Ida Sirgiovanni

Pain-related stress during the Neonatal Intensive Care Unit stay and SLC6A4 methylation in very preterm infants

Very preterm (VPT) infants need long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU) during which they are daily exposed to pain-related stress. Alterations of DNA methylation at the promoter region of the SLC6A4 have been associated with early adverse experiences in infants. The main aim of the present work was to investigate the association between level of exposure to pain-related stress during hospitalization and changes in SLC6A4 DNA methylation at NICU discharge in VPT infants. In order to exclude the potential effect of birth status (i.e., preterm vs. full-term birth) on SLC6A4 methylation, we preliminarily assessed SLC6A4 epigenetic differences between VPT and full-term (FT) infants at birth. Fifty-six VPT and thirty-two FT infants participated in the study. The level of exposure to pain-related stress was quantified on the basis of the amount of skin-breaking procedures to which they were exposed. VPT infants were divided in two sub-groups: low-pain exposure (LPE, N = 25) and high-pain exposure (HPE, N = 31). DNA methylation was evaluated at birth for both VPT and FT infants, assessing 20 CpG sites within the SLC6A4 promoter region. The same CpG sites were re-evaluated for variations in DNA methylation at NICU discharge in LPE and HPE VPT infants. No differences in SLC6A4 CpG sites methylation emerged between FT and VPT infants at birth. Methylation at CpG sites 5 and 6 significantly increased from birth to NICU discharge only for HPE VPT infants. Findings show that preterm birth per se is not associated with epigenetic alterations of the SLC6A4, whereas higher levels of pain-related stress exposure during NICU stay might alter the transcriptional functionality of the serotonin transporter gene.

From germinal matrix to cerebellar haemorrhage.

Abstract For many years cerebellar development after preterm birth has been poorly investigated and has been studied without taking germinal matrix-intraventricular haemorrhage into account. Advanced neuroimaging techniques like magnetic resonance imaging, as well as the use of various acoustic windows (mastoid fontanelle, occipital foramen) have allowed for in vivo diagnosis of acquired focal haemorrhagic lesions in the cerebellum of very preterm babies. The vulnerability of the cerebellum also seems to be related to specific gestational ages, i.e., between 23 and 27 weeks, when rapid growth in cerebellar volume occurs and at a much faster rate than mean brain volume increase. In this paper, the contribution of the cerebellum in long-term motor cognitive, learning and behavioural functions, including psychiatric ones, is discussed.

The Impact of Twin Birth on Early Neonatal Outcomes

OBJECTIVEnThis study aims to describe the impact of twin birth, chorionicity, intertwin birth weight (BW) discordance and birth order on neonatal outcomes.nnnSTUDY DESIGNnWe 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.nnnRESULTSnOverall, 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.nnnCONCLUSIONnPrematurity 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.

From early stress to 12-month development in very preterm infants: Preliminary findings on epigenetic mechanisms and brain growth

Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain.

Cranial ultrasound findings in late preterm infants and correlation with perinatal risk factors

BackgroundLate preterm infants are the most represented premature babies. They are exposed to a wide spectrum of brain lesions which are often clinically silent, supporting a possible role of cerebral ultrasound screening. Aim of the study is to describe the pattern of cranial ultrasound abnormalities in late preterm infants and to define the need for cranial ultrasound according to perinatal risk factors.MethodsA hospital-based cranial ultrasound screening was carried out by performing two scans (at 1 and 5xa0weeks). Unfavorable cranial ultrasound at 5xa0weeks was defined as either persistent periventricular hyperechogenicity or severe abnormalities.ResultsOne thousand one hundred seventy-two infants were included. Periventricular hyperechogenicity and severe abnormalities were observed in, respectively, 19.6xa0% and 1xa0% of late preterms at birth versus 1.8xa0% and 1.4xa0% at 5xa0weeks. Periventricular hyperechogenicity resolved in 91.3xa0%. At the univariate analysis gestational age (OR 0.5, 95xa0% CI 0.32-0.77), Apgar score <5 at 5’ (OR 15.3, 1.35-173) and comorbidities (OR 4.62, 2.39-8.98) predicted unfavorable ultrasound at 5xa0weeks. At the multivariate analysis the accuracy in predicting unfavorable ultrasound, estimated by combined gestational age/Apgar/comorbidities ROC curve, was fair (AUC 74.6) and increased to excellent (AUC 89.4) when ultrasound at birth was included.ConclusionGestational age and comorbitidies are the most important risk factors for detecting brain lesions. The combination of being born at 34xa0weeks and developing RDS represents the strongest indication to perform a cranial ultrasound. Differently from other studies, twin pregnancy doesn’t represent a risk factor.

Clinical safety of 3-T brain magnetic resonance imaging in newborns

BackgroundThe effects and potential hazards of brain magnetic resonance imaging (MRI) at 3 T in newborns are debated.ObjectiveAssess the impact of 3-T MRI in newborns on body temperature and physiological parameters.Material and methodsForty-nine newborns, born preterm and at term, underwent 3-T brain MRI at term-corrected age. Rectal and skin temperature, oxygen saturation and heart rate were recorded before, during and after the scan.ResultsA statistically significant increase in skin temperature of 0.6xa0°C was observed at the end of the MRI scan (P<0.01). There was no significant changes in rectal temperature, heart rate or oxygen saturation.ConclusionCore temperature, heart rate and oxygen saturation in newborns were not affected by 3-T brain MR scanning.

Maternal Sensitivity Buffers the Association between SLC6A4 Methylation and Socio-Emotional Stress Response in 3-Month-Old Full Term, but not very Preterm Infants

Background Very preterm (VPT) infants are hospitalized in Neonatal Intensive Care Units (NICUs) and are exposed to life-saving procedures eliciting pain-related stress. Recent research documented that pain-related stress might result in birth-to-discharge increased methylation of serotonin transporter gene (SLC6A4) in VPT infants, leading to poorer stress regulation at 3u2009months of age in VPT infants compared to their full-term (FT) counterparts. Maternal sensitivity is thought to support infants’ stress response, but its role in moderating the effects of altered SLC6A4 methylation is unknown. Main aim To assess the role of maternal sensitivity in moderating the association between altered SLC6A4 methylation and stress response in 3-month-old VPT and FT infants. Methods 53 infants (27 VPTs, 26 FTs) and their mothers were enrolled. SLC6A4 methylation was obtained from peripheral blood samples at NICU discharge for VPT infants and from cord blood at birth for FT infants. At 3u2009months (age corrected for prematurity), both groups participated to the face-to-face still-face (FFSF) paradigm to measure both infants’ stress response (i.e., negative emotionality) and maternal sensitivity. Results Maternal sensitivity did not significantly differ between VPT and FT infants’ mothers. In VPT infants, higher SLC6A4 methylation at hospital discharge associates with higher negative emotionality during the FFSF. In FT infants, SLC6A4 methylation and maternal sensitivity significantly interacted to predict stress response: a positive significant association between SLC6A4 methylation and negative emotionality emerged only in FT infants of less-sensitive mothers. Discussion Although no differences emerged in caregiving behavior in the two groups of mothers, maternal sensitivity was effective in moderating the effects of SLC6A4 methylation in FT infants, but not in VPT infants at 3u2009months. Speculatively, the buffering effect of maternal sensitivity observed in FT infants was disrupted by the altered early mother–infant contact due to NICU stay of the VPT group. These findings indirectly support that the effects of maternal sensitivity on infants’ socio-emotional development might be time dependent, and that mother–infant interventions in the NICU need to be provided precociously within a narrow sensitive period after VPT birth.

Fetal development of the corpus callosum : Insights from a 3T DTI and tractography study in a patient with segmental callosal agenesis

Commissural embryology mechanisms are not yet completely understood. The study and comprehension of callosal dysgenesis can provide remarkable insights into embryonic or fetal commissural development. The diffusion tensor imaging (DTI) technique allows the in vivo analyses of the white-matter microstructure and is a valid tool to clarify the disturbances of brain connections in patients with dysgenesis of the corpus callosum (CC). The segmental callosal agenesis (SCAG) is a rare partial agenesis of the corpus callosum (ACC). In a newborn with SCAG the DTI and tractography analyses proved that the CC was made of two separate segments consisting respectively of the ventral part in the genu and body of the CC, connecting the frontal lobes, and the dorsal part in the CC splenium and the attached hippocampal commissure (HC), connecting the parietal lobes and the fornix. These findings support the embryological thesis of a separated origin of the ventral and the dorsal parts of the CC.

Cranial ultrasound screening in late preterm infants

Late preterm births have enormously increased in the last decades and there is mounting evidence showing that infants born late preterm are less healthy than infants born at term [1] and they are more likely to develop neonatal morbidities (temperature instability, respiratory distress syndrome, excessive weight loss and dehydration requiring intravenous infusion, sepsis, hypoglycemia and jaundice requiring phototherapy) [2]. n nMore recently, an increased neuromorbidity has been documented and long-term neurodevelopmental impairments (poor school performance, early intervention services, special education needs) have been reported in this population [3,4]. The neuromorbidity of the late preterm infants has been attributed to both the potential detrimental neurological effects (extrinsic vulnerability) of the morbidities these babies experience in the neonatal period, and to the intrinsic brain vulnerability. Advances in neuroimaging techniques have highlighted a higher intrinsic vulnerability of the late preterm brain due to the structural and molecular immaturity of the developing brain at specific gestational ages [5,6]. n nTherefore, late preterm infants have a risk to develop brain lesions which is lower than more premature babies but higher than term newborns and they can be affected by brain lesions common to both preterm and term infants [7]. However, the incidence of brain abnormalities in this specific population has never been investigated as late preterm infants have long been considered a large and low-risk population. n nConsidering that most of the brain lesions are clinically subtle or silent during the neonatal period, a cranial ultrasound screening may play a role in: 1. detecting babies at risk of impaired neurodevelopment later in childhood and who may benefit from early intervention programs; 2. identifying the most significant perinatal risk factors associated with brain abnormalities in such a large low-risk population in order to target the potential need for cranial ultrasound at birth. Based on these assumptions we performed a cranial ultrasound screening project on late preterm infants. Our preliminary data (unpublished data) suggest that lower gestational age, within the late preterm period, and early neonatal morbidities, can provide an indication at birth to undergo a cranial ultrasound scan as they are associated with a higher risk to develop brain abnormalities. Late preterm infants represent a vulnerable population and investigation and follow-up program should be modulated according to the prenatal, perinatal and postnatal characteristics. n nFollow-up studies are needed to correlate neonatal ultrasound findings with long-term neurobehavioral outcomes in late preterm infants.

How has research changed our clinical practice in the last years

Abstract Research plays an important role in influencing clinical decisions and building up a safe clinical practice although it must be taken into consideration that the practice of the evidence based medicine derives from the integration of the best available external clinical evidence from systematic research with own individual clinical expertise. The practice of neonatology aims to provide the optimal individualized care for the mother and her baby. In this paper we will address some of the main research findings that have brought recent changes in neonatal clinical practice although frequently raising new questions and therefore making research pathways still incomplete.