The Brain is vulnerable to numerous insults that can act in the pre-, peri-, and post-natal period. There is growing evidence that demonstrate how oxidative stress (OS) could represent the final common pathway of all these insults. Fetuses and newborns are particularly vulnerable to OS due to their inability to active the antioxidant defenses. Specific molecules involved in OS could be measured in biologic fluids as early biomarkers of neonatal brain injury with an essential role in neuroprotection. Although S-100B seems to be the most studied biomarker, its use in clinical practice is limited by the complexity of brain damage etiopathogenesis and the time of blood sampling in relation to the brain injury. Reliable early specific serum markers are currently lacking in clinical practice. It is essential to determine if there are specific biomarkers that can help caregivers to monitor the progression of the disease in order to active an early neuroprotective strategy. We aimed to describe, in an educational review, the actual evidence on serum biomarkers for the early identification of newborns at a high risk of neurological diseases. To move the biomarkers from the bench to the bedside, the assays must be not only be of a high sensitivity but suitable for the very rapid processing and return of the results for the clinical practice to act on. For the best prognosis, more studies should focus on the association of these biomarkers to the type and severity of perinatal brain damage.

Bronchopulmonary dysplasia (BPD) still represents an important burden of neonatal care. The definition of the disease is currently undergoing several revisions, and, to date, BPD is actually defined by its treatment rather than diagnostic or clinic criteria. BPD is associated with many prenatal and postnatal risk factors, such as maternal smoking, chorioamnionitis, intrauterine growth restriction (IUGR), patent ductus arteriosus (PDA), parenteral nutrition, sepsis, and mechanical ventilation. Various experimental models have shown how these factors cause distorted alveolar and vascular growth, as well as alterations in the composition and differentiation of the mesenchymal cells of a newborn’s lungs, demonstrating a multifactorial pathogenesis of the disease. In addition, inflammation and oxidative stress are the common denominators of the mechanisms that contribute to BPD development. Vascular endothelial growth factor-A (VEGFA) constitutes the most prominent and best studied candidate for vascular development. Animal models have confirmed the important regulatory roles of epithelial-expressed VEGF in lung development and function. This educational review aims to discuss the inflammatory pathways in BPD onset for preterm newborns, focusing on the role of VEGFA and providing a summary of current and emerging evidence.

Protective strategies against perinatal brain injury represent a major challenge for modern neonatology. Erythropoietin (Epo) enhances endogenous mechanisms of repair and angiogenesis. In order to analyse the newest evidence on the role of Epo in prematurity, hypoxic ischemic encephalopathy (HIE) and perinatal stroke, a critical review using 2020 PRISMA statement guidelines was conducted. This review uncovered 26 clinical trials examining the use of Epo for prematurity and brain injury-related outcomes. The effects of Epo on prematurity were analysed in 16 clinical trials. Erythropoietin was provided until 32–35 weeks of corrected postnatal age with a dosage between 500–3000 UI/kg/dose. Eight trials reported the Epo effects on HIE term newborn infants: Erythropoietin was administered in the first weeks of life, at different multiple doses between 250–2500 UI/kg/dose, as either an adjuvant therapy with hypothermia or a substitute for hypothermia. Two trials investigated Epo effects in perinatal stroke. Erythropoietin was administered at a dose of 1000 IU/kg for three days. No beneficial effect in improving morbidity was observed after Epo administration in perinatal stroke. A positive effect on neurodevelopmental outcome seems to occur when Epo is used as an adjuvant therapy with hypothermia in the HIE newborns. Administration of Epo in preterm infants still presents inconsistencies with regard to neurodevelopmental outcome. Clinical trials show significant differences mainly in target population and intervention scheme. The identification of specific markers and their temporal expression at different time of recovery after hypoxia-ischemia in neonates might be implemented to optimize the therapeutic scheme after hypoxic-ischemic injury in the developing brain. Additional studies on tailored regimes, accounting for the risk stratification of brain damage in newborns, are required.

Bone health starts with maternal health and nutrition, which influences bone mass and density already in utero. The mechanisms underlying the effect of the intrauterine environment on bone health are partly unknown but certainly include the ‘foetal programming’ of oxidative stress and endocrine systems, which influence later skeletal growth and development. With this narrative review, we describe the current evidence for identifying patients with risk factors for developing osteopenia, today’s management of these populations, and screening and prevention programs based on gestational age, weight, and morbidity. Challenges for bone health prevention include the need for new technologies that are specific and applicable to pregnant women, the foetus, and, later, the newborn. Radiofrequency ultrasound spectrometry (REMS) has proven to be a useful tool in the assessment of bone mineral density (BMD) in pregnant women. Few studies have reported that transmission ultrasound can also be used to assess BMD in newborns. The advantages of this technology in the foetus and newborn are the absence of ionising radiation, ease of use, and, above all, the possibility of performing longitudinal studies from intrauterine to extrauterine life. The use of these technologies already in the intrauterine period could help prevent associated diseases, such as osteoporosis and osteopenia, which are characterised by a reduction in bone mass and degeneration of bone structure and lead to an increased risk of fractures in adulthood with considerable social repercussions for the related direct and indirect costs.

Oxygen supplementation is widely used in neonatal care, however, it can also cause toxic effects if not used properly. Therefore, it appears crucial to find a balance in oxygen administration to avoid damage as a consequence of its insufficient or excessive use. Oxygen toxicity is mainly due to the production of oxygen radicals, molecules normally produced in humans and involved in a myriad of physiological reactions. In the neonatal period, an imbalance between oxidants and antioxidant defenses, the so-called oxidative stress, might occur, causing severe pathological consequences. In this review, we focus on the mechanisms of the production of oxygen radicals and their physiological functions in determining a set of diseases grouped together as “free radical diseases in the neonate”. In addition, we describe the evolution of the oxygenation target recommendations during neonatal resuscitation and post-stabilization phases with the aim to define the best oxygen administration according to the newest evidence.

Physiological oxidative stress plays a pivotal role in supporting proper growth and development. While moderate oxidative stress is essential for activating key metabolic pathways and maintaining normal cellular signaling, excessive production of reactive oxygen species (ROSs) can overwhelm the immature antioxidant systems of newborns, potentially leading to cellular damage and impaired physiological function. This vulnerability is particularly pronounced in the central nervous system, where limited detoxification capacity exacerbates the risk of oxidative damage, following hypoxic–ischemic events. Antioxidants agents—such as melatonin, erythropoietin, allopurinol, N-acetylcisteine, selenium, iminobiotin, taurine, and acetyl-L-carnitine—have demonstrated significant neuroprotective effects in preclinical experimental studies, reducing markers of oxidative injury and improving neurological outcomes. These neuroprotective agents have also been evaluated in clinical trials, demonstrating antioxidant effects. A major issue lies in the complexity of neurological damage, which is not associated with a single pathological pathway. Additionally, the inability of these agents to reach effective concentrations within the central nervous system, along with inconsistencies across clinical trials in terms of dosage and administration methods, hinders the ability to obtain robust results. Future efforts should therefore focus on the development of delivery systems capable of crossing the blood–brain barrier and on establishing standardized clinical trial protocols and study designs. This educational review aims to provide a comprehensive overview of emerging protective strategies, including antioxidant bioactive agents and nutritional interventions. It also explores the underlying mechanisms of oxidative stress and its impact on neonatal brain injury.