C. Michael Cotten

Early CPAP versus surfactant in extremely preterm infants

BACKGROUND There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

Target ranges of oxygen saturation in extremely preterm infants.

BACKGROUND Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. METHODS We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. RESULTS The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events. CONCLUSIONS A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)

Prolonged Duration of Initial Empirical Antibiotic Treatment Is Associated With Increased Rates of Necrotizing Enterocolitis and Death for Extremely Low Birth Weight Infants

OBJECTIVES. Our objectives were to identify factors associated with the duration of the first antibiotic course initiated in the first 3 postnatal days and to assess associations between the duration of the initial antibiotic course and subsequent necrotizing enterocolitis or death in extremely low birth weight infants with sterile initial postnatal culture results. METHODS. We conducted a retrospective cohort analysis of extremely low birth weight infants admitted to tertiary centers in 1998–2001. We defined initial empirical antibiotic treatment duration as continuous days of antibiotic therapy started in the first 3 postnatal days with sterile culture results. We used descriptive statistics to characterize center practice, bivariate analyses to identify factors associated with prolonged empirical antibiotic therapy (≥5 days), and multivariate analyses to evaluate associations between therapy duration, prolonged empirical therapy, and subsequent necrotizing enterocolitis or death. RESULTS. Of 5693 extremely low birth weight infants admitted to 19 centers, 4039 (71%) survived >5 days, received initial empirical antibiotic treatment, and had sterile initial culture results through the first 3 postnatal days. The median therapy duration was 5 days (range: 1–36 days); 2147 infants (53%) received prolonged empirical therapy (center range: 27%–85%). Infants who received prolonged therapy were less mature, had lower Apgar scores, and were more likely to be black. In multivariate analyses adjusted for these factors and center, prolonged therapy was associated with increased odds of necrotizing enterocolitis or death and of death. Each empirical treatment day was associated with increased odds of death, necrotizing enterocolitis, and the composite measure of necrotizing enterocolitis or death. CONCLUSION. Prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing enterocolitis or death and should be used with caution.

Association of H2-Blocker Therapy and Higher Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants

OBJECTIVE. We sought to determine if an association exists between the use of histamine-2 receptor (H2) blockers and the incidence of necrotizing enterocolitis (NEC) in infants of 401 to 1500 g in birth weight. STUDY DESIGN. Data from the National Institute of Child Health and Human Development Neonatal Research Network very low birth weight (401–1500 g) registry from September 1998 to December 2001 were analyzed. The relation between the diagnosis of NEC (Bell stage II or greater) and antecedent H2-blocker treatment was determined by using case-control methodology. Conditional logistic regression was implemented, controlling for gender, site of birth (outborn versus inborn), Apgar score of <7 at 5 minutes, and postnatal steroids. RESULTS. Of 11072 infants who survived for at least 12 hours, 787 (7.1%) developed NEC (11.5% of infants 401–750 g, 9.1% of infants 751–1000 g, 6.0% of infants 1001–1250 g, and 3.9% of infants 1251–1500 g). Antecedent H2-blocker use was associated with an increased incidence of NEC (P < .0001). CONCLUSIONS. H2-blocker therapy was associated with higher rates of NEC, which is in agreement with a previous randomized trial of acidification of infant feeds that resulted in a decreased incidence of NEC. In combination, these data support the hypothesis that gastric pH level may be a factor in the pathogenesis of NEC.

Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants

BACKGROUND Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth. METHODS We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%). RESULTS Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation. CONCLUSIONS Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.).

The Association of Third-Generation Cephalosporin Use and Invasive Candidiasis in Extremely Low Birth-Weight Infants

OBJECTIVES. Previous studies have shown that incidence of invasive candidiasis varies substantially among centers, and previous use of broad-spectrum antibiotics is a risk factor for candidiasis in extremely low birth-weight infants. Differences in center practices, such as antibiotic strategies and the effects of these strategies on center incidence of candidiasis, are not reflected in assessments of an individuals risk of candidiasis. We evaluated the relationship between empirical antibiotic practices for extremely low birth-weight infants and center incidence of candidiasis. METHODS. We studied a cohort of extremely low birth-weight infants who survived ≥72 hours and were admitted to 1 of 12 tertiary centers between 1998 and 2001. Multivariable logistic regression was used to validate previous broad-spectrum antibiotics use as a risk factor for subsequent candidiasis in individual infants. We calculated correlation coefficients to assess the relationship between center incidence of candidiasis with antibiotic practice patterns. RESULTS. There were 3702 infants from 12 centers included, and 284 (7.7%) developed invasive candidiasis. Broad-spectrum antibiotics use was associated with candidiasis for individual infants. Center candidiasis incidence ranged from 2.4% to 20.4%. Center incidence of candidiasis was correlated with average broad-spectrum antibiotics use per infant and average use of broad-spectrum antibiotics with negative cultures per infant. CONCLUSIONS. Center incidences of invasive candidiasis differ substantially, and antibiotic practice differences are possible contributors to center variation in candidiasis risk.

Early and late onset sepsis in late preterm infants.

Background: Preterm birth is increasing worldwide, and late preterm births, which comprise more than 70% of all preterm births, account for much of the increase. Early and late onset sepsis results in significant mortality in extremely preterm infants, but little is known about sepsis outcomes in late preterm infants. Methods: This is an observational cohort study of infants <121 days of age (119,130 infants less than or equal to 3 days of life and 106,142 infants between 4 and 120 days of life) with estimated gestational age at birth between 34 and 36 weeks, admitted to 248 neonatal intensive care units in the United States between 1996 and 2007. Results: During the study period, the cumulative incidence of early and late onset sepsis was 4.42 and 6.30 episodes per 1000 admissions, respectively. Gram-positive organisms caused the majority of early and late onset sepsis episodes. Infants with early onset sepsis caused by Gram-negative rods and infants with late onset sepsis were more likely to die than their peers with sterile blood cultures (odds ratio [OR]: 4.39, 95% CI: 1.71–11.23, P = 0.002; and OR: 3.37, 95% CI: 2.35–4.84, P < 0.001, respectively). Conclusion: Late preterm infants demonstrate specific infection rates, pathogen distribution, and mortality associated with early and late onset sepsis. The results of this study are generalizable to late preterm infants admitted to the special care nursery or neonatal intensive care unit.

Aggressive vs. conservative phototherapy for infants with extremely low birth weight

BACKGROUND It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less). METHODS We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments. RESULTS Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g. CONCLUSIONS Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)

Optimizing Hand-held Spectral Domain Optical Coherence Tomography Imaging for Neonates, Infants, and Children

PURPOSE To describe age-related considerations and methods to improve hand-held spectral domain optical coherence tomography (HH-SD OCT) imaging of eyes of neonates, infants, and children. METHODS Based on calculated optical parameters for neonatal and infant eyes, individualized SD OCT scan parameters were developed for improved imaging in pediatric eyes. Forty-two subjects from 31 weeks postmenstrual age to 1.5 years were imaged with a portable HH-SD OCT system. Images were analyzed for quality, field of scan, magnification, and potential clinical utility. RESULTS The axial length of the premature infant eye increases rapidly in a linear pattern during the neonatal period and slows progressively with age. Refractive error shifts from mild myopia in neonates to mild hyperopia in infants. These factors affect magnification and field of view of optical diagnostic tools applied to the infant eye. When SD OCT parameters were corrected based on age-related optical parameters, SD OCT image quality improved in young infants. The field of scan and ease of operation also improved, and the optic nerve, fovea, and posterior pole were successfully imaged in 74% and 87% of individual eye imaging sessions in the intensive care nursery and clinic, respectively. No adverse events were reported. CONCLUSIONS SD OCT in young children and neonates should be customized for the unique optical parameters of the infant eye. This customization, not only improves image quality, but also allows control of the density of the optical sampling directed onto the retina.

Dynamics of Human Foveal Development after Premature Birth

PURPOSE To determine the dynamic morphologic development of the human fovea in vivo using portable spectral domain-optical coherence tomography (SD-OCT). DESIGN Prospective, observational case series. PARTICIPANTS Thirty-one prematurely born neonates, 9 children, and 9 adults. METHODS Sixty-two neonates were enrolled in this study. After examination for retinopathy of prematurity (ROP), SD-OCT imaging was performed at the bedside in nonsedated infants aged 31 to 41 weeks postmenstrual age (PMA) (= gestational age in weeks + chronologic age) and at outpatient follow-up ophthalmic examinations. Thirty-one neonates met eligibility criteria. Nine children and nine adults without ocular pathology served as control groups. Semiautomatic retinal layer segmentation was performed. Central foveal thickness, foveal to parafoveal (FP) ratio (central foveal thickness divided by thickness 1000 μm from the foveal center), and 3-dimensional thickness maps were analyzed. MAIN OUTCOME MEASURES In vivo determination of foveal morphology, layer segmentation, analysis of subcellular changes, and spatiotemporal layer shifting. RESULTS In contrast with the adult fovea, several signs of immaturity were observed in the neonates: a shallow foveal pit, persistence of inner retinal layers (IRLs), and a thin photoreceptor layer (PRL) that was thinnest at the foveal center. Three-dimensional mapping showed displacement of retinal layers out of the foveal center as the fovea matured and the progressive formation of the inner/outer segment band in the opposite direction. The FP-IRL ratios decreased as IRL migrated before term and minimally after that, whereas FP-PRL ratios increased as PRL subcellular elements formed closer to term and into childhood. A surprising finding was the presence of cystoid macular edema in 58% of premature neonates that appeared to affect inner foveal maturation. CONCLUSIONS This study provides the first view into the development of living cellular layers of the human retina and of subcellular specialization at the fovea in premature infant eyes using portable SD-OCT. Our work establishes a framework of the timeline of human foveal development, allowing us to identify unexpected retinal abnormalities that may provide new keys to disease activity and a method for mapping foveal structures from infancy to adulthood that may be integral in future studies of vision and visual cortex development. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.