Maternal singing sustains preterm hospitalized newborns' autonomic nervous system maturation: an RCT.

BACKGROUND: Premature birth is known to affect the newborn's autonomic nervous system (ANS) maturation, with potential short and long-term impact on their neurobehavioral development. The purpose of the study was to investigate the effects of maternal directed singing and speaking on the preterm infants' autonomic nervous system (ANS) maturation as measured by the heart rate variability (HRV) parameters. METHODS: In this multi-center randomized clinical trial, 30 stable preterm infants (m = 29,6 weeks of gestational age), without any abnormalities were randomized into an intervention (16) or a control group (14). HRV was measured weekly, for a total of 80 recordings during hospitalization, as well as before and after each session of singing or speaking. RESULTS: The intervention group showed a significant increase of the percentage value of HRV power in the high frequency range when compared to the control group (p = 0.044). More specifically, the maternal singing significantly increased the high frequency power and decreased the low/high frequency power ratio (p = 0.037). CONCLUSIONS: The preterm infant's vagal activity significantly increased in the intervention group, potentially enhancing their ANS maturation. The effect is specifically evidenced in the singing condition. IMPACT: Maternal singing affects the autonomic nervous system maturation of preterm hospitalized newborns in the NICU. No previous studies investigated how early vocal parental intervention can affect preterm infants developement, throught their autonomic nervous system maturation. Early Vocal Contact as an early intervention involving parents has a positive impact on preterm infant's development and it can be easily implemented in the care of preterm infants. TRIAL REGISTRATION: NCT04759573, retrospectively registered, 17 February 2021.

Continuous Fentanyl Infusion in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia: Background, Aims, and Study Protocol for Time-Concentration Profiles.

Therapeutic hypothermia (TH) is the standard of care for newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE). Discomfort and pain during treatment are common and may affect the therapeutic efficacy of TH. Opioid sedation and analgesia (SA) are generally used in clinical practice, and fentanyl is one of the most frequently administered drugs. However, although fentanyl's pharmacokinetics (PKs) may be altered by hypothermic treatment, the PK behavior of this opioid drug in cooled newborns with HIE has been poorly investigated. The aim of this phase 1 study protocol (Trial ID: FentanylTH; EUDRACT number: 2020-000836-23) is to evaluate the fentanyl time-concentration profiles of full-term newborns with HIE who have been treated with TH. Newborns undergoing TH receive a standard fentanyl regimen (2 mcg/Kg of fentanyl as a loading dose, followed by a continuous infusion-1 mcg/kg/h-during the 72 h of TH and subsequent rewarming). Fentanyl plasma concentrations before bolus administration, at the end of the loading dose, and 24-48-72-96 h after infusion are measured. The median, maximum, and minimum plasma concentrations, together with drug clearance, are determined. This study will explore the fentanyl time-concentration profiles of cooled, full-term newborns with HIE, thereby helping to optimize the fentanyl SA dosing regimen during TH.

Neurodevelopmental Outcome and Neuroimaging of Very Low Birth Weight Infants from an Italian NICU Adopting the Family-Centered Care Model.

BACKGROUND: Improvements in perinatal care have substantially decreased mortality rates among preterm infants, yet their neurodevelopmental outcomes and quality of life persist as a pertinent public health concern. Family-centered care has emerged as a holistic philosophy that promotes effective alliances among patients, families, and healthcare providers to improve the quality of care. AIMS: This longitudinal prospective study aims to evaluate the neurodevelopmental outcomes and brain MRI findings in a cohort of preterm newborns admitted to a neonatal intensive care unit (NICU) adopting a family-centered care model. METHODS: Very low birth weight (VLBW) infants admitted to the NICU of Modena between 2015 and 2020 were enrolled. Infants who underwent conventional brain magnetic resonance imaging (MRI) at term-equivalent age were included. Neurodevelopmental follow-up was performed until the age of 24 months by a multidisciplinary team using the Amiel-Tison neurological assessment and the Griffiths Mental Developmental Scales (GMDS-R). Neurodevelopmental outcomes were classified as major sequelae (cerebral palsy, DQ ≤ 70, severe sensory impairment), minor sequelae (minor neurological signs such as clumsiness or DQ between 71 and 85), and normal outcomes (no neurological signs and DQ > 85). Risk factors for severe outcomes were assessed. RESULTS: In total, 49 of the 356 infants (13.8%) died before hospital discharge, and 2 were excluded because of congenital disorders. Of the remaining 305 infants, 222 (72.8%) completed the 24 month follow-up and were included in the study. Neurodevelopmental outcomes were classified as normal (n = 173, 77.9%), minor (n = 34, 15.3%), and major sequelae (n = 15, 6.8%). Among 221 infants undergoing brain MRI, 76 (34.4%) had major lesions (intraventricular hemorrhage, hemorrhagic parenchymal infarction, periventricular leukomalacia, and large cerebellar hemorrhage). In the multivariate regression model, the retinopathy of prematurity (OR 1.8; p value 0.016) and periventricular-intraventricular hemorrhage (OR 5.6; p value < 0.004) were associated with major sequelae. CONCLUSIONS: We reported low rates of severe neurodevelopmental outcomes in VLBW infants born in an Italian NICU with FCC. Identifying the risk factors for severe outcomes can assist in tailoring and optimizing early interventions on an individual basis, both within the NICU and after discharge.

Sudden Unexpected Postnatal Collapse and Therapeutic Hypothermia: What's Going On?

Sudden unexpected postnatal collapse (SUPC) is a rare event, potentially associated with catastrophic consequences. Since the beginning of the 2000s, therapeutic hypothermia (TH) has been proposed as a treatment for asphyxiated neonates after SUPC. However, only a few studies have reported the outcome of SUPC after TH. The current study presents the long-term neurodevelopmental outcome of four cases of SUPC treated with TH in a single Italian center. Furthermore, we reviewed the previous literature concerning 49 cases of SUPC treated with TH. Among 53 total cases (of whom four occurred in our center), 15 (28.3%) died before discharge from the NICU. A neurodevelopmental follow-up was available only for 21 (55.3%) out of the 38 surviving cases, and seven infants developed neurodevelopmental sequelae. TH should be considered in neonates with asphyxia after SUPC. However, SUPC is a rare event, and there is a lack of comparative clinical data to establish the risk/benefit of TH after SUPC with different degrees of asphyxia. Analysis of large cohorts of newborns with SUPC, whether treated with TH or untreated, are needed in order to better identify infants who should undergo TH.

Maternal Singing but Not Speech Enhances Vagal Activity in Preterm Infants during Hospitalization: Preliminary Results.

BACKGROUND: Early parental interventions in the Neonatal Intensive Care Units (NICUs) have beneficial effects on preterm infants' short and long-term outcomes. The aim of this study was to investigate the effects of Early Vocal Contact (EVC)-singing and speaking-on preterm infants' vagal activity and autonomic nervous system (ANS) maturation. METHODS: In this multi-center randomized clinical trial, twenty-four stable preterm infants, born at 25-32 weeks gestational age, were randomized to either the EVC group or control group, where mothers did not interact with the babies but observed their behavior. Heart Rate Variability (HRV) was acquired before intervention (pre-condition), during vocal contact, and after it (post condition). RESULTS: No significant effect of the vocal contact, singing and speaking, was found in HRV when the intervention group was compared to the control group. However, a significant difference between the singing and the pre and post conditions, respectively, preceding and following the singing intervention, was found in the Low and High Frequency power nu, and in the low/high frequency features (p = 0.037). By contrast, no significant effect of the speaking was found. CONCLUSIONS: Maternal singing, but not speaking, enhances preterm infants' vagal activity in the short-term, thus improving the ANS stability. Future analyses will investigate the effect of enhanced vagal activity on short and long-term developmental outcomes of preterm infants in the NICU.

Fentanyl analgesia in asphyxiated newborns treated with therapeutic hypothermia.

INTRODUCTION: Therapeutic hypothermia is the standard care for asphyxiated newborns. Discomfort and pain during treatment are common and may affect therapeutic efficacy of hypothermia. Opioid analgosedation is commonly used in the clinical setting, but its effects in the cooled newborns is poorly investigated. OBJECTIVE: The aim of this study was to assess the safety of fentanyl analgosedation during therapeutic hypothermia, by evaluating severe adverse effects and possible correlation with the neurodevelopmental outcome. METHODS: We analyzed asphyxiated newborns treated with hypothermia receiving fentanyl intravenous infusion (years 2013-2018). Severe neurodevelopmental outcome was defined as cerebral palsy or Griffith's developmental quotient <70 or major sensorineural deficit. Severe brain lesions were defined as cortical or/and basal ganglia extensive involvement. RESULTS: Fentanyl cumulative dose was variable (61.7 ± 18.5 µg/kg; range 34.3-120.3 µg/kg) among 45 enrolled patients. Respiratory depression was recorded in 13.3% cases of 30 spontaneously breathing patients. Severe brain lesions and severe neurodevelopmental disability were found in 24.4 and 11.1% of all included cases, respectively. Higher cumulative fentanyl dose was not associated with poor outcome. CONCLUSIONS: Fentanyl treatment during therapeutic hypothermia does not negatively affect the neurodevelopmental outcome, thus on the contrary, it may contribute to ameliorate neuroprotection in the asphyxiated cooled newborns.

Subtle impairment of neurodevelopment in infants with late fetal growth restriction.

INTRODUCTION: Children with late fetal growth restriction (FGR) are at high risk of being born small for gestational age (SGA). These categories of newborns are at increased risk for neurodevelopment impairment. The general movements assessment, in particular at fidgety age, has been used to predict neurological dysfunctions. This study aimed to evaluate growth recovery, presence of fidgety movements at 3 months, and neurodevelopmental outcome at 2 years of age in term late FGR infants and adequate for gestational age (AGA) controls. METHODS: Prospective clinical evaluation. At 3 months auxological parameters (AP) and neurological examination were evaluated while at 24 months neurodevelopment outcome by Griffiths Mental Development Scales (GMDS-R) was evaluated. RESULTS: 38 late FGR and 20 AGA controls completed the study. Despite a significant catch up, at 3 months 13% of late FGR presented at least one auxological parameter <3° percentile. Moreover, 23.7% of late FGR infants did not show fidgety movements compared to 100% AGA controls (p < .001). Cranial circumference at birth resulted a positive predictive factor for FMs (p = .039). At 2 years of age, a difference statistically significant between late FGR and AGA was detected in GMDS-R. CONCLUSION: Independently from growth recovery, fidgety movements resulted less expressed in late FGR infants, and at 2 years of age the neurodevelopmental assessment revealed differences in each domain of evaluation between late FGR and AGA infants, although within normal ranges.

Effects of Early Vocal Contact in the Neonatal Intensive Care Unit: Study Protocol for a Multi-Centre, Randomised Clinical Trial.

Preterm infants are at risk for developing altered trajectories of cognitive, social, and linguistic competences compared to a term population. This is mainly due to medical and environmental factors, as they are exposed to an atypical auditory environment and simultaneously, long periods of early separation from their parents. The short-term effects of early vocal contact (EVC) on an infant's early stability have been investigated. However, there is limited evidence of its impact on the infant's autonomic nervous system maturation, as indexed by heart rate variability, and its long-term impact on infant neurodevelopment. Our multi-centric study aims to investigate the effects of EVC on a preterm infant's physiology, neurobehaviour, and development. Eighty stable preterm infants, born at 25-32 weeks and 6 days gestational age, without specific abnormalities, will be enrolled and randomised to either an intervention or control group. The intervention group will receive EVC, where mothers will talk and sing to their infants for 10 min three times per week for 2 weeks. Mothers in the control group will be encouraged to spend the same amount of time next to the incubator and observe the infant's behaviour through a standard cluster of indicators. Infants will be assessed at baseline; the end of the intervention; term equivalent age; and 3, 6, 12, and 24 months corrected age, with a battery of physiological, neurobehavioral, and developmental measures. Early interventions in the neonatal intensive care unit have demonstrated effects on the neurodevelopment of preterm infants, thereby lowering the negative long-term effects of an atypical auditory and interactional environment. Our proposed study will provide new insight into mother-infant early contact as a protective intervention against the sequelae of prematurity during this sensitive period of development. Early intervention, such as EVC, is intuitive and easy to implement in the daily care of preterm infants. However, its long-term effects on infant neurodevelopment and maternal sensitivity and stress are still unclear. Trial Registration: NCT04759573, retrospectively registered, 17 February 2021.

Foot-to-Foot Contact Among Initial Goal-Directed Movements Supports the Prognostic Value of Fidgety Movements in HIE-Cooled Infants.

Background: Few studies conducted to date have observed general movements in infants affected by hypoxic-ischemic encephalopathy (HIE) who underwent therapeutic hypothermia. We investigated whether foot-to-foot contact (FF) could support the predictive value of fidgety movements (FMs) in infants affected by HIE and treated with brain cooling. Methods: Spontaneous motility was video recorded for 3-5 min at 12 weeks post-term age in 58 full-term newborn infants affected by perinatal asphyxia who were cooled due to moderate to severe HIE. FF and FMs were blindly scored by three independent observers. At 24 months, each patient underwent a neurological examination by Amiel-Tison and Grenier. Results: At 24 months, 47 infants had developed typically at neurological examination, eight had developed mild motor impairment, and three developed cerebral palsy (CP). At 12 weeks, 34 (58.6%) infants had shown normal FMs, four of whom developed mild motor impairment. Twenty-four infants (41.4%) exhibited abnormal or no FMs, four of whom developed mild motor impairment and three developed CP. FF was present in 20 infants (34.5%), two of whom developed mild motor impairment. FF was absent in 38 infants (65.5%), six of whom developed mild motor impairment and three developed CP. Both FMs and FF, considered separately, were 100% sensitive for predicting CP at 24 months, but only 61 and 36%, respectively, were specific. Summing the two patterns together, the specificity increases to 73%, considering only CP as an abnormal outcome, and increases to 74% when considering CP plus mild motor impairment. Unexpectedly, fidgety movements were absent in 24 infants with typical motor outcomes, 17 of whom showed a typical motor outcome. Conclusions: FF is already part of motor repertoire at 12 weeks and allows a comparison of spontaneous non-voluntary movements (FMs) to pre-voluntary movements (FF). FF supports FMs for both sensitivity and specificity. A second video recording at 16-18 weeks, when pedipulation is present in healthy infants, is suggested: it may better define the presence or absence of goal-directed motility.

Brain cooling reduces the risk of postneonatal epilepsy in newborns affected by moderate to severe hypoxic-ischemic encephalopathy.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is still a significant cause of neonatal death and neurodevelopmental disabilities, such as cerebral palsy, mental delay, and epilepsy. After the introduction of therapeutic hypothermia, the prognosis of hypoxic-ischemic encephalopathy has improved, with reduction of death and disabilities. However, few studies evaluated whether hypothermia affects rate and severity of postneonatal epilepsy. We evaluated rates, characteristics and prognostic markers of postneonatal epilepsy in infants with moderate to severe hypoxic-ischemic encephalopathy treated or not with therapeutic hypothermia. METHODS: We analyzed clinical data, EEG recordings, cerebral Magnetic Resonance Imaging (MRI) and outcome in 23 cooled and 26 non-cooled asphyxiated neonates (≥36 weeks' gestation), admitted from 2004 to 2012. RESULTS: Among 49 neonates 11 (22%) had postneonatal epilepsy, of which 9 (18%) were non-cooled and 2 (4%) were cooled (P=0.05). Six of 11 infants (55%) had West syndrome, 4 (36%) had focal epilepsy and 1 (9%) had Lennox-Gastaut Syndrome. At multiple logistic regression analysis MRI pattern significantly correlated with postneonatal epilepsy (OR 0.19, 95% CI 0.04-0.88, P=0.03). Extensive lesions in basal ganglia and thalami plus cortical and white matter were associated with postneonatal epilepsy. CONCLUSIONS: Only perinatal asphyxia with extensive lesions in basal ganglia and thalami plus cortical and white matter lesion conveys a high risk for early and severe postneonatal epilepsy. Moreover, therapeutic hypothermia is associated with a decrease of the risk of developing postneonatal epilepsy.

Overwhelming sepsis in a neonate affected by Zellweger syndrome due to a compound heterozygosis in PEX 6 gene: a case report.

BACKGROUND: Peroxisome biogenesis disorders (PBDs) are a group of metabolic diseases caused by dysfunction of peroxisomes. Different forms of PBDs are described; the most severe one is the Zellweger syndrome (ZS). We report on an unusual presentation of Zellweger syndrome manifesting in a newborn with severe and fulminant sepsis, causing death during the neonatal period. CASE PRESENTATION: A term male Caucasian neonate presented at birth with hypotonia and poor feeding associated with dysmorphic craniofacial features and skeletal abnormalities. Blood tests showed progressive leukopenia; ultrasounds revealed cerebral and renal abnormalities. He died on the fourth day of life because of an irreversible Gram-negative sepsis. Post-mortem tests on blood and urine samples showed biochemical alterations suggestive of ZS confirmed by genetic test. CONCLUSIONS: ZS is an early and severe forms of PBDs. Peroxisomes are known to be involved in lipid metabolism, but recent studies suggest their fundamental role in modulating immune response and inflammation. In case of clinical suspicion of ZS it is important to focus the attention on the prevention and management of infections that can rapidly progress to death.

Motor and Postural Patterns Concomitant with General Movements Are Associated with Cerebral Palsy at Term and Fidgety Age in Preterm Infants.

General movements (GMs) in combination with neurological examination and magnetic resonance imaging at term age can accurately determine the risk of cerebral palsy. The present study aimed to assess whether 11 motor and postural patterns concomitant with GMs were associated with cerebral palsy. Video recordings performed after birth in 79 preterm infants were reviewed retrospectively. Thirty-seven infants developed cerebral palsy at 2 years corrected age and the remaining 42 showed typical development. GMs were assessed from preterm to fidgety age and GM trajectories were defined. The 11 motor and postural patterns were evaluated at each age and longitudinally, alone and in combination with GM trajectories. A logistic regression model was used to assess the association between GMs, concomitant motor and postural patterns, and cerebral palsy. We confirmed that high-risk GM trajectories were associated with cerebral palsy (odds ratio = 44.40, 95% confidence interval = 11.74-167.85). An association between concomitant motor and postural patterns and cerebral palsy was found for some of the patterns at term age and for all of them at fidgety age. Therefore, at term age, concomitant motor and postural patterns can support GMs for the early diagnosis of cerebral palsy.

Two Overlapping Clusters of Group B Streptococcus Late-onset Disease in a Neonatal Intensive Care Unit.

OBJECTIVES: Current predominant routes of group B Streptococcus (GBS) transmission in preterm neonates admitted to neonatal intensive care unit (NICU) are poorly defined. We report 2 overlapping clusters of GBS late-onset disease (LOD) from June to September 2015 in an Italian NICU. METHODS: During the outbreak, possible sources of transmission (equipment, feeding bottles and breast pumps) were swabbed. Specimens from throat and rectum were collected on a weekly basis from all neonates admitted to NICU. Colonized or infected neonates had cohorting. Bacterial isolates were characterized by serologic and molecular typing methods. RESULTS: GBS was isolated in 2 full-term and 7 preterm neonates. Strains belonged to serotype III, with 3 different sequence types (ST17, ST182 and ST19). Full-term neonates were colonized with GBS strains unrelated to the clusters (ST182 and ST19). Two distinct ST17 strains caused 2 clusters in preterm neonates: a first cluster with 1 case of LOD and a second, larger cluster with 6 LOD in 5 neonates (one of them had recurrence). ST17 strains were isolated from vaginorectal and milk samples of 2 mothers. Two preterm neonates had no evidence of colonization for weeks, until they presented with LOD. CONCLUSIONS: Molecular analyses identified the presence of multiclonal GBS strains and 2 clusters of 7 cases of GBS-LOD. The dynamics of transmission of GBS within the NICU were complex. Breast milk was suspected to be one of the possible sources. In a research setting, the screening of GBS carrier mothers who deliver very preterm could contribute to the tracking of GBS transmission.

Prognostic value of diffusion-weighted imaging summation scores or apparent diffusion coefficient maps in newborns with hypoxic-ischemic encephalopathy.

BACKGROUND: The diagnostic and prognostic assessment of newborn infants with hypoxic-ischemic encephalopathy (HIE) comprises, among other tools, diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps. OBJECTIVE: To compare the ability of DWI and ADC maps in newborns with HIE to predict the neurodevelopmental outcome at 2 years of age. MATERIALS AND METHODS: Thirty-four term newborns with HIE admitted to the Neonatal Intensive Care Unit of Modena University Hospital from 2004 to 2008 were consecutively enrolled in the study. All newborns received EEG, conventional MRI and DWI within the first week of life. DWI was analyzed by means of summation (S) score and regional ADC measurements. Neurodevelopmental outcome was assessed with a standard 1-4 scale and the Griffiths Mental Developmental Scales - Revised (GMDS-R). RESULTS: When the outcome was evaluated with a standard 1-4 scale, the DWI S scores showed very high area under the curve (AUC) (0.89) whereas regional ADC measurements in specific subregions had relatively modest predictive value. The lentiform nucleus was the region with the highest AUC (0.78). When GMDS-R were considered, DWI S scores were good to excellent predictors for some GMDS-R subscales. The predictive value of ADC measurements was both region- and subscale-specific. In particular, ADC measurements in some regions (basal ganglia, white matter or rolandic cortex) were excellent predictors for specific GMDS-R with AUCs up to 0.93. CONCLUSIONS: DWI S scores showed the highest prognostic value for the neurological outcome at 2 years of age. Regional ADC measurements in specific subregions proved to be highly prognostic for specific neurodevelopmental outcomes.

Serratia marcescens in a neonatal intensive care unit: two long-term multiclone outbreaks in a 10-year observational study.

We investigated two consecutive Serratia marcescens (S. marcescens) outbreaks which occurred in a neonatal intensive care unit (NICU) of a tertiary level hospital in North Italy in a period of 10 years (January 2003-December 2012). Risk factors associated with S. marcescens acquisition were evaluated by a retrospective case-control study. A total of 21,011 clinical samples was examined: S. marcescens occurred in 127 neonates: 43 developed infection and 3 died. Seven clusters were recorded due to 12 unrelated clones which persisted for years in the ward, although no environmental source was found. The main epidemic clone A sustaining the first cluster in 2003 reappeared in 2010 as an extended spectrum ?-lactamase (ESBL)-producing strain and supporting the second epidemic. Birth weight, gestational age, use of invasive devices and length of stay in the ward were significantly related to S. marcescens acquisition. The opening of a new ward for non-intensive care-requiring neonates, strict adherence to alcoholic hand disinfection, the timely identification and isolation of infected and colonized neonates assisted in containing the epidemics. Genotyping was effective in tracing the evolution and dynamics of the clones demonstrating their long-term persistence in the ward.

Preterm birth and developmental problems in infancy and preschool age Part II: cognitive, neuropsychological and behavioural outcomes.

Few studies focus on the neuropsychological and behavioural outcomes of preterm children at preschool age. This article reviews the most recent and relevant contributions on cognitive, neuropsychological and behavioural outcomes, and the neuroradiological findings in extremely and very preterm infants. In the first 2 years of life, cognitive impairment is common: it has an incidence of 30-40% and a higher prevalence than neuromotor and neurosensorial impairments. Recent studies report that even preterm infants with no major disabilities at preschool age perform more poorly than term peers in multiple neuropsychological domains, such as language, attention, memory, visuomotor and visuospatial processing and executive functions. The incidence and severity of problems increase with decreasing gestational age. A delayed acquisition of neuropsychological functions and/or the occurrence of behavioural problems at preschool age are likely to be predictive of the high rate of cognitive deficits at school age and in adolescence. Neuropsychological functions across multiple developmental domains should be assessed longitudinally during routine follow-up checks.

Preterm birth and developmental problems in the preschool age. Part I: minor motor problems.

Nearly half of very preterm (VP) and extremely preterm (EP) infants suffers from minor disabilities. The paper overviews the literature dealing with motor problems other than cerebral palsy (CP) during infancy and preschool age. The term "minor motor problems" indicates a wide spectrum of motor disorders other than CP; "minor" does not mean "minimal", as a relevant proportion of the preterm infants will develop academic and behavioural problems at school age. Early onset disorders consist of abnormal general movements (GMs), transient dystonia and postural instability; these conditions usually fade during the first months. They were underestimated in the past; recently, qualitative assessment of GMs using Prechtl's method has become a major item of the neurological examination. Late onset disorders include developmental coordination disorder (DCD) and/or minor neurological dysfunction (MND): both terms cover partly overlapping problems. Simple MND (MND-1) and complex MND (MND-2) can be identified and MND-2 gives a higher risk for learning and behavioural disorders. A relationship between the quality of GMs and MND in childhood has been recently described. The Touwen infant neurological examination (TINE) can reliably detect neurological signs of MND even in infancy. However, the prognostic value of these disorders requires further investigations.