of organisms' physiology and it could determine pathological consequences to living beings. Neonatal oxidative stress is essentially due to decreased antioxidants, increased ROS, or both. Studies have demonstrated that antioxidant capacity is lower in preterm newborns than term babies. This well-known deficiency of antioxidant factors is only a piece of a cohort of factors, which can be involved in the neonatal oxidative stress and the increased production of ROS may be a main factor. Mechanisms of ROS generation are: mitochondrial respiratory chain, free iron and Fenton reaction, inflammation, hypoxia and/or ischemia, reperfusion, and hyperoxia. Oxidative stress following hyperoxia has been recognized to be responsible for lung, central nervous system, retina, red blood cell injuries, and possibly generalized tissue damage. When supplemental oxygen is needed for care, it would be prudent to avoid changes and fluctuations in SpO2. The definition of the safest level of oxygen saturations in the neonate remains an area of active research. Currently, on the basis of the published evidences, the most suitable approach would be to set alarm limits between 90 and 95%. It should allow to avoid SpO2 values associated with potential hypoxia and/or hyperoxia. Although the usefulness of antioxidant protection in the neonatal period is still under investigation, the risk of tissue damage due to oxidative stress in perinatal period should not be underestimated.

Blue Light and Ultraviolet Radiation Exposure from Infant Phototherapy Equipment.

Phototherapy is the use of light for reducing the concentration of bilirubin in the body of infants. Although it has become a mainstay since its introduction in 1958, a better understanding of the efficacy and safety of phototherapy applications seems to be necessary for improved clinical practices and outcomes. This study was initiated to evaluate workers' exposure to Optical Radiation from different types of phototherapy devices in clinical use in Italy. During infant phototherapy the staff monitors babies periodically for around 10 min every hour, and fixation of the phototherapy beam light frequently occurs: almost all operators work within 30 cm of the phototherapy source during monitoring procedures, with most of them commonly working at ≤25 cm from the direct or reflected radiation beam. The results of this study suggest that there is a great variability in the spectral emission of equipments investigated, depending on the types of lamps used and some phototherapy equipment exposes operators to blue light photochemical retinal hazard. Some of the equipment investigated presents relevant spectral emission also in the UVA region. Taking into account that the exposure to UV in childhood has been established as an important contributing factor for melanoma risk in adults and considering the high susceptibility to UV-induced skin damage of the newborn, related to his pigmentary traits, the UV exposure of the infant during phototherapy should be "as low as reasonably achievable," considering that it is unnecessary to the therapy. It is recommended that special safety training be provided for the affected employees: in particular, protective eyewear can be necessary during newborn assistance activities carried out in proximity of some sources. The engineering design of phototherapy equipment can be optimized. Specific requirements for photobiological safety of lamps used in the phototherapy equipment should be defined in the safety product standard for such equipment.

Music provided through a portable media player (iPod) blunts pain during physical therapy.

This research studied, 25 adult patients who underwent physical therapy to assess the analgesic effect of distraction with the use of music during physical therapy. Patients randomly underwent physical therapy once with music provided by an iPod and once without music. In both sessions patients underwent identical physical procedures. At end of both sessions patients filled in 5-item questionnaire where they scored pain and other parameters, such as stress, enjoyment, interaction, and satisfaction, on 10-cm visual analog scale. The mean scores (range, 0-10) of the two sessions were statistically compared. Mean pain scores were significantly lower (p = .031) during the session in which patients received music (4.8 ± 2.5) than during the session without music (5.8 ± 2.3). The other items of the questionnaire did not disclose any statistically significant difference when the sessions with versus without music were compared. Enjoyment (8.5 ± 1.6), interaction (8.3 ± 1.9), and satisfaction (8.6 ± 1.7) scores with music did not significantly differ in the sessions without music (8.5 ± 2.1, 8.5 ± 1.9, and, 8.5 ± 1.5, respectively); mean stress score was, 3.9 in both sessions. The conclusion of the study is that music provided through a portable media player has an analgesic effect. This can be an effective analgesic strategy during painful physical therapy.

Resuscitation with supplementary oxygen induces oxidative injury in the cerebral cortex.

Isoprostanes, neuroprostanes, isofurans, and neurofurans have all become attractive biomarkers of oxidative damage and lipid peroxidation in brain tissue. Asphyxia and subsequent reoxygenation cause a burst of oxygen free radicals. Isoprostanes and isofurans are generated by free radical attacks of esterified arachidonic acid. Neuroprostanes and neurofurans are derived from the peroxidation of docosahexanoic acid, which is abundant in neurons and could therefore more selectively represent oxidative brain injury. Newborn piglets (age 12-36 h) underwent hypoxia until the base excess reached -20 mmol/L or the mean arterial blood pressure dropped below 15 mm Hg. They were randomly assigned to receive resuscitation with 21, 40, or 100% oxygen for 30 min and then ventilation with air. The levels of isoprostanes, isofurans, neuroprostanes, and neurofurans were determined in brain tissue (ng/g) isolated from the prefrontal cortex using gas chromatography-mass spectrometry (GC/MS) with negative ion chemical ionization (NICI) techniques. A control group underwent the same procedures and observations but was not submitted to hypoxia or hyperoxia. Hypoxia and reoxygenation significantly increased the levels of isoprostanes, isofurans, neuroprostanes, and neurofurans in the cerebral cortex. Nine hours after resuscitation with 100% oxygen for 30 min, there was nearly a 4-fold increase in the levels of isoprostanes and isofurans compared to the control group (P=0.007 and P=0.001) and more than a 2-fold increase in neuroprostane levels (P=0.002). The levels of neuroprostanes and neurofurans were significantly higher in the piglets that were resuscitated with supplementary oxygen (40 and 100%) compared to the group treated with air (21%). The significance levels of the observed differences in neuroprostanes for the 21% vs 40% comparison and the 21% vs 100% comparison were P<0.001 and P=0.001, respectively. For neurofurans, the P values of the 21% vs 40% comparison and the 21% vs 100% comparison were P=0.036 and P=0.025, respectively. Supplementary oxygen used for the resuscitation of newborns increases lipid peroxidation in brain cortical neurons, a result that is indicative of oxidative brain damage. These novel findings provide new knowledge regarding the relationships between oxidative brain injury and resuscitation with oxygen.

Is fetal pain a real evidence?

UNLABELLED: Due to the progress in fetal surgery, it is important to acquire data about fetal pain. MATERIAL AND METHODS: We performed a Medline research from 1995, matching the following key words: "pain" and "fetus", with the following: "subplate", "thalamocortical", "myelination", "analgesia", "anesthesia", "brain", "behavioral states", "substance p". We focused on: (a) fetal development of nociceptive pathways; (b) fetal electrophysiological, endocrinological and behavioral reactions to stimuli and pain. RESULTS: We retrieved 217 papers of which 157 were highly informative; some reported similar data or were only case-reports, and were not quoted. Most endocrinological, behavioral and electrophysiological studies of fetal pain are performed in the third trimester, and they seem to agree that the fetus in the 3rd trimester can experience pain. But the presence of fetal pain in the 2nd trimester is less evident. In favor of a 2nd trimester perception of pain is the early development of spino-thalamic pathways (approximately from the 20th week), and the connections of the thalamus with the subplate (approximately from the 23rd week). Against this possibility, some authors report the immaturity of the cortex with the consequent lack of awareness, and the almost continuous state of sleep of the fetus. CONCLUSIONS: Most studies disclose the possibility of fetal pain in the third trimester of gestation. This evidence becomes weaker before this date, though we cannot exclude its increasing presence since the beginning of the second half of the gestation.

Efficacy of Arnica Echinacea powder in umbilical cord care in a large cohort study.

BACKGROUND: Today healthy newborns are discharged after 48 h-72 h of life until umbilical cord (UC) detachment. Complications due to an inappropriate management are: erythema, edema, bleeding, omphalitis and sepsis. Hence the importance of a safe, effective, easy to do, and cheap method. AIM: This study tests the effects and the efficacy of arnica echinacea powder by evaluating the time of cord detachment and the risk of side effects in a large cohort of newborns. METHODS: 6323 babies were treated with Arnica Echinacea powder twice a day until cord stump detachment. Medications started in hospital ward and continued at home until stump detachment. RESULTS: The UC stump detachment occurred in 89.09% of newborns during the first 4 days of life. This percentage increase to 96.13% at 6 days. CONCLUSIONS: Our study demonstrates the efficacy and the safety of arnica echinacea in UC separation. No infections or even bacterial colonizations were found. The use of arnica echinacea reduces hospital costs as a consequence of complications. In addition arnica use is well received by medical staff and parents. In conclusion due to its potential benefits, low cost and feasibility, we recommend the use of arnica echinacea powder as routine procedure in all nurseries.

Current Italian practices regarding the management of hyperbilirubinaemia in preterm infants.

AIM: To assess the current practices existing in Italy for the management of jaundice in preterm infants as preliminary achievement to a call for national guidelines and establishment of a kernicterus registry. METHODS: A questionnaire (in Supporting Information online) was sent to the 109 level III neonatal units in Italy to ascertain existing guidelines for total bilirubin monitoring and treatment of hyperbilirubinaemia in preterm infants and occurrence of kernicterus. RESULTS: There was a 61% (67/109) response rate. Eighty-five per cent of responding units had either written guidelines coming from different literature sources or locally developed. The monitoring of bilirubin varied greatly in timing before, during and after jaundice development. Phototherapy and exchange transfusion were given to 56.0 ± 21.0% and 0.2 ± 0.4% of admitted preterm infants in participating centres. Five cases of kernicterus in preterm infants and eleven cases in term infants were documented over the last 10 years. CONCLUSION: The management of hyperbilirubinaemia in preterm infants is not uniform in Italy and would benefit from shared national guidance together with establishment of a kernicterus registry to guide therapy.

Superoxide dismutase and catalase activity in naturally derived commercial surfactants.

Despite the role of reactive oxygen species in the development of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants, the anti-oxidant properties of commercial surfactants have never been studied. We measured the superoxide dismutase (SOD) and catalase (CAT) activity, the scavenger activity against hydrogen peroxide (H(2)O(2)), and its changes after the addition of SOD and CAT in four natural surfactants, namely Infasurf, Curosurf, Survanta, and Alveofact. We found that they contain measurable amount of SOD and CAT. Curosurf and Survanta seem to have higher antioxidant effect than Infasurf and Alveofact. Moreover, the highest phospholipid concentration and recommended dose of Curosurf imply that its scavenger activity for each treatment dose in preterm infants is likely higher than that of Survanta. Finally, the supplementation with SOD and CAT induced a remarkable increase of antioxidant action in all studied surfactants.

Glutathione synthesis rates after amino acid administration directly after birth in preterm infants.

BACKGROUND: The availability of glutathione, the main intracellular antioxidant, is compromised in preterm neonates. A possible explanation is the low availability of substrate for synthesis, because many neonatologists are reluctant to administer amino acids in the direct postnatal period for fear of intolerance. OBJECTIVE: The objective of the study was to determine the effects of amino acid administration directly after birth on glutathione synthesis rates and markers of oxidative stress. DESIGN: Premature infants (<1500 g) received from birth onward either dextrose (control group; n = 10) or dextrose plus 2.4 g amino acids . kg (- 1) . d(-1) (intervention group; n = 10). On postnatal day 2, [1-(13)C]glycine was administered to determine glutathione fractional synthesis rates (FSR(GSH)) and absolute synthesis rates (ASR(GSH)) in erythrocytes. In plasma, advanced oxidized protein products and dityrosine, both markers of oxidative stress, were measured. The results are expressed as means +/- SDs. RESULTS: The FSR(GSH) was not different between groups: 44 +/- 6 and 48 +/- 9%/d in the control and intervention groups, respectively (P = 0.28). The concentration of erythrocyte glutathione was higher (P < 0.001) in the intervention group (2.28 +/- 0.35 mmol/L) than in the control group (1.73 +/- 0.37 mmol/L). ASR(GSH) values were 6.5 +/- 1.5 and 11.3 +/- 1.9 mg . kg(-1) . d(-1) in the control and intervention groups, respectively (P < 0.001). Advanced oxidized protein products and dityrosine concentrations were not significantly different between groups. CONCLUSIONS: Amino acid administration directly after birth increases ASR(GSH) in preterm infants. Our data are consistent, however, with higher glutathione concentrations rather than a higher FSR(GSH). Greater availability of glutathione, nevertheless, did not decrease markers of oxidative stress.

Oxidative stress and nutrition in the preterm newborn.

Oxidative stress occurs when the production of free radicals exceeds the cells' ability to eliminate them. Many events leading to overproduction of free radicals may easily induce oxidative stress in the earliest phases of human life. Given the growing role of oxidative stress in newborn preterm morbidity, one of the goals of modern neonatology is to minimize free radical production and promote the development of adequate antioxidant systems through an adequate nutritional strategy. Appropriate administration of total parenteral solutions and lipid emulsions with light protection can minimize the risk of peroxidation. Providing the baby with amino acid substrates for cellular glutathione synthesis immediately after birth promotes antioxidant defenses at the early stages of life. Breast milk has been found to have many advantages over formula, including the potential to provide antioxidant protection to infants. It is conceivable that these antioxidants in breast milk help to eliminate free radicals in infants. The role of vitamin administration in preterm nutrition has not yet been established. Clinical trials carried out to test the efficacy of antioxidant drugs or vitamins were inconclusive. At present, there are no evidence-based recommendations about the use of nutritional strategies or antioxidant drugs to minimize oxidative stress in the management of preterm infants.

Blink-startle reflex habituation in 30-34-week low-risk fetuses.

OBJECTIVE: To investigate whether the blink-startle reflex (BSR) is a good marker of habituation to vibroacoustic stimulation in healthy preterm fetuses. MATERIALS AND METHODS: A total of 22 women with uncomplicated pregnancies at 30-34 weeks participated in the study. Vibroacoustic stimulus was repeatedly applied to the maternal abdomen above the fetal head for a period of 2 s every 10 s. Fetal eye tightening monitored by ultrasound within 2 s of the stimulus was considered a positive response. The habituation rate was defined as the number of stimuli applied before the fetus stopped responding to two consecutive stimuli. Results were compared using the Mann-Whitney U-test. RESULTS: All 22 fetuses showed habituation at a rate that varied from 1 to 9 (mean 4.2+/-1.8). CONCLUSION: BSR is a good marker of habituation in preterm fetuses. Further study is needed to ascertain whether abnormal BSR habituation could be a sign of fetal distress.