Altered functional network connectivity relates to motor development in children born very preterm.

Individuals born very preterm (<32 weeks gestation) are at increased risk for neuromotor impairments. The ability to characterize the structural and functional mechanisms underlying these impairments remains limited using existing neuroimaging techniques. Resting state-functional magnetic resonance imaging (rs-fMRI) holds promise for defining the functional network architecture of the developing brain in relation to typical and aberrant neurodevelopment. In 58 very preterm and 65 term-born children studied from birth to age 12 years, we examined relations between functional connectivity measures from low-motion rs-fMRI data and motor skills assessed using the Movement Assessment Battery for Children, 2nd edition. Across all subscales, motor performance was better in term than very preterm children. Examination of relations between functional connectivity and motor measures using enrichment analysis revealed between-group differences within cerebellar, frontoparietal, and default mode networks, and between basal ganglia-motor, thalamus-motor, basal ganglia-auditory, and dorsal attention-default mode networks. Specifically, very preterm children exhibited weaker associations between motor scores and thalamus-motor and basal ganglia-motor network connectivity. These findings highlight key functional brain systems underlying motor development. They also demonstrate persisting developmental effects of preterm birth on functional connectivity and motor performance in childhood, providing evidence for an alternative network architecture supporting motor function in preterm children.

Plasma vitamin A levels in the very low birthweight infant--relationship to respiratory outcome.

OBJECTIVE: To examine the association between plasma vitamin A levels and outcome measures in very low birthweight (VLBW) infants, including meta-analysis of all observational studies. DESIGN: A prospective observational longitudinal study of plasma vitamin A levels measured in the cord blood; maternal blood in the first 48 h after delivery; and the infants' blood at 48 h, 7 days and 28 days of age and correlated with antenatal and postnatal events. A meta-analysis of all published observational studies on the association of vitamin A with respiratory outcome in the VLBW infant was undertaken. PATIENTS: Fifty-seven infants (88% of all eligible) VLBW infants (< 1500 g) admitted from January through October 1993 to one of two regional neonatal intensive care units in the South Island of New Zealand. RESULTS: Exposure to antenatal steroids led to a significant increase in infant cord plasma vitamin A levels (P = 0.003), but no influence on infant plasma vitamin A levels at any other time. Exposure to postnatal steroids produced a significant rise in infant plasma vitamin A levels between 7 and 28 days (P = 0.008). After controlling for gestational age, antenatal and postnatal steroid exposure, low vitamin A levels at 48 h increased the risk of developing chronic lung disease (odds ratio for 50 microg/l decrease: 2.04, 95% CI 1.19-5.77) and bronchopulmonary dysplasia (odds ratio 1.96, 95% CI 1.14-6.87). On combining our results in meta-analysis with those of other published prospective observational studies, infants with chronic lung disease had lower plasma vitamin A levels at all times. CONCLUSIONS: Our results support an association between low plasma vitamin A levels and adverse outcome in the VLBW infant.

Prophylactic oral antifungal agents to prevent systemic candida infection in preterm infants.

BACKGROUND: Systemic fungal infection has increased in prevalence in neonatal intensive care units (NICU) caring for very low birth weight infants. It is associated with a prolonged stay and an increase in morbidity and mortality. An assessment of the use of oral prophylactic antifungals to prevent systemic infection is needed. OBJECTIVES: To assess whether the prophylactic administration of oral antifungal agents to very preterm infants reduces the occurrence of systemic fungal infection. SEARCH STRATEGY: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Searches were carried out up to July 2003 on the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 2, 2003), MEDLINE from 1966, EMBASE from 1980, CINAHL from 1992. Abstracts from SPR (1993 - 2003) and ESPR (1995 to 2002) were hand searched. SELECTION CRITERIA: Randomized and quasi randomized controlled trials in very low birth weight or very preterm infants in which an oral antifungal agent was compared with placebo or no treatment or another oral antifungal agent DATA COLLECTION AND ANALYSIS: Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of the trial quality and data extraction undertaken by each author. Results were reported using relative risk (RR) and risk difference (RD) and weighted mean difference (WMD). 95% confidence intervals were reported. MAIN RESULTS: We identified three eligible trials, one comparing nystatin with no treatment (67 infants), one comparing miconazole with placebo (600 infants), and one comparing nystatin with fluconazole (21 infants). As the two trials comparing nystatin or miconazole with placebo or no treatment were clinically quite different, meta-analysis was not performed. In the trial of nystatin versus no treatment, systemic fungal infection was significantly reduced [RR 0.19 (0.04,0.78)] in the group treated with nystatin. In the study comparing miconazole with placebo there was no significant effect on systemic fungal infection [RR 1.32 (0.46,3.75)]. Neither study found a significant effect on mortality, and there was no significant difference in the mean number of days infants received ventilation or stayed in the neonatal intensive care unit. In the small trial comparing oral fluconazole with nystatin, no significant difference in systemic fungal infection [RR 0.17 (0.01, 2.84)] or mortality [RR 0.17 (0.01, 2.84)] was reported. Adverse drug reactions were not reported in any study. REVIEWER'S CONCLUSIONS: There is insufficient evidence to support the use of prophylactic oral antifungal agents in very low birth weight infants in the neonatal intensive care unit. Randomised controlled trials in current neonatal practice settings are needed, comparing oral antifungal agents with placebo and with each other and including an assessment of side effects, in order to determine whether oral antifungal agents have a role in preventing systemic fungal infections in preterm infants.

Selenium supplementation to prevent short-term morbidity in preterm neonates.

BACKGROUND: Selenium is an essential trace element and component of a number of selenoproteins including glutathione peroxidase, which has a role in protecting against oxidative damage. Selenium is also known to play a role in immunocompetence. Blood selenium concentrations in newborns are lower than those of their mothers and lower still in preterm infants. In experimental animals low selenium concentrations appear to increase susceptibility to oxidative lung disease. In very preterm infants low selenium concentrations have been associated with an increased risk of chronic neonatal lung disease and retinopathy of prematurity. OBJECTIVES: To assess the benefits and harms of selenium supplementation in preterm or very low birthweight infants. SEARCH STRATEGY: Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2003), MEDLINE (1966-May 2003), and Embase (1980-May 2003). The reference lists of recent trials were also searched and abstracts from the Society for Pediatric Research from 1990 were hand-searched. SELECTION CRITERIA: Randomised controlled trials which compared selenium supplementation either parenterally or enterally with placebo or nothing from soon after birth in preterm or very low birthweight infants and which reported clinical outcomes were considered for the review. DATA COLLECTION AND ANALYSIS: Data on selenium supplementation dose, formulation and route of administration; mortality, oxygen requirement at 28 days and 36 weeks post-menstrual age, retinopathy of prematurity, and one or more episodes of sepsis; blood selenium and glutathione peroxidase concentrations at or close to 28 days, were excerpted by both reviewers independently. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Three eligible trials were identified. Two trials, including one trial with a much larger sample size than the others combined, were from geographical areas with low population selenium concentrations. Meta-analysis of the pooled data showed a significant reduction in the proportion of infants having one or more episodes of sepsis associated with selenium supplementation [summary RR 0.73 (0.57, 0.93); RD -0.10 (-0.17, -0.02); NNT 10 (5.9, 50)]. Supplementation with selenium was not associated with improved survival, a reduction in neonatal chronic lung disease or retinopathy of prematurity. REVIEWER'S CONCLUSIONS: Supplementing very preterm infants with selenium is associated with benefit in terms of a reduction in one or more episodes of sepsis. Supplementation was not associated with improved survival, a reduction in neonatal chronic lung disease or retinopathy of prematurity. Supplemental doses of selenium for infants on parenteral nutrition higher than those currently recommended may be beneficial. The data are dominated by one large trial from a country with low selenium concentrations and may not be readily translated to other populations.

Vitamin K administration in neonates: survey of compliance with recommended practices in the Dunedin area.

AIMS: A three dose oral regimen for vitamin K prophylaxis was introduced as an alternative to a single intramuscular injection in August 1992. An assessment of the acceptance of this regimen was needed to determine if the risk of developing haemorrhagic disease of the newborn had altered. METHODS: A survey of compliance with the recommendations was made using a telephone questionnaire to 179 parents. RESULTS: One hundred and fifty three breast fed infants received oral vitamin K. Repeated doses were given to 133 (97%) of 138 breast fed infants at 1 week and 115 (94%) of 122 breast fed infants at 6 weeks. Twenty three of the infants were given the third dose of vitamin K later than recommended. CONCLUSION: Although the majority of infants received all three recommended doses, a quarter of infants given oral prophylaxis are at an increased risk of haemorrhagic disease of the newborn in our sample population.

Very preterm birth: maternal experiences of the neonatal intensive care environment.

OBJECTIVE: Examine sources, predictors and child outcomes associated with neonatal intensive care unit (NICU)-related stress for mothers of infants born very preterm (VPT). STUDY DESIGN: Participants were 133 mothers of VPT infants admitted to a regional level-III NICU. At term equivalent, mothers completed the Parental Stressor Scale: NICU and were interviewed about their psychological well-being and family circumstances. Infant clinical data were also collected. At corrected age 4 years, 49 children were assessed for cognition, language and socio-emotional development. RESULT: Mothers reported moderate to low stress, with parental role alteration considered most stressful and parent-staff communications least stressful. Predictors of overall stress included maternal educational underachievement, stressful life events, postnatal depression and infant unsettled-irregular behavior. NICU-related stress was associated with child anxiety and poorer language development. CONCLUSION: Parental well-being is an important focus of care in the neonatal setting. Strategies are needed to optimize early engagement and reduce stress levels to assist improved child outcomes.

Very preterm children show impairments across multiple neurodevelopmental domains by age 4 years.

OBJECTIVES: Neurodevelopmental outcomes associated with preterm birth are of major health and educational concern. This study examined the neuromotor, cognitive, language and emotional/behavioural outcomes of a regional cohort of 4-year-old children born extremely preterm (EPT: 23-27 weeks' gestation), very preterm (VPT: 28-33 weeks) and full term (FT: 38-41 weeks). Of particular interest were children's risks of impairment across multiple neurodevelopmental domains. METHODS: Data were gathered as part of a prospective longitudinal study of 105 very preterm (< or = 33 weeks gestation) and 107 FT children born during 1998-2000. At 4 years corrected age, children underwent a comprehensive multidisciplinary assessment that included a paediatric neurological examination, cognitive and language testing, and an assessment of child emotional and behavioural adjustment. RESULTS: At age 4 years, compared to FT children, EPT and VPT children had increased risks of cerebral palsy (EPT 18%, VPT 15%, FT 1%), cognitive delay (EPT 33%, VPT 36%, FT 13%), language delay (EPT 29%, VPT 29%, FT 10%) and emotional/behavioural adjustment problems (EPT 37%, VPT 13%, FT 11%). EPT and VPT children were three times more likely to have multiple domain impairments than FT children (EPT 30%, VPT 29%, FT 10%). CONCLUSIONS: A substantial proportion of preschool children born very preterm show clinically significant problems in at least one neurodevelopmental domain, with impairment in multiple domains being common. There is a need to monitor preschool development across a range of functional domains and to consider the likely cascading effects of multiple impairments on later development.

Inter- and intra-rater reliability for classification of medication related events in paediatric inpatients.

BACKGROUND: In medication safety research studies medication related events are often classified by type, seriousness, and degree of preventability, but there is currently no universally reliable "gold standard" approach. The reliability (reproducibility) of this process is important as the targeting of prevention strategies is often based on specific categories of event. The aim of this study was to determine the reliability of reviewer judgements regarding classification of paediatric inpatient medication related events. METHODS: Three health professionals independently reviewed suspected medication related events and classified them by type (adverse drug event (ADE), potential ADE, medication error, rule violation, or other event). ADEs and potential ADEs were then rated according to seriousness of patient injury using a seven point scale and preventability using a decision algorithm and a six point scale. Inter- and intra-rater reliabilities were calculated using the kappa (kappa) statistic. RESULTS: Agreement between all three reviewers regarding event type ranged from "slight" for potential ADEs (kappa = 0.20, 95% CI 0.00 to 0.40) to "substantial" agreement for the presence of an ADE (kappa = 0.73, 95% CI 0.69 to 0.77). Agreement ranged from "slight" (kappa = 0.06, 95% CI 0.02 to 0.10) to "fair" (kappa = 0.34, 95% CI 0.30 to 0.38) for seriousness classifications but, by collapsing the seven categories into serious versus not serious, "moderate" agreement was found (kappa = 0.50, 95% CI 0.46 to 0.54). For preventability decision, overall agreement was "fair" (kappa = 0.37, 95% CI 0.33 to 0.41) but "moderate" for not preventable events (kappa = 0.47, 95% CI 0.43 to 0.51). CONCLUSION: Trained reviewers can reliably assess paediatric inpatient medication related events for the presence of an ADE and for its seriousness. Assessments of preventability appeared to be a more difficult judgement in children and approaches that improve reliability would be useful.

Regional cerebral blood flow velocity changes after indomethacin infusion in preterm infants.

Cerebral blood flow velocity was assessed during infusion of indomethacin over 30 minutes. Eleven preterm infants with symptomatic patent ductus arteriosus were studied on 12 occasions. Indomethacin infusion was associated with a significant reduction in time averaged mean velocity (TAMV), peak systolic velocity (PSV), and end diastolic velocity in both the anterior cerebral artery and middle cerebral artery. The fall in the TAMV and PSV was gradual with maximal change 30-40 minutes after the start of the infusion. It was concluded that administration of indomethacin by slow infusion produces haemodynamic alterations to the cerebral circulation comparable in magnitude with changes described with bolus administration. Indomethacin remains a useful and effective treatment for patent ductus arteriosus in preterm infants, but should continue to be used with caution.

High iron status in very low birth weight infants is associated with an increased risk of retinopathy of prematurity.

OBJECTIVE: To explore the hypothesis that excessive iron loads may increase the formation of free radicals and the development of retinopathy of prematurity in preterm infants, we carried out a prospective observational study of the association between transfusion volume, iron status, and retinopathy.

Vitamin A and E status in very low birth weight infants: development of an improved parenteral delivery system.

Plasma vitamin A and E levels were inadequate in very low birth weight infants receiving a continuous infusion of a parenteral multivitamin preparation, 1.5 ml/kg per day, in dextrose-amino acid solution. A new delivery system using 2 ml/kg per day, infused for 6 hours from the first day of life, avoided loss during infusion and significantly improved plasma vitamin A and E levels during the first 28 days of life in very low birth weight infants.

Turnover of exogenous artificial surfactant.

The turnover of the artificial surfactant Exosurf after its administration to infants with respiratory distress syndrome was studied. High performance liquid chromatography was used to compare the phosphatidylcholine (PC) composition of serial endotracheal tube secretions from three groups of infants. There were 22 infants who received two doses of Exosurf in 24 hours (group 1), 10 infants who received four doses in 36 hours (group 2), and 41 control infants who did not receive Exosurf. Two parameters were studied: (i) dipalmitoylphosphatidylcholine (DPPC), which is present in both Exosurf and endogenous surfactant, expressed as a percentage of total PC (% DPPC) and (ii) the ratio of DPPC to the entirely endogenous palmitoyloleoylphosphatidylcholine (DPPC:POPC ratio). The administration of Exosurf produced changes in endotracheal tube aspirate PC composition that were detectable for over one week. Four doses of Exosurf in 36 hours prolonged the persistence of these changes compared with two doses in 24 hours, but the numbers of infants were small, and should not be over-interpreted. We conclude that after giving two doses of Exosurf, further doses might best be delayed until after two days, and that further clinical evaluation of dosage regimens is required.

The effect of selenium supplementation on outcome in very low birth weight infants: a randomized controlled trial. The New Zealand Neonatal Study Group.

BACKGROUND: Low selenium (SE) status has been documented in preterm infants and has been suggested to be a risk factor for chronic lung disease. METHODS: A total of 534 infants with birth weight <1500 g were enrolled in 8 New Zealand centers in a double-blind placebo-controlled randomized trial of SE supplementation from week 1 of life until 36 weeks' postmenstrual age or discharge home. Supplemented infants received 7 microg/kg/d of SE when fed parenterally and 5 microg/kg/d when fed orally. Plasma SE and glutathione peroxidase concentrations were measured in mothers after delivery and in infants before randomization and at 28 days and 36 weeks' postmenstrual age. Primary outcome measures were oxygen dependency at 28 days and total days oxygen dependency. RESULTS: No significant differences were seen between the groups with respect to primary or secondary outcome measures, with the exception that fewer supplemented infants had an episode of sepsis after the first week of life (P <.038). Mean plasma SE concentrations were 0.33 micromol/L before randomization in both groups and at 28 days had risen in the supplemented group (0.56 micromol/L) but fallen in the control group (0.29 micromol/L) (P <.0001). There was no association between outcome measures and SE concentrations at 28 days or 36 weeks' postmenstrual age. However, lower maternal and infant prerandomization SE concentrations were associated with increased respiratory morbidity. CONCLUSIONS: Postnatal SE supplementation in very low birth weight infants did not improve neonatal outcome. Further investigation of SE supplementation of mothers from the second half of pregnancy is warranted.