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BY 4.0 license Open Access Published by De Gruyter October 31, 2022

Interventions for reducing late-onset sepsis in neonates: an umbrella review

  • Abdul Razak ORCID logo EMAIL logo , Omar Ibrahim Alhaidari and Javed Ahmed
From the journal Journal of Perinatal Medicine
https://doi.org/10.1515/jpm-2022-0131
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Abstract

Objectives

Neonatal sepsis is one of the leading causes of neonatal deaths in neonatal intensive care units. Hence, it is essential to review the evidence from systematic reviews on interventions for reducing late-onset sepsis (LOS) in neonates.

Methods

PubMed and the Cochrane Central were searched from inception through August 2020 without any language restriction. Cochrane reviews of randomized clinical trials (RCTs) assessing any intervention in the neonatal period and including one or more RCTs reporting LOS. Two authors independently performed screening, data extraction, assessed the quality of evidence using Cochrane Grading of Recommendations Assessment, Development and Evaluation, and assessed the quality of reviews using a measurement tool to assess of multiple systematic reviews 2 tool.

Results

A total of 101 high-quality Cochrane reviews involving 612 RCTs and 193,713 neonates, evaluating 141 interventions were included. High-quality evidence showed a reduction in any or culture-proven LOS using antibiotic lock therapy for neonates with central venous catheters (CVC). Moderate-quality evidence showed a decrease in any LOS with antibiotic prophylaxis or vancomycin prophylaxis for neonates with CVC, chlorhexidine for skin or cord care, and kangaroo care for low birth weight babies. Similarly, moderate-quality evidence showed reduced culture-proven LOS with intravenous immunoglobulin prophylaxis for preterm infants and probiotic supplementation for very low birth weight (VLBW) infants. Lastly, moderate-quality evidence showed a reduction in fungal LOS with the use of systemic antifungal prophylaxis in VLBW infants.

Conclusions

The overview summarizes the evidence from the Cochrane reviews assessing interventions for reducing LOS in neonates, and can be utilized by clinicians, researchers, policymakers, and consumers for decision-making and translating evidence into clinical practice.

Keywords: infection; late-onset sepsis; neonatal sepsis; neonate; overview; sepsis

Introduction

Sepsis is traditionally defined as the isolation of the pathogen from sterile body fluid such as blood or cerebrospinal fluid. In adults, the consensus definition includes life-threatening organ dysfunction caused by a dysregulated response to infection [1]. However, in neonates, no such consensus definition is available [2]. Sepsis manifesting in neonates within the first 72 h of life is classified as early-onset, whereas it is considered late-onset if the manifestations appear beyond 72 h of life. Advances in obstetric care and prophylactic intrapartum antibiotics have reduced the risk of early-onset sepsis [3, 4]. However, the incidence of late-onset sepsis (LOS) has increased in parallel with the improved survival of extremely premature (gestational age <28 weeks) and very low birth weight (VLBW, birth weight <1,500 g) neonates [3, 4]. It affects 0.61–14.2 percent of hospitalized newborn infants and is inversely related to the degree of prematurity [5].

Sepsis remains the major contributor to global mortality, and the World Health Organization has declared it a global health priority [6]. Despite effective treatment strategies, including appropriate antimicrobial treatment, it remains a leading cause of neonatal death and a significant contributor to neonatal morbidities in neonatal intensive care units and the community. It is therefore imperative to identify the preventive measures that reduce the risk of sepsis in the neonatal period. Randomized clinical trials (RCTs) and their systematic reviews investigating a broad range of interventions realize the potential for interventions of interest to reduce the risk of neonatal sepsis. Given that several risk factors impact the risk of neonatal sepsis, there is a need to systematically examine all potentially relevant interventions that can contribute to the prevention of neonatal sepsis. To our knowledge, no published overview has compiled and summarized the evidence from systematic reviews on interventions for preventing neonatal sepsis in one coherent document. This overview will help clinicians, researchers, policymakers, funding bodies, and consumers assist decision-making and evidence translation.

Materials and methods

We conducted this systematic review as per Preferred Reporting Items for Overviews of Systematic Reviews including Harms (PRIO-harms) guideline [7] and the approach outlined in the Cochrane Handbook for Systematic Reviews of Interventions [8]. We registered the protocol for the systematic review with PROSPERO (registration number CRD42020192513), the international prospective register for systematic reviews (https://www.crd.york.ac.uk/PROSPERO).

Search strategy

We conducted a comprehensive search of the literature using appropriate pre-specified search terms within the following databases: PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception (Supplemental Information) through August 6, 2020. We did not apply language restrictions. We also read the reference lists of included systematic reviews to identify eligible studies. Finally, we searched the “related articles” feature in PubMed and hand searched in Cochrane Neonatal (https://neonatal.cochrane.org) for missing reviews.

Study selection (eligibility criteria)

Type of studies

In this overview, we included Cochrane reviews RCTs or quasi-RCTs assessing neonatal interventions. The Cochrane review must consist of one or more RCTs reporting at least one of the pre-specified outcomes of this review. We excluded non-Cochrane reviews, Cochrane reviews of non-randomized studies, and Cochrane reviews with no RCTs reporting the outcome.

Population

We included Cochrane reviews assessing interventions in term and preterm neonates. We also included reviews reporting data on mixed infant (age less than one year) populations as long as separate data was provided for neonates.

Interventions and comparisons

We considered all types of interventions following the birth of the newborn infant (delivery room interventions) or interventions in the neonatal period (neonatal interventions within 28 days from the birth) in a neonatal intensive care unit or community, compared with placebo, no treatment, or an alternative treatment. We excluded Cochrane reviews assessing non-neonatal interventions (interventions in pregnancy or before childbirth) and interventions beyond the neonatal period. However, interventions initiated in the neonatal period and continued beyond the neonatal period were also included.

Outcomes

Primary outcomes

  1. Any LOS: Clinically suspected or microbiologically confirmed LOS, as defined by the Cochrane review authors.

  2. Culture-proven LOS: Microbiologically confirmed LOS, as defined by the Cochrane review authors.

Secondary outcomes

  1. Bacterial LOS: LOS caused by a bacterial organism, as defined by the Cochrane review authors.

  2. Fungal LOS: LOS caused by a fungal organism, as defined by the Cochrane review authors.

We excluded Cochrane reviews evaluating early-onset sepsis as our overview focuses on neonatal interventions and not childbirth or pregnancy interventions. However, we included Cochrane reviews evaluating both early-onset and late-onset sepsis as long as reviews reporting separate data on LOS were available.

Study selection and data extraction

The author (A.R.) performed the literature search across the databases using pre-specified terms (Supplementary Information). We managed the citations retrieved through the search using Covidence. Authors, J.A. and O.A., independently performed the titles and abstracts screening, independently evaluated the full-text articles of the shortlisted reports, and independently extracted the information, including review title and authors, date last assessed as up-to-date, number of trials, number of participants and their characteristics, interventions and comparisons, outcomes relevant to this overview, and quality of RCTs assessed by review authors, and summary intervention effects (relative risks (RR), odds risk or absolute risk differences and their 95% confidence intervals (CI), model used for meta-analysis) for all neonates and subgroup of neonates (preterm and term neonates).

Assessment of methodological quality of included reviews

Quality of included reviews

Two authors (J.A. and A.R.) independently assessed the methodological quality of each Cochrane systematic review using the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2) instrument [9]. AMSTAR 2 evaluates the review methodology against 16 distinct domains, of which 7 are critical domains. Eleven domains on AMSTAR 2 are rated as yes or no, and five domains are rated as yes, partially yes, and no. The overall confidence in the results of the review was rated as high (no or one non-critical weakness), moderate (more than one non-critical weakness), low (one critical flaw with or without non-critical weaknesses), and critically low (more than one critical flaw with or without non-critical weaknesses).

Quality of included studies within reviews

We reported, instead of reassessing, the quality of included RCTs within reviews according to the review authors’ judgment.

Quality of evidence in the included reviews

We reported the quality of evidence using the Cochrane Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach according to the review authors’ judgment as high certainty, moderate certainty, low certainty, or very low certainty [10]. Two authors (J.A. and O.A.) independently assessed the evidence certainty using the Cochrane GRADE if the Cochrane review authors did not provide the assessment of the evidence certainty. Discussions and consensus with the third author (A.R.) resolved discrepancies in the review process.

Data synthesis

We summarized the results of included reviews in the summary of the findings table. We categorized the interventions into 5 categories: effective interventions (high certainty in the evidence of effectiveness), possible effective interventions (moderate certainty in the evidence of effectiveness), ineffective interventions (high certainty in the evidence of lack of effectiveness (or harm)), possible ineffective interventions (moderate certainty in the evidence of lack of effectiveness (or harm)), and no conclusions possible (low or very low certainty in the evidence) [8].

Results

The database search results and study selection log are shown in Figure 1. The search yielded 1,047 from databases and 1 article from other sources. After removing the duplicates and unrelated articles by title and abstract screening, we included 286 reviews for full-text screening. Finally, 101 Cochrane reviews were included after excluding 185 reviews [11–111]. All the 101 included Cochrane reviews were of high quality, and the detailed evaluation as per AMSTAR 2 tool is provided in Table 1 of the Supplementary Information.

Figure 1: Study flow diagram outlining stages of search results and filtering process.
Figure 1:

Study flow diagram outlining stages of search results and filtering process.

Table 1 provides the details of the included reviews, including the summary assessment of the primary and secondary outcomes of the study. The subgroup and sensitivity analysis details are provided in Table 2 of the Supplementary Information. Most reviews evaluated one intervention, but few evaluated two or more interventions. Overall, 101 included reviews evaluated 141 interventions with LOS as one of the primary or secondary outcomes. Few reviews assessed various types of LOS (any, bacterial or fungal), and the majority of them evaluated LOS as culture-positive sepsis (n=65), followed by any sepsis (n=55), bacterial sepsis (n=34), and fungal sepsis (n=10).

Table 1:

Summary of Cochrane reviews assessing intervention on late-onset neonatal sepsis.

Review ID Population Intervention Comparison Sepsis No. of RCTs No. of patients included in the RCTs Summary of measure Estimate (95% CI) Certainty of evidence, GRADE
Abiramalatha 2019 <37 w Routine monitoring of gastric residuals No monitoring CP 2 141 RR, fixed 1.46 [0.85, 2.52] Low1,3,a
Criteria 1 gastric residue monitoring Criteria 2 gastric residue monitoring CP 1 87 RR, fixed 5.35 [0.26, 108.27] Low1,3,a
Aher 2020 <37 w or LBW Late ESAs P/NI CP 5 551 RR, fixed 0.75 [0.52, 1.09] Low1,3,a
Ainsworth 2015 Neonates requiring PN Percutaneous CVC Peripheral cannula CP 6 549 RR, fixed 0.95 [0.72, 1.25] Moderate1,a
Ardell 2015 <37 w Animal derived surfactant Protein free synthetic surfactant Bacterial 10 5,219 RR, fixed 1.00 [0.91, 1.10] Moderate1,a
Ardell 2018 <37 w 0.2 mg IV vit K 0.2 mg IM Any 1 52 RR, fixed 1.0 [0.28, 3.58] Low1,3
0.5 mg IM Any 1 54 RR, fixed 0.86 [0.26, 2.86] Low1,3
Any IM Any 1 80 RR, fixed 0.92 [0.31, 2.72] Low1,3,a
Austin 2015 <32 w or VLBW Oral/topical antifungal P/NI Fungal 4 1800 RR, fixed 0.20 [0.14, 0.27] Low1,2,a
Systemic Fungal 3 326 RR, fixed 1.89 [0.66, 5.39] Low1,3,a
Bahadue 2012 RDS Early surfactant (animal derived surfactant) Delayed Bacterial 1 75 RR, fixed 1.14 [0.81, 1.60] Low1,3,a
Balain 2015 Neonates with CVC Antimicrobial-impregnated CVC Non-impregnated CVC CP 1 86 RR, fixed 0.11 [0.01, 0.87] Low1,3,a
Bottino 2011 <32 w or VLBW Insulin infusion No glucose reduction Bacterial 1 23 RR, fixed 0.61 [0.29, 1.25] Low1,3,a
Glucose reduction Bacterial 1 23 RR, fixed 0.46 [0.10, 2.03] Low1,3,a
Fungal 1 23 RR, fixed 0.18 [0.01, 3.47] Low1,3,a
Brion 2003 <37 w Vitamin E P/NI Any 4 1,009 RR, fixed 1.52 [1.13, 2.04] Moderate1,a
Another vitamin E Any 1 44 RR, fixed 0.33 [0.04, 2.96] Low1,3,a
Brown 2014 Neonates with severe GI disease Glutamine P/NI CP 3 263 RR, fixed 1.37 [0.89, 2.11] Moderate3,a
Carr 2003 Neonates requiring NICU G-CSF or GM-CSF prophylaxis P/NI CP 1 75 RR, fixed 0.66 [0.36, 1.20] Low1,3,a
Any 2 284 RR, fixed 1.02 [0.76, 1.37] Low1,3,a
Cleminson 2015 <32 w or VLBW Systemic antifungal P/NI Fungal 10 1,371 RR, fixed 0.43 [0.31, 0.59] Moderate1,a
Oral/Topical Fungal 3 326 RD, fixed −0.03 [-0.07, 0.02] Low1,3,a
Cleminson 2016 <37 w Topical ointment or cream (sunflower seed oil, aquaphor, petroleum jelly, beiersdorf inc., bepanthen, 70% lanolin, 30% olive oil, eucerin crème) Routine care CP 8 2086 RR, fixed 1.13 [0.97, 1.31] Low1,3
CoNS 6 1839 RR, fixed 1.30 [1.03, 1.65] Moderate1,a
Other bacteria 6 1839 RR, fixed 0.84 [0.63, 1.12] Moderate1,a
Fungal 6 1839 RD, fixed 0.01 [-0.01, 0.03] Moderate1,a
Topical oil (sunflower oil, sunflower seed oil, aquaphor, coconut oil, mineral oil, soybean oil, sunflower seed oil) Routine care CP 6 844 RR, fixed 0.71 [0.51, 1.01] Low1,3
CoNS 5 775 RR, fixed 0.15 [0.02, 1.16] Low1,3,a
Other bacteria 5 775 RR, fixed 0.70 [0.47, 1.05] Very low1,2,3,a
Fungal 5 775 RR, fixed 1.93 [0.42, 8.78] Very low1,2,3,a
Topical ointment or cream (sunflower seed oil, aquaphor) Topical oil (sunflower seed oil, aquaphor) CP 1 316 RR, fixed 0.91 [0.57, 1.46] Low1,3,a
Other bacteria 1 316 RR, fixed 0.90 [0.53, 1.50] Low1,3,a
Fungal 1 316 RR, fixed 1.35 [0.31, 5.94] Low1,3,a
Collins 2015 <37 w Early discharge (on gavage feeds) Late discharge (once full suckling is established) Any 1 88 RR, fixed 0.35 [0.17, 0.69] Low1,a
Collins 2016 <37 w Breast feeding, with supplements without bottle feeding BF + supplementary feeding by bottle Infection (any) 3 500 RR, fixed 0.70 [0.35, 1.42] Moderate1,4
Conde 2016 LBW infant Kangaroo care Conventional care Any (latest follow up) 8 1,463 RR, fixed 0.50 [0.36, 0.69] Moderate1
Any (at discharge or 40–41 w) 5 1,239 RR, fixed 0.35 [0.22, 0.54] Moderate1,a
Early kangaroo care Late kangaroo care Any 1 73 RR, fixed 0.42 [0.12, 1.49] Low1,3,a
Craft 2000 Neonates <1,500 g or with CVC requiring PN Prophylactic vancomycin P/NI Any 4 290 RR, fixed 0.11 [0.05, 0.24] Moderate1, a
CoNS 4 221 RR, fixed 0.33 [0.19, 0.59] Low1,2,a
Darlow 2003 <37 w or <2000 g Selenium supplementation P/NI Bacterial 3 583 RR, fixed 0.73 [0.57, 0.93] Low1,3,a
Darlow 2016 <32 w or VLBW Vitamin A P/NI Any 3 947 RR, fixed 0.89 [0.76, 1.04] Low1,3,a
High dose vit A Standard dose Any 1 80 RR, fixed No difference b/w groups Low1,3,a
Once a week vit A Standard dose Any 1 80 RR, fixed No difference b/w groups Low1,3,a
De paoli 2008 <37 w requiring CPAP Short binasal prongs Single nasal prong CP 1 87 RR, fixed 1.02 [0.66, 1.58] Low1,3,a
Suspected 1 87 RR, fixed 0.93 [0.60, 1.44] Low1,3,a
Infant flow driver Medicorp prong CP 1 100 RR, fixed 1.09 [0.53, 2.24] Low1,3,a
Doyle 2017 (early PNCS) Preterm at risk of BPD Early corticosteroids (dexamethasone and hydrocortisone) P/NI Infection (LOS, any) 25 4,101 RR, fixed 1.05 [0.96, 1.15] Moderate1,a
Doyle 2017 (late PNCS) Preterm at risk of BPD Late corticosteroids (dexamethasone or hydrocortisone) P/NI Infection (LOS, any) 18 1,349 RR, fixed 1.14 [0.97, 1.34] High
Fenton 2020 LBW High protein intake (>3 g/kg) Low (<3 g/kg) CP 1 30 RR, fixed 0.44 [0.04, 4.32] Low1,3,a
Flenady 2003 Neonates Radiant warmers Incubators Any 2 90 RR, fixed 0.93 [0.66, 1.30] Low1,3,a
CP 1 60 RR, fixed 0.6 [0.16, 2.29] Low1,3, a
Foster 2015 Neonates with IV IV filter P/NI CP 2 530 RR, fixed 0.86 [0.59, 1.27] Moderate1
Foster 2017 Term or preterm Routine oro-or-nasopharyngeal suction at birth No Infection (LOS (<7 days), any) 1 509 RR, fixed 0.76 [0.42, 1.36] Low1
Gordon 2017 Neonates with UVC Early planned UVC removal Later planned UVC removal CP 1 210 RR, fixed 0.65 [0.35, 1.22] Low1,3
CoNS 1 210 RR, fixed 0.49 [0.19, 1.26] Low1,3
Other bacteria 1 210 RR, fixed 0.61 [0.21, 1.81] Low1,3
Fungi 1 210 RR, fixed 1.96 [0.18, 21.31] Low1,3
Gray 2011 <37 w Cot-nursing Incubator Any 2 108 RR, fixed 0.27 [0.01, 6.41] Low1,3
Howlett 2019 <37 w or LBW Inositol (IV followed by PO) P/NI Bacterial 2 701 RR, fixed 1.33 [1.00, 1.75] High
Inositol (repeat dose) P/NI Bacterial 4 1,067 RR, fixed 1.21 [0.95, 1.54] Moderate3
Inositol (single dose) P/NI Bacterial 1 74 RR, fixed 1.46 [0.71, 2.97] Moderate3,a
Ibrahim 2011 <37 w (primary treatment for hypotension) Steroids P/NI Bacterial 1 18 RR, fixed 0.33 [0.09, 1.23] Moderate3,a
Other drug (e.g. inotrope) Bacterial 1 40 RR, fixed 0.60 [0.20, 1.82] Low1,3,a
<37 w (treatment for refractory hypotension) Steroids P/NI Bacterial 2 65 RR, fixed 1.09 [0.29, 4.10] Low1,3,a
Imdad 2013 Neonates Antiseptics (chlorhexidine) Antiseptics (salicylic acid powder) Any 1 213 RR, random 1.11 [0.07, 17.50] Low1,3,a
Inglis 2005 (antibiotics for UVC Neonates with UVC Any prophylactic antibiotic P/NI Any 1 29 N/A N/A (no difference between groups/no events) Low1,3,a
Inglis 2007 (antibiotics for UAC) Neonates with UAC Any prophylactic antibiotic P/NI Any 2 212 N/A Not done (one trial reported no significant difference whereas another trial reported significant difference between groups) Low1,3,a
Inglis 2007 (antibiotics for ventilated neonates) Ventilated neonates Antibiotic P/NI Any 2 N/A N/A Meta-analysis for sepsis is N/A (one trial reported no difference in LOS) Low1,3,a
Jacobs 2013 >35 w Therapeutic hypothermia P/NI CP 8 1,222 RR, fixed 0.87 [0.60, 1.26] Moderate1,a
Jardine 2008 Neonates with CVC Antibiotics (vancomycin, amoxicillin) P/NI Bacterial 2 201 RR, fixed 0.38 [0.18, 0.82] Moderate1,a
Any 2 201 RR, fixed 0.40 [0.20, 0.78] Moderate1,a
Kabra 2005 Neonates with UVC ML-UVCs SL-UVCs Suspected 2 56 RR, fixed 0.89 [0.29, 2.78] Low1,3,a
Kapoor 2019 (lipid for term and late preterm) >37 w with surgical problems Fish oil LE Non-fish oil LE CP 2 51 RR, fixed 1.05 [0.47, 2.34] Very low1,3
Any 3 93 RR, fixed 1.04 [0.53, 2.02] Low1,3,a
>37 w cholestasis Fish oil LE Non-fish oil LE Any 2 40 RR, fixed 1.21 [0.50, 2.92] Very low1,3
Kapoor 2019 (lipid for preterm) <37 w Fish oil LE Non-fish oil LE CP 7 774 RR, fixed 1.16 [0.91, 1.48] Low1,3
Another fish oil LE Any 1 55 RR, fixed 1.69 [0.56, 5.11] Low1,3
Alternative LE Another alternative-LE Any 1 59 RR, fixed 1.93 [0.65, 5.73] Low1,3
Alternative LE Soybean LE CP 2 164 RR, fixed 1.22 [0.54, 2.78] Low1,3
Kelly 2017 Asymptomatic newborns with MSAF Antibiotics P/NI CP 1 250 RD, fixed −0.01 [-0.07, 0.04] Low1,3
Suspected 1 250 RD, fixed −0.03 [-0.10, 0.05] Low1,3
Symptomatic newborns with MSAF Antibiotics P/NI CP 3 445 RD, fixed 0.00 [-0.02, 0.03] Low1,3
Kuti 2021 Pregnant women, mothers, other caregivers, and HCWs 2% chlorhexidine gluconate Alcohol hand sanitizer CP 1 2,932 RR, fixed 2.26 [1.73, 2.93] Very low1,3
Any 1 2,932 RR, fixed 2.19 [1.79, 2.69] Very low1,3
4% chlorhexidine gluconate Triclosan 1% Any 1 1916 RR, fixed 6.01 [3.56, 10.14] Low1,3,a
Lai 2016 (antimicrobial dressing for CVC) Neonates with CVC Chlorhexidine dressing Polyurethane dressing CP 1 655 RR, fixed 1.18 [0.53, 2.65] Moderate3
Suspected 1 705 RR, fixed 1.06 [0.75, 1.52] Moderate3
Lai 2016 (co bedding) <37 w, twins Co-bedding P/NI Any 2 59 RR, fixed 0.45 [0.07, 2.86] Very low1,3,a
CP 3 65 RR, fixed 0.84 [0.30, 2.31] Very low1,3
Lassi 2019 Neonates Maternal and neonates care education P/NI Infection, including sepsis (any) 2 42,043 RR, random 0.88 [0.72, 1.08] Moderate1,a
Lemyre 2016 <37 w NIPPV for RDS NCPAP for RDS Any 2 136 RR, fixed 0.78 [0.36, 1.70] Moderate1
Malviya 2013 <37 w or LBW with symptomatic PDA Surgical ligation Medical treatment Any 1 154 RR, fixed 1.14 [0.62, 2.09] Low1,3,a
McCall 2018 <37 w or LBW Plastic wrap or bag Routine care Bacterial 2 830 RR, fixed 0.88 [0.70, 1.10] Low1,3,a
Thermal mattress Routine care Bacterial 1 102 RR, fixed 0.92 [0.48, 1.79] Low1,3,a
McMullan 2018 Neonates undergoing CVC removal Cephazolin P/NI CP 1 88 RR, fixed 0.09 [0.01, 1.60] Low1,3
Suspected 1 88 RR, fixed 0.33 [0.01, 7.97] Low1,3
Meyer 2018 <37 w Respiratory support before cord clamping P/N CP 1 150 RR, fixed 1.67 [0.41, 6.73] Low1,3,a
Moe-Byrne 2016 <37 w Glutamine P/NI CP 11 2,815 RR, fixed 0.94 [0.86, 1.04] Moderate2,4
Moon K 2020 >34 w Early PN Late PN CP 1 209 RR, fixed 0.22 [0.05, 1.01] Low1,3
Any 1 209 RR, fixed 0.53 [0.32, 0.89] Low1,3
Morgan 2013 VLBW or <32 w Early trophic feeding No trophic feeds CP 3 237 RR, fixed 1.06 [0.72, 1.56] Low1,3,a
Morgan 2014 VLBW or <32 w Delayed feeds (4/> days after birth) Early feeds CP 2 457 RR, fixed 1.27 [0.95, 1.70] Low1,3,a
Muelbert 2019 <37 w Smell and taste of milk P/NI CP 1 51 RR, fixed 2.46 [0.27, 22.13] Low1,3
Nasuf 2018 <37 w OPC P/NI CP 6 335 RR, fixed 0.86 [0.56, 1.33] Very low1,3
Ng 2016 <37 w at risk of CLD Salbutamol P/NI CP 1 173 RR, fixed 1.06 [0.54, 2.06] Low1,3,a
Ng 2017 <37 w Cromolyn sodium P/NI Any 2 64 RR, fixed 0.82 [0.41, 1.63] Low1,3,a
Ng 2019 <37 w Hydrolyzed formula Standard formula CP 1 60 RR, fixed 1.50 [0.27, 8.34] Low1,3,a
Oddie 2017 <32 w or VLBW Slow feeding advancement Faster feed advancement CP 8 3,392 RR, fixed 1.15 [1.00, 1.32] Low1,3
Ohlsson 2020 (ibuprofen for prevention of PDA) <37 w and LBW Ibuprofen P/NI Bacterial 2 201 RR, fixed 2.70 [1.10, 6.59] Low1,3,a
EOS
Ohlsson 2020 (ibuprofen for treatment of PDA) <37 w or LBW Ibuprofen Indomethacin Bacterial 7 735 RR, fixed 1.22 [0.84, 1.76] Low1,3,a
Ibuprofen, PO Indomethacin, IV/PO Bacterial 2 53 RD, fixed 0.03 [-0.22, 0.28] Low1,3,a
Ibuprofen, PO Ibuprofen, IV Bacterial 3 236 RR, fixed 0.82 [0.54, 1.25] Low1,3,a
High dose ibuprofen Standard dose ibuprofen Bacterial 1 70 RR, fixed 0.93 [0.51, 1.68] Low1,3,a
Early ibuprofen Expectant Bacterial 1 105 RR, fixed 0.90 [0.58, 1.41] Moderate3,a
Ohlsson 2020 (IVIG for prevention of infection) Preterm and LBW IVIG P/NI CP 10 3,975 RR, fixed 0.85 [0.74, 0.98] Moderate2
CP ‘serious infection’ 16 4,986 RR, fixed 0.82 [0.74, 0.92] Moderate2
Ohlsson 2020 (paracetamol for PDA) PDA <37 w or LBW Paracetamol Ibuprofen Bacterial 4 472 RR, fixed 0.88 [0.64, 1.21] Low1,3,a
P/NI Bacterial 1 48 RR, fixed 1.45 [0.36, 5.79] Moderate3,a
Indomethacin Bacterial 2 277 RR, fixed 1.14 [0.59, 2.19] Low1,3,a
Ohlsson 2020 (early EPO) <37 w and/or LBW Erythropoietin P/NI CP 12 2,180 RR, fixed 0.87 [0.74, 1.02] Moderate1,a
Darbepoetin alfa P/NI CP 1 62 RR, fixed 1.13 [0.38, 3.30] Low1,3,a
Onland 2017 (late inhaled steroid for prevention of BPD) <36 w Inhaled corticosteroids (budesonide, fluticasone, beclomethasone) P/NI Any 5 107 RR, fixed 0.90 [0.50, 1.64] Low1,3,a
Onland 2017 (systemic steroid for prevention of BPD) Preterm at risk of BPD Lower cumulative dexamethasone dose Higher cumulative dexamethasone dose CP 6 230 RR, fixed 0.91 [0.60, 1.38] Low1,3,a
Suspected 2 72 RR, fixed 1.03 [0.62, 1.70] Low1,3,a
Osborn 2007 <37 w Thyroid hormone therapy P/NI Any 3 278 RR, fixed 0.78 [0.53, 1.16] Moderate3,a
Osborn 2018 Neonates requiring PN High amino acid Low Bacterial 15 1,255 RR, fixed 0.96 [0.79, 1.18] Low1,4,a
High amino acid (at the start) Low Bacterial 5 319 RR, fixed 0.94 [0.65, 1.38] Low1,3,a
High amino acid (at max dose) Low Bacterial 1 127 RR, fixed 0.94 [0.63, 1.41] Moderate3,a
Pammi 2020 <37 w Lactoferrin P/NI Any 12 5,425 RR, fixed 0.80 [0.72, 0.89] Low1,4
CP 12 5,425 RR, fixed 0.83 [0.72, 0.94] Low1,2
Bacterial 8 3,565 RR, fixed 0.86 [0.74, 1.00] Low1,2
Fungal 6 3,266 RR, fixed 0.23 [0.10, 0.54] Low1,2
Lactoferrin + probiotics Any 3 564 RR, fixed 0.25 [0.14, 0.46] Low1,3
Bacterial 1 319 RR, fixed 0.28 [0.11, 0.72] Low1,3
Fungal 2 494 RR, fixed 0.24 [0.08, 0.71] Low1,3
Pfister 2009 <37 w or LBW Protein with surfactant Protein-free surfactant CP 1 1,036 RR, fixed 1.00 [0.87, 1.14] Moderate1,a
Premkumar 2019 <37 w Human milk fortifier Bovine milk fortifier CP 1 125 RR, fixed 0.54 [0.25, 1.21] Low1,3
Quigley 2019 <37 w or LBW Formula Donor human milk CP 5 1,025 RR, fixed 0.94 [0.79, 1.12] Moderate1,a
Rojas-Reyes 2012 <32 w Prophylactic surfactant Rescue surfactant Bacterial 6 2,438 RR, fixed 0.83 [0.64, 1.08] Low1,2,a
Schulzke 2014 (pentoxifylline for BPD) <32 w or VLBW Nebulized pentoxifylline P/NI CP 1 100 RR, fixed 1.22 [0.63, 2.36] Low1,3,a
Schulzke 2014 (physical activity for bone mineralization) <37 w Physical activity P/NI CP 1 16 N/A The trial reported no difference in sepsis between the groups Low1,3,a
Seger 2009 <37 w Animal surfactant P/NI Any 4 1,012 RR, fixed 1.14 [0.87, 1.48] Moderate1,a
Shah 2008 Term or preterm requiring CVC Heparin infusion P/NI Any 3 477 RR, fixed 0.82 [0.43, 1.57] Higha
Shah 2009 <32 w or VLBW Anti-staphylococcal immunoglobulin INH A-21 P/NI CoNS 2 2,488 RR, fixed 1.07 [0.94, 1.22] Moderate1,a
Other bacterial 2 2,488 RR, fixed 0.87 [0.72, 1.06] Moderate1,a
Any 2 2,488 RR, fixed 1.00 [0.91, 1.09] Moderate1,a
Anti-staphylococcal immunoglobulin altastaph P/NI CoNS 1 206 RR, fixed 0.86 [0.32, 2.28] Moderate3,a
Other bacterial 1 206 RR, fixed 0.93 [0.53, 1.64] Moderate3,a
Any 1 206 RR, fixed 0.93 [0.54, 1.62] Moderate3,a
Shah 2017 (prevention of BPD) VLBW neonates Early inhaled steroids P/NI CP 6 1,121 RD, fixed 1.17 [0.99, 1.38] Moderate1,a
Shah 2017 (prevention of BPD) VLBW or <32 w Inhaled steroid Systemic corticosteroids Any 1 278 RR, fixed 1.04 [0.73, 1.49] Low1,3,a
Shah 2017 (treatment of BPD) VLBW or <32 w Inhaled steroid Systemic corticosteroids CP 2 368 RR, fixed 1.07 [0.79, 1.45] Low1,3,a
Shah 2018 Neonates requiring RBC transfusion Short transfusion Longer transfusion Suspected 1 52 RR, random 1.25 [1.00, 1.56] Low1,3,a
Sharif 2020 <32 w Probiotics P/NI CP 47 9,762 RR, fixed 0.89 [0.82, 0.97] Moderate1
Sinclair 2011 <32 w or VLBW Early parenteral lipid Delayed CP 1 29 RR, fixed 0.81 [0.13, 5.01] Low1,3,a
Insulin infusion for hyperglycemia Standard care CP 1 386 RR, fixed 0.92 [0.63, 1.34] Low1,3,a
Singh 2015 <32 w Bovine lung lavage surfactant extract (prophylaxis) Modified bovine minced lung surfactant extract Bacterial 2 1,123 RR, fixed 1.08 [0.91, 1.28] Moderate1,a
<37 w Bovine lung lavage surfactant extract (rescue) Modified bovine minced lung surfactant extract Bacterial 6 2,228 RR, fixed 1.00 [0.87, 1.15] Moderate1,a
Modified bovine minced lung (rescue) Porcine minced lung Bacterial 6 526 RR, fixed 1.13 [0.87, 1.46] Low1,3,a
Sinha 2015 Term or late preterm Chlorhexidine for skin or cord care, in hospital P/NI Any 2 13,033 RR, fixed 0.98 [0.82, 1.16] Moderate1,a
Chlorhexidine for skin or cord care in the community P/NI Any 1 203 RR, fixed 0.69 [0.49, 0.95] Moderate3,a
Soll 1997 <30 w Animal surfactant P/NI CP 4 914 RR, fixed 1.06 [0.81, 1.38] Low1,2,a
Soll 2009 <30 w <1,250 g with RDS or at risk Multiple doses of surfactant (synthetic surfactant, curosurf) Single dose Bacterial 2 1,169 RR, fixed 0.85 [0.70, 1.04] Moderate1,a
Spence 1999 Neonates who required endotracheal intubation Nasal intubation Oral CP 1 86 RR, fixed 1.0 [0.15, 6.78] Low1,3,a
Suspected 1 91 RR, fixed 2.1 [0.89, 4.91] Low1,3,a
Subramaniam 2016 <32 w or VLBW Prophylactic CPAP Supportive care Any 3 568 RR, fixed 1.04 [0.64, 1.69] Moderate1, a
Assisted ventilation Any 1 425 RR, random 0.59 [0.33, 1.04] Low1,3,a
Symington 2006 <37 w NIDCAP P/NI Any 1 21 RR, fixed 0.92 [0.71, 1.18] Low1,3,a
Taylor 2015 Neonates with CVC Antibiotic lock P/NI CP 3 271 RR, fixed 0.15 [0.06, 0.40] High
Any 3 271 RR, fixed 0.25 [0.12, 0.49] High
Ullman 2013 Neonate with any IV/arterial catheter Less frequent for intravenous administration set replacement Frequent CP 1 148 RR, fixed 0.58 [0.25, 1.35] Low1,3,a
Ungerer 2004 Term born to mothers with risk of infection (GBS) Prophylactic antibiotic (intramuscular penicillin G) Selective antibiotics use CP 1 67 RD, fixed 0.00 [-0.06, 0.06] Low1,3,a
Term with other risk factors, PROM, fever) Prophylactic antibiotics (intramuscular penicillin and kanamycin) Selective antibiotics use CP 1 49 RR, fixed 0.12 [0.01, 2.04] Low1,3,a
Walsh 2019 <37 w Iodine supplementation P/NI Any 1 1,259 RR, fixed 1.09 [0.96, 1.24] Higha
Webster 2003 Visitors Over gowns No gowns Any 4 3,979 RR, random 0.95 [0.40, 2.23] Low1,2,a
Whitelaw 2001 Infants <3 months with severe IVH Acetazolamide + furosemide Standard therapy CNS infection 1 117 RR, fixed 1.20 [0.57, 2.52] Low1,3,a
Whitelaw 2017 Infants with IVH Repeated lumbar/Ventricular tapping Conservative CNS infection 2 195 RR, fixed 1.73 [0.53, 5.67] Low1,3
Wilkinson 2016 <37 w HFNC CPAP (primary respiratory support after birth) CP 4 439 RR, fixed 1.29 [0.66, 2.54] Low1,3,a
CPAP (post-extubation) CP 2 529 RR, fixed 0.92 [0.59, 1.43] Low1,3,a
NIPPV (primary respiratory support after birth) CP 1 76 RR, fixed 1.33 [0.32, 5.56] Low1,3,a
Zupan 2004 Neonates Topical cord antiseptics P/NI Any 7 N/A RR, fixed No meta-analysis was conducted; No sepsis was noted in either arm in all the trials Low1,a

  1. aCochrane reviews, where evidence’s certainty was unavailable, were evaluated by two independent authors based on Grading of Recommendations, Assessment, Development and Evaluation (1, Risk of bias; 2, heterogeneity, 3, imprecision/wide confidence interval; 4, publication bias (asymmetry in funnel plot)/other reasons; 5, indirectness), with conflicts resolved by consensus and discussion with the third author; The effect estimates highlighted in bold represent statistically significant differences between the groups; BPD, bronchopulmonary dysplasia; CC, catheter colonization; CLD, chronic lung disease; CoNS, coagulase-negative staphylococcus; CP, culture-proven; CPAP, continuous positive airway pressure; CVC, central venous catheter; DBM, donor breast milk; ESAs, erythropoiesis-stimulating agents; GBS, group B streptococcus; G-CSF, granulocyte colony stimulating factor; GI, gastrointestinal; GM-CSF, granulocyte-macrophage colony stimulating factor; GRADE, grading of recommendations,assessment development and evaluation; HFNC, high flow nasal cannula; IVH, intraventricular hemorrhage; IVIG, intravenous immunoglobulin; IV, intravenous infusions; LBW, low birth weight; LE, lipid emulsion; ML-UVCs, multiple lumen umbilical venous catheters; MSAF, meconium-stained amniotic fluid; N/A: not available; NCPAP, nasal continuous positive airway pressure; NICU, neonatal intensive care unit; NIDCAP, neonates individualized developmental care and assessment program; NIPPV, nasal intermittent positive pressure ventilation; OPC, oropharyngeal colostrum; PCVC, percutaneous central venous catheters; PDA, patent ductus arteriosus; PO, per oral; PN, parenteral nutrition; P/NI: placebo/no intervention; PNCS, postnatal corticosteroids; PSBI, possible serious bacterial infection; RBCs, red blood cells; RDS, respiratory distress syndrome; RCTs, randomised clinical trials; RR, risk ratio; RD, risk difference; SL-UVCs, single lumen umbilical venous catheters; UAC, umbilical artery catheters; UVC, umbilical venous catheters; VLBW, very low birth weight.

The number of RCTs in 101 reviews ranged from one to 47. The number of neonatal participants in each trial ranged from 16 to 42,043. In total, there were 612 RCTs involving 193,713 term and preterm neonates. Of the 101 included reviews, 28 provided GRADE assessments for one or more LOS outcomes. For the remainder of the reviews (n=73), two study authors performed the GRADE assessment independently for all the primary and secondary outcomes. The details are provided in Table 1. The interventions on LOS were categorized into five categories based on the effectiveness and certainty of the evidence, as summarized in Table 2.

Table 2:

Summary of effectiveness of interventions on late-onset neonatal sepsis.

LOS, any (suspected or confirmed) LOS, culture-proven LOS, bacterial LOS, fungal
Effective interventions

  1. Antibiotic lock for CVC

  1. Antibiotic lock for CVC

  1. None

  1. None
Possible effective interventions

  1. Kangaroo care for LBW babies

  2. Vancomycin prophylaxis for VLBW babies requiring PN or babies with CVC requiring PN

  3. Antibiotic prophylaxis for neonates with CVC

  4. Chlorhexidine for skin or cord care (in community setting)a

  1. IVIG prophylaxis (<37 w or LBW)

  2. Probiotics supplementation (<32 w)

  1. Antibiotic prophylaxis for neonates with CVC

  1. Systemic antifungal prophylaxis
Ineffective interventions

  1. Late postnatal corticosteroids for BPD prevention

  2. Heparin infusion for CVC

  3. Iodine supplementation (<37 w)

  1. None

  1. Inositol supplementation (>1 dose) (<37 w)

  1. None
Possible ineffective interventions

  1. Vitamin E supplementation

  2. Supplemental feeds with bottle vs. not (<37 w)

  3. Early postnatal corticosteroids for BPD prevention

  4. Chlorhexidine vs. Polyurethane dressing for CVC

  5. Maternal education bundle

  6. NIPPV vs. NCPAP for RDS (<37 w)

  7. Thyroid hormone prophylaxis

  8. Animal-derived surfactant for RDS (<37 w)

  9. Anti-staphylococcal immunoglobulin prophylaxis

  10. Chlorhexidine for skin or cord care (in hospital setting)a

  11. Prophylactic NCPAP (<32 w)

  1. PCVC vs. PVC for parenteral nutrition

  2. Glutamine supplementation for severe GI disease or preterm infants

  3. Intravenous inline filter

  4. Therapeutic hypothermia for HIE

  5. Chlorhexidine vs. Polyurethane dressing for CVC

  6. Early erythropoietin prophylaxis (<37 w)

  7. Protein vs. Protein-free surfactant

  8. Formula vs. donor human milk (<37 w)

  9. Early inhaled steroids for CLD prevention

  1. Animal-derived surfactant vs. protein-free synthetic surfactant

  2. Topical ointment/cream

  3. Inositol supplementation (1 dose) (<37 w)

  4. Steroid as primary treatment for hypotension (<37 w)

  5. Early vs. expectant ibuprofen for PDA (<37 w)

  6. Paracetamol prophylaxis for PDA (<37 w)

  7. Anti-staphylococcal immunoglobulin prophylaxis

  8. Bovine lung lavage vs. modified bovine minced surfactant for RDS (rescue or prophylaxis)

  9. Multiple vs. single dose surfactant (<30 w)

  1. Topical ointment/cream
No conclusions possible

  1. Prophylactic intravenous vs. intramuscular vitamin K

  2. Aqueous vs. oil-based vitamin E

  3. G-CSF or GM-CSF prophylaxis

  4. Early discharge on gavage feeds

  5. Early vs. Late kangaroo care

  6. Vitamin a (any dose, high dose) supplementation (<32 w)

  7. Radiant warmer vs. incubator care

  8. Routine oro-or-nasopharyngeal suction at birth

  9. Cot-nursing vs. incubator care

  10. Cord antisepsis care (chlorhexidine vs. salicylic acid)

  11. Antibiotics prophylaxis for UAC/UVC/Ventilated neonates

  12. ML-UVCs vs. SL-UVCs

  13. Fish- vs. non-fish-oil LE (<37 w with surgical problems or cholestasis)

  14. Antibiotics for asymptomatic babies born through MSAF

  15. Co-bedding preterm twin babies

  16. Surgical ligation vs. medical treatment for PDA (<37 w)

  17. Cephazolin for CVC removal

  18. Early vs. Late PN (>34 w)

  19. Cromolyn sodium nebulization (<37 w, CLD)

  20. Late inhaled corticosteroids (<37 w, BPD)

  21. High vs. low dexamethasone (<37 w, BPD)

  22. Lactoferrin or lactoferrin with probiotics supplementation (<37 w)

  23. Short binasal prongs vs. single nasal prongs for NCPAP support

  24. Inhaled vs. systemic steroids for CLD prevention

  25. Short vs. long RBC transfusion

  26. Nasal vs. Oral intubation

  27. Prophylactic NCPAP vs. Assisted ventilation (<32 w)

  28. NIDCAP (<37 w)

  29. Gowns for attendants of the neonates

  30. Acetazolamide and frusemide for babies with severe IVH

  31. Repeated lumbar/Ventricular tapping for infants with IVH

  32. Alcohol vs. chlorhexidine for hand hygiene

  1. Routine monitoring of gastric residuals

  2. Criterion-based monitoring of gastric residuals

  3. Late ESAs

  4. Antimicrobial-impregnated CVC

  5. G-CSF or GM-CSF prophylaxis

  6. Topical ointment/cream or oil

  7. High vs. low protein intake

  8. Radiant warmer vs. incubator care

  9. Early vs. late UVC removal

  10. Fish- vs. non-fish-oil LE (<37 w, <37 w with surgical problems)

  11. Antibiotics for babies born through MSAF

  12. Co-bedding preterm twin babies

  13. Cephazolin for CVC removal

  14. Respiratory support before cord clamping

  15. Early vs. Late PN (>34 w)

  16. Trophic feeds (<32 w)

  17. Delayed feeding (4/> days after birth) in <32 w

  18. Smell and taste of milk (<37 w)

  19. Oropharyngeal colostrum (<37 w)

  20. Salbutamol (<37 w, CLD)

  21. Hydrolyzed formula feeding (<37 w)

  22. Slow vs. faster feed advancement (<32 w)

  23. Darbepoetin prophylaxis (<37 w)

  24. High vs. low dexamethasone (<37 w, BPD)

  25. Lactoferrin supplementation (<37 w)

  26. Human milk vs. bovine milk fortifier (<37 w)

  27. Short binasal prongs vs. single nasal prongs for NCPAP support

  28. Nebulized pentoxifylline for CLD (<32 w)

  29. Physical activity for bone mineralization (<37 w)

  30. Inhaled vs. systemic steroids for CLD prevention or treatment

  31. Early vs. late parenteral lipids (<32 w)

  32. Insulin infusion for hyperglycemia (<32w)

  33. Animal-derived surfactant for all <30 w preterm infants

  34. Nasal vs. Oral intubation

  35. Less frequent vs. frequent intravenous administration set replacement

  36. Antibiotic prophylaxis for neonates with risk factors

  37. HFNC vs. CPAP (primary support or post-extubation) OR NIPPV (primary support)

  38. Alcohol vs. chlorhexidine for hand hygiene

  1. Early vs. delayed animal-derived surfactant

  2. Insulin infusion for hyperglycemia

  3. Topical oil

  4. Vancomycin prophylaxis for VLBW babies requiring PN via CVC

  5. Ibuprofen prophylaxis for PDA

  6. Selenium supplementation (<37 w)

  7. Early vs. late UVC removal

  8. Steroid vs. inotrope primary treatment for hypotension (<37 w)

  9. Steroid for refractory hypotension (<37 w)

  10. Plastic wrap or thermal mattress during delivery (<37 w)

  11. Ibuprofen vs. Indomethacin for PDA treatment (<37 w)

  12. Ibuprofen: PO vs. IV and high dose vs. standard dose (<37 w)

  13. Paracetamol vs. Ibuprofen or indomethacin for PDA (<37 w)

  14. High vs. low amino acid PN (overall, at initiation, and at maximum dose)

  15. Lactoferrin or lactoferrin with probiotics supplementation (<37 w)

  16. Prophylactic vs. rescue surfactant (<32 w)

  17. Bovine vs. porcine surfactant for RDS (rescue) (<37 w)

  1. Prophylactic oral/topical antifungal

  2. Prophylactic vs. systemic antifungal

  3. Insulin infusion for hyperglycemia

  4. Topical oil

  5. Early vs. late UVC removal

  6. Lactoferrin or lactoferrin with probiotics supplementation (<37 w)

  1. aMothers of infants were also participants and received vaginal chlorhexidine washes. The interventions are categorized into 5 categories based on the effectiveness of the intervention and the certainty of the evidence as (1) effective interventions (high certainty in the evidence of effectiveness) (2) possible effective interventions (moderate certainty in the evidence of effectiveness) (3) ineffective interventions (high certainty in the evidence of lack of effectiveness (or harm)) (4) possible ineffective interventions (moderate certainty in the evidence of lack of effectiveness (or harm)), and (5) no conclusions possible (low or very low certainty in evidence). CLD, chronic lung disease; CVC, central venous catheter; ESA, erythropoietin stimulating agents; G-CSF, granulocyte colony-stimulating factor; GI: gastrointestinal; GM-CSF, granulocyte monocyte colony-stimulating factor; HIE: hypoxic-ischemic encephalopathy; HFNC, high flow nasal cannula; IV, intravenous; IVH, intraventricular hemorrhage; LBW, low birth weight; LE, lipid emulsion; LOS, late-onset sepsis; ML-UVCs, multiple lumen umbilical venous catheters; MSAF, meconium-stained amniotic fluid; NCPAP, nasal continuous positive airway pressure; NIDCAP, neonates individualized developmental care and assessment program; NIPPV, nasal intermittent positive pressure ventilation; PCVC, percutaneous central venous catheter; PDA, patent ductus arteriosus; PN, parenteral nutrition; PO, per oral; PVC, peripheral venous cannula; RDS, respiratory distress syndrome; SL-UVCs, single lumen umbilical venous catheters; UAC, umbilical artery catheters; UVC, umbilical venous catheters.

Effective interventions

High-quality evidence showed reduced LOS (any sepsis, RR (95% CI) 0.15 (0.06, 0.40) [103] or culture-proven sepsis, RR (95% CI) 0.25 (0.12, 0.49)) [103] when antibiotic lock therapy, compared with placebo, was used for neonates with central venous catheters (CVC). We found no high-quality, effective intervention for reducing bacterial or fungal sepsis.

Possible effective interventions

Any sepsis

Moderate-quality evidence showed antibiotic prophylaxis for neonates with CVC (RR (95% CI) 0.38 (0.18, 0.82)) [47], vancomycin prophylaxis for neonates requiring parenteral nutrition or neonates with CVC (RR (95% CI) 0.11 (0.05, 0.24)) [28], chlorhexidine for skin or cord care (RR (95% CI) 0.69 (0.49, 0.95) [97], and kangaroo care for low birth weight babies (RR (95% CI) 0.50 (0.36, 0.69)) [27] reduced any LOS.

Culture-proven sepsis

Moderate-quality evidence showed intravenous immunoglobulin prophylaxis (RR (95% CI) 0.85 (0.74, 0.98)) [72] for preterm infants and probiotic supplementation for VLBW infants (RR (95% CI) 0.89 (0.82, 0.97) [94]) reduced culture-proven sepsis.

Bacterial sepsis

Moderate-quality evidence showed antibiotic prophylaxis for neonates with CVC (RR (95% CI) 0.40 (0.20, 0.78)) [47] reduced bacterial LOS.

Fungal sepsis

Moderate-quality evidence showed systemic antifungal prophylaxis VLBW infants (RR (95% CI) 0.43 (0.31, 0.59)) [23] reduced fungal LOS.

Ineffective interventions

High-quality evidence showed no difference in LOS with use of late postnatal corticosteroids for bronchopulmonary dysplasia prevention (RR (95% CI) 1.14 (0.97, 1.34)) [32], heparin infusion for neonates with CVC (RR (95% CI) 0.82 (0.43, 1.57)) [90], iodine supplementation (RR (95% CI) 1.09 (0.96, 1.24)) [106], and inositol supplementation (RR (95% CI) 1.33 (1.00, 1.75)) [40].

Possible ineffective interventions and no conclusions possible

Many interventions where the evidence certainty was moderate-quality with lack of effectiveness (or harm) and where the evidence certainty was low-to very low-quality were categorized in these groups as listed in Table 2.

Discussion

Summary of main results

This overview included 101 high-quality Cochrane reviews involving 612 RCTs and 193,713 neonates that evaluated 141 interventions.

Overall completeness and applicability of evidence

Only 101 reviews (around 20% of 496 reviews in the Cochrane Neonatal) were eligible for inclusion in the overview. Although there were 101 reviews involving 612 RCTs and 193,713 neonates, the body of evidence was reduced as not all the included reviews reported the primary outcome of interest of the overview. Further, the data on secondary outcomes was limited as only one-third of reviews reported bacterial sepsis, and 10% reported fungal sepsis. All reviews explicitly defined various types of LOS; however, there was some variation in the definition between and within the trials included in the reviews.

The overview’s scope was limited to studying the effectiveness of interventions on LOS; hence, we did not examine the effects of interventions on other outcomes. This is important as some interventions found ineffective in reducing sepsis may have considerable influence on other important outcomes. For example, in this overview, we found high-quality evidence that late postnatal corticosteroids for preventing bronchopulmonary dysplasia [32] are ineffective in reducing sepsis; however, they are beneficial in lowering extubation failure, death, or bronchopulmonary dysplasia, which are other important outcomes that were not studied [32]. Furthermore, clinicians must consider many other factors, such as effect size, harms, cost-effectiveness, and generalizability, by referring to the original studies or individual Cochrane reviews for considering any therapy in neonatal practice [112], [113], [114]. For example, though the overview found moderate-quality evidence of effectiveness that probiotics supplementation reduces LOS in very preterm infants, clinicians must consider other factors, such as harms, including probiotics-associated sepsis, anticipated benefit, quality assurance, cost-effectiveness, and so on [112–115].

Quality of evidence

All the 101 included Cochrane reviews were high-quality and rated a low risk of bias based on the AMSTAR 2 tool [9]. The risk of bias of included RCTs in those reviews, assessed using the approach outlined in the Cochrane Handbook for Systematic Reviews of Interventions, was variable; however, it was incorporated in the GRADE approach for evaluating the certainty of the evidence. The most common reason for downgrading the quality was study limitations, followed by imprecision and heterogeneity.

Strengths and limitations

This is a first overview providing a comprehensive summary of Cochrane reviews evaluating interventions to reduce LOS and shall be helpful for clinicians and researchers to aid in choosing interventions for reducing LOS. Also, the overview examines the certainty of the evidence for sepsis-related outcomes that were not evaluated in nearly three-fourths of the Cochrane reviews. Further, the overview provides a rigorous assessment of the evidence depending on the effectiveness of interventions and the certainty of the evidence. The search was comprehensive, and the reporting was transparent, based on the PRIO-harms guideline.

The overview focuses on interventions to reduce LOS and only evaluates sepsis-related outcomes. It did not assess other important outcomes, so clinicians should be careful while inferring this data and consider various other factors, as mentioned above, while applying the evidence to their clinical practice. In addition, the overview did not assess early-onset sepsis as the overview focuses on neonatal interventions and not childbirth or pregnancy interventions. Finally, the overview included only Cochrane reviews, but we realize that most interventions were likely assessed in the Cochrane reviews.

To conclude, the overview summarizes the evidence from the Cochrane reviews assessing interventions in the neonatal period for reducing LOS. Clinicians, researchers, policymakers, and consumers can utilize it for evidence translation and decision-making. Clinicians, however, are recommended to assess the effects of the interventions on other outcomes, including harms, and consider other aspects, such as feasibility, generalizability, anticipated benefit based on the effect size, and others, while translating evidence into clinical practice.

Corresponding author: Dr. Abdul Razak, MD, Monash Newborn, Monash Children’s Hospital, Department of Paediatrics, Monash University, 246 Clayton Road, Clayton, VIC 3168, Australia; and Division of Neonatology, Department of Pediatrics, King Abdullah Bin Abdulaziz University Hospital, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia, Phone: +966560636849, E-mail:

Funding source: No specific funding was sought for this project. Dr. Razak's research is supported by Monash University, Australia.

Acknowledgments

Authors would like to acknowledge Ahmed Hamed for initial screening of the articles for the systematic review.

  1. Research funding: No specific funding was sought for this project. Dr. Razak’s research is supported by Monash University, Australia.

  2. Author contributions: Abdul Razak conceptualized and designed the study, oversaw the conduct of the review, assessed the quality of systematic reviews, provided intellectual content, drafted the manuscript and approved the final version. Javed Ahmed co-conceptualized and designed the study, performed the initial screening of the articles, abstracted the data, assessed the quality of systematic reviews, revised the manuscript and approved the final version. Omar Ibrahim Alhaidari co-conceptualized and designed the study, performed the screening of the articles, abstracted the data, revised the manuscript and approved the final version. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Conflict of interest: The authors have indicated they have no potential conflict of interest to disclose.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

  6. Protocol registration: The protocol for the systematic review was registered with PROSPERO (registration number CRD42020192513), the international prospective register for systematic reviews.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/jpm-2022-0131).

Received: 2022-03-11
Accepted: 2022-08-17
Published Online: 2022-10-31
Published in Print: 2023-03-28

© 2022 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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A Celebration of Professor Joachim Dudenhausen
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Midwives’ personal and professional attitudes towards women’s delivery choices, interventions and neonatal care
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Original Articles – Neonates
Interventions for reducing late-onset sepsis in neonates: an umbrella review
Maternal knowledge of recommendations for safe infant sleep and intentions for implementation – a cross sectional analysis of data from the KUNO-Kids birth cohort study
Short Communication
Lysophosphatidylcholine acyltransferase 1 protein is present in maternal blood in the third trimester and is upregulated by antenatal corticosteroids
Letters to the Editor
Peripartum hysterectomy at a tertiary university perinatal center – retrospective analysis of the 25-year period
Neonate, infected mother and monkeypox: the present concern
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