Lung ultrasound supports clinical evaluation of feeding competence development in preterm neonates.

Introduction: The achievement of alimentary competencies is a milestone in the development of preterm neonates. Ten percent of neonates <37 weeks of gestational age and 25% of those VLBW experience swallowing disorders, with an increased risk of problems in the early phase of life (failure to thrive, growth retardation, inhalation, and consequent risk of pulmonary infection) and later in life due to delayed development of oromotor skills.The main diagnostic tools for swallowing disorders are endoscopic (fiber-optic endoscopic examination of swallowing, FEES) or radiographic (videofluoroscopic swallowing study, VFSS) exams. Given the invasiveness of these methods and the bias due to rheologic differences between bolus and contrast medium, FEES and VFSS are poorly reproducible. Moreover, neither of the technique is capable of detecting post-meal inhalations, especially microinhalations or those consequent to a whole meal rather than to a single swallowing.Lung ultrasound (LUS) is a widespread, repeatable, safe, fast point-of-care tool and we reported previous encouraging results in detecting silent and overt inhalation related to the meal in children with dysphagia/gastroesophageal reflux disease (GERD) risk factors. Methods: We report a pilot study, that investigated LUS approach (performing imaging before and after meals) to assess feeding competence development in a cohort of n. 19 newborns <32 weeks of age. Results: Meal monitoring by LUS did not show any significant difference in scoring before/after eating. The achievement of full enteral feeding correlates with GA at birth (p < 0.001) but not with LUS scoring. The introduction of the first meal by bottle correlates both with gestational age (p < 0.001) and ultrasound scores (p = 0.004). LUS score at 7 days of life resulted predictive for length of invasive/non-invasive respiratory support (p = 0.002) and length of oxygen supply (p = 0.001), while LUS score at 48 h of life did not (p n.s.). Discussion: Our study suggests that the development of oral feeding skills is not strictly dependent on gestational age. Moreover, our research suggests the predominant role of LUS in predicting the time of readiness to oral feeding, as the LUS score can be a marker of respiratory and lung wellness, and consequently a predictor of neonate stability during deglutitory apnea.

Prognostic Role of Lung Ultrasound in Children with Bronchiolitis: Multicentric Prospective Study.

There is increasing recognition of the role of lung ultrasound (LUS) to assess bronchiolitis severity in children. However, available studies are limited to small, single-center cohorts. We aimed to assess a qualitative and quantitative LUS protocol to evaluate the course of bronchiolitis at diagnosis and during follow-up. This is a prospective, multicenter study. Children with bronchiolitis were stratified according to clinical severity and underwent four LUS evaluations at set intervals. LUS was classified according to four models: (1) positive/negative; (2) main LUS pattern (normal/interstitial/consolidative/mixed) (3) LUS score; (4) LUS score with cutoff. Two hundred and thirty-three children were enrolled. The baseline LUS was significantly associated with bronchiolitis severity, using both the qualitative (positive/negative LUS p < 0.001; consolidated/normal LUS pattern or mixed/normal LUS p < 0.001) and quantitative models (cutoff score > 9 p < 0.001; LUS mean score p < 0.001). During follow-up, all LUS results according to all LUS models improved (p < 0.001). Better cut off value was declared at a value of >9 points. Conclusions: Our study supports the role of a comprehensive qualitative and quantitative LUS protocol for the identification of severe cases of bronchiolitis and provides data on the evolution of lung aeration during follow-up.

Feasibility of Early Intervention Through Home-Based and Parent-Delivered Infant Massage in Infants at High Risk for Cerebral Palsy.

Infant massage (IM) can be considered an early intervention program that leads to the environmental enrichment framework. The effectiveness of IM to promote neurodevelopment in preterm infants has been proved, but studies on infants with early brain damage are still lacking. The main aim of this study was to assess the feasibility, acceptability and usability of IM, carried out by parents at home, on infants at high risk for Cerebral Palsy. An IM daily diary and an ad hoc questionnaire, called Infant Massage Questionnaire Parent-Infant Experiences (IMQPE), were developed. IMQPE consisted of a total of 30 questions, divided into 5 areas. The parents were trained to carry out the IM with a home-based course, conducted by an expert therapist. The intensive IM program was set according to a defined daily length of at least 20 min, with a frequency of at least 5 days per week for a total of 8 weeks. Data collection consisted in the selection of the variables around the characteristics, both of the infants and the mothers, IM dosage and frequency, different body parts of the infants involved and IMQPE scores. Variable selection was carried out by minimizing the Bayesian Information Criteria (BIC) over all possible variable subsets. Nineteen high-risk infants, aged 4.83 ± 1.22 months, received IM at home for 8 weeks. The massage was given by the infants' mothers with a mean daily session dose of 27.79 ± 7.88 min and a total of 21.04 ± 8.49 h. 89.74% and 100% of mothers performed the IM for the minimum daily dosage and the frequency recommended, respectively. All the families filled in the IMQPE, with a Total mean score of 79.59% and of 82.22% in General Information on IM, 76.30% in Infant's intervention-related changes, 76.85% in IM Suitability, 79.07% in Infant's acceptance and 83.52% in Time required for the training. Different best predictors in mothers and in infants have been found. These data provide evidence of the feasibility of performing IM at home on infants at high risk for CP. Study registration: www.clinicaltrial.com (NCT03211533 and NCT03234959).

Concurrent and predictive validity of the infant motor profile in infants at risk of neurodevelopmental disorders.

BACKGROUND: Preterm infants and infants with perinatal brain injury show a higher incidence of neurodevelopmental disorders (NDD). The Infant Motor Profile (IMP) is a clinical assessment which evaluates the complexity of early motor behaviour. More data are needed to confirm its predictive ability and concurrent validity with other common and valid assessments such as the Alberta Infant Motor Scale (AIMS) and Prechtl's General Movement Assessment (GMA). The present study aims to evaluate the concurrent validity of the IMP with the AIMS, to assess its association with the GMA, to evaluate how the IMP reflects the severity of the brain injury and to compare the ability of the IMP and the AIMS to predict an abnormal outcome in 5-month-old infants at risk of NDD. METHODS: 86 infants at risk of NDD were retrospectively recruited among the participants of two clinical trials. Preterm infants with or without perinatal brain injury and term infants with brain injury were assessed at 3 months corrected age (CA) using the GMA and at 5 months CA using the IMP and the AIMS. The neurodevelopmental outcome was established at 18 months. RESULTS: Results confirm a solid concurrent validity between the IMP Total Score and the AIMS (Spearman's ρ 0.76; p < .001) and a significant association between IMP Total Score and the GMA. Unlike the AIMS, the IMP Total score accurately reflects the severity of neonatal brain injury (p < .001) and proves to be the strongest predictor of NDD (p < .001). The comparison of areas under receiver operating characteristic curves (AUC) confirms that the IMP Total score has the highest diagnostic accuracy at 5 months (AUC 0.92). For an optimal IMP Total Score cut-off value of 70, the assessment shows high sensitivity (93%) and specificity (81%) (PPV 84%; NPV 90%). CONCLUSIONS: Early motor behaviour assessed with the IMP is strongly associated with middle-term neurodevelopmental outcome. The present study confirms the concurrent validity of the IMP with the AIMS, its association with the GMA and its ability to reflect brain lesion load, hence contributing to the construct validity of the assessment. TRIAL REGISTRATION: NCT01990183 and NCT03234959 (clinicaltrials.gov).

Feasibility Analysis of CareToy-Revised Early Intervention in Infants at High Risk for Cerebral Palsy.

Infants with perinatal brain injury are at high risk for Cerebral Palsy (CP). Progresses in detection of early signs of brain injury and of CP allow early intervention (EI) programs for improving the outcome of these infants. CareToy system (CT), developed within a European project (Trial Registration: NCT01990183), allows providing, by means of tele-rehabilitation, a highly personalized, family-centered, home-based EI for young infants, remotely managed by clinicians. CareToy, already used with pre-terms without brain injury, has been adapted for high-risk infants in a project funded by the Italian Ministry of Health, and the CareToy-Revised (CareToy-R) has been realized (Trial registration: NCT03211533 and NCT03234959). Before assessing its efficacy, it was crucial to evaluate the acceptability, usability, and feasibility of CareToy-R EI. Nineteen high-risk infants with perinatal brain injury, aged 5.95 ± 2.13 months (range 3.12-10.78 months), carried out an 8-week training with CareToy-R at home, performing customized playful activities with their parents, tailored to their rehabilitative needs, remotely managed by clinicians. The feasibility of training and study procedures was assessed through criteria derived from literature; acceptability and usability have been analyzed from data about individual training and an ad hoc questionnaire. All CareToy-R trainings were planned by the clinical staff with a daily personalized use for each infant between 30 and 45 min (mean 34.37 min). The amount of executed training by the infants was very high (daily mean 30.30 min), with no differences related to infant age, sex, and gestational age. All the nine feasibility criteria were achieved, family compliance to the project was very good, data collection was completed and the CareToy-R system worked properly and easily for parents. The answers to the questionnaire had a total mean score of 84.49% and they ranged from a minimum of 81.05% (in "easy to use" area) to a maximum of 86.49% ("changes due to the training" area), with no differences related to nationality or familiarity with technology of the mothers. This study reports preliminary evidence to the feasibility of a home-based EI with CareToy-R system in infants at high risk for CP. Results of the RCT will provide data about the potential effectiveness of this approach.

A de novo KCNQ2 Gene Mutation Associated With Non-familial Early Onset Seizures: Case Report and Revision of Literature Data.

Among neonatal epileptic syndromes, benign familial neonatal seizures (BFNS) are often due to autosomal-dominant mutations of the KCNQ2 gene. Seizures are usually characterized by asymmetric tonic posturing with apnea with onset in the first 7 days of life; they may even occur more than 10 times per day or evolve into status epilepticus. The delivery course of our patient was uneventful and family history was negative; on the second day of life the baby became pale, rigid, and apnoic during breastfeeding and appeared jittery and irritable when stimulated or examined. At age 3 days, she experienced clusters of generalized tonic seizures with pallor, desaturation, bradycardia, and partial response to intravenous phenobarbital; during her 4th and 5th days of life, three episodes of tonic seizures were noticed. At age 6 days, the patient experienced about 10 episodes of tonic seizures involving both sides of the body, which gradually responded to intravenous phenytoin. Electroencephalograms revealed abnormalities but brain MRI was normal. The patient is seizure-free since postnatal day 21; she is now 12 months old with cognitive development within normal limits at Bayley III Scale and mild motor delay. The patient is on maintenance therapy with phenobarbital since she was 7 months old. A de novo heterozygous mutation (c.853C>T/p.P285S) in the KCNQ2 gene was identified. We therefore describe a case of de novo KCNQ2-related neonatal convulsions with necessity of multiple anticonvulsants for the control of seizures, mutation occurring in the pore channel of the voltage-gated potassium channel subfamily Q member 2 associated with a likely benign course; furthermore, the same mutation of the KCNQ2 gene and a similar one (c.854C>A/p.P285H) have already been described in association with Ohtahara syndrome. Probably acquired environmental, perinatal and genetic risk factors are very important in determining the different phenotype; we hope that the rapid progress of analysis tools in molecular diagnosis can also be used in the search of an individualized therapeutic approach for these patients.

Early intervention at home in infants with congenital brain lesion with CareToy revised: a RCT protocol.

BACKGROUND: Congenital brain lesions expose infants to be at high-risk for being affected by neurodevelopmental disorders such as cerebral palsy (CP). Early interventions programs can significantly impact and improve their neurodevelopment. Recently, in the framework of the European CareToy (CT) Project ( www.caretoy.eu ), a new medical device has been created to deliver an early, intensive, customized, intervention program, carried out at home by parents but remotely managed by expert and trained clinicians. Reviewing results of previous studies on preterm infants without congenital brain lesion, the CT platform has been revised and a new system created (CT-R). This study describes the protocol of a randomised controlled trial (RCT) aimed to evaluate, in a sample of infants at high-risk for CP, the efficacy of CT-R intervention compared to the Infant Massage (IM) intervention. METHODS/DESIGN: This RCT will be multi-centre, paired and evaluator-blinded. Eligible subjects will be preterm or full-term infants with brain lesions, in first year of age with predefined specific gross motor abilities. Recruited infants will be randomized into CT-R and IM groups at baseline (T0). Based on allocation, infants will perform an 8-week programme of personalized CareToy activities or Infant Massage. The primary outcome measure will be the Infant Motor Profile. On the basis of power calculation, it will require a sample size of 42 infants. Moreover, Peabody Developmental Motor Scales-Second Edition, Teller Acuity Cards, standardized video-recordings of parent-infant interaction and wearable sensors (Actigraphs) will be included as secondary outcome measures. Finally, parents will fill out questionnaires (Bayley Social-Emotional, Parents Stress Index). All outcome measures will be carried out at the beginning (T0) and at end of 8-weeks intervention period, primary endpoint (T1). Primary outcome and some secondary outcomes will be carried out also after 2 months from T1 and at 18 months of age (T2 and T3, respectively). The Bayley Cognitive subscale will be used as additional assessment at T3. DISCUSSION: This study protocol paper is the first study aimed to test CT-R system in infants at high-risk for CP. This paper will present the scientific background and trial methodology. TRIAL REGISTRATION: NCT03211533 and NCT03234959 ( www.clinicaltrials.gov ).

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study.

PURPOSE: To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE). MATERIALS AND METHODS: Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes. RESULTS: Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM. CONCLUSIONS: Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

A randomized clinical trial in preterm infants on the effects of a home-based early intervention with the 'CareToy System'.

CareToy system is an innovative tele-rehabilitative tool, useful in providing intensive, individualized, home-based, family-centred Early Intervention (EI) in infants. Our aim was to evaluate, through a Randomized Clinical Trial (RCT) study, the effects of CareToy intervention on early motor and visual development in preterm infants. 41 preterm infants (range age: 3.0-5.9 months of corrected age) were enrolled and randomized into two groups, CareToy and Standard Care. 19 infants randomized in CareToy group performed a 4-week CareToy program, while 22 allocated to control group completed 4 weeks of Standard Care. Infant Motor Profile (IMP) was primary outcome measure, Alberta Infant Motor Scale (AIMS) and Teller Acuity Cards were secondary ones. Assessments were carried out at baseline (T0) and at the end of CareToy training or Standard Care period (T1). T1 was the primary endpoint. After RCT phase, 17 infants from control group carried out a 4-week CareToy program, while 18 infants from the CareToy group continued with Standard Care. At the end of this phase, infants were re-assessed at T2. In RCT phase, delta IMP total score and variation and performance sub-domains were significantly higher (P<0.050) in CareToy group if compared to Standard Care group. Similar results were found for Teller Acuity Cards, while no differences between groups were found for AIMS. No differences were found in any outcome measure results (T2-T0), between infants who started CareToy training before or after one month of standard care. This RCT study confirms the results of a previous pilot study, indicating that CareToy system can provide effective home-based EI. TRIAL REGISTRATION: This trial has been registered at www.clinicaltrials.gov (Identifier NCT01990183).

A pilot study on early home-based intervention through an intelligent baby gym (CareToy) in preterm infants.

BACKGROUND: CareToy is an intelligent system, inspired by baby gyms, aimed to provide an intensive, individualized, home-based and family-centred early intervention (EI) program. AIMS: A pilot study was carried out to explore the feasibility of CareToy intervention in preterm infants, aged 3-9 months of corrected age. METHODS: Twenty low-risk preterm infants, without brain lesion or other clinical complications (14 allocated to CareToy intervention and 6 to Standard Care) were recruited. The Infant Motor Profile (IMP) was predefined as the primary outcome measure and Alberta Infant Motor Scale and Teller Acuity Cards as secondary measures. Moreover, 202 pre-programmed training scenarios were developed and instructions for the management of CareToy intervention were defined as general guidelines. OUTCOMES AND RESULTS: All infants received 4 weeks of their allocated intervention and were evaluated with the selected tests before and immediately after the 4 weeks. The mean difference changes in IMP total score and Teller Acuity Cards over the intervention period were higher in the CareToy group than in the Standard Care group. CONCLUSIONS AND IMPLICATIONS: CareToy seems a feasible device for providing EI. An adequately powered randomized clinical trial is warranted.

Serum cortisol concentrations during induced hypothermia for perinatal asphyxia are associated with neurological outcome in human infants.

Birth asphyxia is a cause of neonatal death or adverse neurological sequelae. Biomarkers can be useful to clinicians in order to optimize intensive care management and communication of prognosis to parents. During perinatal adverse events, increased cortisol secretion is due to hypothalamo-pituitary-adrenal axis activation. We aimed to investigate if cortisol variations during therapeutic hypothermia are associated with neurodevelopmental outcome. We compared 18 cases (neonates with birth asphyxia) with 18 controls (healthy term newborns) and confirmed increased serum cortisol concentrations following the peri-partum adverse event. Among cases, we stratified patients according to neurological outcome at 18 months (group A - good; group B - adverse) and found that after 24 h of therapeutic hypothermia serum cortisol concentration was significantly lower in group A vs group B (28.7 ng/mL vs 344 ng/mL, *p = 0.01). In group B serum, cortisol concentration decreased more gradually during therapeutic hypothermia. We conclude that monitoring serum cortisol concentration during neonatal therapeutic hypothermia can add information to clinical evaluation of neonates with birth asphyxia; cortisol values after the first 24 h of hypothermia can be a biomarker associated with neurodevelopmental outcome at 18 months of age.

Elevated serum creatine kinase and small cerebellum prompt diagnosis of congenital muscular dystrophy due to FKRP mutations.

Fukutin-related protein (FKRP) is a putative glycosyltransferase that mediate O-linked glycosylation of the α-dystroglycan. Mutations in the FKRP gene cause a spectrum of diseases ranging from a limb girdle muscular dystrophy 2I (LGMD2I), to severe Walker-Warburg or muscle-eye-brain forms and a congenital muscular dystrophy (with or without mental retardation) termed MDC1C. This article reports on a Moroccan infant who presented at birth with moderate floppiness, high serum creatine kinase (CK) levels, and brain ultrasonograph suggestive of widening of the posterior fossa. Muscle biopsy displayed moderate dystrophic pattern with complete absence of α-distroglycan and genetic studies identified a homozygous missense variant in FKRP. Mutations in FKRP should be looked for in forms of neonatal-onset hyperCKaemia with floppiness and small cerebellum.

Lutein administration to pregnant women with gestational diabetes mellitus is associated to a decrease of oxidative stress in newborns.

Oxidative stress (OS) is defined as an imbalance between pro- and antioxidant factors that can lead to cellular and tissue damage. Under condition of gestational diabetes, OS is exacerbated and can cause vascular dysfunction in the placenta, leading to fetal and perinatal complications. We investigated the oxidative status of diabetic pregnant women and of their babies. A group of those diabetic women received lutein, and another group did not receive anything. In order to verify a possible antioxidant function of lutein, we compared the OS values of the two groups. OS appeared lower in treated gravidas than in untreated ones; however, there was not a statistically significant difference between the two groups. As far as newborns are concerned, there was a significant difference of OS values between babies born to mothers treated with lutein and newborns to mothers untreated at 2 h of life. However, at 48 h, there was not a significant difference between the two groups. In conclusion, lutein administration during pregnancy significantly reduced neonatal OS at birth. Further studies are necessary to evaluate the effects of combined administration to mother and infants.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI).

BACKGROUND: Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2-3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. METHODS/DESIGN: Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.