Giulio Bevilacqua

European consensus guidelines on the management of neonatal respiratory distress syndrome

Abstract Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the recommendations of a European panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. Strong evidence exists for the role of antenatal steroids in RDS prevention, but it is not clear if repeated courses are safe. Many practices involved in preterm neonatal stabilization at birth are not evidence based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in management of RDS but the best preparation, optimal dose and timing of administration at different gestations is not always clear. Respiratory support in the form of mechanical ventilation may also be life saving but can cause lung injury, and protocols should be directed to avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure. For babies with RDS to have the best outcome, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate blood pressure.

Early diagnosis of bacterial infection in the neonate

The diagnosis of neonatal bacterial infection remains one of the greatest and most tantalizing challenges to neonatologists. At birth it must be based on the history of pregnancy and take into account a number of now well-defined risk factors. In addition, if promptly started, antibiotic therapy can reduce its sequelae and improve the prognosis. However, the number of tests that obstetricians can rely on for the diagnosis of infection is quite limited. Tests of maternal inflammation indicators have a low specificity, culture tests are not immune from the risk of contamination, and the measurement of interleukins in the amniotic fluid and maternal blood serum is not yet routine. Observation of clinical signs therefore remains crucial to neonatologists, at the same time that new and more sophisticated laboratory tests enable them to establish a diagnosis of infection at an increasingly earlier stage. In recent years, several infection markers have been investigated, such as procalcitonin and especially C-reactive protein (CRP). Currently, the measurement of plasma concentrations of interleukins (IL), IL-6 and IL-8 in particular, appears to be one of the most sensitive and specific infection indicators in newborns. Cytokine levels are increased even before infants develop any clinical symptoms and routine laboratory tests turn positive. However, owing to their short half-life, their sensitivity decreases after 12-24 h from the onset of inflammation, increasing the risk of false negatives. Ideally, they should then be used in combination with other inflammation indicators, such as CRP. The measurement of cytokines and other new inflammatory markers might be helpful in the early diagnosis of both early-onset infection (assay in umbilical cord blood) and late-onset infection (serial assays performed during the stay in the neonatal intensive care unit). In spite of their time-consuming techniques, culture tests remain of the utmost importance to plan a targeted treatment; blood culture, in particular, is crucial to the diagnosis of sepsis.

Preterm infants with video-EEG confirmed seizures:outcome at 30 months of age

OBJECTIVE Our aim was to identify early predictors of poor neurodevelopmental outcome and of subsequent epilepsy in very early preterm and late preterm newborns with neonatal seizures. STUDY DESIGN Fifty-one preterm infants with gestational age (GA) <or=36 weeks were identified among those admitted to the NICU of University Hospital of Parma between January 1999 and December 2003 and prospectively followed-up. They were subdivided in two Groups: early preterm newborns with a GA <or=29 weeks and those with GA between 30 and 36 weeks. Selection criteria included multiple digital-video-EEG confirmed neonatal seizures and a follow-up of at least 30 months. Independent variables considered for analysis included neonatal risk factors, etiology and type of seizures, EEG activity, and cerebral ultrasound scan examinations. RESULTS Ten infants had a favorable outcome, 17 died, and 23 had an adverse outcome. One infant was lost on follow-up. Apgar score at 1 min (O.R.=15.457, 95% CI: 2.236-106.850, p=0.006) and severely abnormal background EEG activity (O.R.=8.298, 95% CI: 1.316-52.301, p=0.024) were independent predictors of abnormal outcome. Nine infants presented post-neonatal epilepsy. Severely abnormal Cerebral Ultrasound scans were predictive of epilepsy (O.R.=13.72, 95% CI: 1.959-96.149, p=0.008). CONCLUSIONS Neonatal seizures in preterm infants are associated to a high rate of mortality and severe morbidity in survivors but no definitive differences between the two groups of preterm infants were found. Risk-factors for development of subsequent epilepsy are strongly related to the underlying brain damage.

Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis

Recent findings demonstrated the role of neurotransmitters in the aetiopathogenesis of sudden unexpected deaths in infancy. Although genes involved in serotonin metabolism have been proposed as risk factors for sudden infant death syndrome (SIDS), the contribution of additional neurotransmitters and genes different from the serotonin transporter (SLC6A4, 5-HTT) has not been investigated. Considering the common metabolic pathway and synergism between dopamine and serotonin, the role of dopamine transporter (SLC6A3, DAT) and monoamine oxidase A (MAOA) genes in SIDS and stillbirth (sudden intrauterine unexplained death, SIUD) was investigated. Genotypes and allelic frequencies of DAT and MAOA were determined in 20 SIDS and five stillbirth cases and compared with 150 controls. No association was found between DAT polymorphisms and SIDS either at genotype (P = 0.64) or allelic (P = 0.86) level; however, a highly significant association was found between MAOA genotypes (P = 0.047) and alleles (P = 0.002) regulating different expression patterns (3R/3R vs 3.5R/3.5R + 4R/4R) in SIDS + SIUD and controls. Analysis of combined 5-HTTLPR (serotonin transporter linked polymorphic region)/MAOA genotypes revealed that frequency of L/L-4R/4R genotype combination was eightfold higher in SIDS + SIUD than in controls (P < 0.001). Findings are discussed considering the metabolic association among DAT, 5-HTT and MAOA with special emphasis on the linked action of 5-HTT/MAOA in regulating serotonin metabolism of SIDS and SIUD infants.

Prophylactic Administration of Porcine-Derived Lung Surfactant Is a Significant Factor in Reducing the Odds for Peri-Intraventricular Haemorrhage in Premature Infants

We hypothesized that prophylactic treatment with a porcine-modified lung surfactant (PLS) reduces the rate of peri-intraventricular haemorrhage (PIVH) more than rescue treatment. We performed a meta-analysis of three prophylactic versus rescue trials conducted with PLS in four countries using individual data. Overall (grades 1–4) or severe (grades 3 and 4) PIVH of 671 newborns was the outcome. A logistic regression analysis was performed. Prophylactic exposure to PLS was a significant independent factor in reducing the incidence of overall (OR 0.65; 95% CI 0.47–0.90) and severe (OR 0.56; 95% CI 0.35–0.89) PIVH. Moreover, for severe PIVH, the adjusted OR for outborn babies exposed to prophylactic treatment with PLS was highly significant (OR 0.11; 95% CI 0.02–to 0.49). The results we obtained show that prophylactic treatment with PLS reduces the rate of PIVH more than rescue treatment.

Can Breast-Feeding Protect against Schizophrenia?

Background: Human milk, unlike formula feeds, contains long-chain polyunsatured fatty acids, such as docosahexaenoic acid and arachidonic acid which are essential in the development of the central nervous system. If human milk is the optimal food for brain development, and if schizophrenia is a neurodevelopment disorder, might people who become schizophrenic in adult life be less likely to have been breast-fed? Aims: To compare the incidence and length of breast-feeding in patients, siblings and normal controls and to examine the relationship between the duration of breast-feeding and age at onset of schizophrenia. Method: 113 schizophrenic patients were recruited, as were 140 siblings of the patients and 113 nonschizophrenic controls. The breast-feeding history of the patients, their siblings and controls was obtained through interviews with the mothers of the patients and controls. Results: There were no significant differences between groups in the incidence of breast- feeding. The duration of breast-feeding was positively correlated with the age at onset of illness (r = +0.25, p < 0.02). Conclusion: Breast-feeding is no less common in those who develop schizophrenia in later life. However, breast milk might postpone the onset of the illness in schizophrenic patients.

Neonatal seizures in preterm infants: clinical outcome and relationship with subsequent epilepsy

OBJECTIVE Neonatal seizures are considered an acute manifestation of disturbance of the neonatal brain. Some of them can be considered as neonatal epilepsy. Our goal was to evaluate perinatal risk factors, electroencephalogram (EEG) findings and ictal semeiological characteristics of our newborns with neonatal seizures in order to identify which clinical variables were the most early predictive factors of poor neurodevelopmental outcome and of epilepsy. METHODS Among all preterm infants consecutively admitted to the neonatal intensive care unit (NICU) of the University Hospital of Parma in the period between January 1999 and June 2003, 28 preterm infants with gestational age<or=36 weeks were selected according to the presence of repetitive neonatal seizures, need of chronic anticonvulsant therapy, more than one EEG performed during the neonatal period, and at least one imaging examination (cerebral ultrasound and/or cerebral magnetic resonance imaging (MRI). These patients were prospectively followed up for at least 6 months to evaluate the clinical outcome. Independent variables considered for analysis included perinatal risk factors, etiology of convulsions, EEG activity and type of seizures. RESULTS The background EEG activity was the strongest predictive factor of the neurodevelopmental outcome, but status epilepticus (SE) also represented a significant variable associated with poor prognosis and subsequent epilepsy. CONCLUSIONS EEG activity was predictive of the developmental outcome and allowed identification of the infants with SE, a condition often related to neonatal epilepsy (71.4%, p<0.05).

Immunohistochemical markers of neural progenitor cells in the early embryonic human cerebral cortex

The development of the human central nervous system represents a delicate moment of embryogenesis. The purpose of this study was to analyze the expression of multiple immunohistochemical markers in the stem/progenitor cells in the human cerebral cortex during the early phases of development. To this end, samples from cerebral cortex were obtained from 4 human embryos of 11 weeks of gestation. Each sample was formalin-fixed, paraffin embedded and immunostained with several markers including GFAP, WT1, Nestin, Vimentin, CD117, S100B, Sox2, PAX2, PAX5, Tβ4, Neurofilament, CD44, CD133, Synaptophysin and Cyclin D1. Our study shows the ability of the different immunohistochemical markers to evidence different zones of the developing human cerebral cortex, allowing the identification of the multiple stages of differentiation of neuronal and glial precursors. Three important markers of radial glial cells are evidenced in this early gestational age: Vimentin, Nestin and WT1. Sox2 was expressed by the stem/progenitor cells of the ventricular zone, whereas the postmitotic neurons of the cortical plate were immunostained by PAX2 and NSE. Future studies are needed to test other important stem/progenitor cells markers and to better analyze differences in the immunohistochemical expression of these markers during gestation.

Plasma Concentrations of Carbohydrates and Sugar Alcohols in Term Newborns after Milk Feeding

Nonglucose carbohydrates such as galactose, mannose, and inositol play a clinically important role in fetal and neonatal nutrition, though little is known about their metabolism in the neonate. The aim of this study was to determine whether postprandial changes in plasma carbohydrate and sugar alcohol concentrations are affected by clinical variables such as postnatal age (PNA), milk type, feeding volume, or feeding duration in term newborns. Neonates (n = 26) taking intermittent enteral feedings were enrolled. Blood samples were obtained at baseline (immediately before the start of a feeding) and at 2–3 subsequent time points up to 110 min. Postprandial rise was only observed for plasma glucose concentrations [Glu] and plasma galactose concentrations [Gal] and clinical variables did not predict this change. Despite equimolar delivery in milk, the median of [Glu] rise minus [Gal] rise from baseline to second postprandial plasma sample was 674 μM (−38, 3333 μM; p < 0.0001), reflecting efficient hepatic first-pass metabolism of galactose. A significant PNA effect on [Gal] was observed such that for each day PNA there was an 18% decrease in [Gal] (p = 0.03). [Gal] are a function of PNA, suggesting maintenance of a significant ductus venosus shunt in term infants.

Current concepts on the pulmonary surfactant in infants.

Surfactant has been a main topic of neonatology in the last 20 years. Many studies have been conducted since the discovery of its role in the pathogenesis of respiratory distress syndrome and the knowledge on its composition and metabolism has become complex. In this article we review the current concepts of its metabolism, ways of acting, properties of its proteins and activities other than the ability of reducing surface tension within the lung as a basis to understand the development of disease in case of its deficiency.