Vagaltone and proinflammatory cytokines predict feeding intolerance and necrotizing enterocolitis risk

Alissa L. Meister, Fumiyuki C. Gardner, Kirsteen N. Browning, R. Alberto Travagli, Charles Palmer, Kim Kopenhaver Doheny

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Background: Necrotizing enterocolitis (NEC) is the leading cause of death due to gastrointestinal disease in preterm neonates; yet, clinicians lack reliable and noninvasive predictive tools. Purpose: We aimed to test that diminished high-frequency heart rate variability (HF-HRV) and elevated levels of proinflammatory cytokines would have utility in NEC prediction. Methods: In this multisite prospective study, we enrolled 250 preterm (26-34 weeks’ postmenstrual age [PMA]) neonates with physiological stability at 72 hours of life. HRV was measured noninvasively using electrocardiograhic data from standardized cardiorespiratory monitors at postnatal week 1 of life and weekly thereafter until 35 weeks’ PMA or discharge; blood was collected for cytokines at postnatal weeks 1 and 3. NEC was diagnosed via Modified Bell’s Staging Criteria. Results: HF-HRV was decreased at weeks 1 and 2 in neonates (47% females) who developed feeding intolerance or stage 2+ NEC. In addition, these neonates displayed elevated levels of IL-8 at week 1 and increased levels of IL-1β, IL-6, TNF-α, and IL-8 at week 3 of life. Low HF-HRV was associated with elevated IL-6 or IL-8 levels at weeks 1 and 3 of life. Logistic regression indicated that only HF-HRV was a significant predictor of feeding intolerance or NEC development. Implications for Practice and Research: HRV is a promising noninvasive modality for NEC risk detection. The association of low HF-HRV with elevated proinflammatory cytokines provides evidence for a putative role of the vagal cholinergic pathway in NEC pathogenesis. Future studies should focus on application of these techniques to test clinical therapeutics. Video Abstract available at

Original languageEnglish (US)
Pages (from-to)452-461
Number of pages10
JournalAdvances in Neonatal Care
Issue number6
StatePublished - Dec 1 2021

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health


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