Publications by authors named "Serafina Perrone"

85 Publications

Management of Infants with Brief Resolved Unexplained Events (BRUE) and Apparent Life-Threatening Events (ALTE): A RAND/UCLA Appropriateness Approach.

Life (Basel) 2021 Feb 22;11(2). Epub 2021 Feb 22.

Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

Unexpected events of breath, tone, and skin color change in infants are a cause of considerable distress to the caregiver and there is still debate on their appropriate management. The aim of this study is to survey the trend in prevention, decision-making, and management of brief resolved unexplained events (BRUE)/apparent life-threatening events (ALTE) and to develop a shared protocol among hospitals and primary care pediatricians regarding hospital admission criteria, work-up and post-discharge monitoring of patients with BRUE/ALTE. For the study purpose, a panel of 54 experts was selected to achieve consensus using the RAND/UCLA appropriateness method. Twelve scenarios were developed: one addressed to primary prevention of ALTE and BRUE, and 11 focused on hospital management of BRUE and ALTE. For each scenario, participants were asked to rank each option from '1' (extremely inappropriate) to '9' (extremely appropriate). Results derived from panel meeting and discussion showed several points of agreement but also disagreement with different opinion emerged and the need of focused education on some areas. However, by combining previous recommendations with expert opinion, the application of the RAND/UCLA appropriateness permitted us to drive pediatricians to reasoned and informed decisions in term of evaluation, treatment and follow-up of infants with BRUE/ALTE, reducing inappropriate exams and hospitalisation and highlighting priorities for educational interventions.
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http://dx.doi.org/10.3390/life11020171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926945PMC
February 2021

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

Congenital Cytomegalovirus Infection: Update on Diagnosis and Treatment.

Microorganisms 2020 Oct 1;8(10). Epub 2020 Oct 1.

Paediatric Clinic Pietro Barilla Children's Hospital, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy.

Congenital cytomegalovirus (cCMV) infection is the most common congenital viral infection and is the leading non-genetic cause of sensorineural hearing loss (SNLH) and an important cause of neurodevelopmental disabilities. The risk of intrauterine transmission is highest when primary infection occurs during pregnancy, with a higher rate of vertical transmission in mothers with older gestational age at infection, while the risk of adverse fetal effects significantly increases if fetal infection occurs during the first half of pregnancy. Despite its prevalence and morbidity among the neonatal population, there is not yet a standardized diagnostic test and therapeutic approach for cCMV infection. This narrative review aims to explore the latest developments in the diagnosis and treatment of cCMV infection. Literature analysis shows that preventive interventions other than behavioral measures during pregnancy are still lacking, although many clinical trials are currently ongoing to formulate a vaccination for women before pregnancy. Currently, we recommend using a PCR assay in blood, urine, and saliva in neonates with suspected cCMV infection. At present, there is no evidence of the benefit of antiviral therapy in asymptomatic infants. In the case of symptomatic cCMV, we actually recommend treatment with oral valganciclovir for a duration of 12 months. The effectiveness and tolerability of this therapy option have proven effective for hearing and neurodevelopmental long-term outcomes. Valganciclovir is reserved for congenitally-infected neonates with the symptomatic disease at birth, such as microcephaly, intracranial calcifications, abnormal cerebrospinal fluid index, chorioretinitis, or sensorineural hearing loss. Treatment with antiviral drugs is not routinely recommended for neonates with the mildly symptomatic disease at birth, for neonates under 32 weeks of gestational age, or for infants more than 30 days old because of insufficient evidence from studies. However, since these populations represent the vast majority of neonates and infants with cCMV infection and they are at risk of developing late-onset sequelae, a biomarker able to predict long-term sequelae should also be found to justify starting treatment and reducing the burden of CMV-related complications.
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http://dx.doi.org/10.3390/microorganisms8101516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599523PMC
October 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

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

The clinical course of SARS-CoV-2 positive neonates.

J Perinatol 2020 10 6;40(10):1462-1469. Epub 2020 Jul 6.

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

The COVID-19 pneumonia was firstly reported in Wuhan, China, in December 2019. The disease had a rapid spread all over the word becoming an international public health emergency. Limited data were available on COVID-19 positive neonates. We reviewed relevant literature to understand the clinical course of disease and transmission routes in affected neonates. The aim of the study was evaluating the clinical course and prognosis of SARS-CoV-2 positive neonates. Based on current literature, the hypothesis of vertical transmission of SARS-CoV-2, though conceivable, remains unproven. A research conducted on PubMed database from December 2019 to April 27, 2020 revealed that were reported 25 neonates affected by SARS-CoV-2. Main symptoms were fever, cough, or shortness of breath but often these neonates did not show other symptoms during length stay in hospital. No deaths occurred.
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http://dx.doi.org/10.1038/s41372-020-0715-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335929PMC
October 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

Report of a series of healthy term newborns from convalescent mothers with COVID-19.

Acta Biomed 2020 May 11;91(2):251-255. Epub 2020 May 11.

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Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmittable virus associated with a significantly increased risk of complications among the infected population. Few data are available for the outcome of pregnancy complicated by serious respiratory disease due to SARS-CoV-2 infection.

Aim: We herein report a series of four neonates whose mothers had recovered from new coronavirus 2019 disease (COVID-19) diagnosed in the third trimester of pregnancy.

Methods: pregnant women with documented COVID-19 infection during their pregnancy, who gave birth in Parma Hospital, University of Parma, Italy, in March and April 2020, during the peak of incidence of COVID-19 in Italy. Clinical records and laboratory tests were retrospectively reviewed.

Results: All neonates were delivered at term in good conditions without congenital COVID-19 infection.

Conclusions: Findings from our series of cases indicated that adverse effects on foetuses from pregnancies complicated by COVID-19 infection in late pregnancy are unlikely.
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http://dx.doi.org/10.23750/abm.v91i2.9743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569646PMC
May 2020

Neuroprem: the Neuro-developmental outcome of very low birth weight infants in an Italian region.

Ital J Pediatr 2020 Feb 22;46(1):26. Epub 2020 Feb 22.

Neonatal Intensive Care Unit, University Hospital of Modena, Via del Pozzo 71, 41100, Modena, Italy.

Introduction: The survival of preterm babies has increased worldwide, but the risk of neuro-developmental disabilities remains high, which is of concern to both the public and professionals. The early identification of children at risk of neuro-developmental disabilities may increase access to intervention, potentially influencing the outcome.

Aims: Neuroprem is an area-based prospective cohort study on the neuro-developmental outcome of very low birth weight (VLBW) infants that aims to define severe functional disability at 2 years of age.

Methods: Surviving VLBW infants from an Italian network of 7 neonatal intensive care units (NICUs) were assessed for 24 months through the Griffiths Mental Developmental Scales (GMDS-R) or the Bayley Scales of Infant and Toddler Development (BSDI III) and neuro-functional evaluation according to the International Classification of Disability and Health (ICF-CY). The primary outcome measure was severe functional disability at 2 years of age, defined as cerebral palsy, a BSDI III cognitive composite score < 2 standard deviation (SD) or a GMDS-R global quotients score < 2 SD, bilateral blindness or deafness.

Results: Among 211 surviving VLBW infants, 153 completed follow-up at 24 months (72.5%). Thirteen patients (8.5%) developed a severe functional disability, of whom 7 presented with cerebral palsy (overall rate of 4.5%). Patients with cerebral palsy were all classified with ICF-CY scores of 3 or 4. BSDI III composite scores and GMDS-R subscales were significantly correlated with ICF-CY scores (p < 0.01).

Conclusion: Neuroprem represents an Italian network of NICUs aiming to work together to ensure preterm neuro-developmental assessment. This study updates information on VLBW outcomes in an Italian region, showing a rate of cerebral palsy and major developmental disabilities in line with or even lower than those of similar international studies. Therefore, Neuroprem provides encouraging data on VLBW neurological outcomes and supports the implementation of a preterm follow-up programme from a national network perspective.
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http://dx.doi.org/10.1186/s13052-020-0787-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036238PMC
February 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

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

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

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

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

Rooming-in Reduces Salivary Cortisol Level of Newborn.

Mediators Inflamm 2018 8;2018:2845352. Epub 2018 Mar 8.

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

Background: Rooming-in practice improves breastfeeding and reduces newborn stress reactivity. When this modality is not available, partial rooming-in after birth can be considered. Salivary cortisol levels (SCLs) are considered reliable biomarkers to indicate stress.

Objective: To test the hypothesis that rooming-in duration impacts neonatal stress response in hospitalized newborns.

Design/methods: Forty term newborns, enrolled in the Neonatology and Obstetrics Nursing, C.G. Ruesch, Naples, Italy, were divided, according to the mother's choice, into the study (SG; = 20) and control (CG; = 20) groups if they received full (24 hs) or partial (14 hs) rooming-in care, respectively. Saliva samples were collected from all babies between 7:00 a.m. and 8:00 a.m. of the 3rd day of life by using oral swab. Salivary cortisol levels were measured using an enzyme immunoassay kit (Salimetrics LLC, PA, USA).

Results: A statistically significant difference in the SCLs between SG and CG was found (median: 258 ng/dl versus 488.5 ng/dl; = 0.048).

Conclusions: Data support the practice of full rooming-in care compared with partial rooming-in. The rooming-in duration clearly reduces SCLs and likely neonatal stress. These lower SCLs may have long-term positive effects reducing the risk of metabolic syndrome, high blood pressure, and cognitive and behavioural changes.
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http://dx.doi.org/10.1155/2018/2845352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863308PMC
September 2018

Rooming-in Reduces Salivary Cortisol Level of Newborn.

Mediators Inflamm 2018 8;2018:2845352. Epub 2018 Mar 8.

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

Background: Rooming-in practice improves breastfeeding and reduces newborn stress reactivity. When this modality is not available, partial rooming-in after birth can be considered. Salivary cortisol levels (SCLs) are considered reliable biomarkers to indicate stress.

Objective: To test the hypothesis that rooming-in duration impacts neonatal stress response in hospitalized newborns.

Design/methods: Forty term newborns, enrolled in the Neonatology and Obstetrics Nursing, C.G. Ruesch, Naples, Italy, were divided, according to the mother's choice, into the study (SG; = 20) and control (CG; = 20) groups if they received full (24 hs) or partial (14 hs) rooming-in care, respectively. Saliva samples were collected from all babies between 7:00 a.m. and 8:00 a.m. of the 3rd day of life by using oral swab. Salivary cortisol levels were measured using an enzyme immunoassay kit (Salimetrics LLC, PA, USA).

Results: A statistically significant difference in the SCLs between SG and CG was found (median: 258 ng/dl versus 488.5 ng/dl; = 0.048).

Conclusions: Data support the practice of full rooming-in care compared with partial rooming-in. The rooming-in duration clearly reduces SCLs and likely neonatal stress. These lower SCLs may have long-term positive effects reducing the risk of metabolic syndrome, high blood pressure, and cognitive and behavioural changes.
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http://dx.doi.org/10.1155/2018/2845352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863308PMC
September 2018

C reactive protein in healthy term newborns during the first 48 hours of life.

Arch Dis Child Fetal Neonatal Ed 2018 Mar 30;103(2):F163-F166. Epub 2017 Jun 30.

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

Background: Early-onset neonatal sepsis (EOS) is a serious and potentially life-threatening disease in newborns. C reactive protein (CRP) is the most used laboratory biomarker for the detection of EOS. Little is known about normal reference values of CRP during the perinatal period as several factors are able to influence it.

Objectives: To identify an appropriate range of CRP values in healthy term newborns during the first 48 hours of life.

Design: CRP determination was performed in 859 term newborns at 12, 24 and 48 hours of life. Mode of delivery, maternal vaginal culture results, intrapartum antimicrobial prophylaxis (IAP) and other perinatal variables were recorded.

Results: CRP mean values were significantly higher at 48 hours (4.10 mg/L) than at both 24 (2.30 mg/L) and 12 hours of life (0.80 mg/L). CRP levels were affected by a number of perinatal proinflammatory variables. In particular, CRP mean values were significantly higher in babies born by vaginal delivery (3.80 mg/L) and emergency caesarean section (3.60 mg/L) than in babies born by elective caesarean section (2.10 mg/L). Completed course of IAP led to lower CRP mean values (2.90 mg/L) than IAP not completed (3.80 mg/L) or not performed (4.70 mg/L).

Conclusions: Postnatal age and mode of delivery significantly influence CRP values. Reliable reference values are crucial in order to obtain an adequate diagnostic accuracy.
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http://dx.doi.org/10.1136/archdischild-2016-312506DOI Listing
March 2018

Oxidative Stress Biomarkers: Establishment of Reference Values for Isoprostanes, AOPP, and NPBI in Cord Blood.

Mediators Inflamm 2017 23;2017:1758432. Epub 2017 Apr 23.

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

Oxidative stress (OS) is a common pathogenic factor involved in the onset of several diseases in humans, from immunologic disorders to malignancy, being a serious public health problem. In perinatal period, OS has been associated with adverse outcome of pregnancy and neonatal diseases. Dangerous effects of OS are mediated by increased production of free radicals (FRs) following various mechanisms, such as hypoxia, ischemia reperfusion, hyperoxia, inflammation, mitochondrial dysfunction, Fenton chemistry, and prostaglandin metabolism. FRs have short half-life, and their measurement in vivo is faced with many challenges. However, oxyradical derivatives are stable and thus may be measured and monitored repeatedly. The quantification of OS is based on the measurement of specific biomarkers in biologic fluids and tissues, which reflect induced oxidative damage to lipids, proteins, and DNA. Prostanoids, non-protein-bound iron (NPBI), and advanced oxidation protein products (AOPP) are actually considered truly specific and reliable for neonatal injury. Defining reference values for these biomarkers is necessary to investigate their role in neonatal diseases or also to evaluate the success of treatments. In this work, we wanted to define laboratory reference values for biomarkers of OS in a healthy population of term newborns.
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http://dx.doi.org/10.1155/2017/1758432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420435PMC
March 2018

Oxidative Stress in the Newborn.

Oxid Med Cell Longev 2017;2017:1094247. Epub 2017 Jan 31.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, Netherlands.

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http://dx.doi.org/10.1155/2017/1094247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307135PMC
January 2019

DHA Reduces Oxidative Stress after Perinatal Asphyxia: A Study in Newborn Piglets.

Neonatology 2017 1;112(1):1-8. Epub 2017 Feb 1.

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

Background: Perinatal hypoxic-ischemic brain damage is a major cause of acute mortality and chronic neurological morbidity in infants and children. Oxidative stress due to free radical formation and the initiation of abnormal oxidative reactions appears to play a key role. Docosahexanoic acid (DHA), a main component of brain membrane phospholipids, may act as a neuroprotectant after hypoxia-ischemia by regulating multiple molecular pathways and gene expression.

Objectives: The aims of this study were to test the hypothesis that DHA provides significant protection against lipoperoxidation damage in the cerebral cortex and hippocampus in a neonatal piglet model of severe hypoxia-reoxygenation.

Methods: Newborn piglets, Noroc (LYLD), were subjected to severe global hypoxia. One group was resuscitated with ambient air (21% group, n = 11) and another also received 5 mg/kg of DHA 4 h after the end of hypoxia (21% DHA group, n = 10). After 9.5 h, tissues from the prefrontal cortex and hippocampus were sampled and the levels of isoprostanes, neuroprostanes, neurofurans, and F2-dihomo-isoprostanes were determined by the liquid chromatography triple quadrupole mass spectrometry technique.

Results: Lipid peroxidation biomarkers were significantly lower in both the cortex and hippocampus in the DHA-treated group compared with the untreated group.

Conclusions: The present study demonstrates that DHA administration after severe hypoxia in newborn piglets has an antioxidative effect in the brain, suggesting a protective potential of DHA if given after injuries to the brain.
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http://dx.doi.org/10.1159/000454982DOI Listing
April 2018