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Autonomic nervous system maturation in the premature extrauterine milieu



In premature infants, we investigated whether the duration of extrauterine development influenced autonomic nervous system (ANS) maturation.


We performed a longitudinal cohort study of ANS maturation in preterm infants. Eligibility included birth gestational age (GA) < 37 weeks, NICU admission, and expected survival. The cohort was divided into three birth GA groups: Group 1 (≤29 weeks), Group 2 (30–33 weeks), and Group 3 (≥34 weeks). ECG data were recorded weekly and analyzed for sympathetic and parasympathetic tone using heart rate variability (HRV). Quantile regression modeled the slope of ANS maturation among the groups by postnatal age to term-equivalent age (TEA) (≥37 weeks).


One hundred infants, median (Q1−Q3) birth GA of 31.9 (28.7–33.9) weeks, were enrolled: Group 1 (n = 35); Group 2 (n = 40); and Group 3 (n = 25). Earlier birth GA was associated with lower sympathetic and parasympathetic tone. However, the rate of autonomic maturation was similar, and at TEA there was no difference in HRV metrics across the three groups. The majority of infants (91%) did not experience significant neonatal morbidities.


Premature infants with low prematurity-related systemic morbidity have maturational trajectories of ANS development that are comparable across a wide range of ex-utero durations regardless of birth GA.


  • Heart rate variability can evaluate the maturation of the autonomic nervous system.

  • Metrics of both the sympathetic and parasympathetic nervous system show maturation in the premature extrauterine milieu.

  • The autonomic nervous system in preterm infants shows comparable maturation across a wide range of birth gestational ages.

  • Preterm newborns with low medical morbidity have maturation of their autonomic nervous system while in the NICU.

  • Modern NICU advances appear to support autonomic development in the preterm infant.

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Fig. 1: ANS spectral metrics over time in preterm newborn cohort.
Fig. 2: ANS time domain metrics over time in preterm newborn cohort.


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We greatly appreciate the support of Inova Women and Children’s Hospital, Fairfax, VA and the families who allowed us to study their newborn infants. This study was supported by the Children’s National Inova Collaborative (CNICA) Research Program, through institutional support from Children’s National Hospital, Washington, DC and the Inova Health System, Fairfax, VA. S.B.M. received support by Award Numbers UL1TR001876 and KL2TR001877 from the NIH National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

Author information




S.B.M.: designed the study, obtained funding, acquired and analyzed the data, drafted the manuscript, critically revised the manuscript, approved the final version for publication. R.B.G.: helped designed the study, analyzed the data, critically revised the manuscript, approved the final version for publication. L.H.: helped design the study, acquired data, critically revised the manuscript, approved the final version for publication. T.A.-S.: helped design the study, acquired data, analyzed data, critically revised the manuscript, approved the final version for publication. N.H., M.B.J., R.M.: biostatistical study design, analyzed data, critically revised the manuscript, approved the final version for publication. C.B.S.: helped design the study, acquired data, critically revised the manuscript, approved the final version for publication. A.E., S.R., S.D.S.: acquired data, critically revised the manuscript, approved the final version for publication. A.K.: contributed to participant enrollment, acquired data, critically revised the manuscript, approved the final version for publication. G.L.M., A.J.d.P.: helped develop the concept of the study, critically revised the manuscript, approved the final version for publication. R.B.: helped develop the concept of the study, contributed to participant enrollment, critically revised the manuscript, approved the final version for publication.

Corresponding author

Correspondence to Sarah B. Mulkey.

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Patient written informed consent was obtained for the study.

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Mulkey, S.B., Govindan, R.B., Hitchings, L. et al. Autonomic nervous system maturation in the premature extrauterine milieu. Pediatr Res 89, 863–868 (2021).

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