Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Clinical Research Article
  • Published:

Effect of early antibiotic exposure on necrotizing enterocolitis and growth in extremely preterm infants

Pediatric Research volume 98, pages 137–143 (2025)Cite this article

Abstract

Background

The relationship between early antibiotic exposure, necrotizing enterocolitis (NEC), and growth faltering (GF) in extremely preterm infants is unknown.

Methods

We evaluated the association between peripartum and postnatal antibiotic exposure in the first week after birth with NEC and GF in this secondary analysis of Preterm Erythropoietin Neuroprotection Trial subjects. NEC was defined as Bell’s stage ≥ IIA; GF was defined as decreased weight, length, or head circumference (HC) z-score from birth to discharge of < −0.8. Multivariable analyses were adjusted with maternal and infant factors.

Results

A total of 891 infants survived the first week and were included in the NEC analyses, while 828 infants survived to discharge and were included in the growth analyses. For every 1-day increase in infant antibiotic exposure during the first week after birth, there was a significantly increased adjusted hazard of NEC (aHR/day 1.14 [1.01–1.28], p = 0.034). Antibiotics for 3–4 days and 5–7 days total in the first week were associated with increased odds of weight GF (aOR 1.90 [1.21–2.99], aOR 2.32 [1.44–3.74]), length GF (aOR 1.76 [1.22–2.59], aOR 1.88 [1.26–2.80]), and HC GF (aOR 1.75 [1.08–2.84], aOR 1.87 [1.14–3.08]).

Conclusion

Increased antibiotic exposure in the first week after birth was associated with NEC and GF risk.

Impact

  • In this post-hoc analysis of a large multi-site trial, we found infant antibiotic exposure in the first week after birth was associated with an increased hazard of necrotizing enterocolitis in the extremely preterm infant after adjusting for maternal and infant factors.

  • First week antibiotic exposure in the extremely preterm infant was associated with an increased odds of weight, linear, and head circumference growth faltering after adjusting for maternal and infant factors.

  • These findings encourage the judicious use of early antibiotics in extremely preterm infants.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The forest plot of Fine–Gray competing risk regression model demonstrates that antibiotic days increased the hazard of necrotizing enterocolitis after adjusting for maternal and infant factors.
Fig. 2: Forest plot of Fine–Gray competing risk regression model examining antibiotic days categorized into three cohorts in the first week and hazard of necrotizing enterocolitis after adjusting for maternal and infant factors.
Fig. 3: Forest plot of generalized estimating equations model examining antibiotic days categorized into three cohorts in the first week and odds of length GF after adjusting for maternal and infant factors.
Fig. 4: Forest plot of generalized estimating equations model examining antibiotic days categorized into three cohorts in the first week and odds of weight GF after adjusting for maternal and infant factors.
Fig. 5: Forest plot of generalized estimating equations model examining antibiotic days categorized into three cohorts in the first week and odds of head circumference GF after adjusting for maternal and infant factors.

Similar content being viewed by others

Data availability

De-identified individual participant data are available through the NINDS Data Archive under “Clinical Research Datasets.” The data are de-identified and a limited access data set is available through a request form on that page. Data dictionaries, in addition to the study protocol, the statistical analysis plan, and the informed consent form will be included. The data will be made available upon publication of all PENUT Trial-related manuscripts to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal.

References

  1. Kostlin-Gille, N. et al. Early initiation of antibiotic therapy and short-term outcomes in preterm infants: a single-centre retrospective cohort analysis. Arch. Dis. Child Fetal Neonatal Ed. 108, 623–630 (2023).

    Article  PubMed  Google Scholar 

  2. Letouzey, M. et al. Early antibiotic exposure and adverse outcomes in very preterm infants at low risk of early-onset sepsis: the Epipage-2 cohort study. J. Pediatr. 243, 91–98.e94 (2022).

    Article  PubMed  Google Scholar 

  3. Dierikx, T. H. et al. Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: a multicenter cohort study. Eur. J. Pediatr. 181, 3715–3724 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vatne, A. et al. Early empirical antibiotics and adverse clinical outcomes in infants born very preterm: a population-based cohort. J. Pediatr. 253, 107–114.e105 (2023).

    Article  PubMed  Google Scholar 

  5. Perez, K. et al. Patterns of infections among extremely preterm infants. J. Clin. Med. 12, 2703 (2023).

  6. Flannery, D. D., Edwards, E. M., Puopolo, K. M. & Horbar, J. D. Early-onset sepsis among very preterm infants. Pediatrics 148, e2021052456 (2021).

  7. Lynch, T. A., Malshe, A., Dozier, A. & Seplaki, C. L. Preterm prelabor rupture of membranes: evaluating latency and neonatal morbidity for pregnancies with expectant management ≥34 weeks. J. Matern. Fetal Neonatal Med. 35, 2135–2148 (2022).

    Article  PubMed  Google Scholar 

  8. Gasparrini, A. J. et al. Antibiotic perturbation of the preterm infant gut microbiome and resistome. Gut Microbes 7, 443–449 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sun, X. Z., Xiao, C., Yao, J. E. & Ling, C. Impact of postnatal exposure to antibiotics on intestinal microbiome in preterm infants. Chin. J. Perinat. Med. 12, 458–464 (2018).

    Google Scholar 

  10. Zou, Z. H. et al. Prenatal and postnatal antibiotic exposure influences the gut microbiota of preterm infants in neonatal intensive care units. Ann. Clin. Microbiol. Antimicrob. 17, 9 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Russell, J. T. et al. Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants. Sci. Rep. 11, 1943 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pammi, M. et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome 5, 31 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Strobel, K. M., Del Vecchio, G., Devaskar, S. U. & Calkins, K. L. Gut microbes and circulating cytokines in preterm infants with growth failure. J. Nutr. 153, 120–130 (2023).

    Article  PubMed  Google Scholar 

  14. Esmaeilizand, R. et al. Antibiotic exposure and development of necrotizing enterocolitis in very preterm neonates. Paediatr. Child Health 23, e56–e61 (2018).

    Article  PubMed  Google Scholar 

  15. Cotten, C. M. et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 123, 58–66 (2009).

    Article  PubMed  Google Scholar 

  16. Alexander, V. N., Northrup, V. & Bizzarro, M. J. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J. Pediatr. 159, 392–397 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kuppala, V. S., Meinzen-Derr, J., Morrow, A. L. & Schibler, K. R. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J. Pediatr. 159, 720–725 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Abdel Ghany, E. A. & Ali, A. A. Empirical antibiotic treatment and the risk of necrotizing enterocolitis and death in very low birth weight neonates. Ann. Saudi Med. 32, 521–526 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cantey, J. B., Pyle, A. K., Wozniak, P. S., Hynan, L. S. & Sanchez, P. J. Early antibiotic exposure and adverse outcomes in preterm, very low birth weight infants. J. Pediatr. 203, 62–67 (2018).

    Article  CAS  PubMed  Google Scholar 

  20. Reid, B. M., Eisenberg, R., Forman, K. & LaTuga, M. S. Relationship between early antibiotic exposure and short-term growth velocity in premature neonates. Am. J. Perinatol. 36, 1014–1022 (2019).

    Article  PubMed  Google Scholar 

  21. Krediet, T. G. et al. Microbiological factors associated with neonatal necrotizing enterocolitis: protective effect of early antibiotic treatment. Acta Paediatr. 92, 1180–1182 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Berkhout, D. J. C. et al. Risk factors for necrotizing enterocolitis: a prospective multicenter case-control study. Neonatology 114, 277–284 (2018).

    Article  PubMed  Google Scholar 

  23. Ting, J. Y. et al. Duration of initial empirical antibiotic therapy and outcomes in very low birth weight infants. Pediatrics 143, e20182286 (2019).

  24. Reed, B. D., Schibler, K. R., Deshmukh, H., Ambalavanan, N. & Morrow, A. L. The impact of maternal antibiotics on neonatal disease. J. Pediatr. 197, 97–103.e103 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Juul, S. E. et al. A randomized trial of erythropoietin for neuroprotection in preterm infants. N. Engl. J. Med. 382, 233–243 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bell, M. J. Neonatal necrotizing enterocolitis. N. Engl. J. Med. 298, 281–282 (1978).

    Article  CAS  PubMed  Google Scholar 

  27. Fenton, T. R. & Kim, J. H. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 13, 59 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Goldberg, D. L. et al. Identifying malnutrition in preterm and neonatal populations: recommended indicators. J. Acad. Nutr. Diet. 118, 1571–1582 (2018).

    Article  PubMed  Google Scholar 

  29. Strobel, K. M. et al. Contemporary definitions of infant growth failure and neurodevelopmental and behavioral outcomes in extremely premature infants at two years of age. J. Perinatol. 44, 811–818 (2024).

  30. Jensen, E. A. et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. An evidence-based approach. Am. J. Respir. Crit. Care Med. 200, 751–759 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang, Z. Survival analysis in the presence of competing risks. Ann. Transl. Med. 5, 47 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Puopolo, K. M. et al. Management of neonates born at ≤34 6/7 weeks’ gestation with suspected or proven early-onset bacterial sepsis. Pediatrics 142, e20182896 (2018).

  33. Puopolo, K. M. et al. Identification of extremely premature infants at low risk for early-onset sepsis. Pediatrics 140, e20170925 (2017).

  34. Hallaian, S. & Payton, K. Stratifying antibiotic use metrics by gestational age and first seven days optimizes antibiotic stewardship in neonatal intensive care units. J. Perinatol. 44, 116–118 (2024).

    Article  PubMed  Google Scholar 

  35. Jones, I. H. & Hall, N. J. Contemporary outcomes for infants with necrotizing enterocolitis – a systematic review. J. Pediatr. 220, 86–92.e83 (2020).

    Article  PubMed  Google Scholar 

  36. Bury, R. G. & Tudehope, D. Enteral antibiotics for preventing necrotizing enterocolitis in low birthweight or preterm infants. Cochrane Database Syst. Rev., CD000405 https://doi.org/10.1002/14651858.CD000405 (2001).

  37. Masi, A. C. et al. Human milk oligosaccharide DSLNT and gut microbiome in preterm infants predicts necrotising enterocolitis. Gut 70, 2273–2282 (2021).

    Article  CAS  PubMed  Google Scholar 

  38. Sim, K. et al. Dysbiosis anticipating necrotizing enterocolitis in very premature infants. Clin. Infect. Dis. 60, 389–397 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Morrow, A. L. et al. Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants. Microbiome 1, 13 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Klopp, J. et al. Meconium microbiome of very preterm infants across Germany. mSphere 7, e0080821 (2022).

    Article  PubMed  Google Scholar 

  41. Morowitz, M. J. et al. The NICU Antibiotics and Outcomes (Nano) Trial: a randomized multicenter clinical trial assessing empiric antibiotics and clinical outcomes in newborn preterm infants. Trials 23, 428 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wan, S. et al. Impact of exposure to antibiotics during pregnancy and infancy on childhood obesity: a systematic review and meta-analysis. Obesity 28, 793–802 (2020).

    Article  PubMed  Google Scholar 

  43. Solans, M., Barcelo, M. A., Morales-Suarez-Varela, M., Moya, A. & Saez, M. Prenatal exposure to antibiotics and risk of childhood overweight or obesity: a systematic review and meta-analysis. Obes. Rev. 23, e13382 (2022).

    Article  PubMed  Google Scholar 

  44. Zhou, P. et al. Perinatal antibiotic exposure affects the transmission between maternal and neonatal microbiota and is associated with early-onset sepsis. mSphere 5, e00984–19 (2020).

  45. Muraoka, J., Kaneko, M., Doi, K., Kodama, Y. & Sameshima, H. Antepartum antibiotic therapy under 34 weeks of gestation and its impact on early-onset neonatal infection and maternal vaginal microbiota. Microbiol. Res. 13, 598–608 (2022).

    Article  Google Scholar 

  46. Hermansson, H. et al. Breast milk microbiota is shaped by mode of delivery and intrapartum antibiotic exposure. Front. Nutr. 6, 4 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Coker, M. O. et al. Specific class of intrapartum antibiotics relates to maturation of the infant gut microbiota: a prospective cohort study. BJOG 127, 217–227 (2020).

    Article  CAS  PubMed  Google Scholar 

  48. Salas, A. A. et al. Risk assessment of cognitive impairment at 2 years of age in infants born extremely preterm using the intergrowth-21st growth standards. J. Pediatr. 275, 114239 (2024).

    Article  PubMed  Google Scholar 

  49. Lin, Y. C. et al. Association of neonatal antibiotic exposure with long-term growth trajectory faltering in preterm-birth children. Neonatology 121, 396–405 (2024).

    Article  CAS  PubMed  Google Scholar 

  50. Trasande, L. et al. Infant antibiotic exposures and early-life body mass. Int J. Obes. 37, 16–23 (2013).

    Article  CAS  Google Scholar 

  51. Bailey, L. C. et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr. 168, 1063–1069 (2014).

    Article  PubMed  Google Scholar 

  52. Gerber, J. S. et al. Antibiotic exposure during the first 6 months of life and weight gain during childhood. JAMA 315, 1258–1265 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Younge, N. E. et al. Disrupted maturation of the microbiota and metabolome among extremely preterm infants with postnatal growth failure. Sci. Rep. 9, 8167 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Neves, L. L., Hair, A. B. & Preidis, G. A. A systematic review of associations between gut microbiota composition and growth failure in preterm neonates. Gut Microbes 15, 2190301 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kumbhare, S. V. et al. Source of human milk (mother or donor) is more important than fortifier type (human or bovine) in shaping the preterm infant microbiome. Cell Rep. Med. 3, 100712 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Salas, A. A. et al. The gut microbiome of extremely preterm infants randomized to the early progression of enteral feeding. Pediatr. Res. 92, 799–804 (2022).

    Article  CAS  PubMed  Google Scholar 

  57. Nolan, L. S., Rimer, J. M. & Good, M. The role of human milk oligosaccharides and probiotics on the neonatal microbiome and risk of necrotizing enterocolitis: a narrative review. Nutrients 12, 3052 (2020).

  58. Fenton, T. R. et al. “Extrauterine growth restriction” and “postnatal growth failure” are misnomers for preterm infants. J. Perinatol. 40, 704–714 (2020).

    Article  PubMed  Google Scholar 

  59. Salas, A. A., Bhatia, A. & Carlo, W. A. Postnatal growth of preterm infants 24 to 26 weeks of gestation and cognitive outcomes at 2 years of age. Pediatr. Res. 89, 1804–1809 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Rochow, N. et al. Physiological adjustment to postnatal growth trajectories in healthy preterm infants. Pediatr. Res. 79, 870–879 (2016).

    Article  PubMed  Google Scholar 

  61. Wood, A. J., Raynes-Greenow, C. H., Carberry, A. E. & Jeffery, H. E. Neonatal length inaccuracies in clinical practice and related percentile discrepancies detected by a simple length-board. J. Paediatr. Child Health 49, 199–203 (2013).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The PENUT Trial was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers U01NS077953 and U01NS077955.

Author information

Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA, USA

    Katie M. Strobel, Thomas R. Wood, Gregory C. Valentine, Olivia C. Brandon, D. Taylor Hendrixson, Dennis E. Mayock, Krystle M. Perez, Mihai Puia-Dumitrescu & Sandra E. Juul

  2. Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, WA, USA

    D. Taylor Hendrixson

  3. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Patrick J. Heagerty

  4. Institute on Human Development and Disability, Seattle, WA, USA

    Sandra E. Juul

Authors
  1. Katie M. Strobel
    View author publications

    Search author on:PubMed Google Scholar

  2. Thomas R. Wood
    View author publications

    Search author on:PubMed Google Scholar

  3. Gregory C. Valentine
    View author publications

    Search author on:PubMed Google Scholar

  4. Olivia C. Brandon
    View author publications

    Search author on:PubMed Google Scholar

  5. D. Taylor Hendrixson
    View author publications

    Search author on:PubMed Google Scholar

  6. Dennis E. Mayock
    View author publications

    Search author on:PubMed Google Scholar

  7. Krystle M. Perez
    View author publications

    Search author on:PubMed Google Scholar

  8. Mihai Puia-Dumitrescu
    View author publications

    Search author on:PubMed Google Scholar

  9. Patrick J. Heagerty
    View author publications

    Search author on:PubMed Google Scholar

  10. Sandra E. Juul
    View author publications

    Search author on:PubMed Google Scholar

Contributions

K.M.S. conceptualized the study. K.M.S., T.R.W., S.E.J., G.C.V., K.M.P., and D.T.H. provided input in the study design. T.R.W. and K.M.S. performed the data analysis. K.M.S. wrote the original draft of the manuscript. T.R.W., G.C.V., K.M.P., O.B., D.T.H., D.E.M., M.P.D., P.J.H., and S.E.J. assisted with revisions to the manuscript. All authors approve the final draft of the manuscript.

Corresponding author

Correspondence to Katie M. Strobel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

The PENUT Trial was approved by the institutional review board at each participating site and was registered with the Food and Drug Administration. The study was performed in accordance with the Declaration of Helsinki.

Informed consent

Each participant participated with informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Strobel, K.M., Wood, T.R., Valentine, G.C. et al. Effect of early antibiotic exposure on necrotizing enterocolitis and growth in extremely preterm infants. Pediatr Res 98, 137–143 (2025). https://doi.org/10.1038/s41390-025-03928-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41390-025-03928-y

This article is cited by

Search

Advanced search

Quick links