Association between Congenital Anomalies and Late-Onset Bacterial Infections in Neonates Admitted to Neonatal Intensive Care Units in Australia and New Zealand: A Population-Based Cohort Study.

INTRODUCTION: Compromised neonatal intensive care unit neonates are at risk of acquiring late-onset infections (late-onset sepsis [LOS]). Neonates born with congenital anomalies (CAs) could have an additional LOS risk. METHODS: Utilising the population-based Australian and New Zealand Neonatal Network data from 2007 to 2017, bacterial LOS rates were determined in very preterm (VPT, <32 week), moderately preterm (MPT, 32-36 weeks), and term (FT, 37-41 weeks) neonates with or without CA. Stratified by major surgery, the association between CA and bacterial LOS was evaluated. RESULTS: Of 102,808 neonates, 37.7%, 32.8%, and 29.6% were born VPT, MPT, and FT, respectively. Among these, 3.4% VPT, 7.5% MPT, and 16.2% FT neonates had CA. VPT neonates had the highest LOS rate (11.1%), compared to MPT (1.8%) and FT (1.8%) neonates. LOS rates were higher in CA neonates than those without (8.2% versus 5.1% adjusted relative risk [aRR] 1.67, 95% confidence interval [CI]: 1.45-1.92). Neonates with surgery had a higher LOS rate (14.2%) than neonates without surgery (4.4%, p < 0.001). Among the neonates without surgery, CA neonates had consistently higher LOS rates than those without CA (VPT 14.3% vs. 9.6% [aRR 1.32, 95% CI: 1.11-1.57]; MPT 4% vs. 0.9% [aRR 4.45, 95% CI: 3.23-6.14]; and FT 2% vs. 0.7% [aRR 2.87, 95% CI: 1.97-4.18]). For the neonates with surgery, CAs were not associated with additional LOS risks. CONCLUSION: Overall, we reported higher rates of LOS in neonates with CA compared to those without CA. Regardless of gestation, CA was associated with an increased LOS risk among non-surgical neonates. Optimisation of infection prevention strategies for CA neonates should be explored. Future studies are needed to evaluate if the infection risk is caused by CA or associated complications.

Variation in clinical practice guidelines for use of palivizumab in preventing severe respiratory syncytial viral (RSV) disease in high-risk infants.

BACKGROUND: Uniformity and compliance with clinical practice guidelines (CPGs) for use of palivizumab in preventing severe respiratory syncytial viral infection in Australian high-risk infants remain unclear. METHODS: An online survey was conducted across the Australian and New Zealand Neonatal Network (ANZNN) to determine clinical practices around palivizumab. A literature search was also performed to identify and compare national and international guidelines. RESULTS: A total of 65 of 422 ANZNN members completed the survey. Respondents included 61 senior medical staff of consultants/staff specialists (78%) and four nursing staff (6%). According to the survey, infants most likely to be recommended palivizumab included preterm infants born <29 weeks gestational age (GA) (30%), children with chronic lung diseases (CLDs) born <32 weeks GA (40%), and with hemodynamically significant heart disease (35%). Many of the respondents (53%) stated that CPGs for palivizumab were developed locally. Literature search identified 20 guidelines (10 international and 10 domestic); 16 (80%) recommended palivizumab use in preterm infants, 16 (80%) recommended use in infants with CLD, 17 (85%) in congenital heart disease and 6 (30%) in bronchopulmonary dysplasia (BPD). Eight (40%) guidelines provided specific recommendations for immunocompromised infants. Canada, Western Australia, and American Academy of Paediatrics provided recommendations for Indigenous children. Frequency and dosage of palivizumab was universal across all CPGs. None of the international guidelines obtained were from low- or middle-income countries. CONCLUSIONS: Standardization of CPGs may improve clinical decision making around use of palivizumab in high-risk infants.

Five-minute Apgar score and outcomes in neonates of 24-28 weeks' gestation.

OBJECTIVES: To assess associations between 5 min Apgar score and mortality and severe neurological injury (SNI) and to report test characteristics in preterm neonates. DESIGN, SETTING AND PATIENTS: Retrospective cohort study of neonates 240 to 286 weeks' gestation born between 2007 and 2016 and admitted to neonatal units in 11 high-income countries. EXPOSURE: 5 min Apgar score. MAIN OUTCOME MEASURES: In-hospital mortality and SNI defined as grade 3 or 4 periventricular/intraventricular haemorrhage or periventricular leukomalacia. Outcome rates were calculated for each Apgar score and compared after adjustment. The diagnostic characteristics and ORs for each value from 0 versus 1-10 to 0-9 versus 10, with 1-point increments were calculated. RESULTS: Among 92 412 included neonates, as 5 min Apgar score increased from 0 to 10, mortality decreased from 60% to 8%. However, no clear increasing or decreasing pattern was identified for SNI. There was an increase in sensitivity and decrease in specificity for both mortality and SNI associated with increasing scores. The Apgar score alone had an area under the curve of 0.64 for predicting mortality, which increased to 0.73 with the addition of gestational age. CONCLUSIONS: In neonates of 24-28 weeks' gestation admitted to neonatal units, higher 5 min Apgar score was associated with lower mortality in a graded manner, while the association with SNI remained relatively constant at all scores. Among survivors, low Apgar scores did not predict SNI.

Outcomes of delivery room resuscitation of bradycardic preterm infants: A retrospective cohort study of randomised trials of high vs low initial oxygen concentration and an individual patient data analysis.

OBJECTIVE: To determine whether hospital mortality (primary outcome) is associated with duration of bradycardia without chest compressions during delivery room (DR) resuscitation in a retrospective cohort study of randomized controlled trials (RCTs) in preterm infants assigned low versus high initial oxygen concentration. METHODS: Medline and EMBASE were searched from 01/01/1990 to 12/01/2020. RCTs of low vs high initial oxygen concentration which recorded serial heart rate (HR) and oxygen saturation (SpO2) during resuscitation of infants <32 weeks gestational age were eligible. Individual patient level data were requested from the authors. Newborns receiving chest compressions in the DR and those with no recorded HR in the first 2 min after birth were excluded. Prolonged bradycardia (PB) was defined as HR < 100 bpm for ≥2 min. Individual patient data analysis and pooled data analysis were conducted. RESULTS: Data were collected from 720 infants in 8 RCTs. Neonates with PB had higher odds of hospital death before [OR 3.8 (95% CI 1.5, 9.3)] and after [OR 1.7 (1.2, 2.5)] adjusting for potential confounders. Bradycardia occurred in 58% infants, while 38% had PB. Infants with bradycardia were more premature and had lower birth weights. The incidence of bradycardia in infants resuscitated with low (≤30%) and high (≥60%) oxygen was similar. Neonates with both, PB and SpO2 < 80% at 5 min after birth had higher odds of hospital mortality. [OR 18.6 (4.3, 79.7)]. CONCLUSION: In preterm infants who did not receive chest compressions in the DR, prolonged bradycardia is associated with hospital mortality.

Inter-center variability in neonatal outcomes of preterm infants: A longitudinal evaluation of 298 neonatal units in 11 countries.

Collaboration and cooperation of clinicians and neonatal units at regional, national, and international levels are key features of many networks or systems that aim to improve neonatal outcomes. Network performance is typically assessed by comparing individual, unit-level outcomes. In this paper, we provide insight into another dimension, i.e., inter-center outcome variation in 10 national/regional neonatal collaborations from 11 high-income countries. We illustrate the use of coefficients of variation for evaluation of mortality and a composite outcome of mortality, severe neurological injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia, as a measure of inter-center variation. These inter-center variation estimates could help to identify areas of opportunities and challenges for each country/region; they also provide "macro"-level evaluations that can be useful for clinicians, administrators, managers and policy makers.

Gestational breast cancer in New South Wales: A population-based linkage study of incidence, management, and outcomes.

BACKGROUND: The incidence of gestational breast cancer (GBC) is increasing in high-income countries. Our study aimed to examine the epidemiology, management and outcomes of women with GBC in New South Wales (NSW), Australia. METHODS: A retrospective cohort study using linked data from three NSW datasets. The study group comprised women giving birth with a first-time diagnosis of GBC while the comparison group comprised women giving birth without any type of cancer. Outcome measures included incidence of GBC, maternal morbidities, obstetric management, neonatal mortality, and preterm birth. RESULTS: Between 1994 and 2013, 122 women with GBC gave birth in NSW (crude incidence 6.8/ 100,000, 95%CI: 5.6-8.0). Women aged ≥35 years had higher odds of GBC (adjusted odds ratio (AOR) 6.09, 95%CI 4.02-9.2) than younger women. Women with GBC were more likely to give birth by labour induction or pre-labour CS compared to women with no cancer (AOR 4.8, 95%CI: 2.96-7.79). Among women who gave birth by labour induction or pre-labour CS, the preterm birth rate was higher for women with GBC than for women with no cancer (52% vs 7%; AOR 17.5, 95%CI: 11.3-27.3). However, among women with GBC, preterm birth rate did not differ significantly by timing of diagnosis or cancer stage. Babies born to women with GBC were more likely to be preterm (AOR 12.93, 95%CI 8.97-18.64), low birthweight (AOR 8.88, 95%CI 5.87-13.43) or admitted to higher care (AOR 3.99, 95%CI 2.76-5.76) than babies born to women with no cancer. CONCLUSION: Women aged ≥35 years are at increased risk of GBC. There is a high rate of preterm birth among women with GBC, which is not associated with timing of diagnosis or cancer stage. Most births followed induction of labour or pre-labour CS, with no major short term neonatal morbidity.

Neonatal outcomes of extremely preterm twins by sex pairing: an international cohort study.

OBJECTIVE: Infant boys have worse outcomes than girls. In twins, the 'male disadvantage' has been reported to extend to female co-twins via a 'masculinising' effect. We studied the association between sex pairing and neonatal outcomes in extremely preterm twins. DESIGN: Retrospective cohort study SETTING: Eleven countries participating in the International Network for Evaluating Outcomes of Neonates. PATIENTS: Liveborn twins admitted at 23-29 weeks' gestation in 2007-2015. MAIN OUTCOME MEASURES: We examined in-hospital mortality, grades 3/4 intraventricular haemorrhage or cystic periventricular leukomalacia (IVH/PVL), bronchopulmonary dysplasia (BPD), retinopathy of prematurity requiring treatment and a composite outcome (mortality or any of the outcomes above). RESULTS: Among 20 924 twins, 38% were from male-male pairs, 32% were from female-female pairs and 30% were sex discordant. We had no information on chorionicity. Girls with a male co-twin had lower odds of mortality, IVH/PVL and the composite outcome than girl-girl pairs (reference group): adjusted OR (aOR) (95% CI) 0.79 (0.68 to 0.92), 0.83 (0.72 to 0.96) and 0.88 (0.79 to 0.98), respectively. Boys with a female co-twin also had lower odds of mortality: aOR 0.86 (0.74 to 0.99). Boys from male-male pairs had highest odds of BPD and composite outcome: aOR 1.38 (1.24 to 1.52) and 1.27 (1.16 to 1.39), respectively. CONCLUSIONS: Sex-related disparities in outcomes exist in extremely preterm twins, with girls having lower risks than boys and opposite-sex pairs having lower risks than same-sex pairs. Our results may help clinicians in assessing risk in this large segment of extremely preterm infants.

Family Rooms in Neonatal Intensive Care Units and Neonatal Outcomes: An International Survey and Linked Cohort Study.

OBJECTIVES: To evaluate the proportion of neonatal intensive care units with facilities supporting parental presence in their infants' rooms throughout the 24-hour day (ie, infant-parent rooms) in high-income countries and to analyze the association of this with outcomes of extremely preterm infants. STUDY DESIGN: In this survey and linked cohort study, we analyzed unit design and facilities for parents in 10 neonatal networks of 11 countries. We compared the composite outcome of mortality or major morbidity, length of stay, and individual morbidities between neonates admitted to units with and without infant-parent rooms by linking survey responses to patient data from 2015 for neonates of less than 29 weeks of gestation. RESULTS: Of 331 units, 13.3% (44/331) provided infant-parent rooms. Patient-level data were available for 4662 infants admitted to 159 units in 7 networks; 28% of the infants were cared for in units with infant-parent rooms. Neonates from units with infant-parent rooms had lower odds of mortality or major morbidity (aOR, 0.76; 95% CI, 0.64-0.89), including lower odds of sepsis and bronchopulmonary dysplasia, than those from units without infant-parent rooms. The adjusted mean length of stay was 3.4 days shorter (95%, CI -4.7 to -3.1) in the units with infant-parent rooms. CONCLUSIONS: The majority of units in high-income countries lack facilities to support parents' presence in their infants' rooms 24 hours per day. The availability vs absence of infant-parent rooms was associated with lower odds of composite outcome of mortality or major morbidity and a shorter length of stay.

Neonatal Outcomes in Very Preterm Infants With Severe Congenital Heart Defects: An International Cohort Study.

Background Very preterm infants are at high risk of death or severe morbidity. The objective was to determine the significance of severe congenital heart defects (CHDs) for these risks. Methods and Results This cohort study included infants from 10 countries born from 2007-2015 at 24 to 31 weeks' gestation with birth weights <1500 g. Severe CHDs were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth (ICD-10) codes and categorized as those compromising systemic output, causing sustained cyanosis, or resulting in congestive heart failure. The primary outcome was in-hospital mortality. Secondary outcomes were neonatal brain injury, necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity. Adjusted and propensity score-matched odds ratios (ORs) were calculated. Analyses were stratified by type of CHD, gestational age, and network. A total of 609 (0.77%) infants had severe CHD and 76 371 without any malformation served as controls. The mean gestational age and birth weight were 27.8 weeks and 1018 g, respectively. The mortality rate was 18.6% in infants with CHD and 8.9% in controls (propensity score-matched OR, 2.30; 95% CI, 1.61-3.27). Severe CHD was not associated with neonatal brain injury, necrotizing enterocolitis, or retinopathy of prematurity, whereas the OR for bronchopulmonary dysplasia increased. Mortality was higher in all types, with the highest propensity score-matched OR (4.96; 95% CI, 2.11-11.7) for CHD causing congestive heart failure. While mortality did not differ between groups at <27 weeks' gestational age, adjusted OR for mortality in infants with CHD increased to 10.9 (95% CI, 5.76-20.70) at 31 weeks' gestational age. Rates of CHD and mortality differed significantly between networks. Conclusions Severe CHD is associated with significantly increased mortality in very preterm infants.

Trends in Outcomes for Neonates Born Very Preterm and Very Low Birth Weight in 11 High-Income Countries.

OBJECTIVE: To evaluate outcome trends of neonates born very preterm in 11 high-income countries participating in the International Network for Evaluating Outcomes of neonates. STUDY DESIGN: In a retrospective cohort study, we included 154 233 neonates admitted to 529 neonatal units between January 1, 2007, and December 31, 2015, at 240/7 to 316/7 weeks of gestational age and birth weight <1500 g. Composite outcomes were in-hospital mortality or any of severe neurologic injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia (BPD); and same composite outcome excluding BPD. Secondary outcomes were mortality and individual morbidities. For each country, annual outcome trends and adjusted relative risks comparing epoch 2 (2012-2015) to epoch 1 (2007-2011) were analyzed. RESULTS: For composite outcome including BPD, the trend decreased in Canada and Israel but increased in Australia and New Zealand, Japan, Spain, Sweden, and the United Kingdom. For composite outcome excluding BPD, the trend decreased in all countries except Spain, Sweden, Tuscany, and the United Kingdom. The risk of composite outcome was lower in epoch 2 than epoch 1 in Canada (adjusted relative risks 0.78; 95% CI 0.74-0.82) only. The risk of composite outcome excluding BPD was significantly lower in epoch 2 compared with epoch 1 in Australia and New Zealand, Canada, Finland, Japan, and Switzerland. Mortality rates reduced in most countries in epoch 2. BPD rates increased significantly in all countries except Canada, Israel, Finland, and Tuscany. CONCLUSIONS: In most countries, mortality decreased whereas BPD increased for neonates born very preterm.

Preventive strategies and factors associated with surgically treated necrotising enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis.

OBJECTIVES: To compare necrotising enterocolitis (NEC) prevention practices and NEC associated factors between units from eight countries of the International Network for Evaluation of Outcomes of Neonates, and to assess their association with surgical NEC rates. DESIGN: Prospective unit-level survey combined with retrospective cohort study. SETTING: Neonatal intensive care units in Australia/New Zealand, Canada, Finland, Israel, Spain, Sweden, Switzerland and Tuscany (Italy). PATIENTS: Extremely preterm infants born between 240 to 286 weeks' gestation, with birth weights<1500 g, and admitted between 2014-2015. EXPOSURES: NEC prevention practices (probiotics, feeding, donor milk) using responses of an on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and sepsis) using cohort data. OUTCOME MEASURES: Surgical NEC rates and death following NEC using cohort data. RESULTS: The survey response rate was 91% (153 units). Both probiotic provision and donor milk availability varied between 0%-100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to link survey results and cohort outcomes, revealed similar baseline characteristics but considerable differences in factors associated with NEC between networks. 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4%-8.4% between networks. Standardised ratios for surgical NEC were lower for Australia/New Zealand, higher for Spain, and comparable for the remaining six networks. CONCLUSIONS: The variation in implementation of NEC prevention practices and in factors associated with NEC in literature could not be associated with the variation in surgical NEC incidence. This corroborates the current lack of consensus surrounding the use of preventive strategies for NEC and emphasises the need for research.

In utero exposure to breast cancer treatment: a population-based perinatal outcome study.

Chemotherapy during a viable pregnancy may be associated with adverse perinatal outcomes. We conducted a prospective cohort study to examine the perinatal outcomes of babies born following in utero exposure to chemotherapy in Australia and New Zealand. Over 18 months we identified 24 births, of >400 g and/or >20-weeks' gestation, to women diagnosed with breast cancer in the first or second trimesters. Eighteen babies were exposed in utero to chemotherapy. Chemotherapy commenced at a median of 20 weeks gestation, for a mean duration of 10 weeks. Twelve exposed infants were born preterm with 11 by induced labour or pre-labour caesarean section. There were no perinatal deaths or congenital malformations. Our findings show that breast cancer diagnosed during mid-pregnancy is often treated with chemotherapy. Other than induced preterm births, there were no serious adverse perinatal outcomes.

Neonatal Outcomes of Very Preterm or Very Low Birth Weight Triplets.

OBJECTIVES: To compare the neonatal outcomes of very preterm triplets with those of matched singletons using a large international cohort. METHODS: A retrospective matched-cohort study of preterm triplets and singletons born between 2007 and 2013 in the International Network for Evaluation of Outcomes in neonates database countries and matched by gestational age, sex, and country of birth was conducted. The primary outcome was a composite of mortality or severe neonatal morbidity (severe neurologic injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia). Unadjusted and adjusted odds ratios with 95% confidence intervals (CIs) were calculated for model 1 (maternal hypertension and birth weight z score) and model 2 (variables in model 1, antenatal steroids, and mode of birth). Models were fitted with generalizing estimating equations and random effects modeling to account for clustering. RESULTS: A total of 6079 triplets of 24 to 32 weeks' gestation or 500 to 1499 g birth weight and 18 232 matched singletons were included. There was no difference in the primary outcome between triplets and singletons (23.4% vs 24.0%, adjusted odds ratio: 0.91, 95% CI: 0.83-1.01 for model 1 and 1.00, 95% CI: 0.90-1.11 for model 2). Rates of severe neonatal morbidities did not differ significantly between triplets and singletons. The results were also similar for a subsample of the cohort (1648 triplets and 4944 matched singletons) born at 24 to 28 weeks' gestation. CONCLUSIONS: No significant differences were identified in mortality or major neonatal morbidities between triplets who were very low birth weight or very preterm and matched singletons.

Hypertriglyceridaemia in extremely preterm infants receiving parenteral lipid emulsions.

BACKGROUND: Lipid emulsions (LE) are routinely administered as part of parenteral nutrition in neonates. There is a wide variation in clinical practice of plasma triglyceride monitoring during LE therapy. Our aim was to evaluate the incidence of hypertriglyceridaemia (Plasma triglyceride > 2.8 mmol/L) and its association with mortality and major morbidities in extremely preterm infants on parenteral nutrition. METHODS: A retrospective review of 195 infants < 29 weeks gestation. Lipid emulsion was commenced at 1 g/kg/day soon after birth and increased by 1 g/kg daily up to 3 g/kg/day and continued until the infant was on at least 120 ml/kg/day of enteral feeds. Plasma triglyceride concentrations were measured at each increment and the lipid emulsion dosage was adjusted to keep plasma triglyceride concentrations ≤2.8 mmol/L. RESULTS: Hypertriglyceridemia was noted in 38 neonates (32.5% in 23-25 weeks and 16.1% in 26-28 weeks). Severe hypertriglyceridemia (> 4.5 mmol/L) was noted in 11 infants (10.0% in 23-25 weeks and 4.5% in 26-28 weeks). Hypertriglyceridemia was associated with an increase in mortality (unadjusted OR 3.5; 95% CI 1.13-10.76; 0.033) and severe retinopathy of prematurity (unadjusted OR 4.06; 95% CI 1.73-9.59; 0.002) on univariate analysis. However, this association became non-significant in multivariate analysis with adjustment for gestation and birthweight. CONCLUSIONS: Hypertriglyceridemia is common in extremely preterm infants receiving parenteral lipid emulsions. Regular monitoring and prompt adjustment of lipid intake in the presence of hypertriglyceridemia, minimising the length of exposure to hypertriglyceridemia, may mitigate potential consequences.

Respiratory Management of Extremely Preterm Infants: An International Survey.

BACKGROUND: There are significant international variations in chronic lung disease rates among very preterm infants yet there is little data on international variations in respiratory strategies. OBJECTIVE: To evaluate practice variations in the respiratory management of extremely preterm infants born at < 29 weeks' gestational age (GA) among 10 neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of Neonates collaboration. METHODS: A web-based survey was sent to the representatives of 390 neonatal intensive care units from Australia/New Zealand, Canada, Finland, Illinois (USA), Israel, Japan, Spain, Sweden, Switzerland, and Tuscany (Italy). Responses were based on practices in 2015. RESULTS: Overall, 321 of the 390 units responded (82%). The majority of units within networks (40-92%) mechanically ventilate infants born at 23-24 weeks' GA on continuous positive airway pressure (CPAP) with 30-39% oxygen in respiratory distress within 48 h after birth, but the proportion of units that offer mechanical ventilation for infants born at 25-26 weeks' GA at similar settings varied significantly (20-85% of units within networks). The most common respiratory strategy for infants born at 27-28 weeks' GA on CPAP with 30-39% oxygen with respiratory distress within 48 h after birth used by units also varied significantly among networks: mechanical ventilation (0-60%), CPAP (3-82%), intubation and surfactant administration with immediate extubation (0-75%), and less invasive surfactant administration (0-68%). CONCLUSIONS: There are marked variations but also similarities in respiratory management of extremely preterm infants between networks. Further collaboration and exploration is needed to better understand the association of these variations in practice with pulmonary outcomes.

Antenatal gastrointestinal anomalies in neonates subsequently found to have alveolar capillary dysplasia.

Alveolar capillary dysplasia (ACD) is a rare condition with variable presentation and clinical course. Clinicians should consider this diagnosis in neonates presenting with nonlethal congenital gastrointestinal malformation, a period of well-being after birth then unremitting hypoxemia and refractory pulmonary hypertension. Lung biopsy and FOXF1 gene testing may help in diagnosis.

Age-dependent variation of fecal calprotectin in cystic fibrosis and healthy children.

BACKGROUND: Fecal calprotectin may be used as a non-invasive method to assess the effect of novel therapies on the gut in cystic fibrosis (CF). METHOD: Stools from CF patients and healthy controls (HC) (0-10years old) were prospectively collected for evaluation of temporal trends. RESULTS: 130 CF samples (64 subjects) and 114 HC samples (101 subjects) were collected. Overall, fecal calprotectin levels were different in CF patients and HC from 0 to 10years (P=0.0002). Fecal calprotectin in CF was significantly lower than HC from 0 to 1years (P=0.03) and demonstrated an upward trajectory until 4years. From >4 to 10years calprotectin was consistently higher in CF patients compared with HC (P=0.007). CONCLUSIONS: Fecal calprotectin levels in children with CF and HC were age-dependent and had distinct trajectories. Careful interpretation of calprotectin is required if used in drug trials for CF, particularly in children less than 4years old.

Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants.

BACKGROUND: Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS: We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS: A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .).

International variations and trends in the treatment for retinopathy of prematurity.

OBJECTIVE: To compare the rates of retinopathy of prematurity (ROP) and treatment of ROP by laser or intravitreal anti-vascular endothelial growth factor among preterm neonates from high-income countries participating in the International Network for Evaluating Outcomes (iNeo) of neonates. METHODS: A retrospective cohort study was conducted on extremely preterm infants weighing <1500 g at 240 to 276 weeks' gestation who were admitted to neonatal units in Australia/New Zealand, Canada, Finland, Israel, Japan, Spain, Sweden, Switzerland, Tuscany (Italy) and the UK between 2007 and 2013. Pairwise comparisons of ROP treatment in survivors between countries were evaluated by Poisson and multivariable logistic regression analyses after adjustment for confounders. A composite outcome of death or ROP treatment was compared between countries using logistic regression and standardised ratios. RESULTS: Of 48 087 infants included in the analysis, 81.8% survived to 32 weeks postmenstrual age, and 95% of survivors were screened for ROP. Rates of any ROP ranged from 25.2% to 91.0% in Switzerland and Japan, respectively, among those examined. The overall rate of those receiving treatment was 24.9%, which varied from 4.3% to 30.4%. Adjusted risk ratios for ROP treatment were lower for Switzerland in all pairwise comparisons, whereas Japan displayed significantly higher ratios. Comparisons of the composite outcome between countries revealed similar, but less marked differences. CONCLUSIONS: Rates of any ROP and ROP treatment varied significantly between iNeo members, while an overall decline in ROP treatment was observed during the study period. It is unclear whether these variations represent differences in care practices, diagnosis and/or treatment thresholds.

Morbidity and mortality among very preterm singletons following fertility treatment in Australia and New Zealand, a population cohort study.

BACKGROUND: Due to high rates of multiple birth and preterm birth following fertility treatment, the rates of mortality and morbidity among births following fertility treatment were higher than those conceived spontaneously. However, it is unclear whether the rates of adverse neonatal outcomes remain higher for very preterm (<32 weeks gestational age) singletons born after fertility treatment. This study aims to compare adverse neonatal outcomes among very preterm singletons born after fertility treatment including assisted reproductive technology (ART) hyper-ovulution (HO) and artificial insemination (AI) to those following spontaneous conception. METHODS: The population cohort study included 24069 liveborn very preterm singletons who were admitted to Neonatal Intensive Care Unit (NICU) in Australia and New Zealand from 2000 to 2010. The in-hospital neonatal mortality and morbidity among 21753 liveborn very preterm singletons were compared by maternal mode of conceptions: spontaneous conception, HO, ART and AI. Univariate and multivariate binary logistic regression analysis was used to examine the association between mode of conception and various outcome factors. Odds ratio (OR) and adjusted odds ratio (AOR) and 95% confidence interval (CI) were calculated. RESULTS: The rate of small for gestational age was significantly higher in HO group (AOR 1.52, 95% CI 1.02-2.67) and AI group (AOR 2.98, 95% CI 1.53-5.81) than spontaneous group. The rate of birth defect was significantly higher in ART group (AOR 1.71, 95% CI 1.36-2.16) and AI group (AOR 3.01, 95% CI 1.47-6.19) compared to spontaneous group. Singletons following ART had 43% increased odds of necrotizing enterocolitis (AOR 1.43, 95% CI 1.04-1.97) and 71% increased odds of major surgery (AOR 1.71, 95% CI 1.37-2.13) compared to singletons conceived spontaneously. Other birth and NICU outcomes were not different among the comparison groups. CONCLUSIONS: Compared to the spontaneous conception group, risk of congenital abnormality significantly increases after ART and AI; the risk of morbidities increases after ART, HO and AI. Preconception planning should include comprehensive information about the benefits and risks of fertility treatment on the neonatal outcomes.