Publications by authors named "Cindy T McEvoy"

49 Publications

Single-Examination Risk Prediction of Severe Retinopathy of Prematurity.

Pediatrics 2021 Nov 23. Epub 2021 Nov 23.

Departments of Ophthalmology.

Background And Objectives: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Screening and treatment reduces this risk, but requires multiple examinations of infants, most of whom will not develop severe disease. Previous work has suggested that artificial intelligence may be able to detect incident severe disease (treatment-requiring retinopathy of prematurity [TR-ROP]) before clinical diagnosis. We aimed to build a risk model that combined artificial intelligence with clinical demographics to reduce the number of examinations without missing cases of TR-ROP.

Methods: Infants undergoing routine ROP screening examinations (1579 total eyes, 190 with TR-ROP) were recruited from 8 North American study centers. A vascular severity score (VSS) was derived from retinal fundus images obtained at 32 to 33 weeks' postmenstrual age. Seven ElasticNet logistic regression models were trained on all combinations of birth weight, gestational age, and VSS. The area under the precision-recall curve was used to identify the highest-performing model.

Results: The gestational age + VSS model had the highest performance (mean ± SD area under the precision-recall curve: 0.35 ± 0.11). On 2 different test data sets (n = 444 and n = 132), sensitivity was 100% (positive predictive value: 28.1% and 22.6%) and specificity was 48.9% and 80.8% (negative predictive value: 100.0%).

Conclusions: Using a single examination, this model identified all infants who developed TR-ROP, on average, >1 month before diagnosis with moderate to high specificity. This approach could lead to earlier identification of incident severe ROP, reducing late diagnosis and treatment while simultaneously reducing the number of ROP examinations and unnecessary physiologic stress for low-risk infants.
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http://dx.doi.org/10.1542/peds.2021-051772DOI Listing
November 2021

The Role of Childhood Asthma in Obesity Development: A Nationwide U.S. Multi-cohort Study.

Epidemiology 2021 Sep 20. Epub 2021 Sep 20.

Department of Preventive Medicine, University of Southern California, Los Angeles, CA Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Department of Civil and Environmental Engineering, Northeastern University, Boston, MA Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston MA Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley NJ and the Albert Einstein College of Medicine, Bronx, NY Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN Departments of Pediatrics and Medicine, The University of Chicago, Chicago, IL University of Colorado, Anschutz Medical Campus, Aurora, CO Nell Hodgson Woodruff School of Nursing and Department of Family & Preventive Medicine, Emory University, Atlanta, GA Avera Research Institute, Sioux Falls, SD Kaiser Permanente Northern California Division of Research Department of Psychology The George Washington University, Washington, DC Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA University of California, Davis, School of Medicine, CA Geisel School of Medicine, Dartmouth College, Hanover, NH Department of Pediatrics & Environmental and Occupational Health Sciences, University of Washington, WA Department of Psychiatry and Human Behavior and Department of Pediatrics, Brown Alpert Medical School and Women and Infants Hospital, Providence, RI. Department of Education, University of Oregon, Eugene, OR Division of Pediatric Pulmonary Medicine, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY Department of Pediatrics, Oregon Health and Science University, Portland, OR Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY Departments of Psychiatry, Psychology, Neuroscience and Obstetrics and Gynecology, University of Rochester, NY Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY Department of Family and Preventive Medicine, University of Utah, Salt Lake City, UT Division of Allergy, Immunology, and Pulmonary Medicine, Department of PediatricsSt. Louis Children's Hospital, Washington University School of Medicine St. Louis, MO Departments of Pediatrics, Environmental Medicine and Population Health, New York University School of Medicine, NY Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY Department of Internal Medicine, University of Utah, Salt Lake City, UT Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY.

Rationale: Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset.

Objectives: To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association.

Methods: We studied 8716 children between ages 6-18.5 years who were non-obese at study entry participating in 18 U.S. cohorts of the Environmental influences on Child Health Outcomes program (among 7299 children with complete covariate data mean [SD] study entry age=7.2 [1.6] years and follow-up=5.3 [3.1] years).

Measurements And Main Results: We defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95%CI: 4%, 44%) higher risk for subsequently developing obesity compared to those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess HR:-0.64 [95%CI:-1.05,-0.23]).

Conclusions: This nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.
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http://dx.doi.org/10.1097/EDE.0000000000001421DOI Listing
September 2021

Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes.

Clin Epigenetics 2021 09 19;13(1):177. Epub 2021 Sep 19.

Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Ave, Beaverton, OR, 97006, USA.

Background: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes.

Results: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers.

Conclusions: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP. Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696 .
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http://dx.doi.org/10.1186/s13148-021-01161-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451157PMC
September 2021

Regional and sociodemographic differences in average BMI among US children in the ECHO program.

Obesity (Silver Spring) 2021 Dec 31;29(12):2089-2099. Epub 2021 Aug 31.

Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Objective: The aim of this study was to describe the association of individual-level characteristics (sex, race/ethnicity, birth weight, maternal education) with child BMI within each US Census region and variation in child BMI by region.

Methods: This study used pooled data from 25 prospective cohort studies. Region of residence (Northeast, Midwest, South, West) was based on residential zip codes. Age- and sex-specific BMI z scores were the outcome.

Results: The final sample included 14,313 children with 85,428 BMI measurements, 49% female and 51% non-Hispanic White. Males had a lower average BMI z score compared with females in the Midwest (β = -0.12, 95% CI: -0.19 to -0.05) and West (β = -0.12, 95% CI: -0.20 to -0.04). Compared with non-Hispanic White children, BMI z score was generally higher among children who were Hispanic and Black but not across all regions. Compared with the Northeast, average BMI z score was significantly higher in the Midwest (β = 0.09, 95% CI: 0.05 to 0.14) and lower in the South (β = -0.12, 95% CI: -0.16 to -0.08) and West (β = -0.14, 95% CI: -0.19 to -0.09) after adjustment for age, sex, race/ethnicity, and birth weight.

Conclusions: Region of residence was associated with child BMI z scores, even after adjustment for sociodemographic characteristics. Understanding regional influences can inform targeted efforts to mitigate BMI-related disparities among children.
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http://dx.doi.org/10.1002/oby.23235DOI Listing
December 2021

Pulmonary Function Tests in Very Low Birth Weight Infants Screened for Pulmonary Hypertension: A Pilot Study.

J Pediatr 2021 Oct 25;237:221-226.e1. Epub 2021 Jun 25.

Division of Neonatology, Department of Pediatrics, Oregon Health & Science University, Portland, OR.

Objective: To compare pulmonary function tests (PFTs), specifically respiratory system resistance (Rrs) and compliance (Crs), in very low birth weight (VLBW) infants with and without pulmonary hypertension.

Study Design: Infants were included who underwent PFTs at 34-38 weeks postmenstrual age (PMA) as part of our pulmonary hypertension screening guidelines for infants born at ≤1500 g requiring respiratory support at ≥34 weeks PMA. One pediatric cardiologist reviewed and estimated right ventricular or pulmonary arterial pressure and defined pulmonary hypertension as an estimated pulmonary arterial pressure or right ventricular pressure greater than one-half the systemic pressure. Rrs and Crs were measured with the single breath occlusion technique and functional residual capacity with the nitrogen washout method according to standardized criteria.

Results: Twelve VLBW infants with pulmonary hypertension and 39 without pulmonary hypertension were studied. Those with pulmonary hypertension had significantly lower birth weight and a trend toward a lower gestational age. There were no other demographic differences between the groups. The infants with pulmonary hypertension had significantly higher Rrs (119 vs 78 cmHO/L/s; adjusted P = .012) and significantly lower Crs/kg (0.71 vs 0.92 mL/cmHO/kg; P = .04).

Conclusions: In this pilot study of VLBW infants screened for pulmonary hypertension at 34-38 weeks PMA, those with pulmonary hypertension had significantly increased Rrs and decreased Crs compared with those without pulmonary hypertension. Additional studies are needed to further phenotype infants with evolving BPD and pulmonary hypertension.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478801PMC
October 2021

Do Standardized Scripts Improve Interpreter Use by Spanish-Speaking Patients?

J Immigr Minor Health 2021 Oct 9;23(5):1021-1025. Epub 2021 Apr 9.

Department of Pediatrics, Oregon Health and Science University, 707 SW Gaines Street, Portland, OR, 97239, USA.

Patients with limited English-proficiency (LEP) who need but do not receive interpreters have lower satisfaction and poorer understanding. A knowledge gap remains regarding the optimal way to offer interpreters. Using standardized scripts, we will determine whether the questions we use to offer interpreters increase utilization. Pilot prospective cohort study of postpartum mothers with LEP. Subjects were assigned one of three unique scripted question offering an interpreter. Data were analyzed using ANOVA, chi-square test, and Fisher's exact test. Fifty-five LEP patients were randomized into three study arms with similar sociodemographics. Overall interpreter use was 80% (44/55). There was a significant difference in interpreter utilization: 82.4%, 63.6%, 100%, respectively by arm (p = 0.015). Highest interpreter utilization occurred with "In what language do you prefer to receive your medical care?". There is opportunity for providers to refine the way they offer interpreters to optimize utilization.
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http://dx.doi.org/10.1007/s10903-021-01195-7DOI Listing
October 2021

Maternal Prenatal Hair Cortisol Is Associated with Child Wheeze among Mothers and Infants with Tobacco Smoke Exposure and Who Face High Socioeconomic Adversity.

Int J Environ Res Public Health 2021 03 9;18(5). Epub 2021 Mar 9.

Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.

The association of co-occurring prenatal stress and tobacco exposures on childhood wheezing and asthma are not well established. In this study, we compared maternal prenatal hair cortisol concentration (HCC) to the maternal report of infant wheezing (y/n) in the first year of life among mother-infant dyads exposed to tobacco smoke and socioeconomic adversity. Data were obtained from the Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function study. Maternal adversity was defined by the level of education, household income, and health insurance provider. Hair was collected at delivery, representing average circulating third-trimester cortisol levels. HCC was log transformed and dichotomized into high/low cortisol groups that were placed into a multivariate model predicting wheeze. Subjects ( = 132) were primarily White with ≤high school education and receiving government-provided health insurance. Forty-five percent of infants wheezed. Average HCC was 3.39 pg/mg hair. Women with HCC > 3.55 pg/mg were more than twice as likely to report having a child who wheezed (odds ratio 2.56, 95% confidence interval 1.22-5.40; = 0.01), adjusting for insurance provider and maternal asthma. Among this sample of dyads with prenatal smoke exposure, elevated maternal HCC was associated with child wheeze that was not diminished after consideration of covariates.
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http://dx.doi.org/10.3390/ijerph18052764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967280PMC
March 2021

Blood metabolomics in infants enrolled in a dose escalation pilot trial of budesonide in surfactant.

Pediatr Res 2021 Oct 19;90(4):784-794. Epub 2021 Jan 19.

Pediatrics, Oregon Health & Science University, Portland, OR, USA.

Background: The pathogenesis of BPD includes inflammation and oxidative stress in the immature lung. Corticosteroids improve respiratory status and outcome, but the optimal treatment regimen for benefit with low systemic effects is uncertain.

Methods: In a pilot dose escalation trial, we administered ≤5 daily doses of budesonide in surfactant to 24 intubated premature infants (Steroid And Surfactant in ELGANs (SASSIE)). Untargeted metabolomics was performed on dried blood spots using UPLC-MS/MS. Tracheal aspirate IL-8 concentration was determined as a measure of lung inflammation.

Results: Metabolomics data for 829 biochemicals were obtained on 121 blood samples over 96 h from 23 infants receiving 0.025, 0.05, or 0.1 mg budesonide/kg. Ninety metabolites were increased or decreased in a time- and dose-dependent manner at q ≤ 0.1 with overrepresentation in lipid and amino acid super pathways. Different dose response patterns occurred, with negative regulation associated with highest sensitivity to budesonide. Baseline levels of 22 regulated biochemicals correlated with lung inflammation (IL-8), with highest significance for sphingosine and thiamin.

Conclusions: Numerous metabolic pathways are regulated in a dose-dependent manner by glucocorticoids, which apparently act via distinct mechanisms that impact dose sensitivity. The findings identify candidate blood biochemicals as biomarkers of lung inflammation and systemic responses to corticosteroids.

Impact: Treatment of premature infants in respiratory failure with 0.1 mg/kg intra-tracheal budesonide in surfactant alters levels of ~11% of detected blood biochemicals in discrete time- and dose-dependent patterns. A subset of glucocorticoid-regulated biochemicals is associated with lung inflammatory status as assessed by lung fluid cytokine concentration. Lower doses of budesonide in surfactant than currently used may provide adequate anti-inflammatory responses in the lung with fewer systemic effects, improving the benefit:risk ratio.
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http://dx.doi.org/10.1038/s41390-020-01343-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814527PMC
October 2021

Prenatal and Childhood Tobacco Smoke Exposure Are Associated With Sleep-Disordered Breathing Throughout Early Childhood.

Acad Pediatr 2021 May-Jun;21(4):654-662. Epub 2020 Nov 5.

Department of Dermatology, Program for Clinical Research, University of California, San Francisco (K Abuabara).

Objective: To determine whether prenatal and childhood tobacco smoke exposure (TSE) are each independently associated with mild sleep-disordered breathing (SDB) symptoms throughout early childhood, and whether the association between childhood TSE and SDB differs according to the level of prenatal exposure.

Methods: Longitudinal cohort study, using data from the Avon Longitudinal Study of Parents and Children, a population-based birth cohort from the United Kingdom. Primary exposures were repeated measures of mother-reported prenatal and childhood TSE through age 7 years. Outcomes were mother-reported measures of mild SDB symptoms, including snoring, mouth breathing, and witnessed apnea, repeated annually through age 7 years.

Results: A total of 12,030 children were followed for a median duration of 7 years. About 24.2% were exposed to prenatal tobacco smoke, 46.2% were exposed at least once in childhood, and 20.6% were exposed during both periods. Both prenatal and childhood TSE were associated with SDB symptoms throughout early childhood (adjusted OR [aOR] for any prenatal TSE 1.23; 95% confidence interval [CI] 1.08, 1.40; aOR for any childhood TSE 1.17; 95% CI 1.06, 1.29). We observed a dose-response effect between TSE and SBD symptoms, and found evidence of effect modification for those exposed during both time periods (combined high level exposure both prenatally and during childhood: aOR snoring 2.43 [95% CI 1.50, 3.93], aOR apnea 2.65 [95% CI 1.46, 4.82]).

Conclusions: Prenatal and childhood TSE were both independently associated with mild SDB symptoms throughout early childhood in a dose-dependent manner, further supporting the critical importance of maintaining a tobacco-free environment throughout gestation and childhood.
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http://dx.doi.org/10.1016/j.acap.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096866PMC
July 2021

Pulmonary function in extremely low birth weight infants with bronchopulmonary dysplasia before hospital discharge.

J Perinatol 2021 01 11;41(1):77-83. Epub 2020 Oct 11.

Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Objective: To compare pulmonary function in extremely low birth weight (ELBW) infants with bronchopulmonary dysplasia (BPD) studied at 34-36 weeks postmenstrual age (PMA) with a reference group of "healthy" infants born at 34-36 weeks. We hypothesized that ELBW infants have decreased functional residual capacity (FRC) and respiratory compliance (Crs).

Study Design: Pulmonary function testing was performed at 34-36 weeks PMA in infants with BPD and within 96 h of age in infants delivered at 34-36 weeks.

Results: Twenty BPD patients and 20 healthy infants were studied. FRC (18.9 versus 26.2 mL/kg; adjusted 95% CI 5.0, 10.9; P < 0.001) and Crs (0.80 versus 1.29-mL/cm HO/kg; 95% CI 0.31, 0.71; P < 0.001) were decreased in BPD patients. Respiratory resistance was increased in BPD patients.

Conclusions: ELBW infants with BPD have decreased pulmonary function compared to healthy infants delivered at 34-36 weeks. This suggests that infants with BPD have smaller lung volumes.
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http://dx.doi.org/10.1038/s41372-020-00856-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548054PMC
January 2021

Trajectories of Lung Function in Infants and Children: Setting a Course for Lifelong Lung Health.

Pediatrics 2020 10 16;146(4). Epub 2020 Sep 16.

Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon.

For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.
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http://dx.doi.org/10.1542/peds.2020-0417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546086PMC
October 2020

Vitamin C to Pregnant Smokers Persistently Improves Infant Airway Function to 12 Months of Age: A Randomised Trial.

Eur Respir J 2020 Jul 2. Epub 2020 Jul 2.

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Vitamin C (500 mg·day) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported.

Objective: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age.

Methods: This is a prespecified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated measures analysis of covariance.

Results: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were: 40.2 mL·sec for FEF (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec for FEF (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec for FEF (95% CI, 9.7 to 100.5; p=0.013).

Conclusions: In offspring of pregnant smokers randomised to vitamin C placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway.
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http://dx.doi.org/10.1183/13993003.02208-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029653PMC
July 2020

Chinstraps are needed for neonatal nasal CPAP: Reflections from a non-human primate model.

Pediatr Pulmonol 2020 05 6;55(5):1087-1088. Epub 2020 Mar 6.

Division of Neonatology, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon.

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http://dx.doi.org/10.1002/ppul.24716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169434PMC
May 2020

Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE).

Pediatr Res 2020 10 1;88(4):629-636. Epub 2020 Feb 1.

Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.

Background: Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown.

Methods: Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3-14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF).

Results: Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls.

Conclusions: Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.
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http://dx.doi.org/10.1038/s41390-020-0792-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223897PMC
October 2020

Hospital Mortality and Functional Outcomes in Pediatric Neurocritical Care.

Hosp Pediatr 2019 12;9(12):958-966

Neonatology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon.

Objectives: Pediatric neurocritical care (PNCC) outcomes research is scarce. We aimed to expand knowledge about outcomes in PNCC by evaluating death and changes in Functional Status Scale (FSS) from baseline among PNCC diagnoses.

Methods: We conducted a 2-year observational study of children aged 0 to 18 years admitted to the ICU with a primary neurologic diagnosis ( = 325). Primary outcomes were death and change in FSS from preadmission baseline to discharge. New disability was defined as an FSS change of ≥1 from baseline, and severe disability was defined as an FSS change of ≥3. Categorical results are reported as relative risk (RR) with 95% confidence interval (CI).

Results: Thirty (9%) patients died. New disability ( = 103; 35%) and severe disability ( = 37; 13%) were common in PNCC survivors. New disability (range 14%-54%) and severe disability (range 3%-33%) outcomes varied significantly among primary diagnoses (lowest in status epilepticus; highest in infectious and/or inflammatory and stroke cohorts). Disability occurred in all FSS domains: mental status (15%), sensory (52%), communication (38%), motor (48%), feeding (40%), and respiratory (12%). Most (64%) patients with severe disability had changes in ≥3 domains. Requiring critical care interventions (RR 2.1; 95% CI 1.5-3.1) and having seizures (RR 1.5; 95% CI 1.1-2.0) during hospitalization were associated with new disability.

Conclusions: PNCC patients have high rates of death and new disability at discharge, varying significantly between PNCC diagnoses. Multiple domains of disability are affected, underscoring the ongoing multidisciplinary health care needs of survivors. Our study quantified hospital outcomes of PNCC patients that can be used to advance future research in this vulnerable population.
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http://dx.doi.org/10.1542/hpeds.2019-0173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877428PMC
December 2019

Sleep-Wake Disturbances After Acquired Brain Injury in Children Surviving Critical Care.

Pediatr Neurol 2020 02 26;103:43-51. Epub 2019 Aug 26.

Pediatric Critical Care and Neurotrauma Recovery Program, Oregon Health and Science University, Portland, Oregon; Division of Pediatric Neurology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon.

Background: Sleep-wake disturbances are underevaluated among children with acquired brain injury surviving critical care. We aimed to quantify severity, phenotypes, and risk factors for sleep-wake disturbances.

Methods: We performed a prospective cohort study of 78 children aged ≥3 years with acquired brain injury within three months of critical care hospitalization. Diagnoses included traumatic brain injury (n = 40), stroke (n = 11), infectious or inflammatory disease (n = 10), hypoxic-ischemic injury (n = 9), and other (n = 8). Sleep Disturbances Scale for Children standardized T scores measured sleep-wake disturbances. Overall sleep-wake disturbances were dichotomized as any total or subscale T score ≥60. Any T score ≥70 defined severe sleep-wake disturbances. Subscale T scores ≥60 identified sleep-wake disturbance phenotypes.

Results: Sleep-wake disturbances were identified in 44 (56%) children and were classified as severe in 36 (46%). Sleep-wake disturbances affected ≥33% of patients within each diagnosis and were not associated with severity of illness measures. The most common phenotype was disturbance in initiation and maintenance of sleep (47%), although 68% had multiple concurrent sleep-wake disturbance phenotypes. One third of all patients had preadmission chronic conditions, and this increased risk for sleep-wake disturbances overall (43% vs 21%, P = 0.04) and in the traumatic brain injury subgroup (52% vs 5%, P = 0.001).

Conclusions: Over half of children surviving critical care with acquired brain injury have sleep-wake disturbances. Most of these children have severe sleep-wake disturbances independent of severity of illness measures. Many sleep-wake disturbances phenotypes were identified, but most children had disturbance in initiation and maintenance of sleep. Our study underscores the importance of evaluating sleep-wake disturbances after acquired brain injury.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042044PMC
February 2020

A review of maternal prenatal exposures to environmental chemicals and psychosocial stressors-implications for research on perinatal outcomes in the ECHO program.

J Perinatol 2020 01 15;40(1):10-24. Epub 2019 Oct 15.

University of California Berkeley, Berkeley, CA, USA.

Exposures to environmental chemicals and psychosocial stressors during pregnancy have been individually associated with adverse perinatal outcomes related to birthweight and gestational age, but are not often considered in combination. We review types of psychosocial stressors and instruments used to assess them and classes of environmental chemical exposures that are known to adversely impact perinatal outcomes, and identify studies relevant studies. We discuss the National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) program that has combined existing longitudinal cohorts that include more than 50,000 children across the U.S. We describe future opportunities for investigators to use this important new resource for addressing relevant and critical research questions to maternal health. Of the 84 cohorts in ECHO, 38 collected data on environmental chemicals and psychosocial stressors and perinatal outcomes. The diverse ECHO pregnancy cohorts provide capacity to compare regions with distinct place-based environmental and social stressors.
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http://dx.doi.org/10.1038/s41372-019-0510-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957228PMC
January 2020

The Effect of Extended Continuous Positive Airway Pressure on Changes in Lung Volumes in Stable Premature Infants: A Randomized Controlled Trial.

J Pediatr 2020 02 10;217:66-72.e1. Epub 2019 Sep 10.

Division of Neonatology, Department of Pediatrics, Oregon Health & Science University, Portland, OR. Electronic address:

Objective: To compare changes in lung volumes, as measured by functional residual capacity (FRC), through to discharge in stable infants randomized to 2 weeks of extended continuous positive airway pressure CPAP (eCPAP) vs CPAP discontinuation (dCPAP).

Study Design: Infants born at ≤32 weeks of gestation requiring ≥24 hours of CPAP were randomized to 2 weeks of eCPAP vs dCPAP when meeting CPAP stability criteria. FRC was measured with the nitrogen washout technique. Infants were stratified by gestational age (<28 and ≥ 28 weeks) and twin gestation. A linear mixed-effects model was used to evaluate the change in FRC between the 2 groups. Data were analyzed blinded to treatment group allocation.

Results: Fifty infants were randomized with 6 excluded, for a total of 44 infants. Baseline characteristics were similar in the 2 groups. The infants randomized to eCPAP vs dCPAP had a greater increase in FRC from randomization through 2 weeks (12.6 mL vs 6.4 mL; adjusted 95% CI, 0.78-13.47; P = .03) and from randomization through discharge (27.2 mL vs 17.1 mL; adjusted 95% CI, 2.61-17.59; P = .01).

Conclusions: Premature infants randomized to eCPAP had a significantly greater increase in FRC through discharge compared with those randomized to dCPAP. An increased change in FRC may lead to improved respiratory health.

Trial Registration: ClinicalTrials.gov: NCT02249143.
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http://dx.doi.org/10.1016/j.jpeds.2019.07.074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986570PMC
February 2020

Pulmonary Function and Systolic Blood Pressure in Very Low Birth Weight Infants at 34 - 36 Weeks of Corrected Age.

Res Rep Neonatol 2019 Sep;9:21-30

Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.

Purpose: Preterm infants are at increased risk of systemic hypertension compared to term infants. Bronchopulmonary dysplasia (BPD) has been shown to be associated with hypertension in preterm infants albeit with no causation reported. BPD is characterized by abnormal pulmonary function tests (PFTs), specifically elevated passive respiratory resistance (Rrs), decreased passive respiratory compliance (Crs) and decreased functional residual capacity (FRC). There have been no studies comparing PFTs in very low birth weight (VLBW) infants with and without hypertension. We hypothesized that stable VLBW infants with hypertension will have altered PFTs.

Patients And Methods: Retrospective cohort study of infants < 1500 grams at birth (VLBW) who had PFTs performed near 34-36 weeks of corrected gestational age (CGA). We excluded infants with congenital anomalies, known hypertensive disorders or those at risk of medication-induced hypertension. Data obtained included PFT parameters (Rrs, Crs, FRC) and mean systolic blood pressure (SBP).

Results: 59 VLBW infants were identified for analysis, 14 with and 45 without hypertension. Hypertensive and normotensive patients were similar in terms of mean gestational age (26.6 vs 27.4 weeks), mean CGA at PFTs (36.1 vs 34.6 weeks) and proportion of BPD (36% vs 36%). The Rrs was significantly higher in hypertensive versus normotensive patients [median Rrs of 0.080 (0.069, 0.090) versus 0.066 (0.054, 0.083) cmHO/mL/sec; = 0.04]. There was no difference in systolic blood pressure in the infants with and without BPD.

Conclusion: In this cohort of contemporary VLBW infants, those with hypertension had increased Rrs. This finding warrants a prospective study with a larger sample size and long-term follow-up.
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http://dx.doi.org/10.2147/rrn.s208194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171237PMC
September 2019

Tobacco and nicotine exposure prevention in pregnancy: a priority to improve perinatal and maternal outcomes.

Am J Obstet Gynecol MFM 2019 03;1(1):19-23

Department of Pediatrics, Division of Neonatology, Oregon Health & Science University, Portland, OR.

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http://dx.doi.org/10.1016/j.ajogmf.2019.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023387PMC
March 2019

Smoke and Gene Interactions: Long-Term Consequences on Respiratory Health.

Am J Respir Crit Care Med 2019 Aug;200(4):409-410

3Oregon National Primate Research CenterBeaverton, Oregon.

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http://dx.doi.org/10.1164/rccm.201902-0312EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701041PMC
August 2019

Development and validation of an assay for quantifying budesonide in dried blood spots collected from extremely low gestational age neonates.

J Pharm Biomed Anal 2019 Apr 29;167:7-14. Epub 2019 Jan 29.

Center for Human Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, United States; Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah, United States.

Budesonide is a potential therapeutic option for the prevention of bronchopulmonary dysplasia in mechanically ventilated premature neonates. The dose and concentrations of budesonide that drive effective prophylaxis are unknown, due in part to the difficulty in obtaining serial blood samples from this fragile population. Of primary concern is the limited total blood volume available for collection for the purposes of a pharmacokinetic study. Dried blood spots (DBS), which require the collection of <200 μL whole blood to fill an entire card, are an attractive low-blood volume alternative to traditional venipuncture sampling. We describe a simple and sensitive method for determining budesonide concentrations in DBS using an ultra-high-performance liquid chromatography - tandem mass spectrometry assay. Budesonide was liberated from a single 6 mm punch using a basified methyl tert-butyl ether extraction procedure. The assay was determined to be accurate and precise in the dynamic range of 1 to 50 ng/mL. The validated assay was then successfully applied to DBS collected as part of a multi-center, dose-escalation study of budesonide administered in surfactant via intra-tracheal instillation to premature neonates between 23 and 28 weeks gestational age. These findings show that DBS are a useful technique for collecting pharmacokinetic samples in premature neonates and other pediatric populations.
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http://dx.doi.org/10.1016/j.jpba.2019.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233423PMC
April 2019

Candida albicans-associated sepsis in a pre-term neonatal rhesus macaque (Macaca mulatta).

J Med Primatol 2019 06 8;48(3):186-188. Epub 2019 Feb 8.

Oregon National Primate Research Center, Division of Comparative Medicine, Oregon Health & Science University, Portland, Oregon.

Invasive Candida infections (ICI) have been associated with neurodevelopmental impairment or death in human pre-term neonates. Candidiasis in nonhuman primates is seen mostly in immunosuppressed animals, and ICI is not commonly reported. Here, we report a case of Candida albicans-associated ICI in a pre-term neonatal rhesus macaque.
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http://dx.doi.org/10.1111/jmp.12401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520160PMC
June 2019

Oral Vitamin C (500 mg/d) to Pregnant Smokers Improves Infant Airway Function at 3 Months (VCSIP). A Randomized Trial.

Am J Respir Crit Care Med 2019 05;199(9):1139-1147

6 Department of Medical Informatics and Clinical Epidemiology.

We reported a randomized trial demonstrating daily supplemental vitamin C to pregnant smokers significantly improved newborn pulmonary function tests. The current study tests these results in a new cohort using infant pulmonary function tests. To determine if infants of pregnant smokers randomized to daily supplemental vitamin C would have improved forced expiratory flows (FEFs) at 3 months of age compared with those randomized to placebo, and to investigate the association of the α5 nicotinic acetylcholine receptor. A randomized, double-blind, placebo-controlled trial was conducted at three centers. Two hundred fifty-one pregnant smokers were randomized at 13-23 weeks of gestation: 125 randomized to vitamin C (500 mg/d) and 126 to placebo. The primary outcome was FEF at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). FEF and FEF obtained from the same expiratory curves were prespecified secondary outcomes. The infants of pregnant smokers randomized to vitamin C ( = 113) had the following FEFs at 3 months of age compared with those randomized to placebo ( =  109) as measured by FEF (200.7 vs. 188.7 ml/s; adjusted 95% confidence interval [CI] for difference, -3.33 to 35.64;  = 0.10), FEF (436.7 vs. 408.5 ml/s; adjusted 95% CI for difference, 6.10-61.30;  = 0.02), and FEF (387.4 vs. 365.8 ml/s; adjusted 95% CI for difference, 0.92-55.34;  = 0.04). Infant FEFs seemed to be negatively associated with the maternal risk alleles for the α5 nicotinic acetylcholine receptor (rs16969968). Although the primary outcome of FEF was not improved after vitamin C supplementation to pregnant smokers, the predetermined secondary outcomes FEF and FEF were significantly improved. These results extend our previous findings and demonstrate improved airway function (FEF and FEF) at 3 months of age in infants after vitamin C supplementation to pregnant smokers. Clinical trial registered with www.clinicaltrials.gov (NCT01723696).
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http://dx.doi.org/10.1164/rccm.201805-1011OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515875PMC
May 2019

Respiratory Compliance in Late Preterm Infants (34-34 Weeks) after Antenatal Steroid Therapy.

J Pediatr 2018 10 25;201:21-26. Epub 2018 Jun 25.

Division of Neonatology, Department of Pediatrics, Oregon Health and Science University, Portland, OR. Electronic address:

Objective: To compare respiratory compliance in late preterm infants (34-34 weeks) who received antenatal steroids vs matched late preterm infants who did not receive antenatal steroids.

Study Design: This was a single-center prospective cohort study. Patients were matched for birth weight, gestational age, race, and sex. Respiratory compliance was the primary outcome measured with the single breath occlusion technique.

Results: We studied 25 late preterm infants treated with antenatal steroids and 25 matched infants who did not receive antenatal steroids. The treated infants had a significantly increased respiratory compliance/kg (adjusted 95% CI 0.05, 0.49; P = .016) and fewer required continuous positive airway pressure (P = .007) or >24 hours of supplemental oxygen (P = .046). There was no difference in surfactant therapy.

Conclusions: Respiratory compliance was significantly increased in this cohort of late preterm infants born at 34-34 weeks who received antenatal steroids compared with matched infants who did not receive antenatal steroids. Although not randomized, these data provide physiologic support for the possible beneficial effects of antenatal steroids in late preterm infants.
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http://dx.doi.org/10.1016/j.jpeds.2018.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153025PMC
October 2018

The window of improved neonatal respiratory compliance after rescue antenatal steroids.

J Perinatol 2018 07 24;38(7):828-833. Epub 2018 May 24.

Division of Neonatology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.

Objective: To evaluate whether premature infants delivered ≤7 days after rescue antenatal steroid treatment (ideal treatment) have increased passive respiratory compliance compared to those delivered >7 days after treatment (remote treatment).

Methods: Secondary analysis of a randomized trial of rescue antenatal steroids on respiratory compliance. Infants in the treatment group were stratified by the interval between rescue antenatal steroids and delivery. We then compared the respiratory compliance in the ideal vs. remote groups.

Results: Forty-four women (56 infants) received rescue antenatal steroids. Forty-nine infants had evaluable respiratory compliance measurements, with 27 (GA 30.1 weeks, BW 1362 g) "ideally" treated, and 22 (GA 33.8 weeks, BW 2248 g) "remotely" treated. Respiratory compliance was significantly higher for the ideal compared to the remote group (1.32 vs. 1.06 mL/cm HO/kg; p = 0.037).

Conclusion: Infants treated with rescue antenatal steroids have a significantly higher respiratory compliance if delivery occurs within 7 days after treatment.
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http://dx.doi.org/10.1038/s41372-018-0124-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070394PMC
July 2018

Cost effectiveness of vitamin c supplementation for pregnant smokers to improve offspring lung function at birth and reduce childhood wheeze/asthma.

J Perinatol 2018 07 22;38(7):820-827. Epub 2018 May 22.

Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.

Objective: To determine the implications of supplemental vitamin C for pregnant tobacco smokers and its effects on the prevalence of pediatric asthma, asthma-related mortality, and associated costs.

Study Design: A decision-analytic model built via TreeAge compared the outcome of asthma in a theoretical annual cohort of 480,000 children born to pregnant smokers through 18 years of life. Vitamin C supplementation (500 mg/day) with a standard prenatal vitamin was compared to a prenatal vitamin (60 mg/day). Model inputs were derived from the literature. Deterministic and probabilistic sensitivity analyses assessed the impact of assumptions.

Result: Additional vitamin C during pregnancy would prevent 1637 cases of asthma at the age of 18 per birth cohort of pregnant smokers. Vitamin C would reduce asthma-related childhood deaths and save $31,420,800 in societal costs over 18 years per birth cohort.

Conclusion: Vitamin C supplementation in pregnant smokers is a safe and inexpensive intervention that may reduce the economic burden of pediatric asthma.
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http://dx.doi.org/10.1038/s41372-018-0135-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414472PMC
July 2018

Update on Vitamin E and Its Potential Role in Preventing or Treating Bronchopulmonary Dysplasia.

Neonatology 2018 7;113(4):366-378. Epub 2018 Mar 7.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Vitamin E is obtained only through the diet and has a number of important biological activities, including functioning as an antioxidant. Evidence that free radicals may contribute to pathological processes such as bronchopulmonary dysplasia (BPD), a disease of prematurity associated with increased lung injury, inflammation and oxidative stress, led to trials of the antioxidant vitamin E (α-tocopherol) to prevent BPD with variable results. These trials were all conducted at supraphysiologic doses and 2 of these trials utilized a formulation containing a potentially harmful excipient. Since 1991, when the last of these trials was conducted, both neonatal management strategies for minimizing oxygen and ventilator-related lung injury and our understanding of vitamin E isoforms in respiratory health have advanced substantially. It is now known that there are differences between the effects of vitamin E isoforms α-tocopherol and γ-tocopherol on the development of respiratory morbidity and inflammation. What is not known is whether improvements in physiologic concentrations of individual or combinations of vitamin E isoforms during pregnancy or following preterm birth might prevent or reduce BPD development. The answers to these questions require adequately powered studies targeting pregnant women at risk of preterm birth or their premature infants immediately following birth, especially in certain subgroups that are at increased risk of vitamin E deficiency (e.g., smokers). The objective of this review is to compile, update, and interpret what is known about vitamin E isoforms and BPD since these first studies were conducted, and suggest future research directions.
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http://dx.doi.org/10.1159/000487388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980725PMC
September 2019

Anti-Vascular Endothelial Growth Factor Antagonists: A Potential Primary Prevention for Bronchopulmonary Dysplasia?

Am J Respir Crit Care Med 2018 03;197(6):703-704

2 Department of Pediatrics University of Southern California Keck School of Medicine Los Angeles, California.

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http://dx.doi.org/10.1164/rccm.201712-2389EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855076PMC
March 2018
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