Publications by authors named "Krisa P Van Meurs"

89 Publications

Growth Rates of Infants Randomized to Continuous Positive Airway Pressure or Intubation After Extremely Preterm Birth.

J Pediatr 2021 Jun 19. Epub 2021 Jun 19.

National Institute of Child Health and Human Development, Bethesda, MD; Department of Global and Community Health, George Mason University, Fairfax, VA.

Objective: To evaluate the effects of early treatment with continuous positive airway pressure (CPAP) on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants.

Study Design: EPT infants (24-27 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks of postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks of PMA and follow-up outcomes at 18-22 months corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed.

Results: Growth data were analyzed for 810 of 1316 infants enrolled in SUPPORT (414 in the intervention group, 396 in the control group). The median gestational age was 26 weeks, and the mean birth weight was 839 g. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between the 2 groups. In a regression model, growth rates between birth and 36 weeks of PMA, as well as growth rates during multiple intervals from birth to day 7, days 7-14, days 14-21, days 21-28, day 28 to 32 weeks PMA, and 32-36 weeks PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of having a Bayley-III cognitive score <85 at 18-22 months corrected age (P = .002).

Conclusions: EPT infants randomized to early CPAP did not have higher in-hospital growth rates than infants randomized to early intubation.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.026DOI Listing
June 2021

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.

J Pediatr 2021 Jun 16. Epub 2021 Jun 16.

Department of Neurology, University of California San Francisco, San Francisco, CA.

Objective: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE.

Study Design: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system.

Results: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities.

Conclusions: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.

Trial Registration: ClinicalTrials.gov: NCT02811263.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.023DOI Listing
June 2021

Umbilical Cord Milking vs Delayed Cord Clamping and Associations with In-Hospital Outcomes among Extremely Premature Infants.

J Pediatr 2021 May 5;232:87-94.e4. Epub 2021 Jan 5.

Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; Leonard Davis Institute of Health Economics, The University of Pennsylvania, Philadelphia, PA. Electronic address:

Objective: To compare in-hospital outcomes after umbilical cord milking vs delayed cord clamping among infants <29 weeks of gestation.

Study Design: Multicenter retrospective study of infants born <29 weeks of gestation from 2016 to 2018 without congenital anomalies who received active treatment at delivery and were exposed to umbilical cord milking or delayed cord clamping. The primary outcome was mortality or severe (grade III or IV) intraventricular hemorrhage (IVH) by 36 weeks of postmenstrual age (PMA). Secondary outcomes assessed at 36 weeks of PMA were mortality, severe IVH, any IVH or mortality, and a composite of mortality or major morbidity. Outcomes were assessed using multivariable regression, incorporating mortality risk factors identified a priori, confounders, and center. A prespecified, exploratory analysis evaluated severe IVH in 2 gestational age strata, 22-24 and 25-28 weeks.

Results: Among 1834 infants, 23.6% were exposed to umbilical cord milking and 76.4% to delayed cord clamping. The primary outcome, mortality or severe IVH, occurred in 21.1% of infants: 28.3% exposed to umbilical cord milking and 19.1% exposed to delayed cord clamping, with an aOR that was similar between groups (aOR 1.45, 95% CI 0.93, 2.26). Infants exposed to umbilical cord milking had higher odds of severe IVH (19.8% umbilical cord milking vs 11.8% delayed cord clamping, aOR 1.70 95% CI 1.20, 2.43), as did the 25-28 week stratum (14.8% umbilical cord milking vs 7.4% delayed cord clamping, aOR 1.89 95% CI 1.22, 2.95). Other secondary outcomes were similar between groups.

Conclusions: This analysis of extremely preterm infants suggests that delayed cord clamping is the preferred practice for placental transfusion, as umbilical cord milking exposure was associated with an increase in the adverse outcome of severe IVH.

Trial Registration: ClinicalTrials.gov: NCT00063063.
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http://dx.doi.org/10.1016/j.jpeds.2020.12.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084979PMC
May 2021

Outcomes of infants with hypoxic ischemic encephalopathy and persistent pulmonary hypertension of the newborn: results from three NICHD studies.

J Perinatol 2021 Mar 6;41(3):502-511. Epub 2021 Jan 6.

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA, USA.

Objective: To determine the association of persistent pulmonary hypertension of the newborn (PPHN) with death or disability among infants with moderate or severe hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia.

Methods: We compared infants with and without PPHN enrolled in the hypothermia arm from three randomized controlled trials (RCTs): Induced Hypothermia trial, "usual care" arm of Optimizing Cooling trial, and Late Hypothermia trial. Primary outcome was death or disability at 18-22 months adjusted for severity of HIE, center, and RCT.

Results: Among 280 infants, 67 (24%) were diagnosed with PPHN. Among infants with and without PPHN, death or disability was 47% vs. 29% (adjusted OR: 1.65, 0.86-3.14) and death was 26% vs. 12% (adjusted OR: 2.04, 0.92-4.53), respectively.

Conclusions: PPHN in infants with moderate or severe HIE was not associated with a statistically significant increase in primary outcome. These results should be interpreted with caution given the limited sample size.
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http://dx.doi.org/10.1038/s41372-020-00905-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954876PMC
March 2021

In-hospital mortality and morbidity among extremely preterm infants in relation to maternal body mass index.

J Perinatol 2021 May 6;41(5):1014-1024. Epub 2020 Oct 6.

Department of Pediatrics, Wayne State University, Detroit, MI, USA.

Objective: The objective of this paper is to compare in-hospital survival and survival without major morbidities in extremely preterm infants in relation to maternal body mass index (BMI).

Methods: This retrospective cohort study included extremely preterm infants (gestational age 22-28 weeks). This study was conducted at National Institute of Child Health and Human Development Neonatal Research Network sites. Primary outcome was survival without any major morbidity.

Results: Maternal BMI data were available for 2415 infants. Survival without any major morbidity was not different between groups: 30.8% in the underweight/normal, 28.1% in the overweight, and 28.5% in the obese (P = 0.65). However, survival was lower in the obese group (76.5%) compared with overweight group (83.2%) (P = 0.02). Each unit increase in maternal BMI was associated with decreased odds of infant survival (P < 0.01).

Conclusions: Survival without any major morbidity was not associated with maternal obesity. An increase in maternal prepregnancy BMI was associated with decreased odds of infant survival.
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http://dx.doi.org/10.1038/s41372-020-00847-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021608PMC
May 2021

Blood myo-inositol concentrations in preterm and term infants.

J Perinatol 2021 Feb 15;41(2):247-254. Epub 2020 Sep 15.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Objective: To describe relationship between cord blood (representing fetal) myo-inositol concentrations and gestational age (GA) and to determine trends of blood concentrations in enterally and parenterally fed infants from birth to 70 days of age.

Design/methods: Samples were collected in 281 fed or unfed infants born in 2005 and 2006. Myo-inositol concentrations were displayed in scatter plots and analyzed with linear regression models of natural log-transformed values.

Results: In 441 samples obtained from 281 infants, myo-inositol concentrations varied from nondetectable to 1494 μmol/L. Cord myo-inositol concentrations decreased an estimated 11.9% per week increase in GA. Postnatal myo-inositol concentrations decreased an estimated 14.3% per week increase in postmenstrual age (PMA) and were higher for enterally fed infants compared to unfed infants (51% increase for fed vs. unfed infants).

Conclusions: Fetal myo-inositol concentrations decreased with increasing GA. Postnatal concentrations decreased with increasing PMA and were higher among enterally fed than unfed infants.
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http://dx.doi.org/10.1038/s41372-020-00799-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889639PMC
February 2021

Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

Pediatr Res 2020 12 12;88(6):871-877. Epub 2020 Sep 12.

Department of Pediatrics, Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Background: Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies.

Methods: A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined.

Results: Birth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates.

Conclusions: In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population.

Impact: Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.
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http://dx.doi.org/10.1038/s41390-020-01140-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704857PMC
December 2020

Cerebral Oxygenation and Autoregulation in Preterm Infants (Early NIRS Study).

J Pediatr 2020 12 17;227:94-100.e1. Epub 2020 Aug 17.

Division of Neonatology, Stanford University School of Medicine, Stanford, CA.

Objective: To determine if decreased cerebral oxygenation or altered cerebral autoregulation as measured by near-infrared spectroscopy (NIRS) in the first 96 postnatal hours is associated with an increased risk of death or severe neuroradiographic abnormalities in very preterm infants.

Study Design: The Early NIRS prospective, multicenter study enrolled very preterm infants with a birth weight of <1250 g from 6 tertiary neonatal intensive care units. Mean arterial blood pressure and cerebral oxygen saturation (Csat) were continuously monitored using a neonatal sensor until 96 hours of age. Moving window correlations between Csat and mean arterial blood pressure determined time periods with altered cerebral autoregulation, and percentiles of correlation were compared between infants with and without the adverse outcome of mortality or severe neuroradiographic abnormalities by early cranial ultrasound.

Results: Of 103 subjects with mean gestational age of 26 weeks, 21 (20%) died or had severe neuroradiographic abnormalities. Infants with adverse outcomes had a lower mean Csat (67 ± 9%) compared with those without adverse outcomes (72 ± 7%; P = .02). A Csat of <50% was identified as a cut-point for identifying infants with adverse outcome (area under the curve, 0.76). Infants with adverse outcomes were more likely to have significant positive or negative correlations between Csat and mean arterial blood pressure, indicating impaired cerebral autoregulation (P = .006).

Conclusions: Early NIRS monitoring may detect periods of lower cerebral oxygenation and altered cerebral autoregulation, identifying preterm infants at risk for mortality or neuroradiographic injury. An improved understanding of the relationship between altered hemodynamics and cerebral oxygenation may inform future strategies to prevent brain injury.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.036DOI Listing
December 2020

Outcomes Following Post-Hemorrhagic Ventricular Dilatation among Infants of Extremely Low Gestational Age.

J Pediatr 2020 Jul 30. Epub 2020 Jul 30.

College of Health and Human Services, George Mason University, Fairfax, VA.

Objective: To assess outcomes following post-hemorrhagic ventricular dilatation (PHVD) among infants born at ≤26 weeks of gestation.

Study Design: Observational study of infants born April 1, 2011, to December 31, 2015, in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and categorized into 3 groups: PHVD, intracranial hemorrhage without ventricular dilatation, or normal head ultrasound. PHVD was treated per center practice. Neurodevelopmental impairment at 18-26 months was defined by cerebral palsy, Bayley Scales of Infant and Toddler Development, 3rd edition, cognitive or motor score <70, blindness, or deafness. Multivariable logistic regression examined the association of death or impairment, adjusting for neonatal course, center, maternal education, and parenchymal hemorrhage.

Results: Of 4216 infants, 815 had PHVD, 769 had hemorrhage without ventricular dilatation, and 2632 had normal head ultrasounds. Progressive dilatation occurred among 119 of 815 infants; the initial intervention in 66 infants was reservoir placement and 53 had ventriculoperitoneal shunt placement. Death or impairment occurred among 68%, 39%, and 28% of infants with PHVD, hemorrhage without dilatation, and normal head ultrasound, respectively; aOR (95% CI) were 4.6 (3.8-5.7) PHVD vs normal head ultrasound scan and 2.98 (2.3-3.8) for PHVD vs hemorrhage without dilatation. Death or impairment was more frequent with intervention for progressive dilatation vs no intervention (80% vs 65%; aOR 2.2 [1.38-3.8]). Death or impairment increased with parenchymal hemorrhage, intervention for PHVD, male sex, and surgery for retinopathy; odds decreased with each additional gestational week.

Conclusions: PHVD was associated with high rates of death or impairment among infants with gestational ages ≤26 weeks; risk was further increased among those with progressive ventricular dilation requiring intervention.
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http://dx.doi.org/10.1016/j.jpeds.2020.07.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855243PMC
July 2020

Placental transfusion and short-term outcomes among extremely preterm infants.

Arch Dis Child Fetal Neonatal Ed 2021 Jan 30;106(1):62-68. Epub 2020 Jul 30.

Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

Objective: To compare short-term outcomes after placental transfusion (delayed cord clamping (DCC) or umbilical cord milking (UCM)) versus immediate cord clamping among extremely preterm infants.

Design: Retrospective study.

Setting: The National Institute of Child Health and Human Development Neonatal Research Network registry.

Patients: Infants born <29 weeks' gestation in 2016 or 2017 without congenital anomalies who received active treatment after delivery.

Intervention/exposure: DCC or UCM.

Main Outcome Measures: Primary outcomes: (1) composite of mortality or major morbidity by 36 weeks' postmenstrual age (PMA); (2) mortality by 36 weeks PMA and (3) composite of major morbidities by 36 weeks' PMA. Secondary composite outcomes: (1) any grade intraventricular haemorrhage or mortality by 36 weeks' PMA and (2) hypotension treatment in the first 24 postnatal hours or mortality in the first 12 postnatal hours. Outcomes were assessed using multivariable regression, adjusting for mortality risk factors identified a priori, significant confounders and centre as a random effect.

Results: Among 3116 infants, 40% were exposed to placental transfusion, which was not associated with the primary composite outcome of mortality or major morbidity by 36 weeks' PMA (adjusted OR (aOR) 1.26, 95% CI 0.95 to 1.66). However, exposure was associated with decreased mortality by 36 weeks' PMA (aOR 0.71, 95% CI 0.55 to 0.92) and decreased hypotension treatment in first 24 postnatal hours (aOR 0.66, 95% CI 0.53 to 0.82).

Conclusion: In this extremely preterm infant cohort, exposure to placental transfusion was not associated with the composite outcome of mortality or major morbidity, though there was a reduction in mortality by 36 weeks' PMA.

Trial Registration Number: NCT00063063.
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http://dx.doi.org/10.1136/archdischild-2019-318710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736256PMC
January 2021

Racial/Ethnic Disparities Among Extremely Preterm Infants in the United States From 2002 to 2016.

JAMA Netw Open 2020 06 1;3(6):e206757. Epub 2020 Jun 1.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Importance: Racial/ethnic disparities in quality of care among extremely preterm infants are associated with adverse outcomes.

Objective: To assess whether racial/ethnic disparities in major outcomes and key care practices were changing over time among extremely preterm infants.

Design, Setting, And Participants: This observational cohort study used prospectively collected data from 25 US academic medical centers. Participants included 20 092 infants of 22 to 27 weeks' gestation with a birth weight of 401 to 1500 g born at centers participating in the National Institute of Child Health and Human Development Neonatal Research Network from 2002 to 2016. Of these infants, 9316 born from 2006 to 2014 were eligible for follow-up at 18 to 26 months' postmenstrual age (excluding 5871 infants born before 2006, 2594 infants born after 2014, and 2311 ineligible infants including 64 with birth weight >1000 g and 2247 infants with gestational age >26 6/7 weeks), of whom 745 (8.0%) did not have known follow-up outcomes at 18 to 26 months.

Main Outcomes And Measures: Rates of mortality, major morbidities, and care practice use over time were evaluated using models adjusted for baseline characteristics, center, and birth year. Data analyses were conducted from 2018 to 2019.

Results: In total, 20 092 infants with a mean (SD) gestational age of 25.1 (1.5) weeks met the inclusion criteria and were available for the primary outcome: 8331 (41.5%) black infants, 3701 (18.4%) Hispanic infants, and 8060 (40.1%) white infants. Hospital mortality decreased over time in all groups. The rate of improvement in hospital mortality over time did not differ among black and Hispanic infants compared with white infants (black infants went from 35% to 24%, Hispanic infants went from 32% to 27%, and white infants went from 30% to 22%; P = .59 for race × year interaction). The rates of late-onset sepsis among black infants (went from 37% to 24%) and Hispanic infants (went from 45% to 23%) were initially higher than for white infants (went from 36% to 25%) but decreased more rapidly and converged during the most recent years (P = .02 for race × year interaction). Changes in rates of other major morbidities did not differ by race/ethnicity. Death before follow-up decreased over time (from 2006 to 2014: black infants, 14%; Hispanic infants, 39%, white infants, 15%), but moderate-severe neurodevelopmental impairment increased over time in all racial/ethnic groups (increase from 2006 to 2014: black infants, 70%; Hispanic infants, 123%; white infants, 130%). Rates of antenatal corticosteroid exposure (black infants went from 72% to 90%, Hispanic infants went from 73% to 83%, and white infants went from 86% to 90%; P = .01 for race × year interaction) and of cesarean delivery (black infants went from 45% to 59%, Hispanic infants went from 49% to 59%, and white infants went from 62% to 63%; P = .03 for race × year interaction) were initially lower among black and Hispanic infants compared with white infants, but these differences decreased over time.

Conclusions And Relevance: Among extremely preterm infants, improvements in adjusted rates of mortality and most major morbidities did not differ by race/ethnicity, but rates of neurodevelopmental impairment increased in all groups. There were narrowing racial/ethnic disparities in important care practices, including the use of antenatal corticosteroids and cesarean delivery.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.6757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287569PMC
June 2020

Early-Onset Neonatal Sepsis 2015 to 2017, the Rise of Escherichia coli, and the Need for Novel Prevention Strategies.

JAMA Pediatr 2020 07 6;174(7):e200593. Epub 2020 Jul 6.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

Importance: Early-onset sepsis (EOS) remains a potentially fatal newborn condition. Ongoing surveillance is critical to optimize prevention and treatment strategies.

Objective: To describe the current incidence, microbiology, morbidity, and mortality of EOS among a cohort of term and preterm infants.

Design, Setting, And Participants: This prospective surveillance study included a cohort of infants born at a gestational age (GA) of at least 22 weeks and birth weight of greater than 400 g from 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from April 1, 2015, to March 31, 2017. Data were analyzed from June 14, 2019, to January 28, 2020.

Main Outcomes And Measures: Early-onset sepsis defined by isolation of pathogenic species from blood or cerebrospinal fluid culture within 72 hours of birth and antibiotic treatment for at least 5 days or until death.

Results: A total of 235 EOS cases (127 male [54.0%]) were identified among 217 480 newborns (1.08 [95% CI, 0.95-1.23] cases per 1000 live births). Incidence varied significantly by GA and was highest among infants with a GA of 22 to 28 weeks (18.47 [95% CI, 14.57-23.38] cases per 1000). No significant differences in EOS incidence were observed by sex, race, or ethnicity. The most frequent pathogens were Escherichia coli (86 [36.6%]) and group B streptococcus (GBS; 71 [30.2%]). E coli disease primarily occurred among preterm infants (68 of 131 [51.9%]); GBS disease primarily occurred among term infants (54 of 104 [51.9%]), with 24 of 45 GBS cases (53.3%) seen in infants born to mothers with negative GBS screening test results. Intrapartum antibiotics were administered to 162 mothers (68.9%; 110 of 131 [84.0%] preterm and 52 of 104 [50.0%] term), most commonly for suspected chorioamnionitis. Neonatal empirical antibiotic treatment most frequently included ampicillin and gentamicin. All GBS isolates were tested, but only 18 of 81 (22.2%) E coli isolates tested were susceptible to ampicillin; 6 of 77 E coli isolates (7.8%) were resistant to both ampicillin and gentamicin. Nearly all newborns with EOS (220 of 235 [93.6%]) displayed signs of illness within 72 hours of birth. Death occurred in 38 of 131 infected infants with GA of less than 37 weeks (29.0%); no term infants died. Compared with earlier surveillance (2006-2009), the rate of E coli infection increased among very low-birth-weight (401-1500 g) infants (8.68 [95% CI, 6.50-11.60] vs 5.07 [95% CI, 3.93-6.53] per 1000 live births; P = .008).

Conclusions And Relevance: In this study, EOS incidence and associated mortality disproportionately occurred in preterm infants. Contemporary cases have demonstrated the limitations of current GBS prevention strategies. The increase in E coli infections among very low-birth-weight infants warrants continued study. Ampicillin and gentamicin remained effective antibiotics in most cases, but ongoing surveillance should monitor antibiotic susceptibilities of EOS pathogens.
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http://dx.doi.org/10.1001/jamapediatrics.2020.0593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199167PMC
July 2020

Ventricular Dysfunction Is a Critical Determinant of Mortality in Congenital Diaphragmatic Hernia.

Am J Respir Crit Care Med 2019 12;200(12):1522-1530

Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston and Children's Memorial Hermann Hospital, Houston, Texas.

Congenital diaphragmatic hernia (CDH) is an anomaly with a high morbidity and mortality. Cardiac dysfunction may be an important and underrecognized contributor to CDH pathophysiology and determinant of disease severity. Our aim was to investigate the association between early, postnatal ventricular dysfunction and outcome among infants with CDH. Multicenter, prospectively collected data in the CDH Study Group (CDHSG) registry, abstracted between 2015 and 2018, were evaluated. Ventricular function on early echocardiograms, defined as obtained within the first 48 hours of life, was categorized into four hierarchical groups: normal function, right ventricular dysfunction only (RV), left ventricular dysfunction only (LV), and combined RV and LV dysfunction (RV&LV). Univariate, multivariate, and Cox proportional hazards regression analyses were performed. Cardiac function data from early echocardiograms were available for 1,173 (71%) cases and categorized as normal in 711 (61%), RV in 182 (15%), LV in 61 (5%), and combined RV&LV in 219 (19%) cases. Ventricular dysfunction was significantly associated with prenatal diagnosis, CDHSG stage, intrathoracic liver, and patch repair (all  < 0.001). Survival varied by category: normal function, 80%; RV, 74%; LV, 57%; and RV&LV, 51% ( < 0.001). The adjusted risk of death (hazard ratio) for cases with LV was 1.96 (95% confidence interval [CI], 1.29-2.98;  = 0.020) and for cases with RV&LV was 2.27 (95% CI, 1.77-2.92;  = 0.011). All cardiac dysfunction categories were associated with use of extracorporeal membrane oxygenation ( < 0.005). Early ventricular dysfunction occurs frequently in CDH and is an independent determinant of severity and clinical outcome.
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http://dx.doi.org/10.1164/rccm.201904-0731OCDOI Listing
December 2019

Inadequate oral feeding as a barrier to discharge in moderately preterm infants.

J Perinatol 2019 09 11;39(9):1219-1228. Epub 2019 Jul 11.

Department of Pediatrics, Duke University, Durham, NC, 27708, USA.

Objectives: The objectives describe the frequency that inadequate oral feeding (IOF) is the reason why moderately preterm (MPT) infants remain hospitalized and its association with neonatal morbidities.

Study Design: Prospective study using the NICHD Neonatal Research Network MPT Registry. Multivariable logistic regression was used to describe associations between IOF and continued hospitalization at 36 weeks postmenstrual age (PMA).

Result: A total of 6017 MPT infants from 18 centers were included. Three-thousand three-seventy-six (56%) remained hospitalized at 36 weeks PMA, of whom 1262 (37%) remained hospitalized due to IOF. IOF was associated with RDS (OR 2.02, 1.66-2.46), PDA (OR 1.86, 1.37-2.52), sepsis (OR 2.36, 95% 1.48-3.78), NEC (OR 16.14, 7.27-35.90), and BPD (OR 3.65, 2.56-5.21) compared to infants discharged and was associated with medical NEC (OR 2.06, 1.19-3.56) and BPD (OR 0.46, 0.34-0.61) compared to infants remaining hospitalized for an alternative reason.

Conclusion: IOF is the most common barrier to discharge in MPT infants, especially among those with neonatal morbidities.
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http://dx.doi.org/10.1038/s41372-019-0422-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246972PMC
September 2019

Differences in patient characteristics and care practices between two trials of therapeutic hypothermia.

Pediatr Res 2019 06 12;85(7):1008-1015. Epub 2019 Mar 12.

Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.

Background: The Induced Hypothermia (IH) and Optimizing Cooling (OC) trials for hypoxic-ischemic encephalopathy (HIE) had similar inclusion criteria. The rate of death/moderate-severe disability differed for the subgroups treated with therapeutic hypothermia (TH) at 33.5 °C for 72 h (44% vs. 29%, unadjusted p = 0.03). We aimed to evaluate differences in patient characteristics and care practices between the trials.

Methods: We compared pre/post-randomization characteristics and care practices between IH and OC.

Results: There were 208 patients in the IH trial, 102 cooled, and 364 in the OC trial, 95 cooled to 33.5 °C for 72 h. In OC, neonates were less ill, fewer had severe HIE, and the majority were cooled prior to randomization. Differences between IH and OC were observed in the adjusted difference in the lowest PCO (+3.08 mmHg, p = 0.005) and highest PO (-82.7 mmHg, p < 0.001). In OC, compared to IH, the adjusted relative risk (RR) of exposure to anticonvulsant prior to randomization was decreased (RR 0.58, (0.40-0.85), p = 0.005) and there was increased risk of exposure during cooling to sedatives/analgesia (RR 1.86 (1.21-2.86), p = 0.005).

Conclusion: Despite similar inclusion criteria, there were differences in patient characteristics and care practices between trials. Change in care practices over time should be considered when planning future neuroprotective trials.
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http://dx.doi.org/10.1038/s41390-019-0371-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857796PMC
June 2019

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks' Gestational Age: A Randomized Clinical Trial.

JAMA 2018 10;320(16):1649-1658

Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City.

Importance: Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety.

Objective: To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age.

Design, Setting, And Participants: Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group.

Interventions: A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks.

Main Outcomes And Measures: Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP.

Results: Among 638 infants (mean, 26 weeks' gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks' postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%).

Conclusions And Relevance: Among premature infants younger than 28 weeks' gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.
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http://dx.doi.org/10.1001/jama.2018.14996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233812PMC
October 2018

Weaning of Moderately Preterm Infants from the Incubator to the Crib: A Randomized Clinical Trial.

J Pediatr 2019 01 15;204:96-102.e4. Epub 2018 Oct 15.

Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, OH.

Objective: To assess whether length of hospital stay is decreased among moderately preterm infants weaned from incubator to crib at a lower vs higher weight.

Study Design: This trial was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants with gestational ages 29-33 weeks, birthweight <1600 g, and in an incubator were randomly assigned to a weaning weight of 1600 or 1800 g. Within 60 to 100 g of weaning weight, the incubator temperature was decreased by 1.0°C to 1.5°C every 24 hours until 28.0°C. The infants were weaned to the crib following stable temperature at 36.5°C to 37.4°C for 8 to 12 hours. Clothing and bedcoverings were standardized. The primary outcome was length of hospital stay from birth to discharge; secondary outcomes included length of stay and growth velocity from weaning to discharge. Adverse events were monitored.

Results: Of 1565 infants screened, 885 were eligible, and 366 enrolled-187 to the 1600-g and 179 to the 1800-g group. Maternal and neonatal characteristics did not differ among weight groups. Length of hospital stay was a median of 43 days in the lower and 41 days in the higher weight group (P = .12). Growth velocity from completion of weaning to discharge was higher in the lower weight group, 13.7 g/kg/day vs 12.8 g/kg/day (P = .005). Groups did not differ in adverse events.

Conclusions: Among moderately preterm neonates, weaning from incubator to crib at a lower weight did not decrease length of stay, but was safe and was accompanied by higher weight gain after weaning.

Trial Registration: ClinicalTrials.gov: NCT02160002.
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http://dx.doi.org/10.1016/j.jpeds.2018.08.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326364PMC
January 2019

NIRS improves hemodynamic monitoring and detection of risk for cerebral injury: cases in the neonatal intensive care nursery.

J Matern Fetal Neonatal Med 2020 May 29;33(10):1802-1810. Epub 2018 Oct 29.

Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.

Near-infrared spectroscopy (NIRS) monitoring provides a noninvasive, bedside measure of cerebral and somatic oxygenation in neonates at risk for hemodynamic instability and brain injury. This technology has been increasingly utilized in the neonatal intensive care unit, however, clinicians perceive a lack of evidence for the added value of NIRS monitoring. We present six clinical scenarios illustrating the value of NIRS monitoring for the diagnosis and management of critically ill newborns.
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http://dx.doi.org/10.1080/14767058.2018.1528223DOI Listing
May 2020

Preterm Neuroimaging and School-Age Cognitive Outcomes.

Pediatrics 2018 07;142(1)

Department of Pediatrics, Duke University, Durham, North Carolina.

Background And Objectives: Children born extremely preterm are at risk for cognitive difficulties and disability. The relative prognostic value of neonatal brain MRI and cranial ultrasound (CUS) for school-age outcomes remains unclear. Our objectives were to relate near-term conventional brain MRI and early and late CUS to cognitive impairment and disability at 6 to 7 years among children born extremely preterm and assess prognostic value.

Methods: A prospective study of adverse early and late CUS and near-term conventional MRI findings to predict outcomes at 6 to 7 years including a full-scale IQ (FSIQ) <70 and disability (FSIQ <70, moderate-to-severe cerebral palsy, or severe vision or hearing impairment) in a subgroup of Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial enrollees. Stepwise logistic regression evaluated associations of neuroimaging with outcomes, adjusting for perinatal-neonatal factors.

Results: A total of 386 children had follow-up. In unadjusted analyses, severity of white matter abnormality and cerebellar lesions on MRI and adverse CUS findings were associated with outcomes. In full regression models, both adverse late CUS findings (odds ratio [OR] 27.9; 95% confidence interval [CI] 6.0-129) and significant cerebellar lesions on MRI (OR 2.71; 95% CI 1.1-6.7) remained associated with disability, but only adverse late CUS findings (OR 20.1; 95% CI 3.6-111) were associated with FSIQ <70. Predictive accuracy of stepwise models was not substantially improved with the addition of neuroimaging.

Conclusions: Severe but rare adverse late CUS findings were most strongly associated with cognitive impairment and disability at school age, and significant cerebellar lesions on MRI were associated with disability. Near-term conventional MRI did not substantively enhance prediction of severe early school-age outcomes.
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http://dx.doi.org/10.1542/peds.2017-4058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128951PMC
July 2018

Renal Saturation and Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia.

J Pediatr 2018 09 1;200:232-239.e1. Epub 2018 Jun 1.

Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, CA.

Objective: To investigate the range of renal near-infrared spectroscopy (NIRS) measures in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) and to determine the association between renal NIRS measures and the development of acute kidney injury (AKI).

Study Design: A retrospective chart review was conducted of neonates with moderate to severe HIE who received therapeutic hypothermia at a tertiary care center from 2014 to 2016. Neonates had routine continuous NIRS monitoring of cerebral and renal saturation (Rsat) as part of their clinical care for 72 hours of cooling and until 24 hours after rewarming. The outcome of AKI was defined by an abnormal rate of decline of serum creatinine over the first 5 days of life. Mixed effects models determined the association between renal NIRS measures and AKI over time.

Results: Of 38 neonates with HIE undergoing cooling, 15 (39%) developed AKI. Rsat was lower than cerebral saturation during cooling (P < .01), but Rsat increased over time after rewarming, while renal oxygen extraction levels decreased (P < .0001). Neonates with AKI had higher Rsat levels (P < .01) compared with those without AKI after 24 hours of life. Using receiver operating characteristic curves, Rsat >75% by 24-48 hours predicted AKI with a sensitivity of 79% and specificity of 82% (area under the receiver operating characteristic curve = 0.76).

Conclusions: Throughout cooling, neonates with AKI had higher Rsat measures than those without AKI. These differences may reflect lower oxygen extraction by the injured kidney. NIRS monitoring of Rsat may identify neonates with HIE at risk of developing AKI.
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http://dx.doi.org/10.1016/j.jpeds.2018.04.076DOI Listing
September 2018

Development of a NeuroNICU with a Broader Focus on All Newborns at Risk of Brain Injury: The First 2 Years.

Am J Perinatol 2018 10 27;35(12):1197-1205. Epub 2018 Apr 27.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.

Objective: Many critically ill neonates have an existing brain injury or are at risk of neurologic injury. We developed a "NeuroNICU" (neurologic neonatal intensive care unit) to better provide neurologically focused intensive care.

Study Design: Demographic and clinical variables, services delivered, and patient outcomes were recorded in a prospective database for all neonates admitted to the NeuroNICU between April 23, 2013, and June 25, 2015.

Results: In total, 546 neonates were admitted to the NeuroNICU representing 32% of all NICU admissions. The most common admission diagnoses were congenital heart disease (30%), extreme prematurity (18%), seizures (10%), and hypoxic-ischemic encephalopathy (9%). Neuromonitoring was common, with near-infrared spectroscopy used in 69%, amplitude-integrated electroencephalography (EEG) in 45%, and continuous video EEG in 35%. Overall, 43% received neurology or neurosurgery consultation. Death prior to hospital discharge occurred in 11%. Among survivors, 87% were referred for developmental follow-up, and among those with a primary neurologic diagnosis 57% were referred for neurology or neurosurgical follow-up.

Conclusion: The NeuroNICU-admitted newborns with or at risk of brain injury comprise a high percentage of NICU volume; 38% had primary neurologic diagnoses, whereas 62% had medical diagnoses. We found many opportunities to provide brain focused intensive care, impacting a substantial proportion of newborns in our NICU.
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http://dx.doi.org/10.1055/s-0038-1646954DOI Listing
October 2018

Oral feeding practices and discharge timing for moderately preterm infants.

Early Hum Dev 2018 05 11;120:46-52. Epub 2018 Apr 11.

Department of Pediatrics, University of Iowa, Iowa City, IA, USA. Electronic address:

Background: Oral feeding skills of moderately preterm infants are not mature at birth.

Aims: To establish the relationship between postmenstrual age at introduction of first oral feeding and attainment of full oral feeding and hospital discharge for moderately preterm infants.

Study Design: Multicenter retrospective analysis of a prospective cohort of moderately preterm infants admitted to a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hospital.

Subjects: 6146 infants born at 29-33 weeks' gestation from January 2012 to November 2013.

Outcome Measures: Postmenstrual age at full oral feeding and at hospital discharge.

Results: The median postmenstrual age at first oral feeding was 33.9 weeks (interquartile range 33.1-34.3). For each week earlier at first oral feeding, full oral feeding occurred 4.5 days earlier (p < 0.0001) and hospital stay was shortened by 3.4 days (p < 0.0001). Higher birth weight (p < 0.0001) and black maternal race (p = 0.0001) were associated with younger postmenstrual age at full oral feeding and at discharge.

Conclusion: Moderately preterm infants with earlier introduction of oral feeding achieved earlier full oral feeding and hospital discharge.
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http://dx.doi.org/10.1016/j.earlhumdev.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951763PMC
May 2018

Outcome of Preterm Infants with Transient Cystic Periventricular Leukomalacia on Serial Cranial Imaging Up to Term Equivalent Age.

J Pediatr 2018 04 2;195:59-65.e3. Epub 2018 Feb 2.

Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL.

Objective: To determine the outcome of preterm infants whose cystic periventricular leukomalacia "disappeared" on serial screening cranial imaging studies.

Study Design: Infants ≤26 weeks of gestation born between 2002 and 2012 who had cranial imaging studies at least twice, the most abnormal study at <28 days of age and another closest to 36 weeks, were reviewed. The outcome of late death (after 36 weeks postmenstrual age) or neurodevelopmental impairment (NDI) in surviving infants at 18-26 months corrected age was compared between the infants with no cystic periventricular leukomalacia on both studies and cystic periventricular leukomalacia that disappeared (cystic periventricular leukomalacia at <28 days but not at 36 weeks), persisted (cystic periventricular leukomalacia on both studies), or appeared late (cystic periventricular leukomalacia only at 36 weeks). Predictors of NDI were evaluated by logistic regression.

Results: Of 7063 eligible infants, 433 (6.1%) had cystic periventricular leukomalacia. Among the 433 infants with cystic periventricular leukomalacia, cystic periventricular leukomalacia disappeared in 76 (18%), persisted in 87 (20%), and 270 (62%) had late cystic periventricular leukomalacia. Loss to follow-up ranged between 3% and 13%. Death or NDI was more common in infants with disappeared cystic periventricular leukomalacia compared with those with no cystic periventricular leukomalacia (38 of 72 [53%] vs 1776 of 6376 [28%]; OR [95% CI] 2.8 [1.8-4.6]). Disappeared, persistent, and late cystic periventricular leukomalacia were all also independently associated with NDI (OR 1.17, 1.21, and 1.16, respectively).

Conclusions: Infants with "disappeared" cystic periventricular leukomalacia are at increased risk of adverse outcome similar to infants with persistent or late cystic periventricular leukomalacia.
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http://dx.doi.org/10.1016/j.jpeds.2017.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407628PMC
April 2018

Delivery Room Resuscitation and Short-Term Outcomes in Moderately Preterm Infants.

J Pediatr 2018 04 3;195:33-38.e2. Epub 2018 Jan 3.

Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH.

Objectives: To describe the frequency and extent of delivery room resuscitation and evaluate the association of delivery room resuscitation with neonatal outcomes in moderately preterm (MPT) infants.

Study Design: This was an observational cohort study of MPT infants delivered at 29 to 33 weeks' gestational age (GA) enrolled in the Neonatal Research Network MPT registry. Infants were categorized into 5 groups based on the highest level of delivery room intervention: routine care, oxygen and/or continuous positive airway pressure, bag and mask ventilation, endotracheal intubation, and cardiopulmonary resuscitation including chest compressions and/or epinephrine use. The association of antepartum and intrapartum risk factors and discharge outcomes with the intensity of resuscitation was evaluated.

Results: Of 7014 included infants, 1684 (24.0%) received routine care and no additional resuscitation, 2279 (32.5%) received oxygen or continuous positive airway pressure, 1831 (26.1%) received bag and mask ventilation, 1034 (14.7%) underwent endotracheal intubation, and 186 (2.7%) received cardiopulmonary resuscitation. Among the antepartum and intrapartum factors, increasing GA, any exposure to antenatal steroids and prolonged rupture of membranes decreased the likelihood of receipt of all levels of resuscitation. Infants who were small for GA (SGA) had increased risk of delivery room resuscitation. Among the neonatal outcomes, respiratory support at 28 days, days to full oral feeds and length of stay were significantly associated with the intensity of delivery room resuscitation. Higher intensity of resuscitation was associated with increased risk of mortality.

Conclusions: The majority of MPT infants receive some level of delivery room resuscitation. Increased intensity of delivery room interventions was associated with prolonged respiratory and nutritional support, increased mortality, and a longer length of stay.
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http://dx.doi.org/10.1016/j.jpeds.2017.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869086PMC
April 2018

Neurodevelopmental and Behavioral Outcomes in Extremely Premature Neonates With Ventriculomegaly in the Absence of Periventricular-Intraventricular Hemorrhage.

JAMA Pediatr 2018 01;172(1):32-42

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Importance: Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood.

Objective: To characterize the outcomes of extremely preterm neonates younger than 27 weeks' gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks' postmenstrual age.

Design, Setting, And Participants: This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks' gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks' postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017.

Main Outcomes And Measures: The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes.

Results: Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ.

Conclusions And Relevance: Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.
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http://dx.doi.org/10.1001/jamapediatrics.2017.3545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833521PMC
January 2018

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

JAMA 2017 10;318(16):1550-1560

Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island.

Importance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours.

Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy.

Design, Setting, And Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size.

Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C).

Main Outcomes And Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization.

Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively.

Conclusions And Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.

Trial Registration: clinicaltrials.gov Identifier: NCT00614744.
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http://dx.doi.org/10.1001/jama.2017.14972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783566PMC
October 2017

Identification of Extremely Premature Infants at Low Risk for Early-Onset Sepsis.

Pediatrics 2017 Nov 5;140(5). Epub 2017 Oct 5.

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children's Medical Center Dallas, Dallas, Texas.

Background: Premature infants are at high risk of early-onset sepsis (EOS) relative to term infants, and most are administered empirical antibiotics after birth. We aimed to determine if factors evident at birth could be used to identify premature infants at lower risk of EOS.

Methods: Study infants were born at 22 to 28 weeks' gestation in Neonatal Research Network centers from 2006 to 2014. EOS was defined by isolation of pathogenic species from blood or cerebrospinal fluid culture at ≤72 hours age. Infants were hypothesized as "low risk" for EOS when delivered via cesarean delivery, with membrane rupture at delivery, and absence of clinical chorioamnionitis. Frequency of prolonged antibiotics (≥5 days) was compared between low-risk infants and all others. Risks of mortality, EOS, and other morbidities were assessed by using regression models adjusted for center, race, antenatal steroid use, multiple birth, sex, gestation, and birth weight.

Results: Of 15 433 infants, 5759 (37%) met low-risk criteria. EOS incidence among infants surviving >12 hours was 29 out of 5640 (0.5%) in the low-risk group versus 209 out of 8422 (2.5%) in the comparison group (adjusted relative risk = 0.24 [95% confidence interval, 0.16-0.36]). Low-risk infants also had significantly lower combined risk of EOS or death ≤12 hours. Prolonged antibiotics were administered to 34% of low-risk infants versus 47% of comparison infants without EOS.

Conclusions: Delivery characteristics of extremely preterm infants can be used to identify those with significantly lower incidence of EOS. Recognition of differential risk may help guide decisions to limit early antibiotic use among approximately one-third of these infants.
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http://dx.doi.org/10.1542/peds.2017-0925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654397PMC
November 2017

Effect of Inhaled Nitric Oxide on Survival Without Bronchopulmonary Dysplasia in Preterm Infants: A Randomized Clinical Trial.

JAMA Pediatr 2017 11;171(11):1081-1089

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City.

Importance: Bronchopulmonary dysplasia (BPD) occurs in approximately 40% of infants born at younger than 30 weeks' gestation and is associated with adverse pulmonary and neurodevelopmental outcomes.

Objective: To test whether administration of inhaled nitric oxide to preterm infants requiring positive pressure respiratory support on postnatal days 5 to 14 improves the rate of survival without BPD.

Design, Setting, And Participants: This intent-to-treat study was a randomized clinical trial performed at 33 US and Canadian neonatal intensive care units. Participants included 451 neonates younger than 30 weeks' gestation with birth weight less than 1250 g receiving mechanical ventilation or positive pressure respiratory support on postnatal days 5 to 14. Enrollment spanned from December 23, 2009, to April 23, 2012, and neurodevelopmental outcome studies were completed by April 4, 2014.

Interventions: Placebo (nitrogen) or inhaled nitric oxide initiated at 20 ppm was decreased to 10 ppm between 72 and 96 hours after starting treatment and then to 5 ppm on day 10 or 11. Infants remained on the 5-ppm dose until completion of therapy (24 days).

Main Outcomes And Measures: The primary outcome was the rate of survival without BPD at 36 weeks' postmenstrual age (PMA). Secondary outcomes included BPD severity, postnatal corticosteroid use, respiratory support, survival, and neurodevelopmental outcomes at 18 to 24 months' PMA.

Results: In total, 222 infants (52.3% male [n = 116]) received placebo, and 229 infants (50.2% male [n = 115]) received inhaled nitric oxide. Their mean (SD) gestation was 25.6 (1.5) vs 25.6 (1.4) weeks, and their mean (SD) birth weight was 750 (164) vs 724 (160) g. Survival without BPD at 36 weeks' PMA was similar between the placebo and inhaled nitric oxide groups (31.5% [n = 70] vs 34.9% [n = 80]) (odds ratio, 1.17; 95% CI, 0.79-1.73). Rates for severe BPD (26.6% [55 of 207] vs 20.5% [43 of 210]) and postnatal corticosteroid use for BPD (41.0% [91 of 222] vs 41.5% [95 of 229]) and the mean (SD) days of positive pressure respiratory support (55 [40] vs 54 [42]), oxygen therapy (88 [41] vs 91 [59]), and hospitalization (105 [37] vs 108 [54]) were equivalent between the 2 groups. No differences in the incidence of common morbidities were observed. Respiratory outcomes on discharge to home, at 1 year, and at age 18 to 24 months' PMA and neurodevelopmental assessments at 18 to 24 months' PMA did not differ between groups.

Conclusions And Relevance: Inhaled nitric oxide, initiated at 20 ppm on postnatal days 5 to 14 to high-risk preterm infants and continued for 24 days, appears to be safe but did not improve survival without BPD at 36 weeks' PMA or respiratory and neurodevelopmental outcomes at 18 to 24 months' PMA.

Trial Registration: clinicaltrials.gov Identifier: NCT00931632.
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http://dx.doi.org/10.1001/jamapediatrics.2017.2618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710365PMC
November 2017

Late-onset Sepsis in Extremely Premature Infants: 2000-2011.

Pediatr Infect Dis J 2017 08;36(8):774-779

From the *Department of Pediatrics, Duke University School of Medicine, †Duke Clinical Research Institute, Duke University School of Medicine, and ‡Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Durham, North Carolina; §Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia; ¶Department of Pediatrics, University of Iowa, Iowa City, Iowa; ‖Division of Neonatology, University of Alabama at Birmingham, Birmingham, Alabama; **Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island; ††Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; ‡‡Department of Pediatrics, Wayne State University, Detroit, Michigan; §§Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California; ¶¶Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio; ‖‖Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland; and ***Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Background: Late-onset sepsis (LOS) is an important cause of death and neurodevelopmental impairment in premature infants. The purpose of this study was to assess overall incidence of LOS, distribution of LOS-causative organisms and center variation in incidence of LOS for extremely premature infants over time.

Methods: In a retrospective analysis of infants 401-1000 g birth weight and 22-28 6/7 weeks of gestational age born at 12 National Institute of Child Health and Human Development Neonatal Research Network centers in the years 2000-2005 (era 1) or 2006-2011 (era 2) who survived >72 hours, we compared the incidence of LOS and pathogen distribution in the 2 eras using the χ test. We also examined the effect of birth year on the incidence of LOS using multivariable regression to adjust for nonmodifiable risk factors and for center. To assess whether the incidence of LOS was different among centers in era 2, we used a multivariable regression model to adjust for nonmodifiable risk factors.

Results: Ten-thousand one-hundred thirty-one infants were studied. LOS occurred in 2083 of 5031 (41%) infants in era 1 and 1728 of 5100 (34%) infants in era 2 (P < 0.001). Birth year was a significant predictor of LOS on adjusted analysis, with birth years 2000-2009 having a significantly higher odds of LOS than the reference year 2011. Pathogens did not differ, with the exception of decreased fungal infection (P < 0.001). In era 2, 9 centers had significantly higher odds of LOS compared with the center with the lowest incidence.

Conclusions: The incidence of LOS decreased over time. Further investigation is warranted to determine which interventions have the greatest impact on infection rates.
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http://dx.doi.org/10.1097/INF.0000000000001570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627954PMC
August 2017

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

JAMA 2017 Jul;318(1):57-67

Department of Pediatrics, University of Michigan, Ann Arbor.

Importance: Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high.

Objective: To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy.

Design, Setting, And Participants: Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016.

Interventions: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83).

Main Outcomes And Measures: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification.

Results: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours.

Conclusions And Relevance: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C.

Trial Registration: clinicaltrials.gov Identifier: NCT01192776.
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http://dx.doi.org/10.1001/jama.2017.7218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793705PMC
July 2017
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