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Comment & Response
March 9, 2020

Neonatal Early-Onset Sepsis Calculator and Antibiotic Therapy—Reply

Author Affiliations
  • 1Department of Pediatrics, Tergooi Hospital, Blaricum, the Netherlands
  • 2Faculty of Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 3Department of Pediatrics and Adolescence Medicine, University Hospital of North Norway, Tromsø, Norway
  • 4Paediatric Research Group, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
JAMA Pediatr. Published online March 9, 2020. doi:10.1001/jamapediatrics.2019.6269

In Reply We thank Zhang and Niu and Aghai for their interest in our systematic review of use of the early-onset sepsis (EOS) calculator. Zhang and Niu worry about study heterogeneity and publication bias. We carefully assessed all 13 included studies and found it appropriate to meta-analyze the 6 studies reporting data before and after EOS calculator implementation with comparable settings in both epochs.1 We grouped these studies based on their inclusion criteria; 4 studies including all newborns and 2 studies only including newborns exposed to maternal chorioamnionitis. We found no evidence of heterogeneity within studies including newborns regardless of exposure to chorioamnionitis (I2 = 0%, Figure 2). Heterogeneity in the chorioamnionitis-exposed subgroup was transparent because it contained only 2 studies.

Different methods to assess risk of publication bias exist. After assessment using the Grading of Recommendations Assessment, Development, and Evaluation method,2 we included 6 studies in the meta-analysis, whereas a rule of thumb requires at least 10 for meaningful funnel plots.3 Another method involves analysis of results from non–peer-reviewed sources (gray literature).4 Our search revealed 15 gray literature reports.1 Five contained otherwise eligible results (data not shown). Results were largely congruent with the studies included in our systematic review, which supports a low risk of publication bias. We acknowledge that included studies are of Western origin, but this likely reflects limited research on this particular topic conducted in other regions rather than publication bias. However, this also limits generalizability of our findings, and we encourage further research, especially in non-Western countries.

Aghai questions why we did not include 39 EOS cases from the study by Kuzniewicz et al5 in the meta-analysis and states that conclusion on noninferiority of safety of the EOS calculator would be different if more cases would be included. This before-after study5 reported 51 EOS cases (eTable 1). Of these, 36 were included in our meta-analysis (12 postimplementation cases in the EOS calculator group and 24 preimplementation cases in the conventional management group) (Table 2).1 We excluded 15 cases (not 39), because they were treated in the learning period and could not be assigned to either group. No other cases were excluded. Hence, in contrast to Aghai’s comment, the total of 46 included cases from all studies exceeds the number of 15 excluded cases.

Studies using hypothetical databases were not included in the meta-analysis but included in the review,1 and their results regarding EOS cases are summarized in Table 2. We could have performed hypothetical application of the EOS calculator on the EOS cases from before-after studies. However, except the aforementioned 15 cases from the learning period of the Kuzniewicz study, these cases would then be analyzed twice and thus be overrepresented in the review. Retrospective hypothetical application of the EOS calculator indeed sometimes does not recommend antibiotics to an EOS case. However, all current risk assessment strategies are imperfect.6 We cautiously concluded that “available evidence regarding safety of the use of the EOS calculator is limited, but shows no indication of inferiority compared with conventional management strategies,”1 and we do not believe Aghai’s comments alter this conclusion.

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Article Information

Corresponding Author: Niek B. Achten, MD, Department of Pediatrics, Tergooi Hospital, Rijksstraatweg 1, Blaricum 1261 AN, the Netherlands (niek.achten@gmail.com).

Published Online: March 9, 2020. doi:10.1001/jamapediatrics.2019.6269

Conflict of Interest Disclosures: None reported.

Achten  NB, Klingenberg  C, Benitz  WE,  et al.  Association of use of the neonatal early-onset sepsis calculator with reduction in antibiotic therapy and safety: a systematic review and meta-analysis.  JAMA Pediatr. 2019;173(11):1032-1040. doi:10.1001/jamapediatrics.2019.2825PubMedGoogle Scholar
Guyatt  GH, Oxman  AD, Montori  V,  et al.  GRADE guidelines, 5: rating the quality of evidence: publication bias.  J Clin Epidemiol. 2011;64(12):1277-1282. doi:10.1016/j.jclinepi.2011.01.011PubMedGoogle ScholarCrossref
The Cochrane Collaboration. In: Higgins , ed.  Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Hoboken, NJ: Wiley; 2011.
Paez  A.  Gray literature: an important resource in systematic reviews.  J Evid Based Med. 2017;10(3):233-240. doi:10.1111/jebm.12266PubMedGoogle ScholarCrossref
Kuzniewicz  MW, Puopolo  KM, Fischer  A,  et al.  A quantitative, risk-based approach to the management of neonatal early-onset sepsis.  JAMA Pediatr. 2017;171(4):365-371. doi:10.1001/jamapediatrics.2016.4678PubMedGoogle ScholarCrossref
Puopolo  KM, Benitz  WE, Zaoutis  TE; Committee on Fetus and Newborn; Committee on Infectious Diseases.  Management of neonates born at ≥35 0/7 weeks’ gestation with suspected or proven early-onset bacterial sepsis.  Pediatrics. 2018;142(6):e20182894. doi:10.1542/peds.2018-2894PubMedGoogle Scholar
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