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Abstract Body

Premature infants have impaired cardiovascular function that persists into adulthood. Preterm infants exhibit impaired systolic and diastolic dysfunction that is intolerant of the adverse loading conditions experienced during the early neonatal period. Young adults born premature demonstrate a unique cardiac phenotype characterized by reduced biventricular volume, relatively lower systolic and diastolic function, and a disproportionate increase in muscle mass. This may clinically manifest by an increased risk of cardiovascular incidents, hypertension, and reduced exercise tolerance. Those consequences appear to result from early postnatal cardiac remodelling due to premature birth and associated comorbidities. Recent evidence suggests that early exposure to breast milk slows down or even arrests those pathophysiological changes, thereby mitigating the long-term adverse effects of premature birth on cardiovascular health. In this talk article, we discuss the role of breast milk in preventing cardiovascular disease in infants born premature. We explore the emerging evidence and examine the possible mechanistic pathways mediating this phenomenon. Furthermore, we aim to demonstrate the vital role of early breast milk exposure in preventing cardiovascular disease in preterm infants.

Abstract Body

Acquired perinatal brain injuries in prematurely born infants are a leading cause of lifelong disability with social, emotional and financial implications, and still represent a challenge for neonatologists as no therapeutic options have been implemented into clinical practice.

Injuries to the preterm brain include diffuse white and grey matter damage which underlie a spectrum of connectivity impairments. Given the relevant role of inflammation in the pathogenesis of preterm brain injuries, immune-modulatory interventions may have a potential to support recovery.

Potential therapeutic interventions include stem cells (and derived exosomes) that seem to reduce perinatal brain injury although evidence is based on highly heterogeneous preclinical and clinical studies and effective protocols for each type of injury and stem cells still need to be defined. Erythropoietin (EPO) at high doses has anti-apoptotic, anti-inflammatory and antioxidant properties with possible neuroprotective and neuroregenerative effects on the brain. However, the optimal EPO regimen is still unknown and a recent large randomized multi-center trial in extremely preterm infants did not demonstrate a beneficial effect of EPO on the risk of severe neurodevelopmental impairment at 2y.

Neonates and infants have remarkable brain plasticity that reflects the capability of the brain to modify by adapting to environmental exposure and underlies the damage-induced processes of brain reorganization. Early evidence-based interventions, focused on parental involvement, multisensory stimulation and enriched environment may enhance neurodevelopment in brain injured preterms despite the correct combination of interventions and the timing in relation to the onset, nature, and degree of injury need to be further explored.

Background and Aims

Preterm birth affects 10% of live births and is associated with an altered left ventricular (LV) and right ventricular (RV) phenotype and increased cardiovascular disease risk in young adulthood. As left atrial (LA) and right atrial (RA) volume and function are known predictors of cardiovascular outcomes, we investigated whether these were altered in preterm-born young adults.

Methods

Preterm-born and term-born adults aged 18 to 39 years underwent cardiovascular magnetic resonance imaging. LA and RA maximal and minimal volumes (absolute, indexed to body surface area, and as a ratio to ventricular volumes) were obtained to study atrial morphology, while LA and RA stroke volume, strain, and strain rate were used to assess atrial function. Secondary analyses consisted of between-group comparisons based on degree of prematurity.

Results

Absolute and indexed LA volumes were similar between preterm-born (n=200) and term-born adults (n=266). However, LA maximal to LV end-diastolic volume ratio was elevated in preterm-born adults (0.447±0.092 vs 0.413±0.096, P<0.001). For the RA, all absolute and indexed volumes were smaller in preterm-born compared to term-born adults, including RA maximal to RV end-diastolic volume (0.418±0.098 vs 0.442±0.092, P=0.012). Additionally, RA deformation was globally increased in preterm-born adults, possibly indicating functional compensation for the smaller RA. LA and RA changes were observed across gestational ages in the preterm group but were greatest in those born very-to-extremely preterm.

Conclusions

Preterm-born adults show changes in LA and RA structure and function, which may indicate subclinical cardiovascular disease. Further research into underlying mechanisms, opportunities for interventions, and their prognostic value is warranted.

Background and Aims

Inflammation is a key mediator of preterm brain injury, resulting in neuro-disabilities like cerebral palsy. We aimed to investigate the combined anti-inflammatory effects of cord-tissue derived mesenchymal stem cells (UC-MSCs) and umbilical cord blood mononuclear cells (UCB-MNCs) in an ovine model of inflammation-induced preterm brain injury.

Methods

Fetal sheep were instrumented at 0.65 gestation and administered lipopolysaccharide (LPS 200mg; n=9) to induce inflammation, daily for three days. 100x10⁶ UCB-MNCs and 10x10⁶ UC-MSCs (n=9) were administered I.V. 6h after last LPS dose, or saline in controls (n=8). Brains were collected 7 days after cell administration and examined for cell death (Caspase-3), white matter development, oligodendrocytes (Olig-2), microglial activation (IBA-1), astrogliosis (GFAP), and white matter integrity (CNPase) by immunohistochemistry in subcortical (SCWM) and periventricular white matter (PVWM).

Results

LPS administration resulted in more cell death in the SCWM (mean (SEM) 13.21(2.11) vs. 7.10(1.33) cells/field, p=0.03), reduced oligodendrocytes in the SCWM (17.71(2.56) vs. 29.81(1.81) cells/field, p=0.002) and decreased density of myelinating axons (CNPase) in the PVWM (1.66(0.24)x10⁷ vs. 7.06(0.58)x10⁷ a.u, p=0.001) compared to controls. Compared to LPS alone, cell treated fetuses showed reduced activated microglia in the PVWM (29.77(5.40) vs. 10.02(1.35) cells/field, p=0.004), and reduced astrogliosis in the SCWM (2.45(0.23)x10⁷ vs. 4.37(0.47) x 10⁷ a.u). There was increased density of CNPase in the PVWM (3.62(0.26)x10⁷ vs. 1.66(0.24)x10⁷ a.u, p=<0.001) in cells-treated fetuses compared to LPS alone.

Conclusions

Combined treatment with UCB-MNCs and UC-MSCs was associated with reduction in inflammation and restoration of white matter integrity following exposure to LPS in a model of inflammation-induced preterm brain injury.

Background and Aims

Previous research have shown regional volumetric differences at term age for children born preterm and extremely preterm (EPT) with and without neonatal risk factors (Padilla et al 2015, Filan et al 2010, Alexander et al 2018). Little is known about volumetric differences associated with specific neonatal conditions for children born EPT during childhood. The aim was to investigate if children born EPT with and without predefined perinatal risk factors had regional volumetric differences at 10 years of age.

Methods

Children born EPT (n=51) in Stockholm without focal brain lesions during 2004-2007 were included. We compared children with any ROP and no ROP, IVH grade I-II and no IVH, PDA ligation and no PDA, PDA ligation and PDA treated with ibuprofen, children born ≤ GA 25+5 and ≥ GA 26+0 weeks. T1 weighted MRI images were pre-processed using the SPM algorithm and then compared with voxel-based morphometry adjusting for sex, gestational age and intracranial volume.

Results

Children born EPT with IVH grade I-II had reduced GM volume in the left hippocampus compared to children with no IVH. Children with PDA ligation had increased grey matter volumes in the occipital lobe. Children with any ROP compared to no ROP and children born ≤ GA 25+5 compared to ≥ GA 26+0 weeks did not have regional volumetric differences. (Figure 1.)

Conclusions

Some but not all neonatal risk factors investigated resulted in limited, but long-lasting, regional brain changes possibly standing for alterations in typical brain trajectories during development.