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Background and Objectives: Late-onset sepsis is associated with significant morbidity and mortality among very low birth weight (VLBW) infants. Our objective was to determine risk factors associated with late-onset sepsis and to present temporal trends in overall and pathogen-specific rates., Methods: Population-based study by the Israel Neonatal Network on VLBW infants (≤1500 g) born between 1995 and 2019. Late-onset sepsis required clinical symptoms and microbiologic confirmation. Bivariate and multivariable analyses were performed to identify risk factors. The study period was divided into 4 epochs. Overall and pathogen-specific late-onset sepsis rates for each epoch were compared., Results: The study population comprised 31 612 VLBW infants, of whom 7423 (23.5%) had late-onset sepsis. An increased adjusted risk of late-onset sepsis was associated with gestational age <27 w (odds ratio [OR] 8.90, 95% confidence interval [CI] 7.85-10.09) and delivery room resuscitation (OR 1.43, 95% CI 1.34-1.52) and a decreased adjusted risk among infants born between 2013 and 2019 (OR 0.32, 95% CI 0.29-0.35). Late-onset sepsis rates declined from 29.5% in 1995 to 2000 to 13.0% in 2013 to 2019. Gram-negative and fungal rates decreased in all epochs, whereas gram-positive rates decreased only in the last epoch. The adjusted hazard ratios (95% CI) decreased in the 2013 to 2019 versus 1995 to 2000 epochs and were: all late-onset sepsis, 0.40 (0.37-0.43); gram-positive, 0.47 (0.37-0.59); gram- negative, 0.54 (0.48-0.61); fungal, 0.17 (0.12-0.22)., Conclusions: The strongest risk factor for late-onset sepsis was gestational age <27 w. Over a 25-year period, the pathogen-specific rates of late-onset sepsis among VLBW infants decreased approximately twofold for gram-positive and gram-negative bacterial infections and sixfold for fungal infections., (Copyright © 2023 by the American Academy of Pediatrics.)

Objective: Post-hemorrhagic hydrocephalus (PHH) is associated with morbidity and mortality among very low birth weight (VLBW) infants. This study aimed to determine risk factors for PHH among VLBW infants with peri-intraventricular hemorrhage (PIVH)., Study Design: This is a population-based cohort of VLBW infants of 24 to 28 weeks gestation, born in Israel from 1995 to 2012. Infants in whom a brain ultrasound was not performed before 28 days or with major congenital malformations were excluded. Univariate and multivariable analyses identified risk factors associated with PHH., Results: The final study cohort comprised 2811 infants with grade 2 or higher PIVH, of whom 610 (21.7%) developed PHH. PHH was independently associated with PIVH severity, with bilateral grade 3 PIVH and PIVH grade 3 and contralateral grade 4 having the highest risks (odds ratio (OR) 12.2, 95% confidence interval (CI) 8.56 to 17.4 and OR 13.7, 95% CI 9.4 to 20.1, respectively). Unilateral grade 3 or 4 PIVH's had moderately increased risks of PHH (OR 3.50, 95% CI 2.26 to 5.42 and OR 3.79, 95% CI 2.35 to 6.12, respectively). PHH was independently associated with increasing gestational age (GA) and with neonatal morbidities including patent ductus arteriosus (OR 1.47, 95% CI 1.15 to 1.88 if medically treated and OR 3.01, 95% CI 2.11 to 4.29 if surgically treated), sepsis (OR 1.79, 95% CI 1.44 to 2.22) and necrotizing enterocolitis (OR 1.60, 95% CI 1.18 to 2.17)., Conclusions: Among VLBW infants with PIVH, PHH was independently associated with PIVH severity group, increasing GA and acute neonatal morbidities. Unilateral grade 3 or 4 PIVH was associated with a moderate risk of developing PHH compared with bilateral severe hemorrhages.

Purpose: To identify risk factors for intestinal perforation in very-low-birth-weight (VLBW) infants with necrotizing enterocolitis (NEC)., Methods: Retrospective case-control study over a 10-year period, using univariate and multivariate logistic regression analyses to compare all VLBW infants treated for perforated NEC, with two age and weight-matched groups: infants with non-perforated NEC and infants without NEC., Results: Twenty infants with perforated NEC were matched to 20 infants with non-perforated NEC and 38 infants without NEC. Infants with perforated NEC were younger (p<0.01) and had higher rates of abdominal distention, metabolic acidosis, hyperglycemia and elevated liver enzymes (p<0.05). On logistic regression analysis, abdominal distention was associated with an increased risk of intestinal perforation (OR 39.8, 95% CI 2.71-585) and late onset of NEC (one-day increments) was associated with a decreased risk (OR 0.93, 95% CI 0.87-1.0)., Conclusion: Identification of abdominal distention at an early age in VLBW infants should lead to increased vigilance for signs of perforated NEC and may enable early intervention., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: We sought to assess the independent effect of perinatal factors on the risk for bronchopulmonary dysplasia (BPD) in very-low-birthweight infants., Study Design: This was a population-based observational study. Data were prospectively collected by the Israel Neonatal Network. Multivariable analyses identified independent risk factors for BPD., Results: Of 12,139 infants surviving to a postmenstrual age of 36 weeks, 1663 (13.7%) developed BPD. BPD was independently associated with young maternal age (odds ratio [OR], 1.53), maternal hypertensive disorders (OR, 1.28), antepartum hemorrhage (OR, 1.26), male gender (OR, 1.41), non-Jewish ethnicity (OR, 1.23), birth defects (OR, 1.94), small for gestational age (GA) (OR, 2.65), and delivery room resuscitation (OR, 1.86). Stratified analysis by GA groups showed that postdelivery resuscitation had a more pronounced effect with increasing maturity., Conclusion: Perinatal factors and pregnancy complications were independently associated with development of BPD in very-low-birthweight infants. Most risk factors identified were consistent within GA groups., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Antifungal prophylaxis is increasingly used in very low birth weight (VLBW) infants who are at risk for severe fungal infections. Our objective was to assess the effectiveness of targeted fluconazole prophylaxis for high-risk VLBW infants. A retrospective cohort study with historical controls was performed. During the period 2007-2008, all high-risk VLBW infants (birth weight, ≤1,000 g; gestational age, ≤28 weeks; seven antimicrobial therapy or additional risk factors present) received fluconazole prophylaxis until risk factors were not present. Treated infants were compared to a gestational age- and birth weight-matched untreated cohort. Statistical analyses used univariate and multivariate analyses. The main outcome variable was a breakthrough fungal bloodstream infection (BSI). The prophylaxis cohort of 130 VLBW infants was compared to 319 control infants. The rate of fungal infections was significantly lower in the fluconazole prophylaxis group (1 of 130 vs. 19 of 319, p = 0.016); however, they did not differ in mortality (16.2 vs. 15 %, p = 0.77) or complications of prematurity. Fluconazole prophylaxis was associated with a significant decrease in candidal BSI (odds ratio, 0.05; 95 % confidence interval, 0.005-0.523). Selective vs. nonselective prophylaxis reduced the number of infants treated from 247 to 130. Conclusion Targeted fluconazole prophylaxis in VLBW infants is effective in preventing fungal infections without increasing the risk of BSI among low-risk infants.

This study sought to expand current knowledge on the clinical and epidemiological characteristics of persistent coagulase-negative Staphylococcus (CoNS) bacteremia in very-low-birth-weight (VLBW) infants. Background and disease-related data were collected prospectively on 143 VLBW infants diagnosed with CoNS bacteremia at a pediatric tertiary medical center in 1995-2003. Findings were compared between those with persistent (positive blood cultures for >72 h under appropriate treatment ) and nonpersistent disease. Fifty-eight infants (40.6%) were found to have persistent bacteremia. There were no between-group differences in maternal characteristics, mode of delivery, newborn characteristics, dwell time of central venous and umbilical catheters, complications of prematurity, or mean hospital stay. The persistent bacteremia group had significantly higher rates of hypothermia at presentation (37.9% vs. 17.6%, p < 0.04), creatinine >1.2 mg% on treatment day 7 (13.7% vs. 2.4%, p < 0.02; transient phenomenon), and endocarditis (p < 0.03); one infant had an aortic thrombus. Predominantly breast-fed infants had a higher rate of negative cultures within 72 h of appropriate treatment than predominantly formula-fed infants (60% vs. 19%, p < 0.02). In conclusion, persistence of CoNS bacteremia is common in VLBW infants. Endocarditis should be excluded in all infants with persistent disease. Breast-feeding is associated with a shorter disease duration.

Background: Early-onset sepsis (EOS) is associated with significant morbidity and mortality among infants with a very low birth weight (VLBW); however, there is a sparse amount of complete data on large cohorts., Objective: To evaluate the mortality and major morbidities among VLBW infants with EOS., Methods: This was a population-based observational study. Data were prospectively collected by the Israel Neonatal Network on all VLBW infants born in Israel from 1995 through 2005. Univariate and multivariable analyses were performed to assess the independent association of EOS on morbidity and mortality of VLBW infants., Results: The study cohort included 15 839 infants, of whom 383 (2.4%) developed EOS. EOS was associated with significantly increased odds for mortality (odds ratio [OR]: 2.57 [95% confidence interval (CI): 1.97-3.35]), severe intraventricular hemorrhage (OR: 2.24 [95% CI: 1.67-3.00]), severe retinopathy of prematurity (OR: 2.04 [95% CI: 1.32-3.16]), and bronchopulmonary dysplasia (OR: 1.74 [95% CI: 1.24-2.43]). EOS was associated with an increased risk of death and/or severe neurologic morbidity (OR: 2.92 [95% CI: 2.27-3.80])., Conclusions: Although only 2.4% of VLBW infants had an episode of EOS, these infants were at an approximately threefold excess risk of death or major neurologic morbidities.

Objective: The purpose of this study was to determine the incidence, causative pathogens, and risk factors for early onset sepsis (EOS) among very-low-birthweight (VLBW) infants., Study Design: This was a population based observational study. Data were prospectively collected by the Israel Neonatal Network between 1995 and 2005. Multivariable analyses identified independent risk factors for EOS., Results: EOS developed in 383 of 15,839 infants (2.42%). Fifty-five percent of pathogens isolated were gram-negative bacteria. Lack of prenatal care (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.32-2.86), delivery room resuscitation (OR, 2.49; 95% CI, 1.91-3.24), membrane rupture > 24 hours without amnionitis (OR, 2.10; 95% CI, 1.53-2.88), amnionitis with membrane rupture < 24 hours (OR, 4.28; 95% CI, 2.97-6.16), and amnionitis with membrane rupture >or= 24 hours (OR, 8.15; 95% CI, 5.98-11.10) were associated with EOS, but not antenatal steroids or gestational age., Conclusion: EOS was caused mainly by gram-negative bacteria. Prolonged rupture of membranes and amnionitis have an additive effect on EOS with an above 8-fold excess risk when both were present.

Objectives: To identify risk factors for pneumothorax in very low birth weight infants., Design: Retrospective case-control study., Setting: Neonatal intensive care unit in a pediatric tertiary care center., Patients: Very low birth weight infants., Interventions: All very low birth weight infants with pneumothorax born during the period January 1997 through December 2002 were identified. These infants were matched to infants without pneumothorax for gestational age, birth weight, and gender. Perinatal, neonatal, and treatment variables were collected for all infants., Measurements and Main Results: Very low birth weight infants with pneumothorax were compared with those without. Univariate analysis was performed using the paired Student's t-test for continuous variables and the McNemar test for categorical variables. All variables were entered into a stepwise logistic regression model using a paired case-control design. Statistical significance was defined at p < .05. Seventy-four of 679 very low birth weight infants (10.9%) admitted to the neonatal intensive care unit developed a pneumothorax and were matched to 74 control infants. Multivariate analysis showed that only factors present on the day of pneumothorax were associated with pneumothorax. An increased risk of pneumothorax was associated with maximal, peak inspiratory pressure (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.07, 1.66), minimal Fio2 (OR 2.18, 95% CI 1.14, 4.17), pulmonary hemorrhage (OR 27.5, 95% CI 2.3, 337), and maximal arterial CO2 (OR 1.94, 95% CI 1.13, 3.34), while a decreased risk was associated with maximal positive end-expiratory pressure (OR 0.71, 95% CI 0.56, 0.91)., Conclusions: Pneumothorax is associated with factors present on day of pneumothorax and not with initial ventilation variables or initial severity of lung disease. Decreasing the risk of pneumothorax requires rigorous control of ventilation, including optimizing positive end-expiratory pressure and minimizing peak inspiratory pressure.

Background: Bronchopulmonary dysplasia (BPD) is associated with prolonged hospital length of stay (LOS) and delayed discharge home., Objectives: To evaluate the association between BPD and LOS and to assess the contribution of concomitant major morbidities on LOS among infants with BPD., Study Design: A population-based observational study of very low birth weight (VLBW) infants born from 1995 through 2003. Multivariate analyses, adjusted for perinatal variables, assessed the association between BPD and concomitant morbidities on LOS., Results: Of 10 134 survivors, 1926 (19.0%) had BPD. The adjusted LOS for infants with and without BPD was 84.1 days (95% CI, 82.8, 85.6) and 58.1 days (95% CI, 57.2, 59.0), respectively. Addition of a single concomitant morbidity increased mean LOS by 4 to 13 days., Conclusions: BPD is a major cause of increased length of hospitalization among VLBW infants. Preventive or therapeutic modalities are required to reduce the significant burden of this condition.

Aim: To identify risk factors for delayed discharge home in a population-based cohort of very-low-birthweight (VLBW) infants., Methods: Demographic, pregnancy, perinatal, and neonatal data were collected in a national population-based database on VLBW infants born from 1995 through 2002. Multivariate analysis determined association with delayed discharge (discharge at a postmenstrual age >42 completed weeks)., Results: 882 infants with delayed discharge comprised 9.4% of survivors but accounted for 19.8% of total hospital days utilized until discharge home. Infants with delayed discharge compared to those discharged by term were born at an earlier mean gestational age, at a lower mean birthweight, and had a longer mean hospital stay. Delayed discharge was independently associated with decreasing birthweight (OR 1.25, 95% CI 1.19, 1.31), congenital anomalies (OR 4.80, 95% CI 3.66, 6.28), bronchopulmonary dysplasia (OR 5.88, 95% CI 4.60, 7.57), intraventricular hemorrhage grades 3-4 (OR 1.78, 95% CI 1.34, 2.36), sepsis (OR 1.87, 95% CI 1.54, 2.26), and surgically treated necrotizing enterocolitis (OR 20.20, 95% CI 12.85, 32.03)., Conclusion: VLBW infants with congenital anomalies or severe complications of preterm birth are at increased risk for delayed discharge home. Early identification of these infants may enable interventions aimed at reducing the detrimental effects of prolonged hospitalization and promoting optimal transition from the hospital to the home environment.

Objective: High-grade intraventricular hemorrhage (IVH) is an important cause of severe cognitive and motor neurologic impairment in very low birth weight infants and is associated with a high mortality rate. The risk of IVH is inversely related to gestational age and birth weight. Previous studies have proposed a number of risk factors for IVH; however, lack of adequate matching for gestational age and birth weight may have confounded the results. The purpose of this study was to identify variables that affect the risk of high-grade IVH, using a retrospective and case-control clinical study., Methods: From a cohort of 641 consecutive preterm infants with a birth weight of <1500 g, 36 infants with IVH grade 3 and/or 4 were identified. A control group of 69 infants, closely matched for gestational age and birth weight, was selected. Maternal factors, labor and delivery characteristics, and neonatal parameters were collected in both groups. Results of cranial ultrasound examinations, whether routine or performed in presence of clinical suspicion, were also collected. Univariate analysis and multivariate logistic regression analysis were performed., Results: High fraction of inspired oxygen in the first 24 hours, pneumothorax, fertility treatment (mostly IVF), and early sepsis were associated with an increased risk of IVH. A higher number of suctioning procedures, a higher first hematocrit, and a relatively low arterial pressure of carbon dioxide during the first 24 hours of life were associated with a lower occurrence. In the multivariate logistic regression model, early sepsis (odds ratio [OR]: 8.19; 95% confidence interval [CI]: 1.55-43.1) and fertility treatment (OR: 4.34; 95% CI: 1.42-13.3) were associated with a greater risk of high-grade IVH, whereas for every dose of antenatal steroid treatment there was a lower risk of high-grade IVH (OR: 0.52; 95% CI: 0.30-0.90) and each decrease in a mmHg unit of arterial pressure of carbon dioxide during the first 24 hours was associated with a lower risk of IVH (OR: 0.91; 95% CI: 0.83-0.98). This multivariate model had a sensitivity of 77%, a specificity of 75%, and a positive predictive value of 76%. The area under the curve derived from the receiver operator characteristic plots is 0.82., Conclusions: Our results confirm that the development of IVH is associated with early sepsis and failure to give antenatal steroid treatment. We propose that fertility treatment (and especially IVF) may be a new risk factor, and more research is needed to assess its role.

Objective: Selenium is an essential trace element, known to be important in thyroid metabolism. We speculated that parenteral selenium supplementation is inadequate in preterm infants and may contribute to the development of hypothyroidism., Study Design: Serum selenium and thyroid function were evaluated on day 10 of life in extremely low birth weight infants. Selenium intake provided by parenteral nutrition was prospectively evaluated., Results: Selenium intake was close to the recommended 2 micrograms/kg per day. Serum selenium values were 0.54 +/- 0.13 microM (mean +/- SD, n = 29). Selenium serum levels were low in 26 of 29 infants. In infants with subnormal serum selenium levels, free T4 was transiently low in 10 of 26 infants but was normal in 16 of 26 infants. No significant correlation was found between serum selenium levels and hypothyroidism., Conclusion: Current selenium supplementation guidelines may be inadequate in extremely low birth weight infants. However, selenium deficiency does not seem to play a major role in neonatal hypothyroidism.