Hyperbilirubinemia and retinopathy of prematurity: a retrospective cohort study.

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease in preterm infants. Oxidative stress plays a key role in the pathogenesis of ROP. Due to its antioxidant effects, bilirubin has been proposed to be protective against ROP. This study explored the association between hyperbilirubinemia and ROP. We analyzed a 10-year cohort from a neonatal intensive care unit in Milan, Italy, including 1606 infants born under 32 weeks and/or < 1500 g. Data from 1606 infants meeting specific inclusion criteria were reviewed. Eighty infants were excluded due to lack of data, 1526 were deemed eligible for analysis, and 1269 had hyperbilirubinemia requiring phototherapy. There was a higher incidence of ROP among infants with hyperbilirubinemia (13.8%) versus those without (7.8%, p<0.01). Infants with any ROP, non-severe or severe ROP, were exposed to hyperbilirubinemia for a significantly higher number of days compared with those without ROP. Each additional day of exposure increases the risk of developing any ROP by 5%, non-severe ROP by 4%, and severe ROP by 6%. However, this correlation was not observed in infants with gestational age less than 27 weeks and/or body weight less than 1000 g.    Conclusion: Our data show that hyperbilirubinemia requiring phototherapy is associated with an increased risk of developing ROP. However, severe hyperbilirubinemia and ROP share many of their risk factors. Therefore, rather than being a risk factor itself, hyperbilirubinemia may be a surrogate for other risk factors for ROP.    Clinical Trial Registration: NCT05806684. What is Known: • The development of retinopathy of prematurity (ROP) is influenced by several critical risk factors, including low gestational age, low birth weight, supplemental oxygen use, and increased oxidative stress. • In vitro, unconjugated bilirubin is an effective scavenger of harmful oxygen species and a reducing agent, highlighting its potential protective role against oxidative stress. What is New: • Hyperbilirubinemia requiring phototherapy was associated with an increased risk of developing ROP, but this association was not observed in the most vulnerable population of extremely preterm infants. • Every additional day of phototherapy for hyperbilirubinemia increases the risk of ROP by 5% for any ROP, 4% for non-severe ROP, and 6% for severe ROP.

Viscoelastic coagulation testing in Neonatal Intensive Care Units: advantages and pitfalls in clinical practice.

The expression "developmental hemostasis" indicates the age-related physiological changes occurring during the maturational process of the hemostatic system. Despite the quantitative and qualitative alterations, the neonatal hemostatic system is competent and well-balanced. Conventional coagulation tests do not provide reliable information as they only explore the procoagulants during the neonatal period. In contrast, viscoelastic coagulation tests (VCTs), such as viscoelastic coagulation monitoring (VCM), thromboelastography (TEG or ClotPro), and rotational thromboelastometry (ROTEM), are point-of-care assays that provide a quick, dynamic and global view of the hemostatic process, allowing prompt and individualized therapeutic intervention when necessary. Their use in neonatal care is on the increase and they could help monitor patients at risk of hemostatic derangement. In addition, they are crucial for anticoagulation monitoring during extracorporeal membrane oxygenation. Moreover, implementing VCT-based monitoring could optimize blood product use.

Human Bone Marrow-Derived Mesenchymal Stromal Cells Reduce the Severity of Experimental Necrotizing Enterocolitis in a Concentration-Dependent Manner.

Necrotizing enterocolitis (NEC) is a devastating gut disease in preterm neonates. In NEC animal models, mesenchymal stromal cells (MSCs) administration has reduced the incidence and severity of NEC. We developed and characterized a novel mouse model of NEC to evaluate the effect of human bone marrow-derived MSCs (hBM-MSCs) in tissue regeneration and epithelial gut repair. NEC was induced in C57BL/6 mouse pups at postnatal days (PND) 3-6 by (A) gavage feeding term infant formula, (B) hypoxia/hypothermia, and (C) lipopolysaccharide. Intraperitoneal injections of PBS or two hBM-MSCs doses (0.5 × 106 or 1 × 106) were given on PND2. At PND 6, we harvested intestine samples from all groups. The NEC group showed an incidence of NEC of 50% compared with controls (p < 0.001). Severity of bowel damage was reduced by hBM-MSCs compared to the PBS-treated NEC group in a concentration-dependent manner, with hBM-MSCs (1 × 106) inducing a NEC incidence reduction of up to 0% (p < 0.001). We showed that hBM-MSCs enhanced intestinal cell survival, preserving intestinal barrier integrity and decreasing mucosal inflammation and apoptosis. In conclusion, we established a novel NEC animal model and demonstrated that hBM-MSCs administration reduced the NEC incidence and severity in a concentration-dependent manner, enhancing intestinal barrier integrity.

Proinflammatory Endothelial Phenotype in Very Preterm Infants: A Pilot Study.

Very preterm infants are exposed to prenatal inflammatory processes and early postnatal hemodynamic and respiratory complications, but limited data are available about the endothelial effect of these conditions. The present pilot study investigates the perinatal endothelial phenotype in very preterm infants (VPIs) and explores its predictive value on neonatal mortality and hemodynamic and respiratory complications. Angiopoietin 1 (Ang-1), Ang-2, E-selectin, vascular adhesion molecule 1 (VCAM-1), tissue factor (TF), and endothelin 1 (ET-1) concentrations were tested in first (T1), 3rd (T2), and 7-10th (T3) day of life in 20 VPIs using Luminex technology and compared with 14 healthy full-term infants (FTIs). Compared to FTIs, VPIs had lower Ang-1 at T1 and T2; higher Ang-2 at T1, T2, and T3; higher Ang-2/Ang-1 ratio at T1, T2, and T3; lower E-selectin at T1, T2, and T3; higher VCAM-1 at T1; higher TF at T2. No differences in concentrations were found in neonatal deaths. VPIs with hemodynamic or respiratory complications had higher Ang-2 at T3. Perinatal low Ang-1 and high Ang-2 associated with high VCAM-1 and TF in VPIs suggest a proinflammatory endothelial phenotype, resulting from the synergy of a pathological prenatal inheritance and a premature extrauterine transition.

Endothelial dysfunction in preterm infants: The hidden legacy of uteroplacental pathologies.

Millions of infants are born prematurely every year worldwide. Prematurity, particularly at lower gestational ages, is associated with high mortality and morbidity and is a significant global health burden. Pregnancy complications and preterm birth syndrome strongly impact neonatal clinical phenotypes and outcomes. The vascular endothelium is a pivotal regulator of fetal growth and development. In recent years, the key role of uteroplacental pathologies impairing endothelial homeostasis is emerging. Conditions leading to very and extremely preterm birth can be classified into two main pathophysiological patterns or endotypes: infection/inflammation and dysfunctional placentation. The first is frequently related to chorioamnionitis, whereas the second is commonly associated with hypertensive disorders of pregnancy and fetal growth restriction. The nature, timing, and extent of prenatal noxa may alter fetal and neonatal endothelial phenotype and functions. Changes in the luminal surface, oxidative stress, growth factors imbalance, and dysregulation of permeability and vascular tone are the leading causes of endothelial dysfunction in preterm infants. However, the available evidence regarding endothelial physiology and damage is limited in neonates compared to adults. Herein, we discuss the current knowledge on endothelial dysfunction in the infectious/inflammatory and dysfunctional placentation endotypes of prematurity, summarizing their molecular features, available biomarkers, and clinical impact. Furthermore, knowledge gaps, shadows, and future research perspectives are highlighted.

Hemostasis in neonatal ECMO.

Extracorporeal membrane oxygenation (ECMO) is a life-saving support for cardio-respiratory function. Over the last 50 years, the extracorporeal field has faced huge technological progress. However, despite the improvements in technique and materials, coagulation problems are still the main contributor to morbidity and mortality of ECMO patients. Indeed, the incidence and survival rates of the main hemorrhagic and thrombotic complications in neonatal respiratory ECMO are relevant. The main culprit is related to the intrinsic nature of ECMO: the contact phase activation. The exposure of the human blood to the non-endothelial surface triggers a systemic inflammatory response syndrome, which chronically activates the thrombin generation and ultimately leads to coagulative derangements. Pre-existing illness-related hemostatic dysfunction and the peculiarity of the neonatal clotting balance further complicate the picture. Systemic anticoagulation is the management's mainstay, aiming to prevent thrombosis within the circuit and bleeding complications in the patient. Although other agents (i.e., direct thrombin inhibitors) have been recently introduced, unfractionated heparin (UFH) is the standard of care worldwide. Currently, there are multiple tests exploring ECMO-induced coagulopathy. A combination of the parameters mentioned above and the evaluation of the patient's underlying clinical context should be used to provide a goal-directed antithrombotic strategy. However, the ideal algorithm for monitoring anticoagulation is currently unknown, resulting in a large inter-institutional diagnostic variability. In this review, we face the features of the available monitoring tests and approaches, mainly focusing on the role of point-of-care (POC) viscoelastic assays in neonatal ECMO. Current gaps in knowledge and areas that warrant further study will also be addressed.

Veno-Arterial Extracorporeal Membrane Oxygenation (ECMO) Impairs Bradykinin-Induced Relaxation in Neonatal Porcine Coronary Arteries.

Extracorporeal membrane oxygenation (ECMO) is a lifesaving support for respiratory and cardiovascular failure. However, ECMO induces a systemic inflammatory response syndrome that can lead to various complications, including endothelial dysfunction in the cerebral circulation. We aimed to investigate whether ECMO-associated endothelial dysfunction also affected coronary circulation. Ten-day-old piglets were randomized to undergo either 8 h of veno-arterial ECMO (n = 5) or no treatment (Control, n = 5). Hearts were harvested and coronary arteries were dissected and mounted as 3 mm rings in organ baths for isometric force measurement. Following precontraction with the thromboxane prostanoid (TP) receptor agonist U46619, concentration−response curves to the endothelium-dependent vasodilator bradykinin (BK) and the nitric oxide (NO) donor (endothelium-independent vasodilator) sodium nitroprusside (SNP) were performed. Relaxation to BK was studied in the absence or presence of the NO synthase inhibitor Nω-nitro-L-arginine methyl ester HCl (L-NAME). U46619-induced contraction and SNP-induced relaxation were similar in control and ECMO coronary arteries. However, BK-induced relaxation was significantly impaired in the ECMO group (30.4 ± 2.2% vs. 59.2 ± 2.1%; p < 0.0001). When L-NAME was present, no differences in BK-mediated relaxation were observed between the control and ECMO groups. Taken together, our data suggest that ECMO exposure impairs endothelium-derived NO-mediated coronary relaxation. However, there is a NO-independent component in BK-induced relaxation that remains unaffected by ECMO. In addition, the smooth muscle cell response to exogenous NO is not altered by ECMO exposure.