Browsing by Author "Higgins, Rosemary D."

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    Apolipoprotein E (APOE) Genotype and Outcome in Infants with Hypoxic-Ischemic Encephalopathy (HIE)
    (Springer Nature, 2014) Cotten, C. Michael; Goldstein, Ricki F.; McDonald, Scott A.; Goldberg, Ronald N.; Salhab, Walid A.; Carlo, Waldemar A.; Tyson, Jon E.; Finer, Neil N.; Walsh, Michele C.; Ehrenkranz, Richard A.; Laptook, Abbot R.; Guillet, Ronnie; Schibler, Kurt; Van Meurs, Krisa P.; Poindexter, Brenda B.; Stoll, Barbara J.; O'Shea, T. Michael; Duara, Shahnaz; Das, Abhik; Higgins, Rosemary D.; Shankaran, Seetha; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of Medicine
    Background: Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE). Methods: We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-. Results: A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups. Conclusion: Disability was not associated with the APOE genotype in this cohort of HIE survivors.
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    Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes
    (Elsevier, 2012) Vohr, Betty R.; Stephens, Bonnie E.; Higgins, Rosemary D.; Bann, Carla M.; Hintz, Susan R.; Epi, M. S.; Das, Abhik; Newman, Jamie E.; Peralta-Carcelen, Myriam; Yolton, Kimberly; Dusick, Anna M.; Evans, Patricia W.; Goldstein, Ricki F.; Ehrenkranz, Richard A.; Pappas, Athina; Adams-Chapman, Ira; Wilson-Costello, Deanne E.; Bauer, Charles R.; Bodnar, Anna; Heyne, Roy J.; Vaucher, Yvonne E.; Dillard, Robert G.; Acarregui, Michael J.; McGowan, Elisabeth C.; Myers, Gary J.; Fuller, Janell; Eunice Kennedy Shriver National Institute of Child Health and Network Human Development Neonatal Research; Pediatrics, School of Medicine
    Objectives: To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development's Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006-2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008-2011 (period 2). Study design: Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates. Results: Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001). Conclusion: Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.
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    Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study
    (American Medical Association, 2021) Chalak, Lina F.; Pappas, Athina; Tan, Sylvia; Das, Abhik; Sánchez, Pablo J.; Laptook, Abbot R.; Van Meurs, Krisa P.; Shankaran, Seetha; Bell, Edward F.; Davis, Alexis S.; Heyne, Roy J.; Pedroza, Claudia; Poindexter, Brenda B.; Schibler, Kurt; Tyson, Jon E.; Ball, M. Bethany; Bara, Rebecca; Grisby, Cathy; Sokol, Gregory M.; D'Angio, Carl T.; Hamrick, Shannon E.G.; Dysart, Kevin C.; Cotten, C. Michael; Truog, William E.; Watterberg, Kristi L.; Timan, Christopher J.; Garg, Meena; Carlo, Waldemar A.; Higgins, Rosemary D.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of Medicine
    Importance: Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective: To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, setting, and participants: This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions: Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main outcomes and measures: The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results: A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and relevance: Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk.
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    Blood myo-inositol concentrations in preterm and term infants
    (Springer Nature, 2021-02) Brion, Luc P.; Phelps, Dale L.; Ward, Robert M.; Nolen, Tracy L.; Hallman, N. Mikko K.; Das, Abhik; Zaccaro, Daniel J.; Ball, M. Bethany; Watterberg, Kristi L.; Frantz, Ivan D., III.; Cotten, C. Michael; Poindexter, Brenda B.; Oh, William; Lugo, Ralph A.; Van Meurs, Krisa P.; O’Shea, T. Michael; Zaterka-Baxter, Kristin M.; Higgins, Rosemary D.; Pediatrics, School of Medicine
    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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    Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy
    (BMJ, 2012) Shankaran, Seetha; Barnes, Patrick D.; Hintz, Susan R.; Laptook, Abbott R.; Zaterka-Baxter, Kristin M.; McDonald, Scott A.; Ehrenkranz, Richard A.; Walsh, Michele C.; Tyson, Jon E.; Donovan, Edward F.; Goldberg, Ronald N.; Bara, Rebecca; Das, Abhik; Finer, Neil N.; Sanchez, Pablo J.; Poindexter, Brenda B.; Van Meurs, Krisa P.; Carlo, Waldemar A.; Stoll, Barbara J.; Duara, Shahnaz; Guillet, Ronnie; Higgins, Rosemary D.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of Medicine
    Objective: The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia. Design and patients: Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age. Results: Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. Conclusions: Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.
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    Bronchopulmonary Dysplasia: Executive Summary of a Workshop
    (Elsevier, 2018-06) Higgins, Rosemary D.; Jobe, Alan H.; Koso-Thomas, Marion; Bancalari, Eduardo; Viscardi, Rose M.; Hartert, Tina V.; Ryan, Rita M.; Kallapur, Suhas G.; Steinhorn, Robin H.; Konduri, Girija G.; Davis, Stephanie D.; Thebaud, Bernard; Clyman, Ronald I.; Collaco, Joseph M.; Martin, Camilia R.; Woods, Jason C.; Finer, Neil N.; Raju, Tonse N. K.; Pediatrics, School of Medicine
    Comment in Bronchopulmonary Dysplasia: The Ongoing Search for One Definition to Rule Them All. [J Pediatr. 2018] Midlife crisis? In its 50th year, BPD redefines itself. [J Pediatr. 2018]
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    Characteristics of extremely low birth weight infant survivors with unimpaired outcomes at 30 months of age
    (Springer Nature, 2013) Kumar, Praveen; Shankaran, Seetha; Ambalavanan, Namasivayam; Kendrick, Douglas E.; Pappas, Athina; Vohr, Betty R.; Poindexter, Brenda B.; Das, Abhik; Higgins, Rosemary D.; NICHD Neonatal Research Network; Pediatrics, School of Medicine
    Objective: To evaluate characteristics of unimpaired outcome in extremely low-birth-weight (ELBW) survivors. Study design: ELBW infants (n=714) with 30 months' assessments were analyzed. Logistic regression was used to develop a model for the binary outcome of unimpaired versus impaired outcome. Result: Thirty-three percent of infants had an unimpaired outcome. Seventeen percent of ELBW survivors had a Bayley II Mental Developmental Index score of ≥ 101 and 2% had a score of ≥ 116. Female gender, use of antenatal steroids (ANS), maternal education ≥ high school and the absence of major neonatal morbidities were independent predictors of unimpaired outcome. The likelihood of an unimpaired outcome in the presence of major neonatal morbidities was higher in infants exposed to ANS. Conclusion: The majority of unimpaired ELBW survivors had cognitive scores shifted toward the lower end of the normal distribution. Exposure to ANS was associated with higher likelihood of an unimpaired outcome in infants with major neonatal morbidities.
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    Definitions of Cardiovascular Insufficiency and Relation to Outcomes in Critically Ill Newborn Infants
    (Thieme, 2015-09) Fernandez, Erika; Watterberg, Kristi L.; Faix, Roger G.; Yoder, Bradley A.; Walsh, Michele C.; Lacy, Conra Backstrom; Osborne, Karen A.; Das, Abhik; Kendrick, Douglas E.; Stoll, Barbara J.; Poindexter, Brenda B.; Laptook, Abbot R.; Kennedy, Kathleen A.; Schibler, Kurt; Bell, Edward F.; Van Meurs, Krisa P.; Frantz, Ivan D. III; Goldberg, Ronald N.; Shankaran, Seetha; Carlo, Waldemar A.; Ehrenkranz, Richard A.; Sánchez, Pablo J.; Higgins, Rosemary D.; Department of Pediatrics, Indiana University School of Medicine
    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 O2. 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.
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    Early Brain and Abdominal Oxygenation in Extremely Low Birth Weight Infants
    (Springer Nature, 2022) Chock, Valerie Y.; Smith, Emily; Tan, Sylvia; Ball, M. Bethany; Das, Abhik; Hintz, Susan R.; Kirpalani, Haresh; Bell, Edward F.; Chalak, Lina F.; Cotten, C. Michael; Widness, John A.; Kennedy, Kathleen A.; Ohls, Robin K.; Seabrook, Ruth B.; Patel, Ravi M.; Laptook, Abbot R.; Mancini, Toni; Sokol, Gregory M.; Walsh, Michele C.; Yoder, Bradley A.; Poindexter, Brenda B.; Chawla, Sanjay; D’Angio, Carl T.; Higgins, Rosemary D.; Van Meurs, Krisa P.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of Medicine
    Background: Extremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined. Methods: A prospective study of ELBW preterm infants utilized NIRS monitoring to assess changes in cerebral and mesenteric saturation (Csat and Msat) over the first week after birth. This secondary study of a multicenter trial comparing hemoglobin transfusion thresholds assessed cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE) and relationships with perinatal variables. Results: In 124 infants, both Csat and Msat declined over the first week, with a corresponding increase in oxygen extraction. With lower gestational age, lower birth weight, and 5-min Apgar score ≤5, there was a greater increase in oxygen extraction in the brain compared to the gut. Infants managed with a lower hemoglobin transfusion threshold receiving ≥2 transfusions in the first week had the lowest Csat and highest cFTOE (p < 0.001). Conclusion: Brain oxygen extraction preferentially increased in more immature and anemic preterm infants. NIRS monitoring may enhance understanding of cerebral and mesenteric oxygenation patterns and inform future protective strategies in the preterm ELBW population. Impact: Simultaneous monitoring of cerebral and mesenteric tissue saturation demonstrates the balance of oxygenation between preterm brain and gut and may inform protective strategies. Over the first week, oxygen saturation of the brain and gut declines as oxygen extraction increases. A low hemoglobin transfusion threshold is associated with lower cerebral saturation and higher cerebral oxygen extraction compared to a high hemoglobin transfusion threshold, although this did not translate into clinically relevant differences in the TOP trial primary outcome. Greater oxygen extraction by the brain compared to the gut occurs with lower gestational age, lower birth weight, and 5-min Apgar score ≤5.
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    Early-Onset Neonatal Sepsis 2015 to 2017, the Rise of Escherichia coli, and the Need for Novel Prevention Strategies
    (American Medical Association, 2020-07) Stoll, Barbara J.; Puopolo, Karen M.; Hansen, Nellie I.; Sánchez, Pablo J.; Bell, Edward F.; Carlo, Waldemar A.; Cotten, C. Michael; D’Angio, Carl T.; Kazzi, S. Nadya J.; Poindexter, Brenda B.; Van Meurs, Krisa P.; Hale, Ellen C.; Collins, Monica V.; Das, Abhik; Baker, Carol J.; Wyckoff, Myra H.; Yoder, Bradley A.; Watterberg, Kristi L.; Walsh, Michele C.; Devaskar, Uday; Laptook, Abbot R.; Sokol, Gregory M.; Schrag, Stephanie J.; Higgins, Rosemary D.; Pediatrics, School of Medicine
    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.