Dan Casalaz

Outcome at 14 years of extremely low birthweight infants: a regional study

OBJECTIVES To determine the neurosensory outcome at 14 years of age of a regional cohort of extremely low birthweight (ELBW) children, to contrast their prognosis with normal birthweight (NBW) controls, and to determine the predictive value of assessments earlier in childhood. DESIGN Geographically determined cohort study. SETTING The state of Victoria, Australia. PATIENTS Consecutive ELBW survivors of birth weight 500–999 g (n = 88) born during 1979–1980, and 60 randomly selected contemporaneous NBW (birth weight > 2499 g) controls. MAIN OUTCOME MEASURES Rates of neurosensory impairments and disabilities at 14 years of age, and earlier in childhood. RESULTS Of 351 ELBW consecutive live births, 88 (25%) survived and 79 (90%) of the survivors were assessed at 14 years of age. Of the 79 ELBW children assessed, eight (10%) had cerebral palsy, five (6%) had bilateral blindness, four (5%) were deaf requiring hearing aids, and 36 (46%) had an intelligence quotient (IQ) < −1 SD compared with the mean for the NBW controls. Overall 11 (14%) ELBW children were severely disabled, 12 (15%) were moderately disabled, 20 (25%) were mildly disabled, and 36 (46%) had no disability. In contrast, only one (2%) of 42 NBW children assessed had a severe disability, six (14%) had a mild disability, and the remaining 35 (83%) were not disabled. Comparing psychological test scores for ELBW children with those for NBW controls, rather than test norms, avoided bias in the assessment of disability earlier in childhood. Relative to assessments earlier in childhood, the prediction of disability at 14 years of age was highly significant at each of 2, 5, and 8 years of age, but the accuracy progressively increased with age. CONCLUSIONS ELBW children have substantially higher rates of neurosensory impairments and disabilities at 14 years of age than NBW controls. Comparison of ELBW children with NBW controls avoids bias in the assessment of disability. Early childhood assessments are highly predictive of disability at 14 years of age.

The influence of bacille Calmette-Guerin vaccine strain on the immune response against tuberculosis: a randomized trial.

RATIONALE Approximately 100 million doses of bacille Calmette-Guérin (BCG) vaccine are given each year to protect against tuberculosis (TB). More than 20 genetically distinct BCG vaccine strains are in use worldwide. Previous studies suggest that BCG vaccine strain influences the immune response and protection against TB. Current data on which BCG vaccine strain induces the optimal immune response in humans are insufficient. OBJECTIVES To compare the immune response to three different BCG vaccine strains given to infants at birth. METHODS Newborn infants in a tertiary womens hospital were immunized at birth with one of three BCG vaccine strains. A stratified randomization according to the mothers region of birth was used. MEASUREMENTS AND MAIN RESULTS The presence of mycobacterial-specific polyfunctional CD4 T cells measured by flow cytometry 10 weeks after immunization. Of the 209 infants immunized, data from 164 infants were included in the final analysis (BCG-Denmark, n = 54; BCG-Japan, n = 54; BCG-Russia, n = 57). The proportion of polyfunctional CD4 T cells was significantly higher in infants immunized with BCG-Denmark (0.013%) or BCG-Japan (0.016%) than with BCG-Russia (0.007%) (P = 0.018 and P = 0.003, respectively). Infants immunized with BCG-Japan had higher concentrations of secreted Th1 cytokines; infants immunized with BCG-Denmark had higher proportions of CD107-expressing cytotoxic CD4 T cells. CONCLUSIONS There are significant differences in the immune response induced by different BCG vaccine strains in newborn infants. Immunization with BCG-Denmark or BCG-Japan induced higher frequencies of mycobacterial-specific polyfunctional and cytotoxic T cells and higher concentrations of Th1 cytokines. These findings have potentially important implications for global antituberculosis immunization policies and future tuberculosis vaccine trials.

Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome

We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions.

Hypothermia: A Neuroprotective Therapy for Neonatal Hypoxic-Ischemic Encephalopathy

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Neonatal BCG Vaccination Influences Cytokine Responses to Toll-like Receptor Ligands and Heterologous Antigens

Background BCG vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain, but long-term modulation of the innate immune response (trained immunity) may be involved. Methods Whole-blood specimens, collected 7 days after randomization from 212 neonates enrolled in a randomized trial of neonatal BCG vaccination, were stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses. Results BCG-vaccinated infants had increased production of interleukin 6 (IL-6) in unstimulated samples and decreased production of interleukin 1 receptor antagonist, IL-6, and IL-10 and the chemokines macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1) following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination. Conclusions Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterized by decreased antiinflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine whether there is an association between these findings and the beneficial nonspecific (heterologous) effects of BCG vaccine on all-cause mortality.

Comparable CD4 and CD8 T cell responses and cytokine release after at-birth and delayed BCG immunisation in infants born in Australia

BACKGROUND More than 120 million doses of BCG vaccine are administered worldwide each year. Most infants are given BCG at birth in accordance with WHO recommendations. However, the effect of the maturing neonatal immune system on the immune response and protection conferred by BCG remains uncertain. Previous studies investigating the influence of age at immunisation on the immune response induced by BCG have reported conflicting results. This study compared BCG given at birth and at two months of age in infants in Australia. METHODS Infants born in Melbourne were randomly allocated to immunisation with BCG-Denmark at birth or two months of age. Ten weeks after immunisation, anti-mycobacterial immune responses were measured in a whole blood assay using intracellular cytokine assays and xMAP multiplex cytokine analysis. RESULTS Result from 98 BCG-immunised infants were included in the final analysis. BCG immunisation at birth (n=54) and at 2months of age (n=44) induced comparable proportions of mycobacteria-specific cytokine-producing CD4 and CD8 T cells, as well as comparable proportions of polyfunctional (TNF(+) IL-2(+) IFN-γ(+)) CD4 T cells. Concentrations of cytokines in supernatants were also similar in both groups. CONCLUSIONS Cellular immunity measured 10weeks after BCG immunisation was similar in infants given BCG at birth and in those given BCG at 2months of age. Although definitive correlates of protection against TB remain uncertain, these results suggest that delaying BCG immunisation does not confer any immunological advantage in cellular immunity.

BNP, troponin I, and YKL-40 as screening markers in extremely preterm infants at risk for pulmonary hypertension associated with bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is often complicated by pulmonary hypertension (PH). We investigated three biomarkers potentially suitable as screening markers for extremely preterm infants at risk of BPD-associated PH. In this prospective observational cohort study conducted in a tertiary neonatal intensive care unit, 83 preterm infants with BPD born <28-wk gestation and still inpatients at 36-wk corrected age received an echocardiogram and blood tests of B-type natriuretic peptide (BNP), troponin I, and YKL-40. Infants were analyzed according to echocardiographic evidence of tricuspid regurgitation (TR). Thirty infants had evidence of TR on echocardiogram at 36-wk corrected age. Infants with or without TR had similar baseline demographics: mean ± SD gestational age 261 ± 12 vs. 261 ± 11 wk and birth weight 830 ± 206 vs. 815 ± 187 g, respectively. There was no difference in duration of respiratory support. The right ventricular systolic pressure of infants with evidence of TR was 40 ± 16 mmHg. BNP was the only biomarker that proved to be significantly higher in infants with evidence of TR: median (interquartile range) serum level 54.5 (35-105) vs. 41.5 (30-59) pg/ml, P = 0.043. Subgroup analysis of infants with severe BPD requiring discharge on home oxygen or BPD-related mortality revealed similar results. There was no difference between groups for troponin I and YKL-40. In conclusion, increased serum levels of BNP were associated with evidence of TR at 36-wk corrected gestational age in extremely preterm infants, suggesting a potential role as a screening biomarker for BPD-associated PH.

Associations between maternal size and health outcomes for women undergoing caesarean section: a multicentre prospective observational study (The MUM SIZE Study)

Objectives To investigate associations between maternal body mass index (BMI) at delivery (using pregnancy-specific BMI cut-off values 5 kg/m2 higher in each of the WHO groups) and clinical, theatre utilisation and health economic outcomes for women undergoing caesarean section (CS). Design A prospective multicentre observational study. Setting Seven secondary or tertiary referral obstetric hospitals. Participants One thousand and four hundred and fifty-seven women undergoing all categories of CS. Data collection Height and weight were recorded at the initial antenatal visit and at delivery. We analysed the associations between delivery BMI (continuous and pregnancy-specific cut-off values) and total theatre time, surgical time, anaesthesia time, maternal and neonatal adverse outcomes, total hospital admission and theatre costs. Results Mean participant characteristics were: age 32 years, gestation at delivery 38.4 weeks and delivery BMI 32.2 kg/m2. Fifty-five per cent of participants were overweight, obese or super-obese using delivery pregnancy-specific BMI cut-off values. As BMI increased, total theatre time, surgical time and anaesthesia time increased. Super-obese participants had approximately 27% (17 min, p<0.001) longer total theatre time, 20% (9 min, p<0.001), longer surgical time and 40% (11 min, p<0.001) longer anaesthesia time when compared with normal BMI participants. Increased BMI at delivery was associated with increased risk of maternal intensive care unit admission (relative risk 1.07, p=0.045), but no increased risk of neonatal admission to higher acuity care. Total hospital admission costs were 15% higher in super-obese women compared with normal BMI women and theatre costs were 27% higher in super-obese women. Conclusions Increased maternal BMI was associated with increased total theatre time, surgical and anaesthesia time, increased total hospital admission costs and theatre costs. Clinicians and health administrators should consider these clinical risks, time implications and financial costs when managing pregnant women.