Quantitative ultrasonographic examination of cerebral white matter by pixel brightness intensity as marker of middle-term neurodevelopment: a prospective observational study.

Non-cystic white matter (WM) injury has become prevalent among preterm newborns and is associated with long-term neurodevelopmental impairment. Magnetic resonance is the gold-standard for diagnosis; however, cranial ultrasound (CUS) is more easily available but limited by subjective interpretation of images. To overcome this problem, we enrolled in a prospective observational study, patients with gestational age at birth < 32 weeks with normal CUS scans or grade 1 WM injury. Patients underwent CUS examinations at 0-7 days of life (T0), 14-35 days of life (T1), 370/7-416/7 weeks' postmenstrual age (T2), and 420/7-520/7 weeks' postmenstrual age (T3). The echogenicity of parieto-occipital periventricular WM relative to that of homolateral choroid plexus (RECP) was calculated on parasagittal scans by means of pixel brightness intensity and its relationship with Bayley-III assessment at 12 months' corrected age was evaluated. We demonstrated that: (1) Left RECP values at T1 negatively correlated with cognitive composite scores; (2) Right RECP values at T2 and T3 negatively correlated with language composite scores; (3) Left RECP values at T1 and T2 negatively correlated with motor composite scores. Thus, this technique may be used as screening method to early identify patients at risk of neurodevelopmental issues and promptly initiate preventive and therapeutic interventions.

The effects of industrial chemicals bonded to plastic materials in newborns: A systematic review.

BACKGROUND: Phthalates are a family of industrial chemicals noncovalently bonded to plastic materials to enhance flexibility and durability. These compounds are extensively used in a variety of consumer products and even in many medical devices. Newborns present a higher susceptibility to phthalates. OBJECTIVE: To assess the short- and long-term health consequences of exposure to phthalates during the neonatal period. METHODS: Systematic review in accordance with the PRISMA statements. Eligible articles in English language were searched in MEDLINE, Scopus, ISI Web of Science, and Ovid databases using the following terms: "phthalate", "newborn", and "neonate". Unpublished data were searched in ClinicalTrials.gov website. All in vivo studies of any design published before May 16th, 2023 and fulfilling the following criteria were included: 1) investigations in which preterm and/or term newborns underwent one or more measurement of concentrations of phthalates on biological samples taken during the neonatal period; 2) studies in which quantitative measurement of phthalates was related to any kind of health outcome. Subgroup analysis was conducted by type of outcome. The quality assessment was performed according to the criteria from the "NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies". RESULTS: 11,895 records were identified; finally, 5 articles were included for review. A mixture of phthalates was associated with improved performance on the NNNS summary scales of Attention, Handling, and Non-optimal reflexes before NICU discharge. At 2 months' corrected age, some phthalates were positively associated with problem-solving and gross motor abilities; increased levels of mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-carboxypentyl) phthalate, and sum of di (2-ethylhexyl) phthalate (DEHP) metabolites (∑3DEHP and ∑4DEHP) were associated with worse fine motor performance. Furthermore, DEHP was associated with transient alteration of gut microbiota and increased IgM production after vaccine. A linear positive association between a mixture of phthalates and slope of the first growth spurt was even reported in preterm newborns. No relationship emerged between phthalates and bronchopulmonary dysplasia. Three studies out of 5 had fair quality. CONCLUSION: Given some methodological issues and the paucity of related studies, further investigations of flawless quality aimed at clarifying the relationship between early exposure to phthalates and health outcomes are needed.

Delayed Macronutrients' Target Achievement in Parenteral Nutrition Reduces the Risk of Hyperglycemia in Preterm Newborn: A Randomized Controlled Trial.

Hyperglycemia (HG) is an independent risk factor of mortality and morbidity in very low birth weight newborns (VLBW). Achievement of high nutritional intakes in the first days of life (DoL) by parenteral nutrition (PN) increases the risk of HG. We aim to assess if a delayed achievement of the PN macronutrient target dose could reduce the occurrence of HG in VLBW. We enrolled 353 VLBW neonates in a randomized controlled clinical trial comparing two PN protocols that differed in the timing of energy and amino acid target dose achievement: (1) early target dose achievement (energy within 4-5 DoL; amino acids within 3-4 DoL) vs. (2) late target dose achievement (energy within 10-12 DoL; amino acids within 5-7 DoL). The primary outcome was the occurrence of HG during the first week of life. An additional endpoint was long-term body growth. We observed a significant difference in the rate of HG between the two groups (30.7% vs. 12.2%, p = 0.003). Significant differences were observed in terms of body growth at 12 months of life between the two groups (weight Z-Score: -0.86 vs. 0.22, p = 0.025; length: -1.29 vs. 0.55, p < 0.001). Delayed achievement of energy and amino acid intake may be useful to reduce the risk of HG along with an increase of growth parameters in VLBW neonates.

Symptoms of post-traumatic stress disorder in parents of preterm newborns: A systematic review of interventions and prevention strategies.

Background: Preterm birth and subsequent NICU admission can be a traumatic experience for parents who may subsequently develop post-traumatic stress (PTS) disorder (PTSD). Given that developmental issues are common among children of parents with PTSD, interventions for prevention and treatment are essential. Objective: To assess the most effective non-pharmacological interventions to prevent and/or treat PTS symptoms in parents of preterm newborns. Methods: Systematic review performed in accordance with the PRISMA statements. Eligible articles in English language were searched in MEDLINE, Scopus, and ISI Web of Science databases using the following medical subject headings and terms: "stress disorder, post-traumatic," "parents," "mothers," "fathers," "infant, newborn," "intensive care units, neonatal," and "premature birth." The terms "preterm birth" and "preterm delivery" were also used. Unpublished data were searched in ClinicalTrials.gov website. All intervention studies published until September 9th, 2022 and including parents of newborns with gestational age at birth (GAb) <37 weeks which underwent ≥1 non-pharmaceutical interventions for prevention and/or treatment of PTS symptoms related to preterm birth were included. Subgroup analyses were conducted by type of intervention. The quality assessment was performed according to the criteria from the RoB-2 and the "NIH Quality Assessment Tool for Before-After studies." Results: Sixteen thousand six hundred twenty-eight records were identified; finally, 15 articles (1,009 mothers, 44 fathers of infants with GAb ≤ 366/7 weeks) were included for review. A good standard of NICU care (effective as sole intervention: 2/3 studies) and education about PTSD (effective in association with other interventions: 7/8 studies) could be offered to all parents of preterm newborns. The 6-session Treatment Manual is a complex intervention which revealed itself to be effective in one study with low risk of bias. However, the effectiveness of interventions still remains to be definitively established. Interventions could start within 4 weeks after birth and last 2-4 weeks. Conclusion: There is a wide range of interventions targeting PTS symptoms after preterm birth. However, further studies of good quality are needed to better define the effectiveness of each intervention.

Risk factors and preventive strategies for post-traumatic stress disorder in neonatal intensive care unit.

Background: Preterm birth and admission to the neonatal intensive care unit (NICU) could induce post-traumatic stress disorder (PTSD). PTSD is an important factor to focus on, as it is associated with parental mental health difficulties and with changes in caregiving quality such as increased intrusiveness, reduced sensitivity, and increased attachment insecurity for the child. Aims: We aimed to study the main risk factors, in the early life of newborns, and preventive measures for PTSD in parents of neonates hospitalized in the NICU. Methods: We included parents of preterm newborns, consecutively admitted to the NICU of the University La Sapienza of Rome. The presence of PTSD following preterm birth and NICU admission was assessed using the Clinician-administered PTSD scale (CAPS) at enrollment and at 28-30 days following NICU admission or the moment of discharge. We also evaluated the Family Environment Scale which measures the social environment of all types of families; the Parental Stressor Scale which measures parental anxiety and stress; the Spielberger State-Trait Anxiety Inventory consisting of two parts measuring the State (response to present situation) and Trait (pre-disposition to be anxious) anxieties separately, and the Beck Depression Inventory Second Edition assessing depressive symptoms. Results: We found, in a multivariate analysis, that the gestational age of newborns admitted to NICU significantly (ß = 2.678; p = 0.040) influences the occurrence of PTSD. We found that the cases showed significantly (ß = 2.443; p = 0.020) more pathological Parental Stressor Scale sights and sounds scores compared to controls. The early Kangaroo-Care (KC) significantly (ß = -2.619; p = 0.015) reduces the occurrence of PTSD. Conclusion: Post-traumatic stress disorder in parents of preterm newborns is a pathological condition that should be properly managed, in the very first days after birth. The NICU environment represents a main risk factor for PTSD, whereas KC has been demonstrated to have a protective role in the occurrence of PTSD.

1H-magnetic resonance spectroscopy and its role in predicting neurodevelopmental impairment in preterm neonates: A systematic review.

To assess the diagnostic utility of proton (1H) magnetic resonance spectroscopy in early diagnosis of neurodevelopmental impairment in preterm newborns. Systematic review performed in compliance with the PRISMA statements. Eligible articles were searched in MEDLINE, Scopus, and ISI Web of Science databases using the following medical subject headings and terms: "magnetic resonance spectroscopy," "infant," and "newborn." Studies of any design published until 20 December 2021 and fulfilling the following criteria were selected: (1) studies including newborns with gestational age at birth <37 weeks which underwent at least one 1H-MRS scan within 52 weeks' postmenstrual age and neurodevelopmental assessment within 4 years of age; (2) studies in which preterm newborns with congenital infections, genetic disorders, and brain congenital anomalies were clearly excluded. Data regarding the relationship between metabolite ratios in basal ganglia, thalamus, and white matter, and neurodevelopment were analysed. The quality assessment of included studies was performed according to the criteria from the QUADAS-2. N-acetylaspartate (NAA)/choline (Cho) was the most studied metabolite ratio. Lower NAA/Cho ratio in basal ganglia and thalamus was associated with adverse motor, cognitive, and language outcomes, and worse global neurodevelopment. Lower NAA/Cho ratio in white matter was associated with cognitive impairment. However, some associations came from single studies or were discordant among studies. The quality of included studies was low. 1H-MRS could be a promising tool for early diagnosis of neurodevelopmental impairment. However, further studies of good quality are needed to define the relationship between metabolite ratios and neurodevelopment.

Enteral and parenteral energy intake and neurodevelopment in preterm infants: A systematic review.

OBJECTIVES: We performed a systematic review to study the effect of enteral and parenteral energy intakes on neurodevelopment (NDV) and cerebral growth in preterm infants, evaluated by NDV scales, magnetic resonance imaging, and head circumference (HC). METHODS: The MEDLINE, Scopus, and ISI Web of Knowledge databases were searched, using the following medical subject headings and terms: "Premature infants," "nutrition," "brain," "nervous system/growth," and "development." A manual search of the reference lists of all eligible articles was conducted. Studies in which the intervention applied was different energy intakes in parenteral nutrition and/or enteral nutrition (EN) during the first weeks of life and NDV was investigated were included. Data regarding nutrition and NDV were collected and analyzed. RESULTS: Thirty-five studies were included, of which 12 were randomized controlled trials (RCTs) and 23 were cohort studies. Eight RCTs and 15 cohort studies investigated NDV using NDV scales. Of these studies, two RTCs and five cohort studies found no significant difference in NDV evaluated with the Bayley scale between neonates fed high-caloric nutrition and those who received lower energy intakes during early life. In one RCT and two cohort studies was observed a positive effect of EN on NDV. Conversely, in one cohort study, a negative correlation between parenteral energy intake and NDV was described. The analysis of the data from RCTs and cohort studies showed greater HC in the groups receiving aggressive parenteral and total enhanced nutrition, respectively. However, two RCTs and one cohort study did not report any differences in terms of HC. Inconclusive results were reported by studies that investigated cerebral growth by magnetic resonance imaging. The studies observing a positive effect of enhanced nutrition on cerebral and basal ganglia growth, caudate nucleus, cerebellum, and thalami volume investigated only the influence of EN. CONCLUSIONS: The impact of energy intake during early life on NDV remains undefined. A positive impact on brain development encourages the administration of recommended energy intake, mainly by EN, and suggests a more cautious approach to enhanced nutritional strategies by the parenteral route. Further studies are advocated to elucidate the optimal nutritional intervention for preterm infants to improve NDV.

Early-onset sepsis risk calculator: a review of its effectiveness and comparative study with our evidence-based local guidelines.

BACKGROUND: According to most early-onset sepsis (EOS) management guidelines, approximately 10% of the total neonatal population are exposed to antibiotics in the first postnatal days with subsequent increase of neonatal and pediatric comorbidities. A review of literature demonstrates the effectiveness of EOS calculator in reducing antibiotic overtreatment and NICU admission among neonates ≥34 weeks' gestational age (GA); however, some missed cases of culture-positive EOS have also been described. METHODS: Single-center retrospective study from 1st January 2018 to 31st December 2018 conducted in the Division of Neonatology at Santa Chiara Hospital (Pisa, Italy). Neonates ≥34 weeks' GA with birth weight ≤ 1500 g, 34-36 weeks' GA neonates with suspected intraamniotic infection and neonates ≥34 weeks' GA with three clinical signs of EOS or two signs and one risk factor for EOS receive empirical antibiotics. Neonates ≥34 weeks' GA with risk factors for EOS or with one clinical indicator of EOS undergo serial measurements of C-reactive protein and procalcitonin in the first 48-72 h of life; they receive empirical antibiotics in case of abnormalities at blood exams with one or more clinical signs of EOS. Two hundred sixty-five patients at risk for EOS met inclusion criteria; they were divided into 3 study groups: 34-36 weeks' GA newborns (n = 95, group A), ≥ 37 weeks' GA newborns (n = 170, group B), and ≥ 34 weeks' GA newborns (n = 265, group A + B). For each group, we compared the number of patients for which antibiotics would have been needed, based on EOS calculator, and the number of the same patients we treated with antibiotics during the study period. Comparisons between the groups were performed using McNemar's test and statistical significance was set at p < 0.05; post-hoc power analysis was carried out to evaluate the sample sizes. RESULTS: 32/265 (12.1%) neonates ≥34 weeks' GA received antibiotics within the first 12 h of life. According to EOS calculator 55/265 (20.7%) patients would have received antibiotics with EOS incidence 2/1000 live births (p < 0.0001). CONCLUSION: Our evidence-based protocol entails a further decrease of antibiotic overtreatment compared to EOS calculator. No negative consequences for patients were observed.

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.

A Novel Missense Mutation of the NSD1 Gene Associated with Overgrowth in Three Generations of an Italian Family: Case Report, Differential Diagnosis, and Review of Mutations of NSD1 Gene in Familial Sotos Syndrome.

Sotos syndrome (SoS) is characterized by overgrowth of prenatal onset, learning disability, and characteristic facial appearance; it is usually due to haploinsufficiency of NSD1 gene at chromosome 5q35. An Italian child was born at 37 weeks of gestation (weight 2,910 g, 25th-50th centiles; length 50 cm, 75th centile; head circumference 36 cm, 97th centile) showing cryptorchidism on the right side, hypertelorism, dolichocephaly, broad and prominent forehead, and narrow jaw; the pregnancy was worsened by maternal preeclampsia and gestational diabetes, and his mother had a previous history of four early miscarriages. The patient showed neonatal jaundice, hypotonia, feeding difficulties, frequent vomiting, and gastroesophageal reflux. After the age of 6 months, his weight, length, and head circumference were above the 97th centile; psychomotor development was delayed. At the age of 9 years, the patient showed also joint laxity and scoliosis. DNA sequence analysis of NSD1 gene detected a novel heterozygous mutation (c.521T>A, p.Val174Asp) in exon 2. The same mutant allele was also found in the mother and in the maternal grandfather of the proband; both the mother and the maternal grandfather of the proband showed isolated overgrowth with height above the 97th centile in absence of other features of SoS. At present 23 familial cases of SoS have been described (two cases with mutation in exon 2 of NSD1 gene); no familial cases of SoS with mutation of NSD1 gene and isolated overgrowth have been reported. Probably, point mutations of NSD1 gene, and particularly mutations between exon 20 and exon 23, are not likely to affect reproductive fitness. Epigenetic mechanisms and intrauterine environment may influence phenotypes, therefore genetic tests are not useful to predict the phenotype but they are indispensable for the diagnosis of SoS. This is the first Italian familial case of SoS with genetic confirmation and the third report in which a missense mutation of NSD1 gene is found in three generations of the same family.

Effects of Anakinra on Health-Related Quality of Life in a Patient with 1129G>A/928G>A Mutations in MVK Gene and Heterozygosity for the Mutation 2107C>A in CIAS1 Gene.

Mevalonate kinase deficiency impairs several aspects of the patient's quality of life, thus early diagnosis and treatment are required to improve health-related quality of life (HRQOL). A 15-year-old patient with double heterozygosity for the mutations 1129G>A and 928G>A in MVK gene, heterozygosity for the mutation 2107C>A in CIAS1 gene and hyper-IgD syndrome phenotype, has been treated with anakinra with a reduction of 50% in the number of fever episodes per month, a reduction of 33% in the days of fever for each attack and normal blood tests in the intercritical phase. The RAND 36-Item Health Survey has been used for the assessment of HRQOL before and after the treatment with anakinra. The patient's quality of life showed an overall improvement of 27%; results showed a better improvement in role limitations due to physical health (50%).

Osteoid osteoma mimicking monoarticular juvenile idiopathic arthritis in a girl.

Osteoid osteoma (OO) is a benign osteogenic neoplasm, usually affecting children and young adults, that is typically characterized by nocturnal pain and response to non-steroidal anti-inflammatory drugs. OO is frequently misdiagnosed because it mimics juvenile idiopathic arthritis (JIA), bone infection or malignancy. Herein we report the case of a girl who presented with chronic monoarthritis of the knee mimicking JIA. After 1 year, OO of the femoral distal metaphysis was diagnosed. OO was treated with computed tomography-guided radiofrequency ablation with disappearance of the symptoms and resolution of the neoplasm. No recurrences have been observed 3 years after the treatment. This case highlights that intra-articular or juxta-articular OO should be suspected in the case of misleading symptoms and signs, such as swelling, lack of typical pain and synovial thickening on ultrasound; needle biopsy of the lesion is necessary in the case of confusing imaging.

Incidental Finding of an Isolated Double-orifice Mitral Valve in an Asymptomatic Man.

Double-orifice mitral valve (DOMV) is a very rare congenital anomaly that usually presents as mitral regurgitation. We present the case of a 39-year-old asymptomatic, healthy man with no previous medical history who was affected by isolated complete bridge type DOMV, incidentally detected by two-dimensional echocardiographic examination in the parasternal short-axis view. The mitral valve of the patient was normally functioning without any other coexistent cardiac abnormalities. Isolated DOMV was also confirmed by cardiac magnetic resonance imaging. The patient is now followed up to detect possible complications.

Clinical Phenotype of DiGeorge Syndrome with Negative Genetic Tests: A Case of DiGeorge-Like Syndrome?

We report a case of DiGeorge-like syndrome in which immunodeficiency coexisting with juvenile idiopathic arthritis, congenital heart disease, delay in emergence of language and in motor milestones, feeding and growing problems, enamel hypoplasia, mild skeletal anomalies, and facial dysmorphisms are associated with no abnormalities found on genetic tests.