Early-childhood linear growth faltering in low- and middle-income countries.

Globally, 149 million children under 5 years of age are estimated to be stunted (length more than 2 standard deviations below international growth standards)1,2. Stunting, a form of linear growth faltering, increases the risk of illness, impaired cognitive development and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering-a key consideration for defining critical windows to deliver preventive interventions. Here we completed a pooled analysis of longitudinal studies in low- and middle-income countries (n = 32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of onset of linear growth faltering and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to the age of 3 months, with substantially higher stunting at birth in South Asia. From 0 to 15 months, stunting reversal was rare; children who reversed their stunting status frequently relapsed, and relapse rates were substantially higher among children born stunted. Early onset and low reversal rates suggest that improving children's linear growth will require life course interventions for women of childbearing age and a greater emphasis on interventions for children under 6 months of age.

Sudden death in epilepsy and ectopic neurohypophysis in Joubert syndrome 23 diagnosed using SNVs/indels and structural variants pipelines on WGS data: a case report.

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.

Association between Transport Risk Index of Physiologic Stability in Extremely Premature Infants and Mortality or Neurodevelopmental Impairment at 18 to 24 Months.

OBJECTIVES: To examine the association between mortality or neurodevelopmental impairment at 18-24 months of corrected age and the Transport Risk Index of Physiologic Stability (TRIPS) score on admission to the neonatal intensive care unit (NICU) in extremely premature infants. STUDY DESIGN: Retrospective cohort study of extremely premature infants (inborn and outborn) born at 22-28 weeks of gestational age and admitted to NICUs in the Canadian Neonatal Network between April 2009 and September 2011. TRIPS scores and clinical data were collected from the Canadian Neonatal Network database. Follow-up data at 18-24 months of corrected age were retrieved from the Canadian Neonatal Follow-Up Network database. Neurodevelopment was assessed using the Bayley Scales of Infant and Toddler Development, Edition III. The primary outcome was death or significant neurodevelopmental impairment at 18-24 months of corrected age. The secondary outcomes were individual components of the Bayley Scales of Infant and Toddler Development, Edition III assessment. RESULTS: A total of 1686 eligible infants were included. A TRIPS score of ≥20 on admission to the NICU was significantly associated with mortality (aOR 2.71 [95% CI, 2.02-3.62]) and mortality or significant neurodevelopmental impairment (aOR 1.91 [95% CI, 1.52-2.41]) at 18-24 months of corrected age across all gestational age groups of extremely premature infants. CONCLUSION: The TRIPS score on admission to the NICU can be used as an adjunctive, objective tool for counselling the parents of extremely premature infants early after their admission to the NICU.

A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction.

Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.

Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study.

BACKGROUND: Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. METHODS: For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. FINDINGS: 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). INTERPRETATION: In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. FUNDING: US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

Neonatal critical illness and development: white matter and hippocampus alterations in school-age neonatal extracorporeal membrane oxygenation survivors.

AIM: To examine the neurobiology of long-term neuropsychological deficits after neonatal extracorporeal membrane oxygenation (ECMO). METHOD: This cross-sectional study assessed white matter integrity and hippocampal volume of ECMO survivors (8-15y) and healthy children (8-17y) using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI) respectively. Neuropsychological outcome was evaluated in ECMO survivors. Included clinical predictors of white matter integrity: age start ECMO, ECMO duration, highest oxygenation index before ECMO, highest mean airway pressure, and mechanical ventilation duration. RESULTS: ECMO survivors (n=23) had lower global fractional anisotropy than healthy children (n=54) (patients=0.368; comparison group=0.381; p=0.018), but similar global mean diffusivity (p=0.410). ECMO survivors had lower fractional anisotropy in the left cingulum bundle (ECMO survivors=0.345; comparison group=0.399; p<0.001) and higher mean diffusivity in a region of the left parahippocampal cingulum (patients=0.916; comparison group=0.871; p<0.001). Higher global mean diffusivity predicted worse verbal memory in ECMO survivors (n=17) (ß=-0.74, p=0.008). ECMO survivors (n=23) had smaller bilateral hippocampal volume than healthy children (n=43) (left, p<0.001; right, p<0.001) and this was related to worse verbal memory (left, ß=0.65, p=0.018; right, ß=0.71, p=0.006). INTERPRETATION: Neonatal ECMO survivors are at risk for long-term brain alterations, which may partly explain long-term neuropsychological impairments. Neuroimaging may contribute to better risk stratification of long-term impairments.

Survival and Neurodevelopmental Outcomes of Very Low Birth Weight Infants in a Regional Core Hospital in Kochi, Japan.

We sought to clarify the survival and neurodevelopmental outcomes of very low birth weight infants (VLBWIs) and to identify risk factors for death or neurodevelopmental impairment (NDI) in VLBWIs at our hospital. The total study population was 217 infants born in 2005-2012 weighing 1,500 g. We compared their outcomes with those from previous reports analyzed the causes of death. Risk factors for death after discharge or NDI were evaluated by a multivariate logistic regression analysis. The incidences of death or NDI reported revealed in this study and the database of Neonatal Research Network of Japan were 25.3% and 19.6% (p＝0.039), respectively. The main causes of death before discharge were intraventricular hemorrhage, sepsis, and persistent pulmonary hypertension of the newborn. The significant risk factors for death after discharge or NDI were early gestational age (weeks) and periventricular leukomalacia (adjusted odds ratio [95% confidence interval, p-value], 0.72 [0.54-0.94, 0.017] and 6.90 [1.35-38.25, 0.021], respectively). These factors must be addressed in order to improve treatment strategies for VLBWIs.

Understanding Information About Mortality Among People with Intellectual and Developmental Disabilities in Canada.

BACKGROUND: This paper reviews what is currently known about mortality among Canadians with intellectual and developmental disabilities and describes opportunities for ongoing monitoring. METHODS: In-hospital mortality among adults with intellectual and developmental disabilities in Ontario was examined using hospital data. Mortality was compared between age-, sex- and residence area-matched groups of Manitobans with and without intellectual and developmental disabilities using linked administrative data. A retrospective cohort study of mortality among individuals with intellectual and developmental disabilities in a region of Ontario focused on measuring excess mortality and risk factors. FINDINGS: There is evidence of excess mortality in persons with intellectual and developmental disabilities in Canada. Some of the excess is attributable to comorbidities that are more common in this population. Women may have a greater risk of death than men. Excess mortality occurs at all ages but is more pronounced in early life. DISCUSSION: High-quality ongoing monitoring of mortality among individuals with intellectual and developmental disabilities is possible in Canada. Examination of sex differences should be a priority.

Mortality of People with Intellectual and Developmental Disabilities from Select US State Disability Service Systems and Medical Claims Data.

BACKGROUND: Monitoring population trends including mortality within subgroups such as people with intellectual and developmental disabilities and between countries provides crucial information about the population's health and insights into underlying health concerns and the need for and effectiveness of public health efforts. METHODS: Data from both US state intellectual and developmental disabilities service system administrative data sets and de-identified state Medicaid claims were used to calculate average age at death and crude mortality rates. RESULTS: Average age at death for people in state intellectual and developmental disabilities systems was 50.4-58.7 years and 61.2-63.0 years in Medicaid data, with a crude adult mortality rate of 15.2 per thousand. CONCLUSIONS: Age at death remains lower and mortality rates higher for people with intellectual and developmental disabilities. Improved case finding (e.g. medical claims) could provide more complete mortality patterns for the population with intellectual and developmental disabilities to inform the range of access and receipt of supportive and health-related interventions and preventive care.

Population study of neurodevelopmental outcomes of extremely premature infants admitted after office hours.

AIM: The aim of the study was to compare neurodevelopmental outcomes of extremely preterm infants admitted during (OH) and after (AH) office hours. METHODS: A retrospective review of the New South Wales and Australian Capital Territory Neonatal Intensive Care Units' (NICUs) Data Collection of all infants <29 weeks gestation admitted to New South Wales and Australian Capital Territory NICUs between January 1998 and December 2004 was conducted. The primary outcome was moderate/severe functional disability (FD) at 2-3 years follow-up defined as developmental delay (Griffiths Mental Developmental Scales general quotient or Bayley Scales of Infant Development-II mental developmental index >2 standard deviations below the mean), cerebral palsy (unable to walk without aids), deafness (requiring bilateral hearing aids) or blindness (visual acuity <6/60 in the better eye). RESULTS: Mortality and age at follow-up were comparable between the AH and OH groups. Developmental outcome was evaluated in 972 (74.9%) infants admitted during AH and 501 (74.6%) admitted during OH. FD was not significantly different between the AH and OH groups (17.1% vs. 14.8%, adjusted odds ratio 1.131, 95% confidence interval 1.131 (0.839-1.523), P = 0.420). There were no significant differences between AH and OH infants with cerebral palsy (9.6% vs. 7.6%), developmental delay (5.4% vs. 5.0%) or any other component of FD. CONCLUSION: There is little circadian variation in mortality and adverse neurodevelopmental outcomes in an NICU network with the current model of after hours staffing and support, and sharing of NICU workload within a network.

[Treatment of neonatal asphyxia with a special focus on therapeutic hypothermia]. / Behandlung der neonatalen Asphyxie unter besonderer Berücksichtigung der therapeutischen Hypothermie.

In recent years the treatment of newborns for neonatal asphyxia has experienced a lot of new developments. A major milestone were the positive results of various trials for prophylactic treatment of hypoxic-ischemic encephalopathy by moderate cooling of the child or of his head. With this paper we attempt to provide a consented guideline to aid in the treatment decision for affected newborns and thus achieve a more homogeneous treatment strategy throughout Germany.

Frank-ter Haar syndrome protein Tks4 regulates epidermal growth factor-dependent cell migration.

Mutations in the SH3PXD2B gene coding for the Tks4 protein are responsible for the autosomal recessive Frank-ter Haar syndrome. Tks4, a substrate of Src tyrosine kinase, is implicated in the regulation of podosome formation. Here, we report a novel role for Tks4 in the EGF signaling pathway. In EGF-treated cells, Tks4 is tyrosine-phosphorylated and associated with the activated EGF receptor. This association is not direct but requires the presence of Src tyrosine kinase. In addition, treatment of cells with LY294002, an inhibitor of PI 3-kinase, or mutations of the PX domain reduces tyrosine phosphorylation and membrane translocation of Tks4. Furthermore, a PX domain mutant (R43W) Tks4 carrying a reported point mutation in a Frank-ter Haar syndrome patient showed aberrant intracellular expression and reduced phosphoinositide binding. Finally, silencing of Tks4 was shown to markedly inhibit HeLa cell migration in a Boyden chamber assay in response to EGF or serum. Our results therefore reveal a new function for Tks4 in the regulation of growth factor-dependent cell migration.

Long-term survival of children with cerebral palsy in Okinawa, Japan.

AIM: The aim of this study was to describe the survival prognosis of children with cerebral palsy (CP) in Okinawa, Japan. METHOD: A cohort study was conducted on all children with CP born between 1988 and 2005 in Okinawa, Japan. Survival proportions were determined with a life table and Kaplan-Meier survival curves were plotted. The effect of each predictor variable was estimated using Cox regression analysis. RESULTS: This study included 580 children with CP (332 males, 248 females). In the cohort, 119 (20.5%) children were classified in Gross Motor Function Classification System (GMFCS) level I, 65 (11.2%) were classified in level II, 40 (6.9%) in level III, 189 (32.6%) in level IV, 166 (28.6%) in level V and GMFCS level was unknown for one. Of the 34 children who died, 29 were classified in GMFCS level V and GMFCS level was unknown for one. Mean age at start of follow-up was 24.5 months (SD 2.6 mo); mean length of follow-up was 8 years 8 months (standard error of the mean 0.214 y). The 5 year- and 18-year survival percentages of the entire cohort were 98% and 89% respectively. In children with CP, significantly lower survival rates were associated with multiple factors, including a birthweight of at least 2500 g (p=0.009), a gestational age of at least 37 weeks (p=0.004), and the most severe gross motor limitation, GMFCS level V (p<0.001). However, multivariate analysis showed GMFCS level V was the only significant predictor variable (p<0.001) for survival of CP. INTERPRETATION: This study is the first to describe survival of children with CP in Japan. Our results are similar to those previously reported in other countries. These results are important in planning adequate provision of social and medical services for individuals with CP.

Effect of inborn vs. outborn delivery on neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy: secondary analyses of the NICHD whole-body cooling trial.

BACKGROUND: The effect of birth location on hypothermia-related outcomes has not been rigorously examined in the literature. In this study, we determined whether birth location had an impact on the benefits of whole-body cooling to 33.5 °C for 72 h in term infants (n = 208) with hypoxic-ischemic encephalopathy (HIE) who participated in the Neonatal Research Network (NRN) randomized controlled trial. METHODS: Heterogeneity by birth location was examined with respect to cooling treatment for the 18-mo primary outcomes (death, moderate disability, severe disability) and secondary outcomes (death, components of disability), and in-hospital organ dysfunction. Logistic regression models were used to generate adjusted odds ratios. RESULTS: Infants born at a location other than an NRN center (outborn) (n = 93) experienced significant delays in initiation of therapy (mean (SD): 5.5 (1.1) vs. 4.4 (1.2) h), lower baseline temperatures (36.6 (1.2) vs. 37.1 (0.9) °C), and more severe HIE (43 vs. 29%) than infants born in an NRN center (inborn) (n = 115). Maternal education <12 y (50 vs. 14%) and African-American ethnicity (43 vs. 25%) were more common in the inborn group. When adjusted for NRN center and HIE severity, there were no significant differences in 18-mo outcomes or in-hospital organ dysfunction between inborn and outborn infants. CONCLUSION: Although limited by sample size and some differences in baseline characteristics, the study showed that birth location does not appear to modify the treatment effect of hypothermia after HIE.

Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008.

BACKGROUND: While survival rates of extremely preterm infants have improved over the last decades, the incidence of neurodevelopmental disability (ND) in survivors remains high. Representative current data on the severity of disability and of risk factors associated with poor outcome in this growing population are necessary for clinical guidance and parent counselling. METHODS: Prospective longitudinal multicentre cohort study of preterm infants born in Switzerland between 24(0/7) and 27(6/7) weeks gestational age during 2000-2008. Mortality, adverse outcome (death or severe ND) at two years, and predictors for poor outcome were analysed using multilevel multivariate logistic regression. Neurodevelopment was assessed using Bayley Scales of Infant Development II. Cerebral palsy was graded after the Gross Motor Function Classification System. RESULTS: Of 1266 live born infants, 422 (33%) died. Follow-up information was available for 684 (81%) survivors: 440 (64%) showed favourable outcome, 166 (24%) moderate ND, and 78 (11%) severe ND. At birth, lower gestational age, intrauterine growth restriction and absence of antenatal corticosteroids were associated with mortality and adverse outcome (p < 0.001). At 36(0/7) weeks postmenstrual age, bronchopulmonary dysplasia, major brain injury and retinopathy of prematurity were the main predictors for adverse outcome (p < 0.05). Survival without moderate or severe ND increased from 27% to 39% during the observation period (p = 0.02). CONCLUSIONS: In this recent Swiss national cohort study of extremely preterm infants, neonatal mortality was determined by gestational age, birth weight, and antenatal corticosteroids while neurodevelopmental outcome was determined by the major neonatal morbidities. We observed an increase of survival without moderate or severe disability.

Early single-channel aEEG/EEG predicts outcome in very preterm infants.

AIM: To characterize early amplitude-integrated electroencephalogram (aEEG) and single-channel EEG (aEEG/EEG) in very preterm (VPT) infants for prediction of long-term outcome. PATIENTS: Forty-nine infants with median (range) gestational age of 25 (22-30) weeks. METHODS: Amplitude-integrated electroencephalogram/EEG recorded during the first 72 h and analysed over 0-12, 12-24, 24-48 and 48-72 h, for background pattern, sleep-wake cycling, seizures, interburst intervals (IBI) and interburst percentage (IB%). In total, 2614 h of single-channel EEG examined for seizures. Survivors were assessed at 2 years corrected age with a neurological examination and Bayley Scales of Infant Development-II. Poor outcome was defined as death or survival with neurodevelopmental impairment. Good outcome was defined as survival without impairment. RESULTS: Thirty infants had good outcome. Poor outcome (n = 19) was associated with depressed aEEG/EEG already during the first 12 h (p = 0.023), and with prolonged IBI and higher IB% at 24 h. Seizures were present in 43% of the infants and associated with intraventricular haemorrhages but not with outcome. Best predictors of poor outcome were burst-suppression pattern [76% correctly predicted; positive predictive value (PPV) 63%, negative predictive value (NPV) 91%], IBI > 6 sec (74% correctly predicted; PPV 67%, NPV 79%) and IB% > 55% at 24 h age (79% correctly predicted; PPV 72%, NPV 80%). In 35 infants with normal cerebral ultrasound during the first 3 days, outcome was correctly predicted in 82% by IB% (PPV 82%, NPV 83%). CONCLUSION: Long-term outcome can be predicted by aEEG/EEG with 75-80% accuracy already at 24 postnatal hours in VPT infants, also in infants with no early indication of brain injury.

[Risk assessment of pre-term infants]. / Risiken bei Zustand nach Frühgeburt. Grundlagen für die medizinische Risikoprüfung.

Pre-term birth occurs when a baby is born before 37 weeks of gestation are completed. Many recent publications on neurodevelopmental and somatic outcome parameters of premature infants are of interest for insurance medicine. Infants born before the 28th week are called extremely pre-term. When examined at five years, 85% had already received or still needed special treatment or support. The results of examinations in early childhood have quite a low predictive value for the further development of the child. In the very and moderately pre-term stages, long-term risks are continuously declining with the length of gravidity. Even "late pre-term" birth (34 to 36 weeks of gestation) is associated with a nearly doubled rate of developmental impairment and chronic disease in childhood and adolescence. Various studies performed in early adulthood showed that former pre-term infants suffered more often from asthma and psychiatric disorders. On average, they also had higher blood pressure, lower insulin sensitivity, and a reduced exercise capacity. It remains to be evaluated how much these risk factors contribute to cardiovascular or pulmonary morbidity and mortality later in life. At least, general mortality after preterm birth seems to be increased up to the oldest age group statistically evaluated up to now, i.e. 18 to 36 years.

Erythropoietin improves neurodevelopmental outcome of extremely preterm infants.

OBJECTIVE: Erythropoietin has been reported to possess neuroprotective properties in animal studies. No previous studies have investigated the neurodevelopmental outcome of extremely low birth weight (ELBW) infants treated with recombinant human erythropoietin (rEpo) and evaluated it at school age. METHODS: Of 200 ELBW infants treated from 1993 to 1998, 171 (86%) survived, and 148 (87%) were followed up to the age of 10 to 13 years. The neurodevelopmental and school outcome of the ELBW infants receiving rEpo treatment for stimulation of erythropoiesis in the first weeks of life (n = 89) was compared to that of untreated children (n = 57). To test for a neuroprotective effect of erythropoietin therapy, analyses of variance (ANOVAs) were conducted with erythropoietin treatment and intraventricular hemorrhage (IVH) as independent variables and Hamburg-Wechsler Intelligence Test for Children-III (HAWIK-III) intelligence quotient (IQ) scores as dependent variables. RESULTS: The rEpo group scored significantly better than untreated children in the overall developmental assessment (55% vs 39% normally developed, p < 0.05) as well as in the psychological examination (mean composite HAWIK-III IQ score, 90.8 vs 81.3, p < 0.005). The results of ANOVAs show that these differences were ascribable to children with IVH. Whereas those children with IVH treated with rEpo scored significantly better than untreated children (52% vs 6% normally developed, composite HAWIK-III IQ score, 90.3 vs 67.0), treated and untreated children without IVH did not differ in their outcome. The treatment and control groups were comparable in perinatal parameters relevant to prognosis. INTERPRETATION: The results of our observational study confirm the hypothesis of a neuroprotective effect of rEpo in ELBW infants with IVH. This offers a promising preventative therapeutic option for the treatment of these high-risk infants.

Ethamsylate for the prevention of morbidity and mortality in preterm or very low birth weight infants.

BACKGROUND: Ethamsylate decreases blood loss in certain clinical situations such as menorrhagia and following some surgical procedures. This potential to reduce bleeding has led to the hypothesis that it may have a role to play in reducing intraventricular haemorrhage in preterm infants. OBJECTIVES: To determine if ethamsylate, when compared to placebo or no treatment, reduces morbidity and/or mortality in preterm infants. SEARCH STRATEGY: We searched the Cochrane Neonatal Group Trials Register (24 August 2009), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2009, Issue 2), MEDLINE and EMBASE (January 1966 to July 2009) and the Oxford Database of Perinatal Trials. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised trials comparing ethamsylate with placebo or no treatment. The initial search for trials enrolling infants born less than 32 weeks gestation was subsequently expanded to include trials enrolling preterm infants < 35 weeks gestation or < 2000 grams birth weight. Studies were included if they reported on outcomes of all children until death or discharge home. Data from reports of neurodevelopmental follow-up were only included if at least 80% of participants were followed up. DATA COLLECTION AND ANALYSIS: Both review authors independently assessed trial quality and extracted data. We calculated relative risk (RR) and risk difference (RD) together with 95% confidence intervals (CI) and used a fixed-effect model for meta-analysis. MAIN RESULTS: Eight studies were identified but only seven trials enrolling 1410 preterm infants were located. There was no significant difference detected in neonatal mortality or neurodevelopmental outcome at two years between infants treated with ethamsylate and controls. Infants treated with ethamsylate had significantly less intraventricular haemorrhage than controls at < 31 weeks (typical RR 0.63, 95% CI 0.47 to 0.86) and < 35 weeks gestation (typical RR 0.77, 0.65 to 0.92). There was also a significant reduction in grade 3 and 4 intraventricular haemorrhage when all infants < 35 weeks gestation (typical RR 0.67, 95% CI 0.49 to 0.94) were analysed as a single group, but not for the group of infants < 32 weeks alone. There was a reduction in symptomatic patent ductus arteriosus at < 31 weeks gestation (typical RR 0.32, 95% CI 0.12 to 0.87). There were no adverse effects of ethamsylate identified from this systematic review. AUTHORS' CONCLUSIONS: Preterm infants treated with ethamsylate showed no reductions in mortality or neurodevelopmental impairment despite the reduction in any grade of intraventricular haemorrhage seen in infants < 35 weeks gestation.

Preoperative acidosis and infant development following surgery for congenital heart disease.

OBJECTIVE: Prenatal diagnosis has been shown to decrease pre-operative acidosis and might prevent the occurrence of disturbed developmental outcome. The aim of this study is to evaluate parameters for acidosis and their predictive value on developmental outcome in newborns with congenital heart disease. METHODS: A total of 117 patients requiring surgery for structural heart disease in the first 31 days of life were included. Diagnosis was established either pre- or postnatally. Preoperative values of lactate, pH and base excess levels were compared to the occurrence of disturbed developmental outcome, i.e. an underperformance of more than 10% on the P90 of a standardized Dutch developmental scale. Patients were divided into groups according to blood levels of acidosis parameters, using receiver operating characteristics curves to determine cut-off values for pH, base excess and lactate. RESULTS: No significant difference in developmental outcome was found using values for pH or base excess as a cut-off level. Preoperative lactate values exceeding 6.1 mmol/l resulted in a significant increase in impaired development compared to infants with a pre-operative lactate lower than 6.1 mmol/l: 40.9% vs 15.1% in (p=0.03). CONCLUSIONS: Pre-operative lactate values might have a prognostic value on developmental outcome in newborns with congenital heart disease. The limited prognostic value of pH can be explained by the fact that pH can be easily corrected, while lactate better reflects the total oxygen debt experienced by these patients.