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.

Hypospadias is a congenital displacement of the urethral meatus in male newborns, being either an isolated defect at birth or a sign of sexual development disorders. The aim of this study was to assess the prevalence rate of hypospadias in different Districts of Italy, in order to make a comparison with other countries all over the world. We reviewed all the newborns file records (years 2001–2004) in 15 Italian Hospitals. We found an overall hypospadias prevalence rate of 3.066 ± 0.99 per 1000 live births (82.48% mild hypospadias, 17.52% moderate-severe). In newborns Small for Gestational Age (birthweight < 10^th percentile) of any gestational age the prevalence rate of hypospadias was 6.25 per 1000 live births. Performing multivariate logistic regression analysis for different degrees of hypospadias according to severity, being born SGA remained the only risk factor for moderate-severe hypospadias (p = 0.00898) but not for mild forms (p > 0.1). In our sample the prevalence of hypospadias results as high as reported in previous European and American studies (3–4 per 1000 live births). Pathogenesis of isolated hypospadias is multifactorial (genetic, endocrine and environmental factors): however, the prevalence rate of hypospadias is higher in infants born small for gestational age than in newborns with normal birth weight.

5α-reductase-2 deficiency is a rare autosomal recessive form of 46,XY disorders of sex differentiation (DSD), caused by mutations in the steroid 5α-reductase type 2 gene (SRD5A2), presenting at birth with variable degrees of undervirilization. We report on three Italian newborns with 46,XY DSD in whom the evaluation of testosterone, dihydrotestosterone, testosterone/dihydrotestosterone (T/DHT) ratio and molecular analysis of the 5α-reductase type 2 gene was made in their first month of life. Baseline T/DHT ratio suggested 5α-reductase-2 deficiency; the diagnosis was confirmed by molecular genetics (homozygous mutation in exon 4 [G196S], heterozygous mutation in exon 1 and 5 [W35X/Y235F], heterozygous mutation plus polymorphism in exon 1 [G34W/A49T]). Proper investigation permitted early reassignment to male sex in two babies, assigned to female sex just after birth. In infancy, the T/DHT ratio, assessed by suitable assay methods and evaluated by age-appropriate reference values, seems to be able to select newborns affected by 5α-reductase-2 deficiency. Molecular analysis of the SRD5A2 gene should be warranted in newborns with abnormal ratio before sex assignment.

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. 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. 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. Current Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25

Purpose: Neonatal respiratory distress syndrome (RDS) is a major cause of mortality and morbidity among preterm infants. Although the INSURE (INtubation, SURfactant administration, Estubation) technique for surfactant replacement therapy is so far the gold standard method, over the last years new approaches have been studied, i.e. less invasive surfactant administration (LISA) or minimally invasive surfactant therapy (MIST). Here we propose an originally modified MIST, called CALMEST (Catheter And Laryngeal Mask Endotracheal Surfactant Therapy), using a particular laryngeal mask as a guide for a thin catheter to deliver surfactant directly in the trachea. Materials and methods: We performed a preliminary study on a mannequin and a subsequent in vivo pilot trial. Results and conclusions: This novel procedure is quick, effective and well tolerated and might represent an improvement in reducing neonatal stress. Ultimately, CALMEST offers an alternative approach that could be extremely useful for medical staff with low expertise in laryngoscopy and intubation.

An unexpected event is not rare in Neonatology and can be dramatic: the operators must act with the right skills and abilities in the shortest time. Often it is a team effort and each member must be trained adequately. According to the “Swiss cheese” model by J. Reason, an accident is never the consequence of a single error, but the very final result of a chain of misunderstandings, irregularities or negligence (cheese holes): several holes allow the final medical error. Therefore, we should avoid those holes in our work. The clinical risk is always around the corner. The legal issues are becoming more and more relevant and lead to a defensive medicine, which is definitely not the best practice. For this reason, raising the safety standards is mandatory. With this purpose, after a decade of experience in “traditional” training courses, we started testing a new strategy of continuous education in Neonatology by means of highfidelity simulation. Since 2008, we have arranged and managed a Center for Neonatal Simulation and Advanced Training in the Neonatology Unit of the University Hospital of Pisa. We have already delivered courses to pediatricians, neonatologists, anesthesiologists, gynecologists, emergency doctors, midwives and nurses, using an advanced Laerdal SimNewB simulator to teach diagnostic and therapeutic skills or communication strategies. The model has been proposed to the Italian Society of Neonatology and it has been decided to create a Task Force to discuss our model and encourage to use it in other Italian areas.