Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Altered plasma-type gelsolin and amyloid-β in neonates with hypoxic-ischaemic encephalopathy under therapeutic hypothermia.

Hypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication responsible for ∼23% of all neonatal deaths. Also, 30-70% of these patients will suffer lifetime disabilities, including learning impairment, epilepsy or cerebral palsy. However, biomarkers for HIE screening, or monitoring disease progression are limited. Herein, we sought to evaluate the clinical usefulness of plasma-type gelsolin (pGSN) and amyloid-beta (Aβ) 40 and 42 as prognostic biomarkers for HIE. pGSN has been previously suggested as a feasible marker in other brain injuries and amyloid-beta 40 and 42 are classically assessed in neurodegenerative diseases. However, to our knowledge, they have not been previously assessed in HIE patients. We have analyzed plasma pGSN and Aβ 40 and 42 levels in 55 newborns (16 controls, 16 mild and 23 moderate-severe HIE) at birth, during 72 h of therapeutic hypothermia, a gold-standard treatment for HIE, and 24 h after hypothermia. Aβ levels were lower in HIE patients, and pGSN levels were progressively reduced in mild and moderate-severe HIE patients. The fact that pGSN reductions could predict the severity of HIE and significantly correlated with the time to undergo hypothermia supports the prognostic value of plasmatic pGSN. Further studies are warranted to investigate the role of pGSN in neonatal HIE

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH

Hepatocyte growth factor as an indicator of neonatal maturity

Hepatocyte growth factor (HGF) is a potent mitogen and morphogen expressed in fetal organs. It requires activation by specific serine proteases. The role of activated HGF during fetal development has not been evaluated. We hypothesized that the serum levels of activated HGF would be increased in preterm neonates. Cord blood total HGF and activated HGF levels were measured in 19 preterm (gestational age, 28.04 ± 2.39 weeks) and 24 term (gestational age, 39.37 ± 0.95 weeks) newborns. Anthropometric parameters and metabolic indices were evaluated. Activated HGF was higher in preterm than in term neonates (0.81 ± 0.05 vs. 0.61 ± 0.06 ng/mL, p < 0.05), whereas total HGF levels did not differ significantly between groups. In addition, total and activated HGF further increased by ∼ 40% in preterm neonates 12 h after birth. Finally, activated HGF correlated inversely with gestational age (r = – 0.369; p = 0.015) and birth weight (r = – 0.440; p = 0.003). Our study demonstrates that regulation of HGF activity and circulating HGF levels differ between term and preterm neonates along fetal development.This work was supported by grants from the Carlos III Health Institute (CP08/00106), the Spanish Ministry of Science and Innovation (SAF2009-11282), and the FP7-PEOPLE-2009-RG (PIRG06-GA-2009-256369) to GP. Our Research Unit facilities at the “ Puerta del Mar ” University Hospital received support from the European Community through the regional development funding program (FEDER).Peer reviewe

Two-dimensional ultrasound measurements vs. magnetic resonance imaging-derived ventricular volume of preterm infants with germinal matrix intraventricular haemorrhage

Background: Post-haemorrhagic ventricular dilatation can be measured accurately by MRI. However, two-dimensional (2-D) cranial US can be used at the bedside on a daily basis. Objective: To assess whether the ventricular volume can be determined accurately using US. Materials and methods: We included 31 preterm infants with germinal matrix intraventricular haemorrhage. Two-dimensional cranial US images were acquired and the ventricular index, anterior horn width and thalamo-occipital distance were measured. In addition, cranial MRI was performed. The ventricular volume on MRI was determined using a previously validated automatic segmentation algorithm. We obtained the correlation and created a linear model between MRI-derived ventricular volume and 2-D cranial US measurements. Results: The ventricular index, anterior horn width and thalamo-occipital distance as measured on 2-D cranial US were significantly associated with the volume of the ventricles as determined with MRI. A general linear model fitted the data best: ∛ventricular volume (ml) = 1.096 + 0.094 × anterior horn width (mm) + 0.020 × thalamo-occipital distance (mm) with R2 = 0.831. Conclusion: The volume of the lateral ventricles of infants with germinal matrix intraventricular haemorrhage can be estimated using 2-D cranial US images by application of a model

Glycogen synthase kinase‑3β inhibitor VP3.15 ameliorates neurogenesis, neuronal loss and cognitive impairment in a model of germinal matrix‑intraventricular hemorrhage of the preterm newborn

17 p.-5 fig.Advances in neonatology have significantly reduced mortality rates due to prematurity. However, complications of prematurity have barely changed in recent decades. Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most severe complications of prematurity, and these children are prone to suffer short- and long-term sequelae, including cerebral palsy, cognitive and motor impairments, or neuropsychiatric disorders. Nevertheless, GM-IVH has no successful treatment. VP3.15 is a small, heterocyclic molecule of the 5-imino-1,2,4-thiadiazole family with a dual action as a phosphodiesterase 7 and glycogen synthase kinase-3β (GSK-3β) inhibitor. VP3.15 reduces neuroinflammation and neuronal loss in other neurodegenerative disorders and might ameliorate complications associated with GM-IVH. We administered VP3.15 to a mouse model of GM-IVH. VP3.15 reduces the presence of hemorrhages and microglia in the short (P14) and long (P110) term. It ameliorates brain atrophy and ventricle enlargement while limiting tau hyperphosphorylation and neuronal and myelin basic protein loss. VP3.15 also improves proliferation and neurogenesis as well as cognition after the insult. Interestingly, plasma gelsolin levels, a feasible biomarker of brain damage, improved after VP3.15 treatment. Altogether, our data support the beneficial effects of VP3.15 in GM-IVH by ameliorating brain neuroinflammatory, vascular and white matter damage, ultimately improving cognitive impairment associated with GM-IVH.Funding for open access publishing: Universidad de Cádiz/CBUA This work was supported by a predoctoral fellowship. Instituto de Investigacion Biomedica de la Provincia de Cadiz (INIBICA) (PAM), Agencia Andaluza del Conocimiento. Proyectos I + D + I—Programa Operativo FEDER Andalucía 2014–2020 fondos FEDER (SOL-201800107189-TRA). Ministerio de Ciencia e Innovación. Programa Estatal de Generacion de Conocimiento y Fortalecimiento Cientifico y Tecnologico del Sistema de I + D + i y del Programa Estatal de I + D + i Orientada a los Retos de la Sociedad, del Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion (PID2020-115499RB-I00). Proyectos de I + D + i, en régimen de concurrencia competitiva, destinadas a las universidades y entidades públicas de investigación calificadas como agentes del Sistema Andaluz del Conocimiento, en el ámbito del Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020). Andalucia se mueve con Europa (P20-00928) (MGA).Peer reviewe