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IntroductionPremature infants (PIs) are at risk of suffering necrotizing enterocolitis (NEC), and infants consuming human milk (HM) show a lower incidence than infants receiving formula. The composition of HM has been studied in depth, but the lipid content of HM-derived small extracellular vesicles (HM sEVs) remains unexplored. Identifying these molecules and their biological effects has potential for the treatment of intestinal disorders in PIs and could contribute to the development of HM-based fortified formulas.MethodsWe isolated HM sEVs from HM samples and analyzed their oxylipin content using liquid chromatography coupled to mass spectrometry, which revealed the presence of anti-inflammatory oxylipins. We then examined the efficacy of a mixture of these oxylipins in combating inflammation and fibrosis, in vitro and in a murine model of inflammatory bowel disease (IBD).ResultsHM-related sEVs contained higher concentrations of oxylipins derived from docosahexaenoic acid, an omega-3 fatty acid. Three anti-inflammatory oxylipins, 14-HDHA, 17-HDHA, and 19,20-DiHDPA (ω3 OXLP), demonstrated similar efficacy to HM sEVs in preventing cell injury, inducing re-epithelialization, mitigating fibrosis, and modulating immune responses. Both ω3 OXLP and HM sEVs effectively reduced inflammation in IBD-model mice, preventing colon shortening, infiltration of inflammatory cells and tissue fibrosis.DiscussionIncorporating this unique cocktail of oxylipins into fortified milk formulas might reduce the risk of NEC in PIs and also provide immunological and neurodevelopmental support.

BackgroundCurrently, the treatment of anemia in preterm infants is based on packed red blood cell (RBC) transfusions from adult donors. Oxygen (O2) is mainly transported to the tissues bound to hemoglobin (Hb). In extremely low gestational age neonates (ELGANs), fetal hemoglobin (HbF), which has a higher affinity for O2, represents up to 95% of circulating hemoglobin. During the first month of life, the majority of ELGANs will require an adult-donor RBC transfusion causing HbF levels to rapidly drop. HbA releases 50% more oxygen in peripheral tissues than HbF. Increased release of O2 in the retina is one of the main factors related to the development of retinopathy of prematurity (ROP). Collecting umbilical cord blood and using autologous umbilical cord whole blood (UCB) transfusions would contribute to maintaining physiological HbF concentrations in newborns and avoid oxygen-in-excess derived damage.MethodsThis is a randomized, double-blinded, multicenter clinical trial. ELGANs ≤28 weeks of gestational age will be randomized 1:1 to receive an autologous umbilical cord blood transfusion (intervention arm) or standard transfusion of packed RBC from an adult donor (control arm) to assess ROP development. Assuming a 50% reduction in ROP incidence, 134 patients (67 per group) will be recruited. When blood transfusion is indicated, the Blook Bank will supply UCB or RCB according to the patient's group. The primary endpoint is the incidence of any ROP. Secondary endpoints are assessessment of treatment safety, results of biomarkers related to ROP and its chronology, and urine oxidative stress markers. In addition, the cellular composition of umbilical cord blood and its relationship with prematurity-related pathologies will be analyzed. All patients will be followed-up to 24 months of corrected age to evaluate their neurodevelopment.DiscussionROP is a major cause of irreversible blindness in preterm newborns. Transfusions with adult donor blood can lead to complications, including ROP. UCB transfusions offer advantages by maintaining physiological HbF levels and potentially optimizing postnatal development. Moreover, autologous UCB transfusion could reduce risks associated with heterologous blood products, although volume collection remains challenging. UCB contains growth factors and progenitor cells that may impact ROP.

Fetuses with congenital heart disease (CHD) have circulatory changes that may lead to predictable blood flow disturbances that may affect normal brain development. Hypoxemia and hypoperfusion may alter the redox balance leading to oxidative stress (OS), that can be assessed measuring stable end-products. OS biomarkers (OSB) were measured in amniotic fluid in fetuses with (n = 41) and without CHD (n = 44) and analyzed according to aortic flow, expected cyanosis after birth, and a CHD classification derived from this. Birth head circumference (HC) was used as a neurodevelopment biomarker. CHD fetuses had higher levels of ortho-Tyrosine (o-Tyr) than controls (p = 0.0003). There were no differences in o-Tyr levels considering aortic flow obstruction (p = 0.617). Fetuses with expected extreme cyanosis presented the highest levels of o-Tyr (p = 0.003). Among groups of CHD, fetuses without aortic obstruction and extreme cyanosis had the highest levels of o-Tyr (p = 0.005). CHD patients had lower HC than controls (p = 0.023), without correlation with OSB. Patients with HC < 10th percentile, presented high levels of o-Tyr (p = 0.024). Fetuses with CHD showed increased OSB and lower HC when compared to controls, especially those with expected extreme cyanosis. Our results suggest that increased levels of OSB are more influenced by the effect of low oxygenation than by aortic flow obstruction. Future studies with larger sample size are needed to further investigate the role of OSB as an early predictor of neurodevelopmental problems in CHD survivors.