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Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions
  1. Sagori Mukhopadhyay1,
  2. Karen M Puopolo1,
  3. Nellie I Hansen2,
  4. Scott A Lorch1,
  5. Sara B DeMauro1,
  6. Rachel G Greenberg3,4,
  7. C Michael Cotten3,
  8. Pablo J Sanchez5,
  9. Edward F Bell6,
  10. Eric C Eichenwald1,
  11. Barbara J Stoll7
  12. on behalf of the NICHD Neonatal Research Network
  1. 1 Pediatrics, Neonatology, The Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  2. 2 Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina, USA
  3. 3 Pediatrics, Neonatology, Duke University, Durham, North Carolina, USA
  4. 4 Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
  5. 5 Pediatrics, Neonatology and Neonatology and Pediatric Infectious Diseases, Nationwide Children's Hospital, The Ohio State University College of Medicine, The Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
  6. 6 Pediatrics, Neonatology, University of Iowa, Iowa City, Iowa, USA
  7. 7 Pediatrics, Neonatology, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, Texas, USA
  1. Correspondence to Dr Sagori Mukhopadhyay, Newborn Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; sagori.mukhopadhyay{at}


Objective Determine risk of death or neurodevelopmental impairment (NDI) in infants with late-onset sepsis (LOS) versus late-onset, antibiotic-treated, blood culture-negative conditions (LOCNC).

Design Retrospective cohort study.

Setting 24 neonatal centres.

Patients Infants born 1/1/2006–31/12/2014, at 22–26 weeks gestation, with birth weight 401–1000 g and surviving >7 days were included. Infants with early-onset sepsis, necrotising enterocolitis, intestinal perforation or both LOS and LOCNC were excluded.

Exposures LOS and LOCNC were defined as antibiotic administration for ≥5 days with and without a positive blood/cerebrospinal fluid culture, respectively. Infants with these diagnoses were also compared with infants with neither condition.

Outcomes Death or NDI was assessed at 18–26 months corrected age follow-up. Modified Poisson regression models were used to estimate relative risks adjusting for covariates occurring ≤7 days of age.

Results Of 7354 eligible infants, 3940 met inclusion criteria: 786 (20%) with LOS, 1601 (41%) with LOCNC and 1553 (39%) with neither. Infants with LOS had higher adjusted relative risk (95% CI) for death/NDI (1.14 (1.05 to 1.25)) and death before follow-up (1.71 (1.44 to 2.03)) than those with LOCNC. Among survivors, risk for NDI did not differ between the two groups (0.99 (0.86 to 1.13)) but was higher for LOCNC infants (1.17 (1.04 to 1.31)) compared with unaffected infants.

Conclusions Infants with LOS had higher risk of death, but not NDI, compared with infants with LOCNC. Surviving infants with LOCNC had higher risk of NDI compared with unaffected infants. Improving outcomes for infants with LOCNC requires study of the underlying conditions and the potential impact of antibiotic exposure.

  • neonatology
  • epidemiology
  • neurology

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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  • SM and KMP contributed equally.

  • Contributors SM conceptualised and designed the study, contributed to interpretation of results, drafted the initial manuscript and reviewed and revised the manuscript. KP conceptualised and designed the study, contributed to interpretation of results and reviewed and revised the manuscript. NIH carried out the statistical analyses, critically reviewed the manuscript and approved the final manuscript as submitted. SL, SBDM, RG, BJS, CMC, PJS, EFB and EE contributed to the study concept, reviewed and revised the manuscript, and approved the final manuscript as submitted.

  • Funding This work was conducted and supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) that provides grant support for the generic database and follow-up studies of the Neonatal Research Network. Please see online supplemental appendix of acknowledgments for full funding information. SM is supported by a grant from the NICHD (K23HD088753).

  • Competing interests RG has received support from industry for research services ( The other authors have no conflicts of interest relevant to this article to disclose.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.