Quantitative measures of autonomic cardiorespiratory maturation in preterm infants are associated with brain volumes at term age

Authors

• Julius Ngwa, The Developing Brain Institute, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University School of Medicine, Washington, DC, USA.
• Nickie N. Andescavage, The Developing Brain Institute, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University School of Medicine, Washington, DC, USA; Division of Neonatology, Children's National Hospital, Washington, DC, USA.
• Sudeepta Basu, The Developing Brain Institute, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University School of Medicine, Washington, DC, USA; Division of Neonatology, Children's National Hospital, Washington, DC, USA.
• Katherine Ottolini, The Developing Brain Institute, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University School of Medicine, Washington, DC, USA; Division of Neonatology, Children's National Hospital, Washington, DC, USA.
• Kushal Kapse, The Developing Brain Institute, Children's National Hospital, Washington, DC, USA.
• Jonathan Murnick, Division of Diagnostic Imaging and Radiology, Children's National Hospital, Washington, DC, USA.
• Catherine Limperopoulos, The Developing Brain Institute, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University School of Medicine, Washington, DC, USA; Division of Diagnostic Imaging and Radiology, Children's National Hospital, Washington, DC, USA; Neurology School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA; The Zickler Family Prenatal Pediatrics Institute, Children's National Hospital, Washington, DC, USA.
• Adre du Plessis, The Developing Brain Institute, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University School of Medicine, Washington, DC, USA; Neurology School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA; The Zickler Family Prenatal Pediatrics Institute, Children's National Hospital, Washington, DC, USA.
• R B. Govindan, The Developing Brain Institute, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University School of Medicine, Washington, DC, USA; The Zickler Family Prenatal Pediatrics Institute, Children's National Hospital, Washington, DC, USA. Electronic address: [email protected].

Document Type

Journal Article

Publication Date

3-24-2026

Journal

Early human development

Volume

218

DOI

10.1016/j.earlhumdev.2026.106542

Keywords

Anatomical regions of the brain; Heart rate metrics; Linear mixed effects modeling; MRI; Oxygen saturation; Preterm infants; Volumetric brain data

Abstract

BACKGROUND: In preterm infants, the development of autonomic function and brain maturation has typically been studied separately. However, the relationship between the two remains poorly understood. This study investigated the association between autonomic maturation and brain volumetric growth in preterm infants. MATERIALS AND METHODS: We applied a longitudinal trajectory clustering approach to weekly averages of several daily autonomic metrics: heart rate (HR, beats per minute), standard deviation of HR, asymmetry index (ASI), percentage of HR <80 bpm, and percentage of SpO₂ <88%. Two distinct clusters were identified. Associations between cluster membership and sequential brain volumes (total, regional, and tissue-specific), measured via magnetic resonance imaging (MRI), were assessed using a linear mixed-effects model across the gestational period. At term, a multivariate linear regression model was used, adjusting for relevant clinical variables. RESULTS: This prospective study enrolled 78 preterm infants (45% female), with a mean (± SD) gestational age at birth of 29.85 ± 3.52 weeks. At term, infants in the higher ASI cluster had significantly greater total and regional brain volumes (P < 0.001) compared to those in the lower ASI cluster. These associations remained significant in the longitudinal analysis. CONCLUSIONS: We found that markers of autonomic immaturity in preterm infants were significantly associated with reduced brain volume growth. These associations emerged shortly after birth and persisted through the extrauterine third trimester. Our findings suggest that autonomic maturation metrics could help identify infants at higher risk for suboptimal brain development. STATEMENT OF SIGNIFICANCE: Preterm infants undergoing third-trimester development in an unnatural ex-utero environment are at risk for unfavorable brain development and adverse long-term neurologic outcomes due to an 'amalgam of destructive-developmental' insults. Overt destructive injury is readily detectable by routine clinical brain imaging during the neonatal intensive care unit stay. However, adverse neurologic outcomes occur even in the absence of major brain injury. In this study, we seek to evaluate the effect of common prematurity-related autonomic function events (bradycardias/desaturations) on brain growth in infants without evidence of early, overt brain injury. Using a cohort of preterm infants, we demonstrated that impairment in autonomic development through term-equivalent age is associated with brain development. Autonomic markers may serve as early prognostic factors to predict neurodevelopmental outcomes in preterm neonates.

APA Citation

Ngwa, Julius; Andescavage, Nickie N.; Basu, Sudeepta; Ottolini, Katherine; Kapse, Kushal; Murnick, Jonathan; Limperopoulos, Catherine; du Plessis, Adre; and Govindan, R B., "Quantitative measures of autonomic cardiorespiratory maturation in preterm infants are associated with brain volumes at term age" (2026). GW Authored Works. Paper 8834.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8834

Department

Pediatrics