by
Dale L. Phelps;
Robert M. Ward;
Rick L. Williams;
Tracy L. Nolen;
Kristi L. Watterberg;
William Oh;
Michael Goedecke;
Richard A. Ehrenkranz;
Timothy Fennell;
Brenda B. Poindexter;
C. Michael Cotten;
Mikko Hallman;
Ivan D. Frantz;
Roger G. Faix;
Kristin M. Zaterka-Baxter;
Abhik Das;
M. Bethany Ball;
Conra B. Lacy;
Michele C. Walsh;
Waldemar A. Carlo;
Pablo J. Sanchez;
Edward F. Bell;
Seetha Shankaran;
David Carlton;
Patricia R. Chess;
Rosemary D. Higgins
Background: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization.
Methods: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored.
Results: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so.
Conclusion: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.
by
Ira Adams-Chapman;
Nellie I. Hansen;
Seetha Shankaran;
Edward F. Bell;
Nansi S. Boghossian;
Jeffrey C. Murray;
Abbot R. Laptook;
Michele C. Walsh;
Waldemar A. Carlo;
Pablo J. Sanchez;
Krisa P. Van Meurs;
Abhik Das;
Ellen C. Hale;
Nancy S. Newman;
M. Bethany Ball;
Rosemary D. Higgins;
Barbara J Stoll
OBJECTIVE:
Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.
METHODS:
Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.
RESULTS:
A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41–3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).
CONCLUSIONS:
Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.
by
Nansi S. Boghossian;
Grier P. Page;
Edward F. Bell;
Barbara Stoll;
Jeffrey C. Murray;
C. Michael Cotten;
Seetha Shankaran;
Michele C. Walsh;
Abbot R. Laptook;
Nancy S. Newman;
Ellen C. Hale;
Scott A. McDonald;
Abhik Das;
Rosemary D. Higgins
Objectives To describe and compare the incidence of late-onset sepsis (LOS) and demographic and clinical characteristics associated with LOS in very low birth weight (VLBW) infants from singleton and multiple births, and to examine the heritability of susceptibility to LOS among VLBW twins by comparing same-sex and unlike-sex twin pairs. Study design The study group comprised infants with birth weight 401-1500 g seen at clinical centers of the Eunice Kennedy Shriver National Institute of Child and Human Development Neonatal Research Network between 2002 and 2008. Only the first episode of LOS was included in our analysis. Stepwise logistic regression models were fitted separately for singleton and multiple pregnancies to examine the maternal and neonatal factors associated with LOS. LOS due solely to gram-negative bacteria in singleton and multiple pregnancies was also examined in separate models. The heritability of LOS was estimated by examining the concordance of LOS in twins from same-sex and unlike-sex pairs. Results LOS occurred in 25.0% (3797 of 15 178) of singleton and 22.6% (1196 of 5294) of multiple-birth VLBW infants. Coagulase-negative staphylococci were the most common infecting organisms, accounting for 53.2% of all LOS episodes in singletons and 49.2% in multiples. Escherichia coli and Klebsiella species were the most commonly isolated gram-negative organisms, and Candida albicans was the most commonly isolated fungus. Concordance of LOS did not differ significantly between same-sex and unlike-sex twin pairs. Conclusion LOS remains a common problem in VLBW infants. The incidence of LOS is similar for singleton and multiple-birth infants. The similar concordance of LOS in same-sex and unlike-sex twin pairs provides no evidence that susceptibility to LOS among VLBW infants is genetically determined.
by
Ravi Patel;
Sarah Kandefer;
Michele C. Walsh;
Edward F. Bell;
Waldemar A. Carlo;
Abbot R. Laptook;
Pablo J. Sánchez;
Seetha Shankaran;
Krisa P. Van Meurs;
M. Bethany Ball;
Ellen C. Hale;
Nancy S. Newman;
Abhik Das;
Rosemary D. Higgins;
Barbara Stoll
BACKGROUND: Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families. METHODS: We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences. RESULTS: The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days. CONCLUSIONS: We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).
by
Cristina T. Navarrete;
Lisa A. Wrage;
Waldemar A. Carlo;
Michele C. Walsh;
Wade Rich;
Marie G. Gantz;
Abhik Das;
Kurt Schibler;
Nancy S. Newman;
Anthony Piazza;
Brenda B. Poindexter;
Seetha Shankaran;
Pablo J. Sanchez;
Brenda H. Morris;
Ivan D. Frantz III;
Krisa P. Van Meurs;
C. Michael Cotten;
Richard A. Ehrenkranz;
Edward F. Bell;
Kristi L. Watterberg;
Rosemary D. Higgins;
Shahnaz Duara
Objective: To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO 2 ]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA) and less growth failure at 36 weeks PMA and 18-22 months corrected age.
Study design: We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n = 402, PMA 26 ± 1 weeks, birth weight 839 ± 186 g) or higher (91%-95%, n = 408, PMA 26 ± 1 weeks, birth weight 840 ± 191 g) SpO 2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA; and 18-22 months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight < 10th percentile at 36 weeks PMA and 18-22 months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression.
Results: Growth outcomes including growth at 36 weeks PMA and 18-22 months corrected age, as well as growth velocity were similar in the lower and higher SpO 2 target groups.
Conclusion: Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants.
by
Michele C. Walsh;
Edward F. Bell;
Sarah Kandefer;
Shampa Saha;
Waldemar A. Carlo;
Carl T. D'angio;
Abbot R. Laptook;
Pablo J. Sanchez;
Barbara Stoll;
Seetha Shankaran;
Krisa P. Van Meurs;
Noah Cook;
Rosemary D. Higgins;
Abhik Das;
Nancy Newman;
Kurt Schibler;
Barbara Schmidt;
C. Michael Cotten;
Brenda B. Poindexter;
Kristi L. Watterberg;
William E. Truog
BackgroundExtremely preterm infants (EPT, < 29 weeks' gestation) represent only 0.9% of births in the United States; yet these infants are the focus of most published research. Moderately preterm neonates (MPT, 29-33 6/7 weeks) are an understudied group of high-risk infants.MethodsTo determine the neonatal outcomes of MPT infants across the gestational age spectrum, and to compare these with EPT infants. A prospective observational cohort was formed in 18 level 3-4 neonatal intensive care units (NICUs) in the Eunice Kennedy Shriver NICHD Neonatal Research Network. Participants included all MPT infants admitted to NICUs and all EPT infants born at sites between January 2012 and November 2013. Antenatal characteristics and neonatal morbidities were abstracted from records using pre-specified definitions by trained neonatal research nurses.ResultsMPT infants experienced morbidities similar to, although at lower rates than, those of EPT infants. The main cause of mortality was congenital malformation, accounting for 43% of deaths. Central Nervous System injury occurred, including intraventricular hemorrhage. Most MPT infants required respiratory support, but sequelae such as bronchopulmonary dysplasia were rare. The primary contributors to hospitalization beyond 36 weeks' gestation were inability to achieve adequate oral intake and persistent apnea.ConclusionsMPT infants experience morbidity and prolonged hospitalization. Such morbidity deserves focused research to improve therapeutic and prevention strategies.
by
Erika Fernandez;
Kristi L. Watterberg;
Roger G. Faix;
Bradley A. Yoder;
Michele C. Walsh;
Conra Backstrom Lacy;
Karen A. Osborne;
Abhik Das;
Douglas E. Kendrick;
Barbara Stoll;
Brenda B. Poindexter;
Abbot R. Laptook;
Kathleen A. Kennedy;
Kurt Schibler;
Edward F. Bell;
Krisa P. Van Meurs;
Ivan D. Frantz, III;
Ronald N. Goldberg;
Seetha Shankaran;
Waldemar A. Carlo;
Richard A. Ehrenkranz;
Pablo J. Sanchez;
Rosemary D. Higgins
Background: We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants.
Objective: This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death.
Study Design: The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed.
Results: All the four definitions were associated with greater number of days on MV and days on O<inf>2</inf>. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death.
Conclusions: The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.
by
Seetha Shankaran;
Abbot R. Laptook;
Athina Pappas;
Scott A. McDonald;
Abhik Das;
Jon E. Tyson;
Brenda B. Poindexter;
Kurt Schibler;
Edward F. Bell;
Roy J. Heyne;
Claudia Pedroza;
Rebecca Bara;
Krisa P. Van Meurs;
Carolyn M. Petrie Huitema;
Cathy Grisby;
Uday Devaskar;
Richard A. Ehrenkranz;
Heidi M. Harmon;
Linda F. Chalak;
Sara B. DeMauro;
Meena Garg;
Michelle E. Hartley-McAndrew;
Amir M. Khan;
Michele C. Walsh;
Namasivayam Ambalavanan;
Jane E. Brumbaugh;
Kristi L. Watterberg;
Edward G. Shepherd;
Shannon Hamrick;
John Barks;
C. Michael Cotten;
Howard W. Kilbride;
Rosemary D. Higgins
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 outcomewas 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.
by
Valerie Y. Chock;
Haresh Kirpalani;
Edward F. Bell;
Sylvia Tan;
Susan R. Hintz;
M. Bethany Ball;
Emily Smith;
Abhik Das;
Yvonne C. Loggins;
Beena G. Sood;
Lina F. Chalak;
Myra H. Wyckoff;
Stephen D. Kicklighter;
Kathleen A. Kennedy;
Ravi Mangal Patel;
Waldemar A. Carlo;
Karen J. Johnson;
Kristi L. Watterberg;
Pablo J. Sánchez;
Abbot R. Laptook;
Ruth B. Seabrook;
C. Michael Cotten;
Toni Mancini;
Gregory M. Sokol;
Robin K. Ohls;
Anna Maria Hibbs;
Brenda B. Poindexter;
Anne Marie Reynolds;
Sara B. DeMauro;
Sanjay Chawla;
Mariana Baserga;
Michele C. Walsh;
Rosemary D. Higgins;
Krisa P. Van Meurs
Importance
Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes.
Objective
To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age.
Design, Setting, and Participants
This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022.
Interventions
Near-infrared spectroscopy monitoring of Csat and Msat.
Main Outcomes and Measures
Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment.
Results
A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower–hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher–hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs −0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03).
Conclusions and Relevance
In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia.
by
Edward F. Bell;
Barbara J Stoll;
Nellie Hansen;
Myra H. Myckoff;
Michele C. Walsh;
Pablo J. Sánchez;
Matthew A. Rysavy;
Jenna H. Gabrio;
Stephanie W. Archer;
Abhik Das;
Rosemary D. Higgins
The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) maintains a database of extremely preterm infants known as the Generic Database (GDB). Begun in 1987, this database now includes more than 91,000 infants, most of whom are extremely preterm (<29 weeks gestation). The GDB has been a backbone of the NRN, providing high quality, prospectively collected data to study the changing epidemiology of extreme prematurity and its outcomes over time. In addition, GDB data have been used to generate hypotheses for prospective studies and to develop new clinical trials by providing information about the numbers and characteristics of available subjects and the expected event rates for conditions and complications to be studied. Since its inception, the GDB has been the basis of more than 200 publications in peer-reviewed journals, many of which have had a significant impact on the field of neonatology.