Publications by authors named "Giuseppe Buonocore"

197 Publications

Sudden Infant Death Syndrome: Beyond Risk Factors.

Life (Basel) 2021 Feb 26;11(3). Epub 2021 Feb 26.

Department of Medicine and Surgery, University Hospital of Parma, 43126 Parma, Italy.

Sudden infant death syndrome (SIDS) is defined as "the sudden death of an infant under 1 year of age which remains unexplained after thorough investigation including a complete autopsy, death scene investigation, and detailed clinical and pathological review". A significant decrease of SIDS deaths occurred in the last decades in most countries after the beginning of national campaigns, mainly as a consequence of the implementation of risk reduction action mostly concentrating on the improvement of sleep conditions. Nevertheless, infant mortality from SIDS still remains unacceptably high. There is an urgent need to get insight into previously unexplored aspects of the brain system with a special focus on high-risk groups. SIDS pathogenesis is associated with a multifactorial condition that comprehends genetic, environmental and sociocultural factors. Effective prevention of SIDS requires multiple interventions from different fields. Developing brain susceptibility, intrinsic vulnerability and early identification of infants with high risk of SIDS represents a challenge. Progress in SIDS research appears to be fundamental to the ultimate aim of eradicating SIDS deaths. A complex model that combines different risk factor data from biomarkers and omic analysis may represent a tool to identify a SIDS risk profile in newborn settings. If high risk is detected, the infant may be referred for further investigations and follow ups. This review aims to illustrate the most recent discoveries from different fields, analyzing the neuroanatomical, genetic, metabolic, proteomic, environmental and sociocultural aspects related to SIDS.
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http://dx.doi.org/10.3390/life11030184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996806PMC
February 2021

Isoprostanes as Biomarker for White Matter Injury in Extremely Preterm Infants.

Front Pediatr 2020 15;8:618622. Epub 2021 Jan 15.

Department of Neonatology, University Medical Center Utrecht and Utrecht University, Utrecht, Netherlands.

Preterm white matter is vulnerable to lipid peroxidation-mediated injury. F2-isoprostanes (IPs), are a useful biomarker for lipid peroxidation. Aim was to assess the association between early peri-postnatal IPs, white matter injury (WMI) at term equivalent age (TEA), and neurodevelopmental outcome in preterm infants. Infants with a gestational age (GA) below 28 weeks who had an MRI at TEA were included. IPs were measured in cord blood (cb) at birth and on plasma (pl) between 24 and 48 h after birth. WMI was assessed using Woodward MRI scoring system. Multiple regression analyses were performed to assess the association between IPs with WMI and then with BSITD-III scores at 24 months corrected age (CA). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of pl-IPs for the development of WMI. Forty-four patients were included. cb-IPs were not correlated with WMI score at TEA, whereas higher pl-IPs and lower GA predicted higher WMI score ( = 0.037 and 0.006, respectively) after controlling for GA, FiO2 at sampling and severity of IVH. The area under the curve was 0.72 (CI 95% = 0.51-0.92). The pl-IPs levels plotted curve indicated that 31.8 pg/ml had the best predictive threshold with a sensitivity of 86% and a specificity of 60%, to discriminate newborns with any WMI from newborns without WMI. IPs were not associated with outcome at 24 months. Early measurement of pl-IPs may help discriminate patients showing abnormal WMI score at TEA, thus representing an early biomarker to identify newborns at risk for brain injury.
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http://dx.doi.org/10.3389/fped.2020.618622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874160PMC
January 2021

Isoprostanes as Biomarker for Patent Ductus Arteriosus in Preterm Infants.

Front Pediatr 2020 8;8:555. Epub 2020 Sep 8.

Division of Neonatology, Careggi University Hospital of Florence, Florence, Italy.

It has been reported that isoprostanes (IPs) have a role in the pathophysiology of ductus arteriosus during the fetal and neonatal period. Our aim in this study was to assess if urinary IPs (uIPs) levels correlate with the risk of developing a hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. Infants with 23 + 0 - 33 + 6 weeks of gestational age and respiratory distress syndrome (RDS) were consecutively enrolled. Urine samples were collected on the 2nd and 10th day of life (DOL) for uIPs measurement. Echocardiography for hsPDA diagnosis was performed between 24 and 48 h of life. Regression analysis was performed to assess the correlation between uIPs and hsPDA. Receiver operating characteristic (ROC) curve analysis was used to evaluate the accuracy of the uIPs in predicting the occurrence of hsPDA. Sixty patients were studied: 33 (55%) developed a hsPDA, 27 (45%) had ibuprofen hsPDA closure, and six (10%) required surgical closure. uIPs levels decreased from the 2nd to the 10th DOL. Adjusted regression analysis demonstrated that uIPs on the 2nd DOL were associated ( = 0.02) with the risk of developing a hsPDA. A cut-off level of 1627 ng/mg of creatinine of uIPs predicted the development of a hsPDA with a sensitivity of 82% and a specificity of 73%. Early measurement of uIPs on the 2nd DOL is a reliable biomarker of hsPDA development and, alone or combined with other markers, might represent a non-invasive tool useful for planning the management of PDA in preterm infants.
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http://dx.doi.org/10.3389/fped.2020.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506157PMC
September 2020

The challenge to define the optimal prophylactic regimen for vitamin K deficiency bleeding in infants.

Acta Paediatr 2021 04 6;110(4):1113-1118. Epub 2020 Oct 6.

Department of Medicine and Surgery, University of Parma, Parma, Italy.

Infants are at risk of vitamin K deficiency that may lead to vitamin K deficiency bleeding (VKDB). Although many vitamin K prophylactic regimens have been developed throughout the years, still cases of late form VKBD may occur. The introduction of combined prophylactic strategy with prolonged oral prophylaxes after the intramuscular dose at birth has showed a decrease of the late severe VKDB incidence. Nevertheless, there is still lack of consensus about the administration scheme after the first dose at birth. CONCLUSION: Late form VKBD is not eradicated, and the best prophylactic regimen in term and preterm infants is still an open debate.
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http://dx.doi.org/10.1111/apa.15566DOI Listing
April 2021

Management of pain in newborn circumcision: a systematic review.

Eur J Pediatr 2021 Jan 3;180(1):13-20. Epub 2020 Aug 3.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Male circumcision (MC) is one of the most common surgical procedures performed on neonates. In the last decades, there have been consistent advances in the understanding of pain mechanisms in newborns, and analgesia has become a fundamental part of neonatal care. MC is still often performed with inappropriate analgesic methods, and there is still great variability among the various centers about surgical and anesthethic techniques to do it. The purpose of this review is to summarize the findings in the literature about pain management and analgesia during newborn MC. We performed a systematic review of neonatal MC studies published in the last 20 years. The most effective technique appeared to be the combination of pharmacological and non-pharmacological methods of analgesia.Conclusion: Combining local anesthesia with non-pharmacological analgesic strategies appears to be effective preventing procedural pain during MC. However, a standardized protocol for analgesia during MC is yet to be determined. Sensorial saturation appeared to help when used in conjunction with the local anesthesia techniques. What is Known: • Male circumcision is a painful procedure and it is frequently performed with inappropriate analgesic methods. • A gold standard practice in analgesia during male circumcision is still lacking and there is a great variability in the modus operandi between centers. What is New: • The combination of RB + EMLA + sucrose appears to be an analgesic strategy superior to other approaches. • We advocate for the integration of sensorial saturation during male circumcision in order to improve the efficacy of current analgesic practices.
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http://dx.doi.org/10.1007/s00431-020-03758-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782363PMC
January 2021

Review of guidelines and recommendations from 17 countries highlights the challenges that clinicians face caring for neonates born to mothers with COVID-19.

Acta Paediatr 2020 Nov 20;109(11):2192-2207. Epub 2020 Aug 20.

Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Aim: This review examined how applicable national and regional clinical practice guidelines and recommendations for managing neonates born to mothers with COVID-19 mothers were to the evolving pandemic.

Methods: A systematic search and review identified 20 guidelines and recommendations that had been published by May 25, 2020. We analysed documents from 17 countries: Australia, Brazil, Canada, China, France, India, Italy, Japan, Saudi Arabia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, the UK and the United States.

Results: The documents were based on expert consensus with limited evidence and were of variable, low methodological rigour. Most did not provide recommendations for delivery methods or managing symptomatic infants. None provided recommendations for post-discharge assimilation of potentially infected infants into the community. The majority encouraged keeping mothers and infants together, subject to infection control measures, but one-third recommended separation. Although breastfeeding or using breastmilk was widely encouraged, two countries specifically prohibited this.

Conclusion: The guidelines and recommendations for managing infants affected by COVID-19 were of low, variable quality and may be unsustainable. It is important that transmission risks are not increased when new information is incorporated into clinical recommendations. Practice guidelines should emphasise the extent of uncertainty and clearly define gaps in the evidence.
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http://dx.doi.org/10.1111/apa.15495DOI Listing
November 2020

Personality, emotional and cognitive functions in young adults born preterm.

Brain Dev 2020 Nov 9;42(10):713-719. Epub 2020 Jul 9.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy. Electronic address:

Background: Survival of preterm very low birthweight infants resulted in high risk for developmental cognitive deficits, poor academic achievement, and behaviour disorders. While numerous studies evaluated the prevalence of neurodevelopmental disability in early childhood, poor literature is available for infants born very low birthweight in adulthood.

Materials And Methods: Fifty-five young adults born preterm (mean age: 18 ± 2.42 years; <33 weeks of gestational age and/or with birth weight <1500 g) were enrolled. The Verbal Intelligence Quotient (vIQ), Performance Intelligence Quotient (pIQ) and Total Intelligence Quotient (tIQ) were assessed through the Wechsler Adult Intelligence Scale - Revised (WAIS-R). Personality profiles were investigated using Rorschach test. Both WAIS-R and Rorschach scores were subsequently compared to 13 matched controls born at term. Data were analysed with the SPSS v20 for Windows statistical package.

Results: Young adults born preterm showed lower IQ scores than young adults born at term: tIQ 90.95 ± 22.46 versus 108.77 ± 16.14, p = 0.006; vIQ 89.85 ± 21.85 versus 107.69 ± 18.33, p = 0.009, and pIQ 92.40 ± 22.90 versus 108.31 ± 14.52, p = 0.011. No differences emerged in personality profile as most subjects showed adequate internal resources in both groups, but a trend towards anxiety and insecurity were identified in young adult born preterm.

Conclusions: Young adults born preterm show psychological fragility and lower cognitive pattern than young adults born at term. Data support the need of an early psychological intervention that could help these individuals at greater risk to face a young society that is changing and that necessarily requires stronger internal resources.
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http://dx.doi.org/10.1016/j.braindev.2020.06.014DOI Listing
November 2020

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

Ital J Pediatr 2020 May 24;46(1):71. Epub 2020 May 24.

Department of Medicine and Surgery, University of Parma, Parma, Italy.

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 SpO 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 SpO 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 SpO, 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.
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http://dx.doi.org/10.1186/s13052-020-00835-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247269PMC
May 2020

Predict respiratory distress syndrome by umbilical cord blood gas analysis in newborns with reassuring Apgar score.

Ital J Pediatr 2020 Feb 12;46(1):20. Epub 2020 Feb 12.

Department of Medicine and Surgery, University of Parma, Parma, Italy.

Background: Neonatal acidaemia at birth can increase neonatal morbidity and mortality and it is predictive of neonatal asphyxia. The umbilical blood gas analysis is a valid tool for the evaluation of neonatal acidaemia. However, umbilical cord blood gas analysis is commonly performed in high-risk situations or in the setting of Apgar scores < 7 at 5 min.

Methods: A retrospective cohort study was conducted from June to December 2018 at the Department of mother's and child's health, Poliambulanza Foundation Hospital Institute. Inclusion criteria were: full term newborns with body weight appropriate for gestational age, born by vaginal delivery or caesarean section, reassuring Apgar Score > 7 at 5 min, arterial cord blood gas analysis showing pH < 7.4 or BE <-8 mmol/l or lactate > 6 mmol/l. The aim was to evaluate the predictive role of blood gas analysis for respiratory distress syndrome in newborns with reassuring Apgar Score.

Results: 352 full term newborns were enrolled. Umbilical cord blood artery pH showed an association with respiratory distress syndrome (χ(1) = 10,084, OR (95% CI): 3,9 × 10(2,9 × 10 - 0,048); p < 0,05). ROC curve revealed that the cut-off point of pH was 7.12, with a sensibility and specificity of 68 and 63%, respectively.

Conclusions: Umbilical cord blood artery pH < 7.12 at birth is associated to respiratory distress syndrome in newborns. Blood gas analysis is an important instrument to help health care providers during assistance in the delivery room, but also to early identify newborns at high risk for respiratory distress syndrome and better manage the care of these newborns after birth.
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http://dx.doi.org/10.1186/s13052-020-0786-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017611PMC
February 2020

Oxidative stress biomarkers in the perinatal period: Diagnostic and prognostic value.

Semin Fetal Neonatal Med 2020 04 23;25(2):101087. Epub 2020 Jan 23.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Perinatal oxidative stress (OS) is involved in the physiopathology of many pregnancy-related disorders and is largely responsible for cellular, tissue and organ damage that occur in the perinatal period especially in preterm infants, leading to the so-called "free-radicals related diseases of the newborn". Reliable biomarkers of lipid, protein, DNA oxidation and antioxidant power in the perinatal period have been demonstrated to show specificity for the disease, to have prognostic power or to correlate with disease activity. Yet potential clinical applications of oxidative stress biomarkers in neonatology are still under study. Overcoming the technical and economic difficulties that preclude the use of OS biomarkers in the clinical practice is a challenge that needs to be overcome to identify high-risk subjects and to predict their short- and long-term outcome. Cord blood, urine and saliva represent valid and ethically acceptable biological samples for investigations in the perinatal period.
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http://dx.doi.org/10.1016/j.siny.2020.101087DOI Listing
April 2020

Newborn metabolomic profile mirrors that of mother in pregnancy.

Med Hypotheses 2020 Apr 27;137:109543. Epub 2019 Dec 27.

Department of Molecular and Developmental Medicine, University of Siena, Italy.

Background: Pregnancy is characterized by multiple metabolic processes to allow proper foetal development and ensure adequate stores. Little is known about the interactions between maternal and foetal metabolism during the last phase of pregnancy. Metabolomic offers potential to discover changes in maternal metabolism in pregnancy and their relation to the newborn metabolic status.

Objective: In this study we tested the hypothesis that metabolomic status in newborns at birth depends upon the metabolomic profile of their mothers in the last phase of pregnancy.

Study Design: Urine samples were collected from 36 pregnant women three weeks before delivery and from 21 healthy term newborns within 48 h after birth. Urines were analysed using proton nuclear magnetic resonance (1H NMR) spectroscopy and NMR urine spectra were evaluated through Principal Components Analysis.

Results: The first component of the PCA analysis showed two distinct metabolic groups: pregnant women and newborns. A significant correlation was found between urine metabolic profiles of newborns and those of their mothers.

Conclusion: Urine metabolomic profiles of newborns at birth mirrors that of their mothers in the last phase of pregnancy. The metabolomic approach appears to be crucial to understand the maternal effects on foetal programming and infant outcomes.
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http://dx.doi.org/10.1016/j.mehy.2019.109543DOI Listing
April 2020

Magnetic Resonance Imaging in Pregnancy with Intrauterine Growth Restriction: A Pilot Study.

Dis Markers 2019 16;2019:4373490. Epub 2019 Nov 16.

Department of Molecular and Developmental Medicine, University of Siena, Italy.

Objective: Intrauterine growth restriction (IUGR) is a major cause of late stillbirth, though not all compromised babies remain small or are considered growth restricted as pregnancy progresses. Fetal Magnetic Resonance Imaging (f-MRI) represents a second-line tool to study pregnancies with IUGR fetuses. The aim of our study was to evaluate the usefulness of f-MRI on predicting fetal growth and the offspring's perinatal respiratory outcome.

Design: All f-MRI performed between 2014 and 2016 in Siena were analysed. Pregnancies with IUGR (Study group (SG)) were recruited together with a control population (Control group (CG)), coupled for gestational age (GA) at the time of f-MRI (mean GA 31 wks). Neonatal information was collected. The f-MRI protocol consisted of T2w images. Six regions of interest (ROI) were placed as follows: 2 on the lung, 2 on the liver, and 2 on the amniotic fluid. The signal intensities (SI) of each ROI were measured. The SI lung to liver ratio (SI lung/liver) and SI lung to amniotic fluid ratio (SI lung/amniotic fluid) were obtained for each fetus. Each ratio was compared between SG and CG. Therefore, SG was divided into two subgroups: adequate and small for gestational age (AGA and SGA) newborns. All measurements were related to offspring's perinatal respiratory outcome.

Results: SI lung/liver was linearly related with GA at the time of f-MRI and with EFW. SI lung/amniotic fluid was significantly higher in SG than in CG ( = 0,014). In contrast, among SG, lower values of SI lung/amniotic fluid were found in the SGA compared to AGA ( = 0,036). The days of oxygen supply were higher in the SGA subgroup than in the AGA subgroup ( = 0,028).

Conclusions: SI lung/liver increases with fetal lung maturation and appears to be useful to estimate intrauterine fetal growth. SI lung/amniotic fluid seems to be a reliable predictive index to distinguish the IUGR fetuses that can recover their growth from those that were born SGA. f-MRI represents a promising frontier to predict IUGR fetus outcome, thus contributing to ameliorate the perinatal management.
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http://dx.doi.org/10.1155/2019/4373490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881754PMC
May 2020

Pre-surgery urine metabolomics may predict late neurodevelopmental outcome in children with congenital heart disease.

Heliyon 2019 Oct 1;5(10):e02547. Epub 2019 Oct 1.

Department of Molecular and Developmental Medicine, University of Siena, Viale Bracci, Siena, 53100, Italy.

Background: From fetal life until cardiac surgery, complex congenital heart diseases (CHD) exhibit different hemodynamic and oxygenation patterns that can lead to alteration of the metabolic profile. We used a metabolomic approach to identify urine metabolic markers before cardiac surgery, aiming to define the physiology of patients with complex CHD and to contribute to predict their neurodevelopmental outcome.

Methods: In a prospective, observational, single-center study we enrolled 28 patients with complex biventricular and univentricular CHD aged less than 5 years, on stable hemodynamic conditions, and with no genetic anomalies. We analyzed urine samples, collected at the induction of anesthesia, by 1H NMR spectroscopy. Profiles of 1H NMR spectra were submitted to unsupervised (principal component) and supervised (partial least squares-discriminant) multivariate analysis. Neurodevelopment was assessed by neuropsychological and adaptive functioning testing.

Results: Principal components analysis divided CHD patients metabolic profiles in two distinct clusters (RED and BLACK). Metabolic profiles belonging to the RED cluster showed higher levels of accumulation of citric acid cycle intermediates and glucose compared to the profiles in the BLACK cluster, indicating a possible switching to anaerobic metabolism. Patients belonging to the RED cluster were significantly more prone to show an adverse neurodevelopment pattern (p = 0.01).

Conclusions: The application of metabolomic analysis to CHD children permitted a deeper insight on their metabolic status that could help to obtain a better understanding of the physiological implications and to predict long-term neurodevelopmental outcome.
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http://dx.doi.org/10.1016/j.heliyon.2019.e02547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812188PMC
October 2019

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Front Pediatr 2019 7;7:180. Epub 2019 May 7.

Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a β-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results.   The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.
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http://dx.doi.org/10.3389/fped.2019.00180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514240PMC
May 2019

Preface.

Curr Pediatr Rev 2019 ;15(1)

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

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http://dx.doi.org/10.2174/157339631501190405115626DOI Listing
May 2019

Biomarkers of oxidative stress in the fetus and in the newborn.

Free Radic Biol Med 2019 10 5;142:23-31. Epub 2019 Apr 5.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

The dynamic field of perinatology entails ever-increasing search for molecular mechanisms of neonatal diseases, especially in the domain of fetal growth and neurodevelopmental outcome. There is an urgent need for new molecular biomarkers, to early identify newborn at high risk for developing diseases and to provide new treatment targets. The interest in biomarkers of oxidative stress in perinatal period have begun to grow in the last century, when it was evidenced the importance of the free radicals generation underlying the various disease conditions. To date, interesting researches have been carried out, representing milestones for implementation of oxidative stress biomarkers in perinatal medicine. Use of a panel of "oxidative stress biomarkers", particularly non protein bound iron, advanced oxidative protein products and isoprostanes, may provide valuable information regarding functional pathways underlying free radical mediated diseases of newborns and their early identification and prevention. Here, we will review recent advances and the current knowledge on the application of biomarkers of oxidative stress in neonatal/perinatal medicine including novel biomarker discovery, defining yet unrecognized biologic therapeutic targets, and linking of oxidative stress biomarkers to relevant standard indices and long-term outcomes.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.03.034DOI Listing
October 2019

Breast milk: To each his own. From metabolomic study, evidence of personalized nutrition in preterm infants.

Nutrition 2019 06 25;62:158-161. Epub 2019 Jan 25.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Objectives: The composition of milk from mothers delivering prematurely differs from that of full-term mature milk and changes over time. The aim of this study is to test the hypothesis that changes in milk metabolomic profile from mothers delivering prematurely persist over time when compared with mothers delivering at term.

Methods: Nuclear magnetic resonance spectroscopy was used to analyze the metabolome pattern of human milk samples collected from 18 mothers. Twelve mothers collected 12 term milk samples (one for each mother) once between 4 and 7 d after delivery. Six mothers delivering prematurely (29-31 wk of gestational age) and collected three samples each, once a week after delivery until the third week after birth.

Results: Principal component analysis identified two distinct metabolite groups, one represented by the 18 preterm milk samples and the other by term milk samples. Metabolite profiling identified that lactose and oligosaccharide levels were significantly more represented in preterm than in milk term samples.

Conclusions: The preterm milk metabolome pattern undergoes maturation during the first 3 wk after birth, but at the end of the third week it still does not resemble the term milk pattern. The specific changes in mothers' milk metabolomic profiles according to their offspring might reflect the different nutritional requirement of each preterm infant. This knowledge is crucial to move from standardized nutritional protocols to tailored, individualized nutrition in preterm infants.
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http://dx.doi.org/10.1016/j.nut.2018.12.015DOI Listing
June 2019

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia.

J Pineal Res 2019 May 18;66(4):e12565. Epub 2019 Mar 18.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Introduction: Neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia may benefit from adjunctive therapy with melatonin. However, melatonin safety, pharmacokinetics (PK), and dosage in this sensitive population are still unknown.

Methods And Results: This study assessed the PK and safety of melatonin enteral administration to neonates with HIE undergoing hypothermia. Melatonin was infused at 0.5 mg/kg in five neonates with HIE undergoing hypothermia. Infusion started 1 hour after the neonates reached the target temperature of 33.5°C. Blood samples were collected before and at selective times after melatonin infusion. Abdominal complications or clinically significant changes in patients' vital signs were not found during or after melatonin. The peak plasma concentration reached 0.25 µg/mL. The area under the curve in 24 hours was 4.35 µg/mL*h.

Discussion: Melatonin half-life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK. In humans high blood concentrations with lower doses can be achieved compared to animal experimentation, although intravenous administration is advised in the neonate population. Our study is a preparatory step for future clinical studies aimed at assessing melatonin efficacy in HIE.
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http://dx.doi.org/10.1111/jpi.12565DOI Listing
May 2019

Oral 24% sucrose associated with nonnutritive sucking for pain control in healthy term newborns receiving venipuncture beyond the first week of life.

J Pain Res 2019 8;12:299-305. Epub 2019 Jan 8.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy,

Objective: To test the hypothesis that oral administration of 24% sucrose associated with nonnutritive sucking in healthy newborns receiving venipuncture beyond the first week of life controls pain and pain-related variation in heart rate (HR) and noninvasive oxygen saturation (SpO).

Methods: A total of 66 term newborns were enrolled between February and September 2017 in the Neonatology Department of AORN Santobono-Pausilipon, Naples. They were randomly assigned to receive oral 1 mL 24% sucrose (treated group [TG], n=33; gestational age 38.53±1.49 weeks; body weight 3,035±55 g; age 22.40±6.82 weeks) or oral 1 mL 10% glucose (control group [CG], n=33; gestational age 38.91±1.45 weeks; body weight 3,203±65 g; age 23.36±7.02 weeks) 1 minute before and during venipuncture. Evaluations were carried out between 8 and 9 am in all newborns. The Neonatal Infant Pain Scale (NIPS) was used to assess pain in newborns. Outcome measurements (HR, SpO) were obtained before (T0), during (T1), and 1 minute after (T2) venipuncture using a Nellcor bedside SpO patient-monitoring system. NIPS scores were recorded throughout the procedure. Statistical analysis was performed using SPSS version 20.0. Changes in HR and SpO were assessed by mixed ANOVA for repeated measures. NIPS scores were evaluated by Mann-Whitney test.

Results: There were no statistically significant differences in HR or SpO between TG and CG at T0. HR was significantly lower in TG than CG at both T1 and T2 (<0.05), whereas SpO was significantly higher in TG than CG at both T1 and T2 (<0.05). NIPS scores were significantly lower in TG (median 0) than CG (median 6) during the entire procedure (<0.05).

Conclusion: Oral administration of 24% sucrose associated with nonnutritive sucking prior to and during a painful procedure has a strong impact on pain response in term newborns, reducing NIPS scores and influencing pain-associated variations in HR and SpO. Complete analgesia during painful procedures in term newborns might prevent pain reactivity and its behavioral and neurodevelopmental consequences. Replication of this study is needed before widespread application of findings.
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http://dx.doi.org/10.2147/JPR.S184504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329346PMC
January 2019

Oxidative Stress as a Primary Risk Factor for Brain Damage in Preterm Newborns.

Front Pediatr 2018 29;6:369. Epub 2018 Nov 29.

Neonatal Intensive Care Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy.

The risk of oxidative stress is high in preterm newborns. Room air exposure of an organism primed to develop in a hypoxic environment, lacking antioxidant defenses, and subjected to hyperoxia, hypoxia, and ischemia challenges the newborn with oxidative stress production. Free radicals can be generated by a multitude of other mechanisms, such as glutamate excitotoxicity, excess free iron, inflammation, and immune reactions. Free radical-induced damage caused by oxidative stress appears to be the major candidate for the pathogenesis of most of the complications of prematurity, brain being especially at risk, with short to long-term consequences. We review the role of free radical oxidative damage to the newborn brain and propose a mechanism of oxidative injury, taking into consideration the particular maturation-dependent vulnerability of the oligodendrocyte precursors. Prompted by our observation of an increase in plasma Adenosine concentrations significantly associated with brain white matter lesions in some premature infants, we discuss a possible bioenergetics hypothesis, correlated to the oxidative challenge of the premature infant. We aim at explaining both the oxidative stress generation and the mechanism promoting the myelination disturbances. Being white matter abnormalities among the most common lesions of prematurity, the use of Adenosine as a biomarker of brain damage appears promising in order to design neuroprotective strategies.
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http://dx.doi.org/10.3389/fped.2018.00369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281966PMC
November 2018

Predictive Role of Urinary Metabolic Profile for Abnormal MRI Score in Preterm Neonates.

Dis Markers 2018 1;2018:4938194. Epub 2018 Oct 1.

Department of Neonatology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Background And Objective: Early identification of neonates at risk for brain injury is important to start appropriate intervention. Urinary metabolomics is a source of potential, noninvasive biomarkers of brain disease. We studied the urinary metabolic profile at 2 and 10 days in preterm neonates with normal/mild and moderate/severe MRI abnormalities at term equivalent age.

Methods: Urine samples were collected at two and 10 days after birth in 30 extremely preterm infants and analyzed using proton magnetic resonance spectroscopy. A 3 T MRI was performed at term equivalent age, and images were scored for white matter (WM), cortical grey matter (cGM), deep GM, and cerebellar abnormalities. Infants were divided in two groups: normal/mild and moderately/severely abnormal MRI scores.

Results: No significant clustering was seen between normal/mild and moderate/severe MRI scores for all regions at both time points. The ROC curves distinguished neonates at 2 and 10 days who later developed a markedly less mature cGM score from the others (2 d: area under the curve (AUC) = 0.72, specificity (SP) = 65%, sensitivity (SE) = 75% and 10 d: AUC = 0.80, SP = 78%, SE = 80%) and a moderately to severely abnormal WM score (2 d: AUC = 0.71, specificity (SP) = 80%, sensitivity (SE) = 72% and 10 d: AUC = 0.69, SP = 64%, SE = 89%).

Conclusions: Early urinary spectra of preterm infants were able to discriminate metabolic profiles in patients with moderately/severely abnormal cGM and WM scores at term equivalent age. Urine spectra are promising for early identification of neonates at risk of brain damage and allow understanding of the pathogenesis of altered brain development.
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http://dx.doi.org/10.1155/2018/4938194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191951PMC
February 2019

Culture-Negative Early-Onset Neonatal Sepsis - At the Crossroad Between Efficient Sepsis Care and Antimicrobial Stewardship.

Front Pediatr 2018 9;6:285. Epub 2018 Oct 9.

Neonatal and Pediatric Intensive Care Unit, Children's Hospital, Lucerne, Switzerland.

Sepsis is a leading cause of mortality and morbidity in neonates. Presenting clinical symptoms are unspecific. Sensitivity and positive predictive value of biomarkers at onset of symptoms are suboptimal. Clinical suspicion therefore frequently leads to empirical antibiotic therapy in uninfected infants. The incidence of culture confirmed early-onset sepsis is rather low, around 0.4-0.8/1000 term infants in high-income countries. Six to 16 times more infants receive therapy for culture-negative sepsis in the absence of a positive blood culture. Thus, culture-negative sepsis contributes to high antibiotic consumption in neonatal units. Antibiotics may be life-saving for the few infants who are truly infected. However, overuse of broad-spectrum antibiotics increases colonization with antibiotic resistant bacteria. Antibiotic therapy also induces perturbations of the non-resilient early life microbiota with potentially long lasting negative impact on the individual's own health. Currently there is no uniform consensus definition for neonatal sepsis. This leads to variations in management. Two factors may reduce the number of culture-negative sepsis cases. First, obtaining adequate blood cultures (0.5-1 mL) at symptom onset is mandatory. Unless there is a strong clinical or biochemical indication to prolong antibiotics physician need to trust the culture results and to stop antibiotics for suspected sepsis within 36-48 h. Secondly, an international robust and pragmatic neonatal sepsis definition is urgently needed. Neonatal sepsis is a dynamic condition. Rigorous evaluation of clinical symptoms ("organ dysfunction") over 36-48 h in combination with appropriately selected biomarkers ("dysregulated host response") may be used to support or refute a sepsis diagnosis.
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http://dx.doi.org/10.3389/fped.2018.00285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189301PMC
October 2018

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures.

Neonatology 2018 28;114(4):364-371. Epub 2018 Aug 28.

Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino,

Background: Hypoxic-ischemic encephalopathy is a major cause of neonatal morbidity. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Thus, adjunctive therapies, such as melatonin, are needed to provide additional neuroprotection.

Objectives: The aim of this study was to determine a range of melatonin concentrations that could result in neuroprotective synergy with hypothermia.

Methods: Hypoxia-ischemia was simulated by transient oxygen-glucose deprivation (OGD) in organotypic hippocampal slice cultures derived from neonatal rats. Cell damage was quantified by propidium iodide (PI) labeling.

Results: Melatonin reduced OGD- induced cell death in a concentration-dependent manner (1-100 μM) with an EC50 of about 25 μM. Hypothermia attenuated cell death in a time-dependent manner, with a nearly full protection upon 24-h exposure (78%) and partial protection (40%) upon 6-h exposure. When submaximal effective concentrations of melatonin (25 or 50 μM, resulting in 54 and 64% protection) were combined with 6 h of hypothermia, nearly full protection (73 and 78%, respectively; p < 0.05 and p < 0.01) was observed.

Conclusion: Melatonin acts in synergy with hypothermia in attenuating OGD-induced damage in organotypic hippocampal cultures. This reductionist approach allows the determination of a range of concentrations of melatonin capable of enhancing hypothermic neuroprotection. This information, coupled with pharmacokinetic data, will help to define the therapeutic dosage of melatonin in vivo and, ultimately, in patients.
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http://dx.doi.org/10.1159/000491859DOI Listing
September 2019

Identification of a panel of cytokines in neonates with hypoxic ischemic encephalopathy treated with hypothermia.

Cytokine 2018 11 22;111:119-124. Epub 2018 Aug 22.

Department of Molecular and Developmental Medicine, General Hospital "Santa Maria alle Scotte", University of Siena, Italy.

Purpose: Inflammation is a crucial but understudied mechanism of neuronal injury after hypoxia-ischemia. The aim was to identify a panel of cytokines involved in brain injury in neonates with hypoxic ischemic encephalopathy (HIE).

Methods: Ten newborns with HIE undergoing to therapeutic hypothermia (TH, HIE Group) and 8 healthy newborns (CTRL Group) were enrolled. For the HIE group, 5 samples were collected: between 0 and 6 h of life (time 1), 12 h (time 2), 24 h (time 3), 48 h (time 4) and 96 h of life (time 5). For the CTRL group, one sample was collected. A panel of 48 inflammatory cytokines was determined in all samples. Data were analyzed using multivariate statistical analysis (Principal component analysis, PCA) RESULTS: 17 cytokines, among 48 analyzed, were found to be significantly different, initially, between the CTRL and HIE groups: 12 with reported pro-inflammatory effects and 5 with reported anti-inflammatory effects. In the HIE group cytokines showed a decreasing trend during the TH and at the end of treatment comparable to the CTRL group. IL-18 did demonstrate a slight increase at time 3 during HT but decreased steadily at sampling times, 4 and 5.

Conclusions: Our data demonstrates that many pathways of the inflammatory cascade are activated following hypoxic-ischemic injury. This information will increase our understanding of changes in cytokines over time in neonates with HIE undergoing TH.
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http://dx.doi.org/10.1016/j.cyto.2018.08.011DOI Listing
November 2018

The Free Radical Diseases of Prematurity: From Cellular Mechanisms to Bedside.

Oxid Med Cell Longev 2018 24;2018:7483062. Epub 2018 Jul 24.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

During the perinatal period, free radicals (FRs) are involved in several physiological roles such as the cellular responses to noxia, the defense against infectious agents, the regulation of cellular signaling function, and the induction of a mitogenic response. However, the overproduction of FRs and the insufficiency of an antioxidant mechanism result in oxidative stress (OS) which represents a deleterious process and an important mediator of damage to the placenta and the developing fetus. After birth, OS can be magnified by other predisposing conditions such as hypoxia, hyperoxia, ischemia, hypoxia ischemia-reperfusion, inflammation, and high levels of nonprotein-bound iron. Newborns are particularly susceptible to OS and oxidative damage due to the increased generation of FRs and the lack of adequate antioxidant protection. This impairment of the oxidative balance has been thought to be the common factor of the so-called "free radical related diseases of prematurity," including retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, kidney damage, and oxidative hemolysis. In this review, we provide an update focused on the factors influencing these diseases refining the knowledge about the role of OS in their pathogenesis and the current evidences of such relationship. Mechanisms governing FR formation and subsequent OS may represent targets for counteracting tissue damage.
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http://dx.doi.org/10.1155/2018/7483062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081521PMC
October 2018

Using the pain principle to provide a new approach to invasive treatments and end-of-life care.

Acta Paediatr 2019 02 17;108(2):206-207. Epub 2018 Sep 17.

Department of Pediatrics, University of Siena, Siena, Italy.

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http://dx.doi.org/10.1111/apa.14535DOI Listing
February 2019

Regional differences of hypothermia on oxidative stress following hypoxia-ischemia: a study of DHA and hypothermia on brain lipid peroxidation in newborn piglets.

J Perinat Med 2018 Dec;47(1):82-89

Department of Pediatric Research, Institute of Surgical Research, University of Oslo, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Background Oxidative stress plays an important part in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) and is reliably measured through prostanoids following lipid peroxidation of polyunsaturated fatty acids (PUFAs). The aim of the study is to measure oxidative stress in the prefrontal cortex, white matter and hippocampus in the brains of hypoxic-ischemic piglets treated with docosahexaenoic acid (DHA) and therapeutic hypothermia (TH) and investigate the additive effects of DHA on hypothermia by factorial design. Methods Fifty-five piglets were randomized as having severe global hypoxia (n=48) or not (sham, n=7). Hypoxic piglets were further randomized: vehicle (VEH), DHA, VEH+hypothermia (HT) or HT+DHA. A total of 5 mg/kg DHA was given intravenously 210 min after the end of hypoxia. Brain tissues were analyzed using liquid chromatography triple quadrupole mass spectrometry technique (LC-MS). A two-way analysis of variance (ANOVA) was performed with DHA and HT as main effects. Results In the white matter, we found main effects of DHA on DH-isoprostanes (P=0.030) and a main effect of HT on F4-neuroprostanes (F4-NeuroPs) (P=0.007), F2-isoprostanes (F2-IsoPs) (P=0.043) and DH-isoprostanes (P=0.023). In the cortex, the ANOVA analysis showed the interactions of main effects between DHA and HT for neurofuranes (NeuroFs) (P=0.092) and DH-isoprostanes (P=0.015) as DHA significantly reduced lipid peroxidation in the absence of HT. DHA compared to VEH significantly reduced NeuroFs (P=0.019) and DH-isoprostanes (P=0.010). No differences were found in the hippocampus. Conclusion After severe hypoxia, HT reduced lipid peroxidation in the white matter but not in the cortical gray matter. HT attenuated the reducing effect of DHA on lipid peroxidation in the cortex. Further studies are needed to determine whether DHA can be an effective add-on therapy for TH.
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http://dx.doi.org/10.1515/jpm-2017-0355DOI Listing
December 2018

Early Prediction of Hypoxic-Ischemic Brain Injury by a New Panel of Biomarkers in a Population of Term Newborns.

Oxid Med Cell Longev 2018 28;2018:7608108. Epub 2018 Jun 28.

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

This research paper is aimed at evaluating the predictive role of a default panel of oxidative stress (OS) biomarkers for the early identification of infants at high risk of HIE and their validation through the correlation with MRI findings. A multicenter prospective observational study was performed between March 2012 and April 2015 in two European tertiary NICUs. Eighty-four term infants at risk for HIE (pH < 7, BE < -13 mmol/L, and 5' Apgar < 5) were enrolled. Three were excluded for chromosomal abnormalities and one due to lack of blood samples. The final population was divided according to the severity of perinatal hypoxia into 2 groups: mild/moderate HIE and severe HIE. Advanced oxidation protein products (AOPP), non-protein-bound iron (NPBI), and F2-isoprostanes (F2-IsoPs) were measured in blood samples at P1 (4-6 hours), P2 (24-72 hours), and P3 (5 days), in both groups. MRIs were scored for the severity of brain injury, using a modified Barkovich score. The mean GA was 39.8 weeks (SD 1.4) and the mean birth weight 3538 grams (SD 660); 37 were females and 43 males. Significantly lower 5' Apgar score, pH, and BE and higher Thompson score were found in group II compared to group I at birth. Group II showed significantly higher AOPP and NPBI levels than group I (mean (SD) AOPP: 15.7 (15.5) versus 34.1 (39.2), = 0.033; NPBI 1.1 (2.5) versus 3.9 (4.4), = 0.013) soon after birth (P1). No differences were observed in OS biomarker levels between the two groups at P2 and P3. A regression model, including adjustment for hypothermia treatment, gender, and time after birth, showed that AOPP levels and male gender were both risk factors for higher brain damage scores (AOPP: OR 3.6, 95% CI (1.1-12.2) and gender: OR 5.6, 95% CI (1.2-25.7), resp.). Newborns with severe asphyxia showed higher OS than those with mild asphyxia at birth. AOPP are significantly associated with the severity of brain injury assessed by MRI, especially in males.
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http://dx.doi.org/10.1155/2018/7608108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046131PMC
October 2018