EARLY INTERVENTION IN PRETERM INFANTS: EFFECTS ON NUTRITION AND NEURODEVELOPMENT

Background: Preterm infants are at high risk for neurodevelopmental disorders, even in the absence of overt brain lesions. NICU stressful environment, inadequate nutritional support and paucity of parental contact seem to negatively impact early brain development. In this context, mother milk feeding, could play a beneficial role although it is known to be challenging. Recent studies have shown how early interventions can reduce stress exposure with a positive effect on mother-infant relationship and subsequent neurodevelopment in preterm infants. Aims: To determine the effectiveness, in preterm infants, of an Early Intervention program on: i) visual function at term equivalent age (TEA) as an early emerging cognitive function; ii) infant’s feeding behavior and in particular on mother milk assumption at discharge; iii) epigenetic changes in DNA methylation status at TEA; iv) brain growth and maturation assessed by advanced Magnetic Resonance Imaging (MRI) at TEA. Methods: We conducted a parallel-group, randomized controlled trial (Trial Registration Number: NCT02983513). We included preterm infants born between 25+0 and 29+6 weeks of gestational age (GA) without severe morbidities and their families. Infants were recruited and randomized to either receiving Early intervention (EI) or Standard Care (SC). EI program included PremieStart, based on parental involvement, together with a multisensory stimulation (both tactile – through infant massage - and visual stimulation). SC, delivered according to NICU protocols, included Kangaroo Mother Care and minimal handling. Infants with major neonatal morbidities (i.e. surgical NEC; severe brain injuries as GMH-IVH>2°, cPVL) were excluded. The following evaluation were performed: i) Visual ability were assessed at TEA according to the protocol developed by Ricci et al. ii) Infants’ human milk intake at discharge was calculated from the infants’ computerized medical chart, as well as time of acquisition of full-oral feeding iii) As a proxy of DNA methylation we explored LINE-1 methylation status. The analyses were conducted using two blood samples: a cord blood sample, collected at birth, and a peripheral blood sample, harvested at TEA. iv) To calculate brain growth automated segmentation was conducted on each neonatal Axial T2 2 mm scan, in conjunction with the T1 scan. Volumetric measures of the structures were extracted from each segmentation. Results: Seventy preterm (EI n=34, SC n=36) infants were enrolled. According to the protocol 3 infants allocated to EI did not receive treatment. All babies in the SC group received allocated treatment as part of routine clinical practice. Main results include: i) Visual abilities: in total, 59% of infants in the EI group achieved the highest score possible in all 9 items of the visual assessment compared to 17% in the SC group (p=0.001). All infants in both groups showed complete maturation in four items, but EI infants showed more mature findings also in the other 5 items (ocular motility both spontaneous and with target, tracking arc, visual acuity and attention at distance). ii) Infant’s feeding behavior: a significantly higher rate of infants fed with any human milk was observed in the EI group (75.9%) compared to SC group (32.1%) (p=0.001) and EI infants were four times more likely to be fed exclusively with human milk at NICU discharge. Full oral feeding was achieved almost one week before in EI infants (mean postmenstrual age 36.8±1.6 vs 37.9±2.4 weeks in EI vs SC, p=0.04). iii) Epigenetic changes: LINE-1 methylation status increased from preterm birth to TEA for both group but was more pronounced in the EI group (p=0.0077) especially when looking at single CpG sites. iv) Brain growth: no differences were observed between the two groups in terms of regional brain volumes for the 48 areas analyzed. Conclusions: The present work provides further insights in the field of EI. Combining parental involvement and multisensory stimulation, our EI strategy showed an overall beneficial effect for preterm infants. This study, despite far to be conclusive, concur with recent evidence that the quality of early experiences influences neurodevelopment in preterm infants.