Publications by authors named "Seetha Shankaran"

264 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

Parental and professional perceptions of informed consent and participation in a time-critical neonatal trial: a mixed-methods study in India, Sri Lanka and Bangladesh.

BMJ Glob Health 2021 05;6(5)

Centre for Perinatal Neuroscience, Imperial College London, London, UK.

Introduction: Time-critical neonatal trials in low-and-middle-income countries (LMICs) raise several ethical issues. Using a qualitative-dominant mixed-methods design, we explored informed consent process in Hypothermia for encephalopathy in low and middle-income countries (HELIX) trial conducted in India, Sri Lanka and Bangladesh.

Methods: Term infants with neonatal encephalopathy, aged less than 6 hours, were randomly allocated to cooling therapy or usual care, following informed parental consent. The consenting process was audio-video (A-V) recorded in all cases. We analysed A-V records of the consent process using a 5-point Likert scale on three parameters-empathy, information and autonomy. In addition, we used exploratory observation method to capture relevant aspects of consent process and discussions between parents and professionals. Finally, we conducted in-depth interviews with a subgroup of 20 parents and 15 healthcare professionals. A thematic analysis was performed on the observations of A-V records and on the interview transcripts.

Results: A total of 294 A-V records of the HELIX trial were analysed. Median (IQR) score for empathy, information and autonomy was 5 (0), 5 (1) and 5 (1), respectively. However, thematic analysis suggested that the consenting was a ceremonial process; and parental decision to participate was based on unreserved trust in the treating doctors, therapeutic misconception and access to an expensive treatment free of cost. Most parents did not understand the concept of a clinical trial nor the nature of the intervention. Professionals showed a strong bias towards cooling therapy and reported time constraints and explaining to multiple family members as key challenges.

Conclusion: Despite rigorous research governance and consent process, parental decisions were heavily influenced by situational incapacity and a trust in doctors to make the right decision on their behalf. Further research is required to identify culturally and context-appropriate strategies for informed trial participation.
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http://dx.doi.org/10.1136/bmjgh-2021-005757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144040PMC
May 2021

Early Determination of Prognosis in Neonatal Moderate or Severe Hypoxic-Ischemic Encephalopathy.

Pediatrics 2021 Jun 13;147(6). Epub 2021 May 13.

Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background And Objectives: Early determination of prognosis is important in neonates with hypoxic-ischemic encephalopathy (HIE). Our objective was to test scoring systems developed earlier (original scoring system) and develop new prognostic models.

Methods: Secondary analysis of data from the multicenter randomized controlled trial of longer, deeper, or usual care cooling in neonatal HIE (NCT01192776) that enrolled 364 neonates diagnosed with moderate or severe HIE. The primary outcome was death or moderate or severe disability at 18 to 22 months, and secondary outcome was death during initial hospitalization. Testing of early neurologic clinical examination (<6 hours of age) and the original scoring system for prognostic ability was done, followed by development of new scoring systems and classification and regression tree (CART) models by using early clinical variables (<6 hours of age).

Results: For death or disability, the original scoring system correctly classified 75% (95% confidence interval: 69%-81%), whereas the new scoring system correctly classified 78% (73%-82%), and the CART model correctly classified 76% (72%-81%). Early neurologic clinical examination also had a correct classification rate of 76% (71%-80%). Depth and duration of cooling did not affect prediction. Only a few components of the early neurologic examination were associated with poor outcome. For death, the original scoring system correctly classified 72% (66%-77%), the new scoring system 68% (63%-72%), the new CART model 87% (83%-90%), and early neurologic evaluation 81% (77%-85%).

Conclusions: The 3 models (scoring system, CART, and early neurologic evaluation) were comparable in predicting death or disability. For in-hospital death, CART models were superior to scoring systems and early neurologic examination.
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http://dx.doi.org/10.1542/peds.2020-048678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168606PMC
June 2021

Association of Total Sarnat Score with brain injury and neurodevelopmental outcomes after neonatal encephalopathy.

Arch Dis Child Fetal Neonatal Ed 2021 May 5. Epub 2021 May 5.

Centre for Perinatal Neuroscience, Brain Sciences Department, Imperial College of Science Technology and Medicine, London, UK.

We examined the association of Total Sarnat Score (TSS) with brain injury on neonatal magnetic resonance (MR) and adverse neurodevelopmental outcome (NDO) (death or moderate or severe disability) at 2 years of age in 145 infants undergoing therapeutic hypothermia for neonatal encephalopathy. TSS was associated with basal ganglia/thalamic injury on conventional MR (p=0.03) and thalamic N-acetyl aspartate on MR spectroscopy (R=0.16, p=0.004) at 2 weeks of age, and Bayley Composite Cognitive (R=0.18, p=0.01), Motor (R=0.15, p=0.02) and Language (R=0.11, p=0.01) Scores at 2 years of age after adjustment for seizures at the time of neurological assessment. The accuracy of TSS (area under the curve (AUC)=0.71) for predicting adverse NDO was similar to the modified Sarnat staging (AUC=0.72). TSS of >12 within 6 hours of birth indicated high risk of adverse NDO, while TSS of <4 indicated intact survival and was reassuring of a good outcome among cooled infants.
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http://dx.doi.org/10.1136/archdischild-2020-321164DOI Listing
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

Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial.

J Pediatr 2021 03 13;230:106-111.e6. Epub 2020 Nov 13.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Pregnancy and Perinatology Branch, Bethesda, MD; George Mason University, Fairfax, VA.

Objective: To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours.

Study Design: Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age.

Results: Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively.

Conclusions: MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia-ischemia.

Trial Registration: Clinicaltrials.gov: NCT00614744.
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http://dx.doi.org/10.1016/j.jpeds.2020.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914162PMC
March 2021

Withholding or withdrawing life-sustaining treatment in extremely low gestational age neonates.

Arch Dis Child Fetal Neonatal Ed 2021 May 20;106(3):238-243. Epub 2020 Oct 20.

Dean's Office, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Objective: To identify sociodemographic and clinical factors associated with withholding or withdrawing life-sustaining treatment (WWLST) for extremely low gestational age neonates.

Design: Observational study of prospectively collected registry data from 19 National Institute of Child Health and Human Development Neonatal Research Network centres on neonates born at 22-28 weeks gestation who died >12 hours through 120 days of age during 2011-2016. Sociodemographic and clinical factors were compared between infants who died following WWLST and without WWLST.

Results: Of 1168 deaths, 67.1% occurred following WWLST. Withdrawal of assisted ventilation (97.4%) was the primary modality. WWLST rates were inversely proportional to gestational age. Life-sustaining treatment was withheld or withdrawn more often for non-Hispanic white infants than for non-Hispanic black infants (72.7% vs 60.4%; 95% CI 1.00 to 1.92) or Hispanic infants (72.7% vs 67.2%; 95% CI 1.32 to 3.72). WWLST rates varied across centres (38.6-92.6%; p<0.001). The centre with the highest rate had adjusted odds 4.89 times greater than the average (95% CI 1.18 to 20.18). The adjusted odds of WWLST were higher for infants with necrotiing enterocolitis (OR 1.77, 95% CI 1.21 to 2.59) and severe brain injury (OR 1.98, 95% CI 1.44 to 2.74).

Conclusions: Among infants who died, WWLST rates varied widely across centres and were associated with gestational age, race, ethnicity, necrotiing enterocolitis, and severe brain injury. Further exploration is needed into how race, centre, and approaches to care of infants with necrotiing enterocolitis and severe brain injury influence WWLST.
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http://dx.doi.org/10.1136/archdischild-2020-318855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055718PMC
May 2021

Blood Biomarkers and 6- to 7-Year Childhood Outcomes Following Neonatal Encephalopathy.

Am J Perinatol 2020 Oct 10. Epub 2020 Oct 10.

Department of Global and Community Health, George Mason University, Fairfax, Virginia.

Objective:  This study aimed to profile the cytokine/chemokine response from day 0 to 7 in infants (≥36 weeks of gestational age) with neonatal encephalopathy (NE) and to explore the association with long-term outcomes.

Study Design:  This was a secondary study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network randomized controlled trial of whole body hypothermia for NE. Eligible infants with moderate-severe NE were randomized to cooling or normothermia. Blood spots were collected on days 0 to 1, 2 to 4, and 6 to 7. Twenty-four cytokines/chemokines were measured using a multiplex platform. Surviving infants underwent neurodevelopmental assessment at 6 to 7 years. Primary outcome was death or moderate-severe impairment defined by any of the following: intelligence quotient <70, moderate-severe cerebral palsy (CP), blindness, hearing impairment, or epilepsy.

Results:  Cytokine blood spots were collected from 109 participants. In total 99 of 109 (91%) were assessed at 6 to 7 years; 54 of 99 (55%) developed death/impairment. Neonates who died or were impaired had lower early regulated upon activation normal T cell expressed and secreted (RANTES) and higher day 7 monocyte chemotactic protein (MCP)-1 levels than neonates who survived without impairment. Though TNF-α levels had no association with death/impairment, higher day 0 to 1 levels were observed among neonates who died/developed CP. On multiple regression analysis adjusted for center, treatment group, sex, race, and level of hypoxic ischemic encephalopathy, higher RANTES was inversely associated with death/impairment (odds ratio (OR): 0.31, 95% confidence interval [CI]: 0.13-0.74), while day seven MCP-1 level was directly associated with death/impairment (OR: 3.70, 95% CI: 1.42-9.61). Targeted cytokine/chemokine levels demonstrated little variation with hypothermia treatment.

Conclusion:  RANTES and MCP-1 levels in the first week of life may provide potential targets for future therapies among neonates with encephalopathy.

Key Points: · Elevation of specific cytokines and chemokines in neonates with encephalopathy has been noted along with increased risk of neurodevelopmental impairment in infancy.. · Cytokine/chemokines at <7 days were assessed among neonates in a trial of hypothermia for HIE.. · Neonates who died or were impaired at 6 to 7 years following hypoxic-ischemic encephalopathy had lower RANTES and higher MCP-1 levels than those who survived without impairment..
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http://dx.doi.org/10.1055/s-0040-1717072DOI Listing
October 2020

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

Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy.

Sci Rep 2020 08 4;10(1):13100. Epub 2020 Aug 4.

Department of Brain Sciences, Centre for Perinatal Neuroscience, Imperial College London, London, UK.

A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth, predicts adverse neurodevelopmental outcome eighteen months after neonatal encephalopathy. We performed next generation sequencing on whole blood ribonucleic acid obtained within six hours of birth from the first 47 encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX) trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855 genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1 and SMC4 were the most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatonin and polo-like kinase in babies with adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanisms and identify novel therapeutic targets for neuroprotection.
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http://dx.doi.org/10.1038/s41598-020-70131-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403382PMC
August 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

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

Association of prenatal opiate exposure with youth outcomes assessed from infancy through adolescence.

J Perinatol 2020 07 22;40(7):1056-1065. Epub 2020 May 22.

Statistics and Epidemiology, RTI International, Research Triangle Park, NC, 27709, USA.

Objective: This study examined acute findings and long-term outcome trajectories between birth and adolescence in children with prenatal opiate exposure.

Study Design: Ninety children (45 opiate-exposed, 45 non-exposed) completed assessments between 1 month and 15 years of age. Outcome variables (medical, anthropomorphic, developmental, and behavioral) were analyzed at individual time points and using longitudinal statistical modeling.

Results: Opiate-exposed infants displayed transient neurologic findings, but no substantial signs or symptoms long term. There were no group differences in growth, cognitive functioning, or behavior at individual time periods; however, the trajectories of outcomes using longitudinal analyses adjusting for variables known to impact outcome demonstrated increased deficits among opiate-exposed children over time with regards to weight, head circumference, cognitive functioning, and behavior.

Conclusions: Findings support concerns that maternal opiate use during pregnancy may negatively impact a child's developmental trajectory, which in turn may impose concerns to society (e.g., increased need for social, medical, and/or educational services).
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http://dx.doi.org/10.1038/s41372-020-0692-3DOI Listing
July 2020

Authors' Response.

Pediatrics 2020 Mar 31. Epub 2020 Mar 31.

Neonatologist, Wayne State University.

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http://dx.doi.org/10.1542/peds.2020-0056BDOI Listing
March 2020

Neonatal oxygen saturations and blood pressure at school-age in children born extremely preterm: a cohort study.

J Perinatol 2020 06 28;40(6):902-908. Epub 2020 Feb 28.

Department of Pediatrics, University of New Mexico, Albuquerque, NM, USA.

Objective: To explore the relationship between neonatal oxygen saturation and BP at age 6-7 years in a cohort of infants born extremely preterm.

Study Design: Infants <28 weeks gestation were assigned to a higher or lower oxygen saturation target. Oximeter data were monitored throughout the neonatal period. A subset of survivors was seen at age 6. BP was measured and compared by group assignment, achieved saturations, and time spent in hypoxemia (saturations <80%).

Results: There was no difference in systolic or diastolic BP between assigned groups. Median achieved weekly oxygen saturation was not associated with BP. Longer duration of hypoxemia during the first week of age was associated with higher systolic BP.

Conclusions: Neither target nor actual median oxygen saturations in this study was associated with BP at school age. Increased duration of hypoxemia in the first postnatal week was associated with higher systolic BP at 6-7 years of age.
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http://dx.doi.org/10.1038/s41372-020-0619-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260090PMC
June 2020

White matter injury after neonatal encephalopathy is associated with thalamic metabolite perturbations.

EBioMedicine 2020 Feb 12;52:102663. Epub 2020 Feb 12.

Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, UK.

Background: Although thalamic magnetic resonance (MR) spectroscopy (MRS) accurately predicts adverse outcomes after neonatal encephalopathy, its utility in infants without MR visible deep brain nuclei injury is not known. We examined thalamic MRS metabolite perturbations in encephalopathic infants with white matter (WM) injury with or without cortical injury and its associations with adverse outcomes.

Methods: We performed a subgroup analysis of all infants recruited to the MARBLE study with isolated WM or mixed WM/cortical injury, but no visible injury to the basal ganglia/thalamus (BGT) or posterior limb of the internal capsule (PLIC). We used binary logistic regression to examine the association of MRS biomarkers with three outcomes (i) WM injury score (1 vs. 2/3); (ii) cortical injury scores (0/1 vs. 2/3); and (iii) adverse outcomes (defined as death, moderate/severe disability) at two years (yes/no). We also assessed the accuracy of MRS for predicting adverse outcome.

Findings: Of the 107 infants included in the analysis, five had adverse outcome. Reduced thalamic N-acetylaspartate concentration [NAA] (odds ratio 0.4 (95% CI 0.18-0.93)) and elevated thalamic Lactate/NAA peak area ratio (odds ratio 3.37 (95% CI 1.45-7.82)) were significantly associated with higher WM injury scores, but not with cortical injury. Thalamic [NAA] (≤5.6 mmol/kg/wet weight) had the best accuracy for predicting adverse outcomes (sensitivity 1.00 (95% CI 0.16-1.00); specificity 0.95 (95% CI 0.84-0.99)).

Interpretation: Thalamic NAA is reduced in encephalopathic infants without MR visible deep brain nuclei injury and may be a useful predictor of adverse outcomes.

Funding: The National Institute for Health Research (NIHR).
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http://dx.doi.org/10.1016/j.ebiom.2020.102663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016374PMC
February 2020

Is It Time for a Randomized Controlled Trial of Hypothermia for Mild Hypoxic-Ischemic Encephalopathy?

J Pediatr 2020 05 14;220:241-244. Epub 2020 Jan 14.

Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2019.11.030DOI Listing
May 2020

Neurodevelopmental Outcomes of Preterm Infants With Retinopathy of Prematurity by Treatment.

Pediatrics 2019 08 23;144(2). Epub 2019 Jul 23.

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

Objective: Among extremely preterm infants, we evaluated whether bevacizumab therapy compared with surgery for retinopathy of prematurity (ROP) is associated with adverse outcomes in early childhood.

Methods: This study was a retrospective analysis of prospectively collected data on preterm (22-26 + 6/7 weeks' gestational age) infants admitted to the National Institute of Child Health and Human Development Neonatal Research Network centers who received bevacizumab or surgery exclusively for ROP. The primary outcome was death or severe neurodevelopmental impairment (NDI) at 18 to 26 months' corrected age (Bayley Scales of Infant and Toddler Development, Third Edition cognitive or motor composite score <70, Gross Motor Functional Classification Scale level ≥2, bilateral blindness or hearing impairment).

Results: The cohort ( = 405; 214 [53%] boys; median [interquartile range] gestational age: 24.6 [23.9-25.3] weeks) included 181 (45%) infants who received bevacizumab and 224 (55%) who underwent ROP surgery. Infants treated with bevacizumab had a lower median (interquartile range) birth weight (640 [541-709] vs 660 [572.5-750] g; = .02) and longer durations of conventional ventilation (35 [21-58] vs 33 [18-49] days; = .04) and supplemental oxygen (112 [94-120] vs 105 [84.5-120] days; = .01). Death or severe NDI (adjusted odds ratio [aOR] 1.42; 95% confidence interval [CI] 0.94 to 2.14) and severe NDI (aOR 1.14; 95% CI 0.76 to 1.70) did not differ between groups. Odds of death (aOR 2.54 [95% CI 1.42 to 4.55]; = .002), a cognitive score <85 (aOR 1.78 [95% CI 1.09 to 2.91]; = .02), and a Gross Motor Functional Classification Scale level ≥2 (aOR 1.73 [95% CI 1.04 to 2.88]; = .04) were significantly higher with bevacizumab therapy.

Conclusions: In this multicenter cohort of preterm infants, ROP treatment modality was not associated with differences in death or NDI, but the bevacizumab group had higher mortality and poor cognitive outcomes in early childhood. These data reveal the need for a rigorous appraisal of ROP therapy.
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http://dx.doi.org/10.1542/peds.2018-3537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855825PMC
August 2019

Birth weight discordance in very low birth weight twins: mortality, morbidity, and neurodevelopment.

J Perinatol 2019 09 16;39(9):1229-1240. Epub 2019 Jul 16.

Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, MD, USA.

Objective: Examine outcomes among birth weight concordant and discordant 401-1500 g twins.

Study Design: Twins (n = 8,114) at NICHD Neonatal Research Network (1994-2011) were studied. Discordance (birth weight difference/larger twin birth weight x 100%) was categorized into: ≤ 14, > 14-20, > 20-30, and > 30%. Separate logistic regression models for the smaller and larger infants assessed the adjusted association between discordance and outcomes.

Results: Compared with the smaller twin with ≤ 14% discordance, mortality, necrotizing enterocolitis, severe retinopathy of prematurity, bronchopulmonary dysplasia, and neurodevelopmental impairment or death were highest among the smaller twins with discordance > 30%. The larger twins with discordance > 30% had higher odds of patent ductus arteriosus, moderate-to-severe cerebral palsy, blindness, cognitive and motor scores < 70. Odds of cerebral palsy and blindness were also higher among the larger twins with discordance > 14-20%.

Conclusions: Discordance > 30% was associated with higher mortality in the smaller twin and higher morbidities among the smaller and larger twins.
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http://dx.doi.org/10.1038/s41372-019-0427-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713585PMC
September 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

Pre-emptive opioid sedation during therapeutic hypothermia.

Arch Dis Child Fetal Neonatal Ed 2020 01 9;105(1):108-109. Epub 2019 May 9.

Department of Paediatrics, Centre for Perinatal Neuroscience, Imperial College London and Imperial Neonatal Service, London, UK.

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http://dx.doi.org/10.1136/archdischild-2019-317050DOI Listing
January 2020

Pitfalls in using neonatal brain NAA to predict infant development - Authors' reply.

Lancet Neurol 2019 05;18(5):423-424

Centre for Perinatal Neuroscience, Imperial College London, London W12 0HS, UK. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(19)30116-4DOI Listing
May 2019

Preemptive Morphine During Therapeutic Hypothermia After Neonatal Encephalopathy: A Secondary Analysis.

Ther Hypothermia Temp Manag 2020 Mar 26;10(1):45-52. Epub 2019 Feb 26.

Centre for Perinatal Neuroscience, Imperial College London, London, United Kingdom.

Although therapeutic hypothermia (TH) improves outcomes after neonatal encephalopathy (NE), the safety and efficacy of preemptive opioid sedation during cooling therapy is unclear. We performed a secondary analysis of the data from a large multicountry prospective observational study (Magnetic Resonance Biomarkers in Neonatal Encephalopathy [MARBLE]) to examine the association of preemptive morphine infusion during TH on brain injury and neurodevelopmental outcomes after NE. All recruited infants had 3.0 Tesla magnetic resonance imaging and spectroscopy at 1 week, and neurodevelopmental outcome assessments at 22 months. Of 223 babies recruited to the MARBLE study, the data on sedation were available from 169 babies with moderate ( = 150) or severe NE ( = 19). Although the baseline characteristics and admission status were similar, the babies who received morphine infusion ( = 141) were more hypotensive (49% vs. 25%,  = 0.02) and had a significantly longer hospital stay (12 days vs. 9 days,  = 0.009) than those who did not ( = 28). Basal ganglia/thalamic injury (score ≥1) and cortical injury (score ≥1) was seen in 34/141 (24%) and 37/141 (26%), respectively, of the morphine group and 4/28 (14%) and 3/28 (11%) of the nonmorphine group ( > 0.05). On regression modeling adjusted for potential confounders, preemptive morphine was not associated with mean (standard deviation [SD]) thalamic N-acetylaspartate (NAA) concentration (6.9 ± 0.9 vs. 6.5 ± 1.5;  = 0.97), and median (interquartile range) lactate/NAA peak area ratios (0.16 [0.12-0.21] vs. 0.13 [0.11-0.18];  = 0.20) at 1 week, and mean (SD) Bayley-III composite motor (92 ± 23 vs. 94 ± 10;  = 0.98), language (89 ± 22 vs. 93 ± 8;  = 0.53), and cognitive scores (95 ± 21 vs. 99 ± 13;  = 0.56) at 22 months. Adverse neurodevelopmental outcome (adjusted for severity of encephalopathy) was seen in 26 (18%) of the morphine group, and none of the nonmorphine group ( = 0.11). Preemptive morphine sedation during TH does not offer any neuroprotective benefits and may be associated with increased hospital stay. Optimal sedation during induced hypothermia requires further evaluation in clinical trials.
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http://dx.doi.org/10.1089/ther.2018.0052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044774PMC
March 2020

Discordance in Antenatal Corticosteroid Use and Resuscitation Following Extremely Preterm Birth.

J Pediatr 2019 05 6;208:156-162.e5. Epub 2019 Feb 6.

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

Objective: To describe discordance in antenatal corticosteroid use and resuscitation following extremely preterm birth and its relationship with infant survival and neurodevelopment.

Study Design: A multicenter cohort study of 4858 infants 22-26 weeks of gestation born 2006-2011 at 24 US hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, with follow-up through 2013. Survival and neurodevelopmental outcomes were available at 18-22 months of corrected age for 4576 (94.2%) infants. We described antenatal interventions, resuscitation, and infant outcomes. We modeled the effect on infant outcomes of each hospital increasing antenatal corticosteroid exposure for resuscitated infants born at 22-24 weeks of gestation to rates observed at 25-26 weeks of gestation.

Results: Discordant antenatal corticosteroid use and resuscitation, where one and not the other occurred, were more frequent for births at 22 and 23 but not 24 weeks (rate ratio [95% CI] at 22 weeks: 1.7 [1.3-2.2]; 23 weeks: 2.6 [2.2-3.2]; 24 weeks: 1.0 [0.8-1.2]) when compared with 25-26 weeks. Among infants resuscitated at 23 weeks, adjusting each hospital's rate of antenatal corticosteroid use to the average at 25-26 weeks (89.2%) was projected to increase infant survival by 7.1% (95% CI 5.4-8.8%) and survival without severe impairment by 6.4% (95% CI 4.7-8.1%). No significant change in outcomes was projected for infants resuscitated at 22 weeks, where few (n = 22) resuscitated infants received antenatal corticosteroids.

Conclusions: Infants born at 23 weeks were more frequently resuscitated without antenatal corticosteroids than other extremely preterm infants. When resuscitation is intended, consistent provision of antenatal corticosteroids may increase infant survival and survival without impairment.

Trial Registration: ClinicalTrials.govNCT00063063 (Generic Database) and NCT00009633 (Follow-Up Study).
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http://dx.doi.org/10.1016/j.jpeds.2018.12.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486854PMC
May 2019

Adrenal function links to early postnatal growth and blood pressure at age 6 in children born extremely preterm.

Pediatr Res 2019 09 12;86(3):339-347. Epub 2018 Dec 12.

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

Background: Low birth weight in term-born individuals correlates with adverse cardiometabolic outcomes; excess glucocorticoid exposure has been linked to these relationships. We hypothesized that cortisol and adrenal androgens would correlate inversely with birthweight and directly with markers of cardiometabolic risk in school-aged children born extremely preterm; further, preterm-born would have increased cortisol and adrenal androgens compared to term-born children.

Methods: Saliva samples were obtained at age 6 from 219 preterm-born children followed since birth and 40 term-born children and analyzed for dehydroepiandrosterone (DHEA) and cortisol. Cortisol was also measured at home (awakening, 30' later, evening).

Results: For preterm-born children, cortisol and DHEA correlated inversely with weight and length Z-scores at 36 weeks PMA and positively with systolic BP. DHEA was higher in preterm-born than term-born children (boys p < 0.01; girls p = 0.04). Cortisol was similar between preterm-born and term-born at study visit; however, preterm-born children showed a blunted morning cortisol. In term-born children, DHEA correlated with BMI (p = 0.04), subscapular, and abdominal skinfold thicknesses (both p < 0.01).

Conclusion: Cortisol and DHEA correlated inversely with early postnatal growth and directly with systolic BP in extremely preterm-born children, suggesting perinatal programming. Blunted morning cortisol may reflect NICU stress, as seen after other adverse childhood experiences (ACEs).
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http://dx.doi.org/10.1038/s41390-018-0243-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561840PMC
September 2019

Therapeutic hypothermia for mild neonatal encephalopathy: a systematic review and meta-analysis.

Arch Dis Child Fetal Neonatal Ed 2020 Mar 19;105(2):225-228. Epub 2018 Dec 19.

Centre for Perinatal Neuroscience, Imperial College London, London, UK.

Objectives: To examine if therapeutic hypothermia reduces the composite outcome of death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE).

Data Source: MEDLINE, Cochrane database, Scopus and ISI Web of Knowledge databases, using 'hypoxic ischaemic encephalopathy', 'newborn' and 'hypothermia', and 'clinical trials' as medical subject headings and terms. Manual search of the reference lists of all eligible articles and major review articles and additional data from the corresponding authors of selected articles.

Study Selection: Randomised and quasirandomised controlled trials comparing therapeutic hypothermia with usual care.

Data Extraction: Safety and efficacy data extracted independently by two reviewers and analysed.

Results: We included the data on 117 babies with mild NE inadvertently recruited to five cooling trials (two whole-body cooling and three selective head cooling) of moderate and severe NE, in the meta-analysis. Adverse outcomes occurred in 11/56 (19.6%) of the cooled babies and 12/61 (19.7%) of the usual care babies (risk ratio 1.11 (95% CIs 0.55 to 2.25)).

Conclusions: Current evidence is insufficient to recommend routine therapeutic hypothermia for babies with mild encephalopathy and significant benefits or harm cannot be excluded.
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http://dx.doi.org/10.1136/archdischild-2018-315711DOI Listing
March 2020

Genetic variants associated with patent ductus arteriosus in extremely preterm infants.

J Perinatol 2019 03 5;39(3):401-408. Epub 2018 Dec 5.

Department of Pediatrics, University of Iowa, Iowa City, IA, USA.

Objective: Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants.

Study Design: Preterm infants (n = 1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables.

Results: SNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p < 0.01). None of the associations were significant after correction for multiple comparisons.

Conclusion: We identified several common genetic variants associated with PDA. These findings may inform further studies on genetic risk factors for PDA in preterm infants.
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http://dx.doi.org/10.1038/s41372-018-0285-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391165PMC
March 2019

Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study.

Lancet Neurol 2019 01 15;18(1):35-45. Epub 2018 Nov 15.

Neonatal-Perinatal Medicine, Wayne State University, Detroit, MI, USA.

Background: In neonatal encephalopathy, the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy.

Methods: We did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy. We excluded infants with life-threatening congenital malformations, syndromic disorders, neurometabolic diseases, or any alternative diagnoses for encephalopathy that were apparent within 6 h of birth. We obtained T-weighted, T-weighted, and diffusion-weighted MRI and thalamic proton MRS 4-14 days after birth. Clinical neurodevelopmental tests were done 18-24 months later. The primary outcome was the association between MR biomarkers and an adverse neurodevelopmental outcome, defined as death or moderate or severe disability, measured using a multivariable prognostic model. We used receiver operating characteristic (ROC) curves to examine the prognostic accuracy of the individual biomarkers. This trial is registered with ClinicalTrials.gov, number NCT01309711.

Findings: Between Jan 29, 2013, and June 25, 2016, we recruited 223 infants who all underwent MRI and MRS at a median age of 7 days (IQR 5-10), with 190 (85%) followed up for neurological examination at a median age of 23 months (20-25). Of those followed up, 31 (16%) had moderate or severe disability, including one death. Multiple logistic regression analysis could not be done because thalamic N-acetylaspartate (NAA) concentration alone accurately predicted an adverse neurodevelopmental outcome (area under the curve [AUC] of 0·99 [95% CI 0·94-1·00]; sensitivity 100% [74-100]; specificity 97% [90-100]; n=82); the models would not converge when any additional variable was examined. The AUC (95% CI) of clinical examination at 6 h (n=190) and at discharge (n=167) were 0·72 (0·65-0·78) and 0·60 (0·53-0·68), respectively, and the AUC of abnormal amplitude integrated EEG at 6 h (n=169) was 0·73 (0·65-0·79). On conventional MRI (n=190), cortical injury had an AUC of 0·67 (0·60-0·73), basal ganglia or thalamic injury had an AUC of 0·81 (0·75-0·87), and abnormal signal in the posterior limb of internal capsule (PLIC) had an AUC of 0·82 (0·76-0·87). Fractional anisotropy of PLIC (n=65) had an AUC of 0·82 (0·76-0·87). MRS metabolite peak-area ratios (n=160) of NAA-creatine (<1·29) had an AUC of 0·79 (0·72-0·85), of NAA-choline had an AUC of 0·74 (0·66-0·80), and of lactate-NAA (>0·22) had an AUC of 0·94 (0·89-0·97).

Interpretation: Thalamic proton MRS measures acquired soon after birth in neonatal encephalopathy had the highest accuracy to predict neurdevelopment 2 years later. These methods could be applied to increase the power of neuroprotection trials while reducing their duration.

Funding: National Institute for Health Research UK.
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http://dx.doi.org/10.1016/S1474-4422(18)30325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291458PMC
January 2019

Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic-ischaemic encephalopathy: a non-randomised cohort study.

Arch Dis Child Fetal Neonatal Ed 2019 Sep 13;104(5):F515-F520. Epub 2018 Nov 13.

Centre for Perinatal Neuroscience, Imperial College London, London, UK.

Objective: To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE).

Design: Non-randomised cohort study.

Setting: Eight tertiary neonatal units in the UK and the USA.

Patients: 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth.

Interventions: Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for <12 hours).

Main Outcome Measures: MRI and MR spectroscopy (MRS) within 2 weeks after birth, and a neurodevelopmental outcome assessment at 2 years.

Results: The baseline characteristics in both groups were similar except for lower 10 min Apgar scores (p=0.02) in the cooled babies. Despite this, the mean (SD) thalamic NAA/Cr (1.4 (0.1) vs 1.6 (0.2); p<0.001) and NAA/Cho (0.67 (0.08) vs 0.89 (0.11); p<0.001) ratios from MRS were significantly higher in the cooled group. Cooled babies had lower white matter injury scores than non-cooled babies (p=0.02). Four (27%) non-cooled babies with mild HIE developed seizures after 6 hours of age, while none of the cooled babies developed seizures (p=0.008). Neurodevelopmental outcomes at 2 years were available in 40 (85%) of the babies. Adverse outcomes were seen in 2 (14.3%) non-cooled babies, and none of the cooled babies (p=0.09).

Conclusions: Therapeutic hypothermia may have a neuroprotective effect in babies with mild HIE, as demonstrated by improved MRS biomarkers and reduced white matter injury on MRI. This may warrant further evaluation in adequately powered randomised controlled trials.
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http://dx.doi.org/10.1136/archdischild-2018-316040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788875PMC
September 2019