Brian A. Darlow

Treatment of Neonatal Sepsis with Intravenous Immune Globulin

BACKGROUND Neonatal sepsis is a major cause of death and complications despite antibiotic treatment. Effective adjunctive treatments are needed. Newborn infants are relatively deficient in endogenous immunoglobulin. Meta-analyses of trials of intravenous immune globulin for suspected or proven neonatal sepsis suggest a reduced rate of death from any cause, but the trials have been small and have varied in quality. METHODS At 113 hospitals in nine countries, we enrolled 3493 infants receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive two infusions of either polyvalent IgG immune globulin (at a dose of 500 mg per kilogram of body weight) or matching placebo 48 hours apart. The primary outcome was death or major disability at the age of 2 years. RESULTS There was no significant between-group difference in the rates of the primary outcome, which occurred in 686 of 1759 infants (39.0%) who received intravenous immune globulin and in 677 of 1734 infants (39.0%) who received placebo (relative risk, 1.00; 95% confidence interval, 0.92 to 1.08). Similarly, there were no significant differences in the rates of secondary outcomes, including the incidence of subsequent sepsis episodes. In follow-up of 2-year-old infants, there were no significant differences in the rates of major or nonmajor disability or of adverse events. CONCLUSIONS Therapy with intravenous immune globulin had no effect on the outcomes of suspected or proven neonatal sepsis.

Infants in a neonatal intensive care unit: parental response

Objective: To compare the psychosocial functioning of the parents (mother and father) of infants admitted to a neonatal intensive care unit (NICU) with the parents of infants born at term and not admitted to the NICU. Design: Random sample of NICU parents and term non-NICU parents were assessed across a variety of psychiatric and psychosocial measures shortly after the birth of their infant. Setting: Christchurch Women’s Hospital, New Zealand. Labour ward and level III NICU. Participants: A total of 447 parents (242 mothers; 205 fathers) with an infant admitted to a regional NICU during a 12 month period; 189 parents (100 mothers; 89 fathers) with infants born at term and not requiring NICU admission. Main outcome measures: Depression and anxiety symptoms, psychosocial functioning. Results: Overall, levels of anxiety and depression were low in both parent groups. Compared with control parents, a higher percentage of NICU parents had clinically relevant anxiety and were more likely to have had a previous NICU admission and be in a lower family income bracket. Infant prematurity was associated with higher levels of symptomatology in both NICU mothers and fathers. Conclusions: Specific interventions are not needed for most parents who have an infant admitted to the NICU as they appear to adapt relatively successfully. Infant prematurity impacts negatively on the father as well as the mother. Consequently these parents may benefit from increased clinical attention.

Prenatal Risk Factors for Severe Retinopathy of Prematurity Among Very Preterm Infants of the Australian and New Zealand Neonatal Network

Objective. To identify prenatal and perinatal risk factors for clinically severe (stage 3 or 4) retinopathy of prematurity (ROP). Methods. Data were collected prospectively as part of the ongoing Australian and New Zealand Neonatal Network audit of high-risk infants (birth weight of <1500 g or gestational age [GA] of <32 weeks) admitted to a level III neonatal unit in Australia or New Zealand. Prenatal and perinatal factors to 1 minute of age were examined for the subset of infants with GA of <29 weeks who survived to 36 weeks’ postmenstrual age and were examined for ROP (n = 2105). The factors significantly associated with stage 3 or 4 ROP were entered into a multivariate logistic regression model. Results. Two-hundred three infants (9.6%) had stage 3 or more ROP. Prematurity was the dominant risk factor, with infants with GA of <25 weeks having 20 times greater odds of severe ROP than infants with GA of 28 weeks. Birth weight for GA also had a “dose-response” effect; the more growth-restricted infants had greater risk, with infants below the 3rd percentile of weight for GA having 4 times greater odds of severe ROP than those between the 25th and 75th percentiles. Male gender was also a significant risk factor (odds ratio: 1.73; 95% confidence interval: 1.25–2.40). Conclusions. These data, for a large, essentially population-based cohort, suggest that factors related to the degree of immaturity, intrauterine growth restriction, and male gender contribute to severe ROP.

The relationship of CSF and plasma cytokine levels to cerebral white matter injury in the premature newborn

Ischemia and systemic infection are implicated in the etiology of periventricular white matter injury, a major cause of adverse motor and cognitive outcome in preterm infants. Cytokines are signaling proteins that can be produced as part of the inflammatory response to both ischemia and infection. The aim of this study was to relate cerebrospinal fluid (CSF) concentrations of IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) to magnetic resonance–defined white matter injury in preterm infants. Relationships between CSF and plasma cytokine concentrations were also examined. Preterm infants (≤32 wk) and more mature infants from The Royal Womens Hospital, Melbourne, Australia, and Christchurch Womens Hospital, Christchurch, New Zealand, were eligible for study if they required a clinically indicated lumbar puncture. Plasma samples were obtained in a subgroup of Christchurch infants. Preterm infants underwent advanced quantitative volumetric magnetic resonance imaging using a 1.5-Tesla scanner at term equivalent. One hundred forty-six infants were enrolled and 190 CSF and 42 plasma samples obtained. There was no significant correlation between paired CSF and plasma concentrations for any cytokine. In comparing plasma and CSF concentrations, levels of IL-8 were significantly higher in CSF than plasma. Preterm infants with MRI-defined cerebral white matter injury had higher levels of IL-6, IL-10, and TNF-α in the CSF than infants without such injury. Plasma cytokine concentrations may not reflect CSF cytokine levels or inflammatory events within the brain. Elevated CSF levels of cytokines in infants with white matter injury suggest an altered inflammatory balance.

Elevated Free Radical Products in the Cerebrospinal Fluid of VLBW Infants with Cerebral White Matter Injury

Free radical mediated cellular injury has been hypothesized to play a key role in the pathogenesis of white matter injury in the premature infant, although direct evidence is lacking. Between April 1999 and May 2001, 22 very low birthweight infants, 30 term infants, and 17 adults had samples of cerebrospinal fluid (CSF) collected for clinical indications. Only CSF samples without any evidence of meningeal inflammation were analyzed for the levels of the lipid peroxidation products, 8-isoprostane and malondialdehyde (MDA), and protein carbonyls as a measure of protein oxidation. Chlorotyrosine was monitored as a measure of neutrophil oxidative activity. In the premature infants with subsequent evidence of white matter injury on magnetic resonance imaging at term, there was a significant elevation in the CSF level of protein carbonyls in comparison with the level in healthy premature infants, term infants, and adult controls (all p < 0.001). A significant difference in the levels of the lipid peroxidation products, 8-isoprostane and MDA, was apparent between premature infants with white matter injury and adult controls (isoprostanes p = 0.02, MDA p = 0.014). There was a trend toward higher levels of 8-isoprostane in the premature infants with white matter injury in comparison with those without white matter injury (p = 0.08), with 5 of the 14 infants with white matter injury having levels that were more than 10-fold higher than the top of the adult range. There was no significant difference in the level of chlorotyrosines among any of the groups. These preliminary data provide evidence of an association of elevated oxidative products during the evolution of white matter injury in the human premature infant.

Improved outcomes for very low birthweight infants: evidence from New Zealand national population based data.

Objective: To compare the survival and short term morbidity of all New Zealand very low birthweight (VLBW) infants born in two epochs, 1986 and 1998–1999. Setting: All level III and level II neonatal intensive care units (NICUs) in New Zealand. Methods: In 1986, data were prospectively collected for a study of retinopathy of prematurity (ROP). In 1998–1999, prospective data were collected by the Australian and New Zealand Neonatal Network (ANZNN). Both cohorts included all VLBW infants born during the calendar year and admitted to a NICU. Data were collected from birth until discharge home or death. Results: More VLBW infants were admitted for care in 1998–1999 (n = 1084, 0.96% of livebirths) than in 1986 (n = 413, 0.78% of livebirths; p < 0.001), including a higher proportion of VLBW infants of < 1000 g birth weight (38% v 32% respectively; p < 0.05). Survival to discharge home increased from 81.8% in 1986 to 90.3% in 1998–1999 (p < 0.001). The 1998–1999 cohort had a higher proportion of infants born in a hospital with a level III NICU (87% v 72% in 1986; p < 0.001) and receiving antenatal corticosteroids (80% v 58% in 1986; p < 0.001). In 1998–1999, the incidence of several morbidities had decreased compared with 1986, including oxygen dependency at 28 days (29% v 39% respectively; p = 0.001) and at 36 weeks postmenstrual age (16% v 23%; p = 0.002), grade 1 intraventricular haemorrhage (IVH) (8% v 24%; p < 0.001), grade 2/3 IVH (5% v 11%; p < 0.001), and stage 3/4 ROP for infants < 1000 g (6% v 13%; p < 0.001). Conclusions: The outlook for VLBW infants in New Zealand has improved since 1986.

3-Chlorotyrosine as a marker of protein damage by myeloperoxidase in tracheal aspirates from preterm infants: association with adverse respiratory outcome

Oxidative injury is implicated in the development of chronic lung disease in preterm infants with respiratory distress. However, direct evidence of a causal role is limited and the source of reactive oxidants has not been identified. We have previously shown that protein carbonyl levels in tracheal aspirates correlate positively with myeloperoxidase, suggesting that neutrophil oxidants could be the source of this protein injury. We have extended these observations by measuring 3-chlorotyrosine, a specific biomarker of the neutrophil oxidant, hypochlorous acid, in tracheal aspirate proteins (144 samples) from 69 infants with birth weight <1500 g. 3-Chlorotyrosine levels were higher in these infants than in larger infants without respiratory distress (median 83 compared with 13 μmol/mol tyrosine). They correlated strongly with myeloperoxidase activity (correlation coefficient 0.75, p < 0.0001) and to a lesser extent with protein carbonyls. 3-Chlorotyrosine levels (at 1 wk after birth) correlated negatively with birth weight or gestational age. They were significantly higher in infants who developed chronic lung disease (oxygen requirement at 36 wk postmenstrual age) than in those who did not (median 88 and 49 μmol/mol tyrosine, respectively) and correlated with days of supplemental oxygen. 3-Chlorotyrosine was also significantly higher in infants who had lung infection or were Ureaplasma urealyticum positive. Our results are the first evidence that chlorinated proteins are produced in the lungs of premature infants and that they are higher in infection. The higher 3-chlorotyrosine levels in infants who develop chronic lung disease suggest that neutrophil oxidants contribute to the pathology of this disease.

Are we there yet? Bevacizumab therapy for retinopathy of prematurity

The publication of the BEAT-ROP study of bevacizumab (Avastin) treatment for Zone I and II retinopathy of prematurity (ROP) has raised hopes that there might now be a simpler, cheaper and more effective treatment than laser therapy, the current standard of care. However, we would urge caution at this point in time. We review the scientific background to the use of intravitreal anti-vascular endothelial growth factor for ROP, highlight a number of design issues in the BEAT-ROP study and problems with interpretation of the results. For example, no visual outcomes were reported and the study was underpowered to assess longer term safety. Intravitreal bevacizumab leaks into the systemic circulation in animals and adult humans and there are real concerns of potential harm to the developing preterm infant because vascular growth factors play a critical role in organogenesis. We conclude that bevacizumab should be reserved for exceptional circumstances and compassionate use pending further studies. Laser remains the proven effective therapy for first line treatment of all forms of ROP with little systemic morbidity. Neonatology and ophthalmology have an impressive record of conducting collaborative multicentre studies and we urgently need further rigorously designed, adequately powered randomised trials of anti-VEGF agents that evaluate visual outcomes as well as short and long term ocular and systemic safety.

Amino-Terminal proCNP: A Putative Marker of Cartilage Activity in Postnatal Growth

Recent evidence from rodents and humans shows that C-type natriuretic peptide (CNP) plays an essential role in endochondral bone growth. We recently identified a stable product of proCNP, amino-terminal proCNP (NT-proCNP), which unlike CNP is readily measurable in human and ovine plasma. Hypothesizing that plasma NT-proCNP concentrations reflect in part CNP synthesis within growth plates of rapidly growing cartilage, we studied levels of CNP forms in both children and lambs and related these to age, growth velocity, and biochemical markers of bone turnover. Plasma NT-proCNP levels were elevated at birth and fell progressively with age. Significant associations between plasma NT-proCNP and height velocity, alkaline phosphatase, and type 1 collagen C telopeptide were identified in children (aged 5–18 y). In longitudinal animal studies, elevated plasma concentration of NT-proCNP in 1-wk-old lambs fell progressively to mature adult levels at age 27 wk. Plasma NT-proCNP showed a highly significant association with alkaline phosphatase and metacarpal growth velocity. Glucocorticoids, a treatment known to inhibit cartilage proliferation, reduced metacarpal growth elongation in 4-wk-old lambs and markedly lowered circulating NT-proCNP levels during the treatment period. In summary, NT-proCNP levels in blood show a strong association with growth velocity and markers of bone formation and may well serve as a useful marker of growth plate activity in humans and other mammals.

Guidelines for the Management of Extremely Premature Deliveries: A Systematic Review.

BACKGROUND AND OBJECTIVES: Available data on survival rates and outcomes of extremely low gestational age (GA) infants (22–25 weeks’ gestation) display wide variation by country. Whether similar variation is found in statements by national professional bodies is unknown. The objectives were to perform a systematic review of management from scientific and professional organizations for delivery room care of extremely low GA infants. METHODS: We searched Embase, PubMed, and Google Scholar for management guidelines on perinatal care. Countries were included if rated by the United Nations Development Programme’s Human Development Index as “very highly developed.” The primary outcome was rating of recommendations from “comfort care” to “active care.” Secondary outcomes were specifying country-specific survival and considering potential for 3 biases: limitations of GA assessment; bias from different definitions of stillbirths and live births; and bias from the use of different denominators to calculate survival. RESULTS: Of 47 highly developed countries, 34 guidelines from 23 countries and 4 international groups were identified. Of these, 3 did not state management recommendations. Of the remaining 31 guidelines, 21 (68%) supported comfort care at 22 weeks’ gestation, and 20 (65%) supported active care at 25 weeks’ gestation. Between 23 and 24 weeks’ gestation, much greater variation was seen. Seventeen guidelines cited national survival rates. Few guidelines discussed potential biases: limitations in GA (n = 17); definition bias (n = 3); and denominator bias (n = 7). CONCLUSIONS: Although there is a wide variation in recommendations (especially between 23 and 24 weeks’ GA), there is general agreement for comfort care at 22 weeks’ GA and active care at 25 weeks’ GA.