To be born twin: effects on long-term neurodevelopment of very preterm infants-a cohort study.

Objective: To examine the effect of twin birth on long-term neurodevelopmental outcomes in a cohort of Italian preterm infants with very low birth weight. Study design: We performed a retrospective cohort study on children born in a tertiary care centre. We included children born between 1 January 2007 and 31 December 2013 with a gestational age (GA) of ≤32 weeks and birth weight of <1,500 g. The infants born from twin pregnancies complicated by twin-to-twin transfusion syndrome and from higher-order multiple pregnancies were excluded. The children were evaluated both at 2 years corrected age and 5 years chronological age with Griffiths mental development scales revised (GMDS-R). The linear mixed effects models were used to study the effect of being a twin vs. being a singleton on GMDS-R scores, adjusting for GA, being born small for gestational age, sex, length of NICU stay, socio-economic status, and comorbidity score (CS) calculated as the sum of the weights associated with each of the major morbidities of the infants. Results: A total of 301 children were included in the study, of which 189 (62.8%) were singletons and 112 (37.2%) were twins; 23 out of 112 twins were monochorionic (MC). No statistically significant differences were observed between twins and singletons in terms of mean general quotient and subscales at both 2 and 5 years. No effect of chorionicity was found when comparing scores of MC and dichorionic twins vs. singletons; however, after adjusting for the CS, the MC twins showed lower scores in the hearing and language and performance subscales at 5 years. Conclusion: Overall, in our cohort of children born very preterm, twin infants were not at higher risk of neurodevelopmental impairment compared with singletons at pre-school age.

Serotonin transporter gene methylation and emotional regulation in preschool children born preterm: A longitudinal evaluation of the role of negative emotionality in infancy.

The aim of the study was to assess the contribution of negative emotionality at 3 months (T1) and serotonin transporter gene (SLC6A4) DNA methylation at 4.5 years of age (T2) to emotion regulation in pre-schoolers born very preterm and full-term. Forty one children (n = 21 born very preterm, n = 20 born full-term) participated in the study. Fretful behavior was assessed at T1 in response to the Face-to-FaceStill-Face (FFSF) paradigm. At T2, SLC6A4 DNA methylation was analyzed and emotion regulation was assessed using an observational procedure (i.e., the Pre-schooler Regulation of Emotional Stress, PRES). The very preterm group displayed higher emotion dysregulation during the PRES Reactivity phase than the full-term group. Higher levels of fretful behavior at 3 months were associated with greater emotional distress only for very preterm children with higher methylation at T2. No significant associations emerged in the full-term group. Despite current findings cannot be generalized owing to the relatively small sample size, this work provides preliminary longitudinal evidence about the link between negative emotionality during infancy, stress-linked epigenetic status at 4.5 years and emotion dysregulation in preschoolers born preterm.

El propósito del estudio fue evaluar la contribución de la emocionalidad negativa a los 3 meses (T1) y la metilación del ADN en el gen transportador de la serotonina (SLC6A4) a los 4 años y medio de edad (T2) a la regulación de la emoción en prescolares nacidos muy antes de la gestación completa o de gestación completa. Cuarenta y un niños (n = 21 nacidos muy antes de la gestación completa, n = 20 nacidos de gestación completa) participaron en el estudio. El comportamiento irritable se evaluó a T1 como respuesta al Cara-a-Cara del paradigma de la Cara Inmóvil (FFSF). A T2, se analizó la metilación de ADN SLC6A4 y se evaluó la regulación de la emoción usando un procedimiento de observación (v.g. La Regulación del Estrés Emocional del Prescolar, PRES). El grupo nacido muy antes de la gestación completa mostró una más alta desregulación durante la fase de Reactividad PRES que el grupo nacido de gestación completa. Los niveles más altos de comportamiento irritable a los 3 meses se asociaron con una mayor angustia emocional solamente para los niños nacidos muy antes de la gestación completa con más alta metilación al T2. Ninguna asociación significativa surgió del grupo nacido de gestación completa. A pesar de que los actuales resultados no se pueden generalizar debido al tamaño relativamente pequeño del grupo muestra, este trabajo ofrece aporta evidencia longitudinal preliminar acerca de la conexión entre la emocionalidad negativa durante la infancia, el estado epigenético relacionado con el estrés a los 4 años y medio y la desregulación de la emoción en prescolares nacidos antes de la completa gestación.

Le but de cette étude était d'évaluer la contribution de l'émotivité négative à 3 mois (T1) et du gène vecteur de la sérotonine (SLC6A4) méthylation de l'ADN à l'âge de 4,5 ans (T2) à la régulation de l'émotion chez les enfants d'âge préscolaire nés très prématurés et à plein terme. Quarante et un enfant (n = 21 nés très prématurés, n = 20 nés à plein terme) ont participé à l'étude. Le comportement agité a été évalué au T1 en réponse au paradigme face-à-face visage inexpressif (abrégé FFSF en anglais). Au T2, la méthylation de l'ADN SLC6A4 a été analysée et la régulation de l'émotion a été évaluée en utilisant un protocole d'observation (à savoir, la Régulation du Stress Emotionnel de l'Enfant d'Age Préscolaire, abrégé en anglais PRES). Le groupe très prématuré a fait état d'une dysrégulation de l'émotion plus élevée durant la phase de Réactivité PRES que le groupe né à plein terme. Des niveaux plus élevés de comportement agité à 3 mois étaient liés à une détresse émotionnelle plus grande uniquement pour les enfants très prématurés avec une méthylation plus élevée au T2. Aucune association importante n'a émergé dans le groupe à plein terme. En dépit du fait que les résultats actuels ne peuvent pas être généralisés à cause de la taille relativement petite de l'échantillon, ce travail offre des preuves longitudinales préliminaires sur le lien entre l'émotivité négative durant la petite enfant, le statut épigénétique lié au stress à 4,5 ans et la dysrégulation de l'émotion chez les enfants d'âge préscolaires nés avant terme.

Cumulative procedural pain and brain development in very preterm infants: A systematic review of clinical and preclinical studies.

Very preterm infants may manifest neurodevelopmental impairments, even in the absence of brain lesions. Pathogenesis is complex and multifactorial. Evidence suggests a role of early adversities on neurodevelopmental outcomes, via epigenetic regulation and changes in brain architecture. In this context, we focused on cumulative pain exposure which preterm neonates experience in neonatal intensive care unit (NICU). We systematically searched for: i) evidence linking pain with brain development and exploring the potential pathogenetic role of epigenetics; ii) preclinical research supporting clinical observational studies. Nine clinical neuroimaging studies, during neonatal or school age, mostly from the same research group, revealed volume reduction of white and gray matter structures in association with postnatal pain exposure. Three controlled animal studies mimicking NICU settings found increased cell death or apoptosis; nevertheless, eligible groups were limited in size. Epigenetic modulation (SLC6A4 promoter methylation) was identified in only two clinical trials. We call for additional research and, although knowledge gaps, we also point out the urgent need of minimizing painful procedures in NICUs.

Pain-related increase in serotonin transporter gene methylation associates with emotional regulation in 4.5-year-old preterm-born children.

AIM: The main goal of this study was to assess the association between pain-related increase in serotonin transporter gene (SLC6A4) methylation and emotional dysregulation in 4.5-year-old preterm children compared with full-term matched counterparts. METHODS: Preterm (n = 29) and full-term (n = 26) children recruited from two Italian hospitals were followed-up from October 2011 to December 2017. SLC6A4 methylation was assessed from cord blood at birth from both groups and peripheral blood at discharge for preterm ones. At 4.5 years, emotional regulation (ie, anger, fear and sadness) was assessed through an observational standardised procedure. RESULTS: Preterm children (18 females; mean age = 4.5, range = 4.3-4.8) showed greater anger display compared with full-term controls (14 females; mean age = 4.5, range = 4.4-4.9) in response to emotional stress. Controlling for adverse life events occurrence from discharge to 4.5 years and SLC6A4 methylation at birth, CpG-specific SLC6A4 methylation in the neonatal period was predictive of greater anger display in preterm children but not in full-term ones. CONCLUSION: These findings contribute to highlight how epigenetic regulation of serotonin transporter gene in response to NICU pain exposure contributes to long-lasting programming of anger regulation in preterm children.

The Impact of Twin Birth on Early Neonatal Outcomes.

OBJECTIVE: This study aims to describe the impact of twin birth, chorionicity, intertwin birth weight (BW) discordance and birth order on neonatal outcomes. STUDY DESIGN: We performed a hospital-based retrospective study on 2,170 twins (6.4% of all live births) and 2,217 singletons inborn 2007 to 2011. Data on neonatal characteristics, morbidities, and mortality were collected and compared. Univariate and multiple (adjusted for gestational age [GA] and gender) linear random intercept regression models were used. RESULTS: Overall, 62.3% of twins were born premature. At multiple regression, twins were similar to singletons for neonatal morbidities, but they were more likely to have lower BW and to be born by cesarean delivery. Monochorionic twins had lower GA and BW compared with dichorionic ones and were more likely to develop respiratory distress syndrome (odds ratio [OR], 1.7), hypoglycemia (OR, 3.3), need for transfusion, (OR, 3.4) but not brain abnormalities. Moderate and severe BW discordance were associated with longer length of stay and increased risk for morbidities but not for death. Birth order had no effects. CONCLUSION: Prematurity was the most common outcome in twins and accounted for the apparently increased risk in morbidities. Monochorionicity was confirmed as risk factor for lower GA and neonatal morbidities. BW discordance may play a role in developing neonatal complications and needs to be further investigated.

Survival rate and neurodevelopmental outcome of extremely premature babies: an 8-year experience of an Italian single neonatal tertiary care center.

Extremely preterm babies are at major risk for adverse neurodevelopmental outcome, being the gestational age (GA) the main determinant for a good-quality survival. Aim of this retrospective study was to investigate the neurodevelopmental outcome in a population of extremely preterm babies admitted to a single neonatal tertiary care unit over an 8-year period. All babies born between 23+0 and 25+6 weeks of GA from January 2003 until December 2010 were retrospectively enrolled. Perinatal and neonatal variables were recorded. Motor and cognitive development was assessed using the neurofunctional scale (NFS) and the Griffith's scales at 2 years. Fifty-five out of 122 infants survived to discharge. Survival rates doubled for each additional gestational week from 23 to 25: 16%, 38% and 74% at 23, 24 and 25 weeks GA respectively. Forty-six infants were evaluated at 2 years. A poor cognitive and motor outcome was observed in all babies born at 23 weeks. Griffith's general quotient (GQ) was ≥76 in 62% and ≥88 in 33% of babies born between 24 and 25 weeks. No severe motor disabilities were found in 81% of babies born between 24 and 25 weeks. Preterm premature rupture of membranes, absence of prenatal steroids, intrauterine growth restriction, male, lower GA and major brain abnormalities at magnetic resonance imaging (MRI) were significantly associated with worse NFS and lower mean GQ at 2 years of age. GA, gender and abnormal MRI findings remained significantly associated with impaired NFS at the multivariate analysis. Survival rates and neurodevelopmental outcome improved with each week of GA. These results are relevant for clinicians counselling families facing an unavoidable extremely preterm birth.

Intracranial haemorrhage: an incidental finding at magnetic resonance imaging in a cohort of late preterm and term infants.

BACKGROUND: Intracranial haemorrhage (ICH) in term newborns has been increasingly recognised but the occurrence in late preterm infants and the clinical presentation are still unclear. OBJECTIVE: To investigate the appearance of intracranial haemorrhage at MRI in a cohort of infants born at 34 weeks' gestation or more and to correlate MRI findings with neonatal symptoms. MATERIALS AND METHODS: We retrospectively reviewed neonatal brain MRI scans performed during a 3-year period. We included neonates ≥34 weeks' gestation with intracranial haemorrhage and compared findings with those in babies without intracranial haemorrhage. Babies were classified into three groups according to haemorrhage location: (1) infratentorial, (2) infra- and supratentorial, (3) infra- and supratentorial + parenchymal involvement. RESULTS: Intracranial haemorrhage was observed in 36/240 babies (15%). All of these 36 had subdural haemorrhage. Sixteen babies were included in group 1; 16 in group 2; 4 in group 3. All infants in groups 1 and 2 were asymptomatic except one who was affected by intraventricular haemorrhage grade 3. Among the infants in group 3, who had intracranial haemorrhage with parenchymal involvement, three of the four (75%) presented with acute neurological symptoms. Uncomplicated spontaneous vaginal delivery was reported in 20/36 neonates (56%), vacuum extraction in 4 (11%) and caesarean section in 12 (33%). Babies with intracranial haemorrhage had significantly higher gestational age (38 ± 2 weeks vs. 37 ± 2 weeks) and birth weight (3,097 ± 485 g vs. 2,803 ± 741 g) compared to babies without intracranial haemorrhage and were more likely to be delivered vaginally than by caesarian section. CONCLUSION: Mild intracranial haemorrhage (groups 1 and 2) is relatively common in late preterm and term infants, although it mostly represents an incidental finding in clinically asymptomatic babies; early neurological symptoms appear to be related to parenchymal involvement.