Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO) : Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017. © 2019 The Author(s).Peer reviewe

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age 65 36 weeks and a birth weight 65 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017

Child trafficking in Europe: what is the paediatrician's role? : A statement by the European Academy of Paediatrics.

Child trafficking is among the most lucrative criminal activities in the world and growing rapidly. Poverty, natural disasters, armed conflicts and, in particular, migration put vulnerable children at high risk of trafficking. Accurate statistics on child trafficking are not available due to its illegal nature. Moreover, trafficking may not be consistently recorded and reported by European countries, mainly because of different perceptions as to who is considered a victim of trafficking. Around 4000-5000 children were identified as presumed victims of trafficking in European Union countries from 2013 to 2014; this is an underestimate of the problem because many victims go unrecognised. Trafficking is linked with issues, such as forced marriage, begging, labour or domestic servitude, slavery and prostitution as well as sexual abuse and child pornography. It may also involve the use of children as soldiers or for criminal activities, such as theft and drug smuggling. Child trafficking also involves the removal of organs and the selling neonates, infants, and children for adoption. Child victims of trafficking should be promptly identified in order to provide them with the necessary care as well as to prosecute the traffickers and stop their illegal activity. Healthcare professionals should be appropriately trained to keep a careful eye out for any signs of trafficking in children. The European Academy of Paediatrics calls on our governments, intergovernmental organisations, paediatricians, and healthcare professionals to collaborate so as to improve the identification and healthcare of victims and to contribute to the disbanding and prosecution of child traffickers by reporting such situations. What is Known: • Child trafficking is a fast growing and among the most lucrative criminal activities in the world. • Poverty, natural disasters, armed conflicts and in particular migration put vulnerable children at high risk of trafficking. What is New: • Child trafficking is an underestimated and often ignored issue, with around 4000-500children identified as presumed victims in European Union countries from 2013 to 2014. • The European Academy of Paediatrics strongly encourages Paediatricians to identify victims as well as provide them with adequate health care and support; it calls on governments, intergovernmental organisations, and fellow compatriots to act within the full extent of the law to identify, disband, and prosecute child traffickers

Hypothermia makes cerebral resistance index a poor prognostic tool in encephalopathic newborns

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Severe neonatal encephalopathy (NE) of hypoxic-ischaemic origin may cause death or life-long disability. Acute encephalopathy may also affect cerebrovascular control. Pourcelot's cerebrovascular resistance index (RI) ≤0.55 was predictive of poor outcome in normothermic NE infants. Recent studies have questioned its predictive power during therapeutic hypothermia (HT). &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; To assess the predictive power of RI during HT and after rewarming. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; 45 infants with NE treated with HT for 72 h had their RI calculated during early (median 11 h) and late (median 62 h) cooling and after rewarming (median 89 h). Poor outcome was defined as death or abnormalities on day 10 magnetic resonance imaging shown to predict severe neuromotor disability. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; RI ≤0.55 during cooling did not differentiate between good and poor outcome (late cooling, p = 0.08), but was powerful after rewarming (p = 0.004). RI ≤0.55 predicted true poor outcome in 43% (95% confidence interval (CI): 12, 80) during late cooling and in 100% (95% CI: 31, 100) after rewarming. RI &gt;0.55 predicted good outcome in 86% (95% CI: 69, 95) during late cooling and in 89% (95% CI: 74, 96) after rewarming. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Low RI is not predictive of poor outcome during HT in NE infants, but regains the predictive power seen in normothermic infants after rewarming.</jats:p

Impact of maternal characteristics on human milk oligosaccharide composition over the first 4 months of lactation in a cohort of healthy European mothers

Human milk oligosaccharide (HMO) composition varies among lactating mothers and changes during the course of lactation period. Interindividual variation is largely driven by fucosyltransferase (FUT2 and FUT3) polymorphisms resulting in 4 distinct milk groups. Little is known regarding whether maternal physiological status contributes to HMO variability. We characterized the trajectories of 20 major HMOs and explored whether maternal pre-pregnancy body mass index (ppBMI), mode of delivery, or parity may affect milk HMO composition. Using longitudinal breastmilk samples from healthy mothers (n = 290) across 7 European countries, we characterized HMO composion and employed mixed linear models to explore associations of maternal characteristics with individual HMOs. We observed HMO-specific temporal trajectories and milk group dependencies. We observed relatively small but significant differences in HMO concentrations based on maternal ppBMI, mode of delivery and parity. Our findings suggest that HMO composition to be regulated time-dependently by an enzyme as well as substrate availability and that ppBMI, mode of delivery, and parity may influence maternal physiology to affect glycosylation marginally within the initital period of lactation. Our observational study is the largest European standardized and longitudinal (up to 4 months) milk collection study assessing HMO concentrations and basic maternal characteristics. Time of lactation and milk groups had the biggest impact on HMO variation. Future studies need to elucidate these observations and assess the physiological significance for the breastfed infant

Human milk oligosaccharides, infant growth, and adiposity over the first 4 months of lactation

Background: The relationship between human milk oligosaccharides (HMOs) and infant growth and adiposity is not fully understood and comprehensive studies are missing from the current literature. Methods: We screened and recruited 370 healthy, pregnant women and their infants from seven European countries. Breastmilk samples were collected using standardized procedures at six time points over 4 months, as were infant parameters. Correlations and associations between HMO area under the curve, anthropometric data, and fat mass at 4 months were tested. Results: Lacto-N-neotetraose had a negative correlation with the change in length (rs = 120.18, P = 0.02). Sialyllacto-N-tetraose c (LSTc) had a positive correlation with weight for length (rs = 0.19, P = 0.015). Infants at the 25th upper percentile were fed milk higher in 3\u2032-sialyllactose and LSTc (P = 0.017 and P = 0.006, respectively) compared to the lower 25th percentile of the weight-for-length z-score gain over 4 months of lactation. No significant associations between growth and body composition and Lewis or secretor-dependent HMOs like 2\u2032-fucosyllactose were identified. Conclusions: Changes in the HMO composition of breastmilk during the first 4 months appear to have little influence on infant growth and body composition in this cohort of healthy mothers and infants. Impact: Modest associations exist between individual HMO and infant growth outcomes at least in healthy growing populations.Our study provides a comprehensive investigation of associations between all major HMO and infant growth and adiposity including several time points. Certain groups of HMOs, like the sialylated, may be associated with adiposity during the first months of lactation.HMO may modulate the risk of future metabolic disease. Future population studies need to address the role of specific groups of HMOs in the context of health and disease to understand the long-term impact