An international comparison of retinopathy of prematurity grading performance within the Benefits of Oxygen Saturation Targeting II trials.

PurposeTo investigate whether the observed international differences in retinopathy of prematurity (ROP) treatment rates within the Benefits of Oxygen Saturation Targeting (BOOST) II trials might have been caused by international variation in ROP disease grading.MethodsGroups of BOOST II trial ophthalmologists in UK, Australia, and New Zealand (ANZ), and an international reference group (INT) used a web based system to grade a selection of RetCam images of ROP acquired during the BOOST II UK trial. Rates of decisions to treat, plus disease grading, ROP stage grading, ROP zone grading, inter-observer variation within groups and intra-observer variation within groups were measured.ResultsForty-two eye examinations were graded. UK ophthalmologists diagnosed treat-requiring ROP more frequently than ANZ ophthalmologists, 13.9 (3.49) compared to 9.4 (4.46) eye examinations, P=0.038. UK ophthalmologists diagnosed plus disease more frequently than ANZ ophthalmologists, 14.1 (6.23) compared to 8.5 (3.24) eye examinations, P=0.021. ANZ ophthalmologists diagnosed stage 2 ROP more frequently than UK ophthalmologists, 20.2 (5.8) compared to 12.7 (7.1) eye examinations, P=0.026. There were no other significant differences in the grading of ROP stage or zone. Inter-observer variation was higher within the UK group than within the ANZ group. Intra-observer variation was low in both groups.ConclusionsWe have found evidence of international variation in the diagnosis of treatment-requiring ROP. Improved standardisation of the diagnosis of treatment-requiring ROP is required. Measures might include improved training in the grading of ROP, using an international approach, and further development of ROP image analysis software.

Perinatal health services organization for preterm births: a multinational comparison.

OBJECTIVE: To explore population characteristics, organization of health services and comparability of available information for very low birth weight or very preterm neonates born before 32 weeks' gestation in 11 high-income countries contributing data to the International Network for Evaluating Outcomes of Neonates (iNeo). STUDY DESIGN: We obtained population characteristics from public domain sources, conducted a survey of organization of maternal and neonatal health services and evaluated the comparability of data contributed to the iNeo collaboration from Australia, Canada, Finland, Israel, Italy, Japan, New Zealand, Spain, Sweden, Switzerland and UK. RESULTS: All countries have nationally funded maternal/neonatal health care with >90% of women receiving prenatal care. Preterm birth rate, maternal age, and neonatal and infant mortality rates were relatively similar across countries. Most (50 to >95%) between-hospital transports of neonates born at non-tertiary units were conducted by designated transport teams; 72% (8/11 countries) had designated transfer and 63% (7/11 countries) mandate the presence of a physician. The capacity of 'step-down' units varied between countries, with capacity for respiratory care available in <10% to >75% of units. Heterogeneity in data collection processes for benchmarking and quality improvement activities were identified. CONCLUSIONS: Comparability of healthcare outcomes for very preterm low birth weight neonates between countries requires an evaluation of differences in population coverage, healthcare services and meta-data.

Hypertensive disorders of pregnancy and outcomes of preterm infants of 24 to 28 weeks' gestation.

OBJECTIVE: To examine the relationship between hypertensive disorders of pregnancy (HDPs) and mortality and major morbidities in preterm neonates born at 24 to 28 weeks of gestation. STUDY DESIGN: Using an international cohort, we retrospectively studied 27 846 preterm neonates born at 240 to 286 weeks of gestation during 2007 to 2010 from 6 national neonatal databases. The incidence of HDP was compared across countries, and multivariable logistic regression analyses were conducted to examine the association of HDP and neonatal outcomes including mortality to discharge, bronchopulmonary dysplasia, severe brain injury, necrotizing enterocolitis and treated retinopathy of prematurity. RESULTS: The incidence of HDP in the entire cohort was 13% (range 11 to 16% across countries). HDP was associated with reduced odds of mortality (adjusted odds ratio (aOR) 0.77; 95% confidence interval (CI) 0.67 to 0.88), severe brain injury (aOR 0.74; 95% CI 0.62 to 0.89) and treated retinopathy (aOR 0.82; 95% CI 0.70 to 0.96), but increased odds of bronchopulmonary dysplasia (aOR 1.16; 95% CI 1.05 to 1.27). CONCLUSIONS: In comparison with neonates born to mothers without HDP, neonates of HDP mothers had lower odds of mortality, severe brain injury and treated retinopathy, but higher odds of bronchopulmonary dysplasia. The impact of maternal HDP on newborn outcomes was inconsistent across outcomes and among countries; therefore, further international collaboration to standardize terminology, case definition and data capture is warranted.

Neonatal renal vein thrombosis and prothrombotic risk.

UNLABELLED: A case of extensive deep venous thrombosis in a four a day old infant was presented. Unusually this patient was shown to be heterozygous for three thrombophilia genes; Factor V Leiden, prothrombin and antithrombin gene mutations, the latter being novel. CONCLUSION: There are no randomized controlled trials to guide management in deep venous thrombosis in the newborn but knowledge of the prothrombotic risk factors may help direct treatment.

Vitamin A supplementation to prevent mortality and short and long-term morbidity in very low birthweight infants.

BACKGROUND: Vitamin A is necessary for normal lung growth and the ongoing integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with increased risk of developing chronic lung disease. Several studies have been undertaken to assess whether vitamin A supplementation beyond that routinely given in multivitamin preparations can reduce the incidence of this outcome. OBJECTIVES: To assess the benefit and risk of supplementation with vitamin A in very low birthweight infants. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE up to November 2006, Cochrane Central Register of Controlled Trials Register (CENTRAL, The Cochrane Library, Issue 4, 2006), and Science Citation Index. The reference lists of relevant trials, recent issues of paediatric and nutrition journals, abstracts and proceedings from relevant conferences in the English language were hand searched. SELECTION CRITERIA: Randomised controlled trials which compared the effects of supplemental vitamin A with standard vitamin A regimes in infants with birthweight

Variation in rates of severe retinopathy of prematurity among neonatal intensive care units in the Australian and New Zealand Neonatal Network.

AIM: To analyse variations in rates of severe retinopathy of prematurity (ROP) among neonatal intensive care units (NICUs) in the Australian and New Zealand Neonatal Network (ANZNN), adjusting for sampling variability and for case mix. METHODS: 25 NICUs were included in the study of 2105 infants born at less than 29 weeks in 1998 and 1999, who survived to 36 weeks post-menstrual age and were examined for ROP. The observed NICU rates of severe ROP were adjusted for case mix using logistic regression on gestation, weight for gestational age and sex, and for sampling variability using shrinkage estimates. The corrected rate in the best 20% of NICUs was identified and NICU variations in rates were compared with those in 2000-1. RESULTS: The overall (unadjusted) rate of severe ROP in the NICUs was 9.6% (interquartile range 5.4-12.8%). After adjusting for both case mix and sampling variability there remained significant variation among the NICUs. 20% of NICUs had a rate of severe ROP

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.

Vitamin C supplementation in very preterm infants: a randomised controlled trial.

OBJECTIVE: To determine whether regulating vitamin C (ascorbic acid: AA) intake to achieve higher or lower plasma concentrations was associated with improved clinical outcome. DESIGN: A double blind, randomised controlled trial. SETTING: Neonatal intensive care unit at Christchurch Women's Hospital. PATIENTS: Infants with birth weight <1500 g or gestation <32 weeks, admitted to the unit within 48 hours of birth. INTERVENTION: Infants were randomised to one of three protocols with regard to AA supplementation for the first 28 days of life: group LL received low supplementation throughout; group LH received low until day 10 and then high: group HH received high throughout. MAIN OUTCOME MEASURES: Primary outcome measures were oxygen requirement at 28 days and 36 weeks postmenstrual age, total days supplemental oxygen, and retinopathy of prematurity. AA concentrations were measured at study entry (day 2), and days 10, 21, and 28. RESULTS: A total of 119 infants were enrolled over 24 months (mean gestation 28.4 weeks; birth weight 1161 g). Six infants died, and these had significantly higher AA concentrations before randomisation than surviving infants (116 micromol/l (95% confidence interval 90 to 142) v 51 micromol/l (45 to 58), p<0.0001). There were no significant differences in primary outcomes between the groups. However, the proportion of surviving infants with an oxygen requirement at 36 weeks postmenstrual age in group HH (19%) was half that in group LL (41%) (p=0.06). CONCLUSIONS: In a randomised controlled trial, no significant benefits or harmful effects were associated with treatment allocation to higher or lower AA supplementation throughout the first 28 days of life.

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.

Outcomes for high risk New Zealand newborn infants in 1998-1999: a population based, national study.

OBJECTIVE: To determine short term morbidity and mortality outcomes, provision of care, and treatments for a national cohort of high risk infants born in 1998-1999 and admitted to New Zealand neonatal intensive care units (NICUs). SETTING: All level III (six) and level II (13) NICUs in New Zealand. METHODS: Prospective audit by the Australian and New Zealand Neonatal Network (ANZNN) of all infants defined as "high risk" (born at < 32 weeks gestation or < 1500 g birth weight, or received assisted ventilation for four hours or more, or had major surgery). Data were collected from birth until discharge home or death. RESULTS: There were 3368 high risk infants (3.0% of all live births), comprising 1241 (37%) < 32 weeks gestation, 1084 (32%) < 1500 g, 3156 (94%) who received assisted ventilation, and 243 (7%) who received major surgery (categories overlap). Most infants (87%) received some care in tertiary hospitals, and 13% were cared for entirely in non-tertiary hospitals. Survival was 91% for infants < 32 weeks gestation, 97% for infants > or = 32 weeks gestation who received assisted ventilation, and 92% for infants > or = 32 weeks gestation who had major surgery. The proportion of very preterm infants who survived free of early major morbidity was 11%, 28%, 53%, 81%, and 90% for infants born at < 24, 24-25, 26-27, 28-29, and 30-31 weeks gestation respectively. CONCLUSIONS: These unique population based national data provide contemporary information on the care and early morbidity and mortality outcomes for all high risk infants, whether cared for in hospitals with level III or level II NICUs.

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.

Early-onset neonatal group B streptococcal infections in New Zealand 1998-1999.

OBJECTIVE: To determine in New Zealand infants the attack rates, risk factors, preventive policies, strain serotype and antibiotic susceptibilities of early-onset neonatal group B streptococcus (GBS) infection. METHOD: A 2-year prospective active surveillance study was conducted in New Zealand's 19 neonatal units. Cases had to present within 48 h of delivery, be unwell, possess abnormal haematological indices and have GBS isolated from sterile sites. RESULTS: Of the 112 402 infants born in New Zealand during 1998-1999, 56 had early-onset GBS infection, an attack rate of 0.5 per 1000 live births (95% confidence interval [CI] 0.38, 0.65). Seven had meningitis and there was one death (case fatality rate of 1.8%; upper 95% CI 9.5%). Univariate analysis identified young maternal age, parity, preterm labour, prolonged membrane rupture, maternal fever and assisted delivery as risk factors. Preventive policies for GBS were reported by 14 (74%) obstetric centres associated with neonatal units. Of the 56 cases, five (9%) were born to mothers receiving intrapartum antibiotics, 32 (57%) had mothers with risk factors but were not treated with antibiotics, and 19 (34%) were born to mothers without identifiable risk factors for GBS prevention. Serotypes Ia and III predominated, while two isolates were resistant to erythromycin and/or clindamycin. CONCLUSIONS: Rates of early-onset GBS infection are similar to other countries following the introduction of prevention policies. Further reductions are possible with full implementation of these guidelines. Meanwhile, emergence of antibiotic resistance complicates the management of women with penicillin allergy. Vaccine development therefore remains a priority.

Vitamin A supplementation for preventing morbidity and mortality in very low birthweight infants.

BACKGROUND: Vitamin A is necessary for normal lung growth and the ongoing integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with increased risk of developing chronic lung disease. Several studies have been undertaken to assess whether vitamin A supplementation beyond that routinely given in multivitamin preparations can reduce the incidence of this outcome. OBJECTIVES: To assess the benefit of supplementation with vitamin A in very low birthweight infants. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE up to June 2002, Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2002), and Science Citation Index. The reference lists of relevant trials, recent issues of paediatric and nutrition journals, abstracts and proceedings from relevant conferences in the English language were hand searched. SELECTION CRITERIA: Randomised controlled trials which compared the effects of supplemental vitamin A with standard vitamin A regimes in infants with birthweight

An extended interval dosing method for gentamicin in neonates.

Traditional gentamicin dosing every 8-24 h depending on age and weight in neonates does not provide the ideal concentration-time profile to both optimize the concentration-dependent killing by aminoglycosides and minimize toxicity. Fifty-three neonates were audited prospectively while receiving gentamicin 2.5 mg/kg every 8-24 h, aiming for peak concentrations (Cmax) of 6-10 mg/L and trough concentrations (Cmin) <2 mg/L. After the first dose, the mean (+/- s.d.) Cmax was 5.5 +/- 0.7 mg/L with sub-therapeutic concentrations (<6 mg/L) in 62% of patients, while the mean Cmin was >2 mg/L in 15% of the neonates. After the third dose the Cmax was 7.5 +/- 1.5 mg/L, with 17% <6 mg/L, whereas the mean Cmin was 2.2 +/- 1.1 mg/L with 49% of values >2 mg/L. An extended interval dosing method (24, 36 and 48 h) for infant weights of 0.75-5 kg was developed by simulation, and audited prospectively in 51 neonates. Prospective analysis of the extended interval dosing method showed a mean Cmax after the first dose of 13.1 +/- 3.6 mg/L, while the mean Cmin was 0.7 +/- 0.6 mg/L. Seventy-eight per cent had Cmax of >10 mg/L after the first dose. The mean area under the concentration versus time curve AUC0-24 was 93 mg*h/L (target = 100 mg*h/L). The extended interval dosing achieved higher Cmax values while ensuring that overall exposure per 24 h was acceptable. Prospective testing of the method demonstrated good predictive ability.

Vitamin C is reduced in human milk after storage.

UNLABELLED: In order to establish how cold storage of human milk affects levels of bioavailable vitamin C, 11 samples were stored for 24 h in the refrigerator or up to 2 mo in the freezer. Total vitamin C levels decreased on average by one-third in the refrigerator or after I mo of freezing, with wide variations between individuals (6 to 76% and 3 to 100%, respectively). After 2 mo of freezing, the average decrease was two-thirds (7-100%). CONCLUSION: We recommend a change in human milk storage practices, to under 24 h in a refrigerator or under 1 mo in a freezer. Alternatively, vitamin C supplementation may be considered.

Limiting light-induced lipid peroxidation and vitamin loss in infant parenteral nutrition by adding multivitamin preparations to Intralipid.

UNLABELLED: Parenteral lipids are susceptible to light-induced peroxidation, particularly under phototherapy. Ascorbic acid is protective. The aim of this study was to investigate whether dark delivery tubing and/or coadministration of multivitamin preparations could prevent peroxidation of Intralipid without undue vitamin loss. In experiments carried out on the benchtop, lipid peroxidation occurred in ambient light and was more extensive under phototherapy. Dark tubing decreased peroxide formation, but only by about 65%. In simulated clinical conditions in which solutions were pumped through standard clear or dark minibore plastic tubing. Intralipid accumulated lipid peroxides as measured by the FOX assay (280 microM) or as triglyceride hydroperoxides (52 microM). Multivitamin preparations (MVIP or Soluvit/Vitlipid) inhibited peroxide formation almost completely, and were fully protective when used with dark tubing. There was loss of riboflavin (65% from Soluvit and 35% from MVIP) in clear tubing but this was decreased to 18% and 11%, respectively, in dark tubing. Ascorbate loss was 20% (MVIP) and 50% (Soluvit) and only slightly less in dark tubing. Ascorbate loss was also seen in the absence of Intralipid and is due to riboflavin-induced photo-oxidation. CONCLUSION: Multivitamin preparations protect Intralipid against light-induced formation of lipid hydroperoxides, and administering multivitamins with Intralipid via dark delivery tubing provides a practical way of preventing peroxidation of the lipid while limiting vitamin loss. This procedure should be considered for routine use as well as with phototherapy.

Lipid peroxide and hydrogen peroxide formation in parenteral nutrition solutions containing multivitamins.

BACKGROUND: Infusion of parenteral solutions containing peroxides may be detrimental to premature infants. Intralipid frequently contains lipid peroxides and undergoes further peroxidation when exposed to light. Peroxidation is inhibited by ascorbate, and we have proposed that administration of peroxides could be minimized by mixing multivitamins with the Intralipid. In contrast, others have reported that multivitamins generate peroxides and have advised against mixing them with lipid. Our objective was to assess whether light-dependent reactions in parenteral solutions containing MVI Pediatric (MVIP) generate hydrogen peroxide and establish whether addition of multivitamins to Intralipid is beneficial or detrimental. RESULTS: We were unable to make accurate peroxide measurements in MVIP using the ferrous oxidation of xylenol orange (FOX) assay, even though others have used it for this purpose, because of interference by ascorbate. Therefore oxygen release on adding catalase was measured to assay for hydrogen peroxide. Freshly reconstituted solutions contained 250 to 500 micromol/L hydrogen peroxide, and this increased dramatically in ambient light. This is presumably due to light-dependent, riboflavin-catalyzed reduction of oxygen by ascorbic acid. The rate of peroxide generation was less for MVIP diluted in Intralipid than in dextrose solution. CONCLUSIONS: Taken together with our previous findings, we conclude that multivitamins protect Intralipid against lipid peroxidation, but light-dependent hydrogen peroxide production and ascorbate loss occur. These latter changes are less than for multivitamins in other total parenteral nutrition solutions, so there is an advantage in mixing multivitamins with Intralipid. However, prevention of ascorbate loss and hydrogen peroxide formation in any multivitamin solution requires protection of the delivery system from light.