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.

Early-onset sepsis (EOS) is defined as a blood or cerebrospinal fluid culture obtained during the first 72 hours of life that grows a pathogenic bacterial species.^1-3 EOS incidence is reported to range from 0.5 to 1 in 1000 live births in full-term (term) newborns (≥37 weeks of gestational age) to 3% to 4% at 22 to 24 weeks of gestational age (GA).^4-6 Case-fatality rate is 0% to 3% in term infants,^4-6 30% at 25 to 28 weeks of age, and 54% at 22 to 24 weeks of age^4-6; considerable risk of long-term neurodevelopmental impairment is demonstrated among survivors.⁷

Preterm newborns are challenged by an excessive oxidative burden, as a result of several perinatal stimuli, as intrauterine infections, resuscitation, mechanical ventilation, and postnatal complications, in the presence of immature antioxidant capacities. “Oxygen radical disease of neonatology” comprises a wide range of conditions sharing a common pathway of pathogenesis and includes bronchopulmonary dysplasia (BPD) and other main complications of prematurity. Antioxidant strategies may be beneficial in the prevention and treatment of oxidative stress- (OS-) related lung disease of the preterm newborn. Endotracheal supplementation or lung-targeted overexpression of superoxide dismutase was proved to reduce lung damage in several models; however, the supplementation in preterm newborn failed to reduce the risk of BPD, although long-term respiratory outcomes were improved. Also melatonin administration to small cohorts of preterm newborns suggested beneficial effects on lung OS. The possibility to identify single nucleotide polymorphism affecting the risk of BPD may help to identify specific populations with particularly high risk of OS-related diseases and may pose the basis for individually targeted treatments. Finally, surfactant replacement may lead to local anti-inflammatory and antioxidant effects, thanks to specific enzymatic and nonenzymatic antioxidants naturally present in animal surfactants.

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.

Background: Oxidative stress (OS) is significantly involved in the development of several complications associated with preterm birth, such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and intraventricular hemorrhage (IVH). Evidence is growing about the associations between single nucleotide polymorphisms (SNPs) in genes involved in OS or antioxidant response and the occurrence of neonatal morbidities. Aim of the study: To assess whether SNPs in genes of superoxide dismutase (SOD) and catalase (CAT), involved in antioxidant pathways, correlate with the occurrence of RDS, BPD, IVH and ROP in preterm neonates. Methods: We performed a retrospective study involving neonates <28 weeks of gestational age. Results: We demonstrated that rs8192287 SOD3 polymorphism is an independent protective factor for IVH, while rs4880 and rs5746136 SOD2 polymorphisms are associated with lower gestational age and birth weight. Haplotypes reconstruction showed that SOD1 (GG) decreased the risk of RDS, IVH and ROP; SOD2 (GT) increased the risk of BPD and decreased the risk of RDS, IVH, and ROP; SOD3 (TGC) decreased the risk of BPD and IVH; and CAT (CTC) decreased the risk of RDS. Conclusions: The study of SNPs or haplotypes reconstruction in genes involved in OS or scavenging activity may be helpful in identifying preterm newborns with a particularly high risk of morbidities, who may benefit from specific prevention strategies.

It has been reported that low platelet count may increase the risk of patent ductus arteriosus (PDA) in preterm infants. Moreover, high mean platelet volume (MPV) has been found to be associated with the development of prematurity complications due to enhanced platelet reactivity. Our aim was to assess the relationship between platelet count and MPV and the occurrence of PDA and its resistance to ibuprofen closure in a cohort of extremely preterm infants. Platelet count <100 (×10³/mm³; odds ratio 4.50; 95% confidence limits 1.39 to 14.61) at birth is an independent risk factor for PDA but does not affect its response to ibuprofen. MPV values did not influence PDA fate. Low platelet count increases the risk of developing a hemodynamically significant PDA but does not affect the ibuprofen closure rate. MPV is unrelated to the DA outcome.