SARS-CoV-2 perinatal transmission and neonatal outcomes across four different waves of COVID-19 pandemic: A nationwide prospective cohort study from the Italian Society of Neonatology.

OBJECTIVES: To describe how SARS-CoV-2 infection at the time of delivery affected maternal and neonatal outcomes across four major waves of the COVID-19 pandemic in Italy. METHODS: This is a large, prospective, nationwide cohort study collecting maternal and neonatal data in case of maternal peripartum SARS-CoV-2 infection between February 2020 and March 2022. Data were stratified across the four observed pandemic waves. RESULTS: Among 5201 COVID-19-positive mothers, the risk of being symptomatic at delivery was significantly higher in the first and third waves (20.8-20.8%) than in the second and fourth (13.2-12.2%). Among their 5284 neonates, the risk of prematurity (gestational age <37 weeks) was significantly higher in the first and third waves (15.6-12.5%). The risk of intrauterine transmission was always very low, while the risk of postnatal transmission during rooming-in was higher and peaked at 4.5% during the fourth wave. A total of 80% of positive neonates were asymptomatic. CONCLUSION: The risk of adverse maternal and neonatal outcomes was significantly higher during the first and third waves, dominated by unsequenced variants and the Delta variant, respectively. Postnatal transmission accounted for most neonatal infections and was more frequent during the Omicron period. However, the paucity of symptoms in infected neonates should lead us not to separate the dyad.

Prognostic accuracy of Neonatal SOFA score versus SIRS criteria in preterm infants with late-onset sepsis.

Neonatal SOFA score was reported as an accurate predictor of mortality while the prognostic accuracy of SIRS criteria is unknown. The aim was to compare neonatal SOFA and SIRS criteria for the prediction of late onset sepsis-related mortality in preterm newborns. Newborns ≤ 32 weeks with late onset sepsis were retrospectively studied. Neonatal SOFA and SIRS criteria were calculated at onset of sepsis (T0), and after 6 ± 1 (T1), 12 ± 3 (T2) and 24 ± 3 h (T3). Outcome was death during antibiotic treatment for late onset sepsis. We studied 112 newborns with gestational age 26.9 ± 2.3 weeks; 11% met the study outcome. Neonatal SOFA was significantly higher in non-survivors vs. survivors at all time intervals; SIRS criteria were significantly higher in non-survivors vs. survivors at T1, T2 and T3. Neonatal SOFA increased over time in non-survivors (p = 0.003). At T0, the area under receiver operating characteristics curve was significantly higher for neonatal SOFA score than SIRS criteria (0.950 vs. 0.569; p = 0.0002), and the best calculated cut-off for T0 neonatal SOFA score was 4. In multivariate analysis T0 and T1 neonatal SOFA were predictors of late onset sepsis-related mortality (p = 0.048 and p < 0.001).  Conclusion: Neonatal SOFA score showed greater discriminatory capacity for mortality than SIRS criteria and might be helpful to plan management for patients at higher risk of death. What is Known: • Neonatal SOFA score may be an accurate prognostic tool. • No prognostic score has been fully standardized for septic newborns in NICU. What is New: • Neonatal SOFA score outperformed SIRS criteria for the prediction of prognosis in preterm infants with late onset sepsis. • Neonatal SOFA score assessed at onset of sepsis and 6 hrs later is a predictor of mortality.

New Antimicrobials for the Treatment of Neonatal Sepsis Caused by Multi-Drug-Resistant Bacteria: A Systematic Review.

BACKGROUND: Infections by multi-drug-resistant (MDR) organisms are sharply increasing in newborns worldwide. In low and middle-income countries, a disproportionate amount of neonatal sepsis caused by MDR Gram negatives was recently reported. Newborns with infections by MDR organisms with limited treatment options may benefit from novel antimicrobials. METHODS: We performed a literature search investigating the use in newborns, infants and children of novel antimicrobials for the treatment of MDR Gram negatives, namely ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, meropenem/vaborbactam, imipenem/relebactam, and Gram positives with resistance of concern, namely ceftaroline and dalbavancin. PubMed, EMBASE, and Web of Science were searched. RESULTS: A total of 50 records fulfilled the inclusion criteria. Most articles were case reports or case series, and ceftazidime/avibactam was the most studied agent. All studies showed favorable efficacy and safety profile in newborns and across different age cohorts. CONCLUSIONS: novel antibiotics may be considered in newborns for the treatment of MDR Gram negatives with limited treatment options and for Gram positives with resistance concerns. Further studies are needed to address their effectiveness and safety in newborns.

Cardiac Hypertrophy Associated with Insulin Therapy in Extremely Preterm Infants.

BACKGROUND: In the neonatal period, cardiac hypertrophy (CH) has been commonly associated with hyperinsulinemic pathologies, and the first case of CH in an extremely preterm infant treated with insulin infusion has recently been reported. To confirm this association, we report a case series of patients who developed CH after insulin therapy. METHODS: Infants with gestational age < 30 weeks and birth weight < 1500 g, born from November 2017 to June 2022, were studied if they developed hyperglycemia requiring treatment with insulin and had echocardiographic diagnosis of CH. RESULTS: We studied 10 extremely preterm infants (24.3 ± 1.4 weeks) who developed CH at a mean age of 124 ± 37 h of life, 98 ± 24 h after the initiation of insulin therapy. All surviving patients had resolution of CH at discharge, while three of four (75%) of the deceased patients had persistent CH. CONCLUSIONS: Our case series supports the association between the development of CH and insulin therapy in extremely preterm infants and suggests further caution and the need for echocardiographic monitoring when treating these fragile patients with insulin.

Cardiovascular Safety and Effectiveness of Bisphosphonates: From Intervention Trials to Real-Life Data.

Both osteoporosis with related fragility fractures and cardiovascular diseases are rapidly outspreading worldwide. Since they are often coexistent in elderly patients and may be related to possible common pathogenetic mechanisms, the possible reciprocal effects of drugs employed to treat these diseases have to be considered in clinical practice. Bisphosphonates, the agents most largely employed to decrease bone fragility, have been shown to be overall safe with respect to cardiovascular diseases and even capable of reducing cardiovascular morbidity in some settings, as mainly shown by real life studies. No randomized controlled trials with cardiovascular outcomes as primary endpoints are available. While contradictory results have emerged about a possible BSP-mediated reduction of overall mortality, it is undeniable that these drugs can be employed safely in patients with high fracture risk, since no increased mortality has ever been demonstrated. Although partial reassurance has emerged from meta-analysis assessing the risk of cardiac arrhythmias during bisphosphonates treatment, caution is warranted in administering this class of drugs to patients at risk for atrial fibrillation, possibly preferring other antiresorptives or anabolics, according to osteoporosis guidelines. This paper focuses on the complex relationship between bisphosphonates use and cardiovascular disease and possible co-management issues.

Presepsin for the Diagnosis of Neonatal Early-Onset Sepsis: A Systematic Review and Meta-analysis.

Importance: Neonatal early-onset sepsis (EOS) is a severe disease, particularly in preterm infants. Timely diagnosis can be challenging owing to unspecific presentation and questionable performance of the common markers of infection. Presepsin was recently proven to be a promising biomarker for the diagnosis of EOS. Objective: To assess presepsin accuracy for the diagnosis of EOS. Data Sources: PubMed Medline, EMBASE, Web of Science, and Google Scholar. No publication date restrictions were applied. The literature search was limited to the English language. Articles were checked for duplication. Study Selection: Inclusion criteria were studies that (1) included term or preterm newborns (defined as newborns with gestational age ≥37 weeks or <37 weeks, respectively); (2) included a diagnosis of EOS, defined as culture-proven sepsis for primary analysis and as either clinical or culture-proven sepsis for secondary analysis; and (3) assessed presepsin values during the initial workup for suspected EOS. Exclusion criteria were studies that (1) did not include EOS cases; (2) lacked data on presepsin sensitivity and/or specificity; and (3) were case reports, commentaries, or reviews. Two independent reviewers performed the study selection. Data Extraction and Synthesis: Two independent reviewers performed data extraction and quality assessment. Quality assessment was performed using the Quality Assessment for Studies of Diagnostic Accuracy 2 tool, and data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were pooled using a random-effects model. Main Outcomes and Measures: The outcomes of interest for both the primary and secondary analyses were presepsin sensitivity, specificity, and diagnostic odds ratio for the diagnosis of EOS. Results: A total of 12 studies of 245 (4.9%) met inclusion criteria for the primary analysis. Twenty-three studies of 245 (9.4%) met the inclusion criteria for the secondary analysis. In the primary analysis, among 12 studies and 828 newborns of any gestational age, pooled sensitivity and specificity were 0.93 (95% CI, 0.86-0.95) and 0.91 (95% CI, 0.85-0.95), respectively; pooled diagnostic odds ratio was 131.69 (95% CI, 54.93-310.94). Subgroup analysis showed that presepsin specificity was associated with the inclusion of only EOS or all neonatal sepsis. Presepsin accuracy was not associated with gestational age, measurement with chemiluminescence enzyme immunoassay or enzyme-linked immunosorbent assay testing, country where the study was performed, or risk of bias judgment. In the secondary analysis, among 23 studies and 1866 newborns, accuracy was significantly associated with only test type. Conclusions and Relevance: Results of this systematic review and meta-analysis suggest that presepsin was an accurate biomarker of EOS. Clinical trials are warranted to assess its usefulness and safety to reduce early antibiotic exposure, particularly in preterm newborns.

Persistence and recurrence in tumor-induced osteomalacia: A systematic review of the literature and results from a national survey/case series.

PURPOSE: Tumor induced osteomalacia (TIO) is a rare disease of mineral metabolism, whose clinical picture is dominated by hypophosphatemia usually due to an excess of circulating FGF23 produced by small mesenchymal tumors. Data on the real prevalence of the disease are lacking, with the knowledge of the disease mainly relying on case reports and small case series. No estimate is available on the prevalence of uncured TIO. METHODS: National multi-center, cross-sectional and retrospective study on persistent or recurrent cases of TIO followed in referral centers for bone diseases; systematic review of the published persistent and recurrent cases of TIO. Data from patients consecutively evaluated in referral Italian centers for bone diseases were collected; a PubMed search on persistent, recurrent and unoperable cases of TIO was carried out. RESULTS: Sixteen patients (mean age at diagnosis 52.5 ± 10.6 years) with persistent (n = 6, 37,5%), recurrent (n = 7, 43.7%) or not operable (n = 3, 18.8%) TIO were described. Delay in diagnosis (2.5 ± 1.3 years) was demonstrated. All patients experienced fragility fractures or pseudofractures and disabling bone and muscle pain. BMD was significantly reduced (mean T-score -2.7 ± 1.7 and -2.7 ± 0.9 at lumbar spine and femoral neck, respectively). Fourteen patients were maintained under therapy with phosphate salts and calcitriol, while in 2 patients therapy with burosumab, an anti-FGF23 antibody, was commenced. CONCLUSION: A significant number of patients with TIO remain either undiagnosed for tumor localization or tumor recur or persist after surgery. These patients with active disease represent possible candidates for burosumab treatment.

Glucose control in diabetes during home confinement for the first pandemic wave of COVID-19: a meta-analysis of observational studies.

AIM: To assess the effect on glycaemic control of confinement due to lockdown measures, during COVID-19 pandemic, in people with type 1 (T1DM) and type 2 (T2DM) diabetes. METHODS: Meta-analysis of observational studies reporting measures of glucose control and variability before and during and/or after periods of confinement caused by COVID-19 in 2020 and/or 2021. RESULTS: We included 27 studies on T1DM. No significant change in Hba1c was observed after lockdown (WMD - 1.474 [- 3.26; 0.31] mmol/mol, I2 = 93.9). TIR significantly increased during and after lockdown (WMD: 2.73 1.47; 4.23 %, I2 = 81% and 3.73 [1.13; 5.33] %, I2 = 85%, respectively).We retrieved nine studies on T2DM patients. No significant variation in HbA1c was detected (WMD - 1.257 - 3.91; 1.39 mmol/mol, I2 = 98.3%). HbA1c had a more favourable trend in studies performed in Asia than in Europe (p = 0.022 between groups). CONCLUSION: Lockdown showed no significant detrimental effect on HbA1c in either T1DM or T2DM. Conversely, home confinement led to a reduction in mean glucose and glucose variability in T1DM, although with a high heterogeneity of results.

Presepsin (Soluble CD14 Subtype) as an Early Marker of Neonatal Sepsis and Septic Shock: A Prospective Diagnostic Trial.

In the context of suspected neonatal sepsis, early diagnosis and stratification of patients according to clinical severity is not yet effectively achieved. In this diagnostic trial, we aimed to assess the accuracy of presepsin (PSEP) for the diagnosis and early stratification of supposedly septic neonates. PSEP, C-reactive protein (CRP), and procalcitonin (PCT) were assessed at the onset of sepsis suspicion (T0), every 12-24 h for the first 48 h (T1-T4), and at the end of antibiotic therapy (T5). Enrolled neonates were stratified into three groups (infection, sepsis, septic shock) according to Wynn and Wong's definitions. Sensitivity, specificity, and area under the ROC curve (AUC) according to the severity of clinical conditions were assessed. We enrolled 58 neonates with infection, 77 with sepsis, and 24 with septic shock. PSEP levels were higher in neonates with septic shock (median 1557.5 pg/mL) and sepsis (median 1361 pg/mL) compared to those with infection (median 977.5 pg/mL) at T0 (p < 0.01). Neither CRP nor PCT could distinguish the three groups at T0. PSEP's AUC was 0.90 (95% CI: 0.854-0.943) for sepsis and 0.94 (95% CI: 0.885-0.988) for septic shock. Maximum Youden index was 1013 pg/mL (84.4% sensitivity, 88% specificity) for sepsis, and 971.5 pg/mL for septic shock (92% sensitivity, 86% specificity). However, differences in PSEP between neonates with positive and negative blood culture were limited. Thus, PSEP was an early biomarker of neonatal sepsis severity, but did not support the early identification of neonates with positive blood culture.

Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial.

BACKGROUND: The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate [IN-SUR-E]). METHODS: We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24 + 0 to 27 + 6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766. FINDINGS: Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 [40%] of 107) compared with the IN-SUR-E group (60 [54%] of 111; adjusted RR 0·75, 95% CI 0·57-0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7-135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 [19%] of 101 in the IN-REC-SUR-E group vs 37 [33%] of 111 in the IN-SUR-E group), pneumothorax (four [4%] of 101 vs seven [6%] of 111), or grade 3 or worse intraventricular haemorrhage (12 [12%] of 101 vs 17 [15%] of 111). INTERPRETATION: A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy. FUNDING: None.

Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial.

Our aim was to assess the efficacy and safety of intravenous (i.v.) paracetamol vs. i.v. ibuprofen for the treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. This is a multicenter randomized controlled study. Infants with a gestational age of 25+0-31+6 weeks were randomized to receive i.v. paracetamol (15 mg/kg/6 h for 3 days) or i.v. ibuprofen (10-5-5 mg/kg/day). The primary outcome was the closure rate of hsPDA after the first treatment course with paracetamol or ibuprofen. Secondary outcomes included the constriction rate of hsPDA, the re-opening rate, and the need for surgical closure. Fifty-two and 49 infants received paracetamol or ibuprofen, respectively. Paracetamol was less effective in closing hsPDA than ibuprofen (52 vs. 78%; P = 0.026), but the constriction rate of the ductus was similar (81 vs. 90%; P = 0.202), as confirmed by logistic regression analysis. The re-opening rate, the need for surgical closure, and the occurrence of adverse effects were also similar.Conclusions: Intravenous paracetamol was less effective in closing hsPDA than ibuprofen, but due to a similar constriction effect, its use was associated with the same hsPDA outcome. These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.Trial registration: Clinicaltrials.gov : NCT02422966, Date of registration: 04/09/2015; EudraCT no: 2013-003883-30. What is Known: • The successful closure of patent ductus arteriosus with oral paracetamol has been recently reported in several preterm infants, but only one randomized controlled study investigated the efficacy of intravenous paracetamol. What is New: • Intravenous paracetamol is less effective in closing hsPDA than ibuprofen, but have a similar constriction effect. • These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.

Reference ranges of Presepsin in preterm infants in the first 48 h of life: A multicenter observational study.

BACKGROUND AND OBJECTIVES: Despite low incidence of early-onset sepsis, the majority of preterm newborns receive early antibiotic prophylaxis. Our aim was to assess reference ranges of Presepsin during the first 48 h of life in preterm infants and to evaluate the possible influence of neonatal and maternal factors on its values. METHODS: This observational study consecutively enrolled newborns ≤ 32 weeks of GA at 0-6 h of life. Enrolled infants were sampled for blood culture, complete white blood cell (WBC) count, and P-SEP at 0-6 (T0) h of life and for P-SEP at 12 ± 3 (T1), 24 ± 3 (T2), and 48 ± 6 (T3) h of life. Cases of EOS were not considered for the statistical analysis. RESULTS: Data analysis was performed for 183 patients. P-SEP median values were 583 ng/L at T0 (IQR 405-800 ng/L, 5th and 95th percentiles 204 and 1200 ng/L), 614 ng/L at T1 (IQR 450-812 ng/L, 5th and 95th percentiles 262 and 1171 ng/L), 604 ng/L at T2 (IQR 445-825 ng/L, 5th and 95th percentiles 292 and 1302 ng/L) and 513 ng/L at T3 (IQR 371-734 ng/L, 5th and 95th percentiles 249 and 1278 ng/L). P-SEP values are negatively associated to gestational age (GA) at T0, T1, and T2. CONCLUSIONS: We determined for the first time the reference ranges of P-SEP during the first 48 h of life in very preterm infants and provided its percentile distribution at T0, T1, T2 and T3. P-SEP measurement was affected by GA at T0, T1, T2.

Lung Ultrasound for the Differential Diagnosis of Respiratory Distress in Neonates.

BACKGROUND: Respiratory distress (RD) is the most common neonatal illness. Lung ultrasound (LUS) is a technique previously tested in neonatal studies on RD, but literature regarding its routine clinical applicability is still lacking. OBJECTIVE: To assess the concordance between LUS performed by neonatologists with different training levels and chest X-ray (CXR) for the diagnosis of RD in newborns during the first 24 h of life. METHODS: We enrolled newborns with RD during the first 24 h of life. Patients underwent LUS and CXR. LUS and CXR diagnosis were compared to evaluate concordance. Twenty percent of patients received two LUS (one from an experienced and one from a novice sonographer) to calculate the interobserver agreement. The difference in time needed to reach a diagnosis with LUS and CXR, and from novice and expert operators, was measured. RESULTS: We studied 124 patients; 134 diagnoses were reported. The concordance between LUS and CXR diagnosis was 91% (95% CI 86-96%) with a κ statistic of 0.88 (95% CI 0.81-0.94). The median time to diagnosis was shorter for LUS (9.5 min, IQR 5-15) than for CXR (50 min, IQR 33-64) (p < 0.0001). In 25/124 patients, LUS was performed by both novice and experienced sonographers with complete concordance. The median time to diagnosis was shorter for expert (9 min, IQR 5-15) than novice operators (15 min, IQR 10-20) (p < 0.0002). CONCLUSION: LUS and CXR have a high concordance in the differential diagnosis of neonatal RD in the first 24 h of life. LUS has a shorter operation time than CXR.

Bilirubin and oxidative stress in term and preterm infants.

Hyperbilirubinemia is the most frequent clinical problem neonatologists must deal with during the newborn period. It has been suggested that bilirubin is involved in the balance between antioxidant and pro-oxidant agents due to its antioxidant properties. However, the relevance of these effects in vivo in term and preterm infants is still debated. We performed a literature review of studies that investigated the association between total serum bilirubin (TSB) and oxidative stress in newborn infants. We found that studies in term infants give contradictory results, while studies in preterm infants suggest that the TSB increase is associated with an oxidative stress increase due to concurrent factors other than bilirubin level, such as heme oxygenase (HO) activity. Moreover, it could be speculated that low physiologic TSB values are associated with antioxidant effects, while high pathologic TSB values are associated with pro-oxidant effects. Literature data do not allow the establishment of whether if the antioxidant properties of bilirubin are important from a clinical point of view and can affect the outcome in ill infants.

Sepsis and Oxidative Stress in the Newborn: From Pathogenesis to Novel Therapeutic Targets.

Sepsis is at present one of the leading causes of morbidity and mortality in the neonatal population. Together with inflammation, oxidative stress is involved in detrimental pathways activated during neonatal sepsis, eventually leading to organ dysfunction and death. The redox cascade during sepsis is mainly initiated by IL-6 and IL-8 stimulation in newborns and includes multiple noxious processes, as direct cell damage induced by reactive oxygen species, activation of gene expression leading to amplification of inflammation and oxidative stress, and impairment of mitochondrial function. Once proinflammatory and prooxidant pathways are established as stimulated by causing pathogens, self-maintaining unfavorable redox cycles ensue, leading to oxidative stress-related cellular damage, independently from the activating pathogens themselves. Despite antioxidant systems are induced during neonatal sepsis, as an adaptive response to an increased oxidative burden, a condition of redox imbalance favoring oxidative pathways occurs, resulting in increased markers of oxidative stress damage. Therefore, antioxidant treatment would exert beneficial effects during neonatal sepsis, potentially interrupting prooxidant pathways and preventing the maintenance of detrimental redox cycles that cannot be directly affected by antibiotic treatment. Among others, antioxidant agents investigated in clinical settings as adjunct treatment for neonatal sepsis include melatonin and pentoxifylline, both showing promising results, while novel antioxidant molecules, as edaravone and endothelin receptor antagonists, are at present under investigation in animal models. Finally, mitochondria-targeted antioxidant treatments could represent an interesting line of research in the treatment of neonatal sepsis.

Changes in bilirubin in infants with hypoxic-ischemic encephalopathy.

Antioxidant properties of bilirubin have been reported in many studies. We hypothesized that bilirubin might be involved in neuroprotection mechanisms against oxidative stress in infants with hypoxic-ischemic encephalopathy (HIE) and that total serum bilirubin (TSB) might increase in these patients. We retrospectively studied infants with gestational age ≥ 35 weeks and birth weight ≥ 1800 g who were admitted to the neonatal intensive care unit (NICU) with a diagnosis of moderate-to-severe HIE and received or did not receive therapeutic hypothermia. We evaluated peak TSB and changes of mean TSB in these patients in comparison with a control group of infants admitted to the NICU with diagnoses other than HIE. Peak and mean TSB values were lower in the no hypothermia and hypothermia groups in comparison with the control group, while differences were not noted between infants who received hypothermia or did not. Regression analysis showed that HIE and hypothermia significantly reduced the risk of developing TSB values higher than median value (> 8.4 mg/dL) in our population.Conclusion: Peak and mean TSB values were lower in infants with moderate-to-severe HIE than in control infants. HIE and hypothermia independently decreased TSB. These results exclude a TSB increase as a neuroprotective mechanism in infants with HIE. We speculated that low TSB values in infants with HIE could be due to hypoxic repression of HO expression and represent a defensive strategy for limiting brain injuries in these patients. What is Known: • The role of oxidative stress in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) has been elucidated in many studies, and other studies have demonstrated the antioxidant properties of bilirubin. • The potential neuroprotective role of bilirubin as antioxidant agent has never been evaluated in infants with HIE. What is New: • Mean total serum bilirubin (TSB) values are lower in infants with moderate-to-severe HIE than in control infants, since HIE and hypothermia independently decreased TSB. • An increase in bilirubin was not a neuroprotective mechanism in infants with HIE possibly because of hypoxic repression of HO expression as defensive strategy for limiting brain injuries.

Circulating MicroRNAs as Biomarkers of Gestational Diabetes Mellitus: Updates and Perspectives.

Gestational diabetes mellitus (GDM) is defined as any degree of carbohydrate intolerance, with onset or first recognition during second or third trimester of gestation. It is estimated that approximately 7% of all pregnancies are complicated by GDM and that its prevalence is rising all over the world. Thus, the screening for abnormal glucose levels is generally recommended as a routine component of care for pregnant women. However, additional biomarkers are needed in order to predict the onset or accurately monitor the status of gestational diabetes. Recently, microRNAs, a class of small noncoding RNAs demonstrated to modulate gene expression, have been proven to be secreted by cells of origin and can be found in many biological fluids such as serum or plasma. Such feature renders microRNAs as optimal biomarkers and sensors of in situ tissue alterations. Furthermore, secretion of microRNAs via exosomes has been reported to contribute to tissue cross talk, thus potentially represents, if disrupted, a mechanistic cause of tissue/cell dysfunction in a specific disease. In this review, we summarized the recent findings on circulating microRNAs and gestational diabetes mellitus with particular focus on the potential use of microRNAs as putative biomarkers of disease as well as a potential cause of GDM complications and ß cell dysfunction.