Am J Perinatol 2022; 39(07): 732-749
DOI: 10.1055/s-0040-1717072
Original Article

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

Athina Pappas
1   Department of Pediatrics, Wayne State University, Detroit, Michigan
Seetha Shankaran
1   Department of Pediatrics, Wayne State University, Detroit, Michigan
Scott A. McDonald
2   Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina
Waldemar A. Carlo
3   Department of Pediatrics, University of Alabama at Birmingham and Children's Hospital of Alabama, Birmingham, Alabama
Abbot R. Laptook
4   Department of Pediatrics, Women & Infant's Hospital, Brown University, Providence, Rhode Island
Jon E. Tyson
5   Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas
6   Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland
Kristin Skogstrand
7   Department for Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark
David M. Hougaard
7   Department for Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark
Rosemary D. Higgins*
8   Department of Global and Community Health, George Mason University, Fairfax, Virginia
› Author Affiliations
Funding The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the NRN's Whole-Body Hypothermia Trial and its 6–7 Year School-age Follow-up through cooperative agreements. While NICHD staff did have input into the study design, conduct, analysis, and manuscript drafting, the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This is a secondary study of ID Whole-Body Cooling for Birth Asphyxia in Term Infants: NCT00005772 (U.S. Department of Health and Human Services, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10 HD21373, M01 RR2588, U10 HD21385, U10 HD27904, U10 HD34216, M01 RR32, and U10 HD36790]).


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.

* A complete list of study investigators appears in the [Supplementary Material] (available in the online version).

Authors' Contributions

A.P. drafted the initial manuscript and revised multiple revisions of the manuscript. S.S. and W.A.C. conceptualized and designed the study, designed the data collection instruments, supervised data collection, and reviewed and revised the manuscript. S.A.M. performed the statistical analysis and critically reviewed the manuscript A.D. supervised the data collection instruments, supervised the analysis, and critically reviewed the manuscript. A.R.L., J.E.T., and R.D.H. critically reviewed draft of the study and critically reviewed the manuscript. K.S. and D.M.H. performed the blood protein analysis and analysis and critically reviewed the manuscript.


Participating NRN sites collected data and transmitted it to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. On behalf of the NRN, Dr. Abhik Das (DCC Principal Investigator) and Mr. Scott A. McDonald (DCC Statistician) had full access to all of the data in the study, and with the NRN Center Principal Investigators, take responsibility for the integrity of the data and accuracy of the data analysis.

Supplementary Material

Publication History

Received: 16 April 2020

Accepted: 24 August 2020

Article published online:
10 October 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

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