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S26 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 41, Number 3S, March 2022

ISSN: 0891-3668/22/4101-0S26 DOI: 10.1097/INF.0000000000003320

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Supplement

The Impact of Interventions to Prevent Neonatal Healthcare-associated Infections in Low- and Middle-income

Countries: A Systematic Review Felicity C. Fitzgerald, PhD,*† Walter Zingg, PhD,‡ Gwendoline Chimhini, MMED, MPH,§ Simbarashe Chimhuya, MMED,§ Stefanie Wittmann, MD,¶ Helen Brotherton, MBChB,¶‖

Ioana D. Olaru, MBBS,†¶ Samuel R. Neal, MRes,* Neal Russell, MBBS,** André Ricardo Araujo da Silva, PhD,†† Mike Sharland, FRCPCH,** Anna C. Seale, DPhil,¶

Mark F. Cotton, M.Med, PhD,‡‡ Susan Coffin, MD,§§ and Angela Dramowski, PhD‡‡

Background: Clinically suspected and laboratory-confirmed bloodstream infections are frequent causes of morbidity and mortality during neonatal care. The most effective infection prevention and control interventions for neonates in low- and middle-income countries (LMIC) are unknown. Aim: To identify effective interventions in the prevention of hospital- acquired bloodstream infections in LMIC neonatal units. Methods: Medline, PUBMED, the Cochrane Database of Systematic Reviews, EMBASE and PsychInfo (January 2003 to October 2020) were searched to identify studies reporting single or bundled interventions for prevention of bloodstream infections in LMIC neonatal units. Results: Our initial search identified 5206 articles; following application of fil- ters, 27 publications met the inclusion and Integrated Quality Criteria for the Review of Multiple Study Designs assessment criteria and were summarized in the final analysis. No studies were carried out in low-income countries, only 1 in Sub-Saharan Africa and just 2 in multiple countries. Of the 18 single-interven- tion studies, most targeted skin (n = 4) and gastrointestinal mucosal integrity (n = 5). Whereas emollient therapy and lactoferrin achieved significant reductions in proven neonatal infection, glutamine and mixed probiotics showed no ben- efit. Chlorhexidine gluconate for cord care and kangaroo mother care reduced

infection in individual single-center studies. Of the 9 studies evaluating bundles, most focused on prevention of device-associated infections and achieved sig- nificant reductions in catheter- and ventilator-associated infections. Conclusions: There is a limited evidence base for the effectiveness of infec- tion prevention and control interventions in LMIC neonatal units; bundled interventions targeting device-associated infections were most effective. More multisite studies with robust study designs are needed to inform infection pre- vention and control intervention strategies in low-resource neonatal units.

Key Words: Infection prevention and control, low-and-middle income countries, systematic review, neonatal infection, hospital-acquired infection

(Pediatr Infect Dis J 2022;41:S26–S35)

The World Health Organization estimates that bacterial infec- tions cause ≈25% of the 2.8 million annual neonatal deaths and

long-term neurodevelopmental disabilities in survivors.1 Hospital- acquired infection (HAI) is a major cause of neonatal morbidity and mortality with prevalence ratios in low- and middle-income countries (LMICs) 3–20× higher than high-income countries.2 Tra- ditional definitions, applied in high-income countries, use a 72-hour cutoff to differentiate early- from late-onset infection: the former associated with vertical transmission of pathogens such as group B Streptococcus, the latter with horizontal transmission of hospital- acquired pathogens, often associated with prematurity and invasive procedures such as intravenous catheterization. However, particu- larly in LMICs, there is recognition that facility-based delivery is itself a risk for HAIs, with pathogens such as Klebsiella pneumoniae (previously associated with late-onset infection) commonly isolated in the first 24 hours of life.2,3 This observation informs the Strength- ening the Reporting of Observational Studies in Epidemiology for Newborn Infection guidelines, which recommend recording the tim- ing of symptom onset rather than the binary early/late-onset dico- hotomy.1 It also raises questions about fundamental differences in the mechanisms of neonatal infections in LMICs, as compared with high-income countries. The leading neonatal pathogens are increas- ingly resistant to first- and second-line antimicrobials, with substan- tial resistance to commonly used agents including ampicillin (89% of Escherichia coli), ceftriaxone (49% of Klebsiella spp. isolates) and cloxacillin (40% of Staphylococcus aureus).3

In this context, effective, feasible and affordable interventions to enhance infection prevention and control (IPC) in LMIC neonatal units are critical to prevent both neonatal mortality and emerging antimicro- bial resistance. However, even in high-income settings, implementing effective prevention measures is challenging, and a robust evidence base on what tools to use is limited. Randomized controlled trials are considered the gold standard for generating evidence in general. How- ever, best practice procedures and quality improvement interventions

Accepted for publication August 12, 2021 From the *Department of Infection, Immunity and Inflammation, UCL Great

Ormond Street Institute of Child Health, London, United Kingdom, †Bio- medical Research and Training Institute, Harare, Zimbabwe, ‡Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, §Department of Paediat- rics and Child Health, University of Zimbabwe College of Health Sciences, Zimbabwe, ¶Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom, ‖MRC Unit, The Gambia at the London School of Hygiene & Tropical Medicine, Fajara, The Gambia, **Paediatric Infectious Diseases Research Group, St George’s University of London, United Kingdom, ††Laboratory of Teaching of Prevention and Control of Healthcare-Associated Infections, Federal Fluminense University, Brazil, ‡‡Department of Paediatrics and Child Health, Division of Paediatric Infectious Diseases, Stellenbosch University, South Africa, and §§Children’s Hospital of Philadelphia, Pennsylvania, Philadelphia.

F.C.F. is supported by the Academy of Medical Sciences, the funders of the Starter Grant for Clinical Lecturers scheme and UCL Great Ormond Street NIHR Biomedical Research Centre. A.D. is supported by the Fogarty Inter- national Center of the National Institutes of Health, Emerging Global Leader Award Number K43-TW010682.

Address for correspondence: Angela Dramowski, PhD, Department of Paediat- rics and Child Health, Division of Paediatric Infectious Diseases, Stellen- bosch University, South Africa. E-mail: [email protected]

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com)

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The Pediatric Infectious Disease Journal • Volume 41, Number 3S, March 2022 Low-income Neonatal Units: Infection Prevention

must be contextual for maximum impact. As interventions are seldom identical across trial sites, patient-level randomization is often not possi- ble. Trials within hospitals (randomizing wards for example) are at risk of bias due to movement between wards of staff and patients. Further- more, matching hospitals for randomization can be complex.4

To address these methodologic challenges, new study designs, such as interrupted time series for cohorts and hospital-level stepped- wedge cluster randomization, have been adopted. In addition, qualita- tive research aiming at understanding behavior change is increasingly used to complement quantitative data.4 For neonates in LMICs, vari- ous HAI prevention strategies have been suggested but only studied in small and single-center studies. To date, the evidence base in these settings has not yet been systematically assessed. We set out to review a broad range of potential interventions (both single and bundled), aiming to reduce healthcare-associated infections, with a focus on bloodstream infections (BSIs) in LMIC neonatal units.

METHODS This systematic review was conducted in adherence with

the Preferred Reporting Items for Systematic Reviews and Meta- Analyses statements of evaluations of healthcare interventions.5 We registered the search strategy on the international prospective register of systematic reviews (CRD42018112346 on International prospective register of systematic reviews; see Supplemental Digi- tal Content, http://links.lww.com/INF/E517).

Search Strategy We searched Medline, the Cochrane Database of Systematic

Reviews, EMBASE and PsychInfo (January 1, 2003, to October 31, 2020) to identify studies reporting on the effectiveness of interven- tions to prevent infections in LMIC neonatal wards and neonatal intensive care units. We selected the year 2003 to reflect the rapid evolution and spread of resistant bacteria causing HAIs in the last 17 years. IPC interventions were defined as any intervention aiming to prevent the development of a healthcare-associated bacterial or fun- gal infection such as BSI, meningitis, laboratory-confirmed urinary tract infection or clinically suspected but culture-negative infections.

We limited results by age [neonates 0–27 days or 0–89 days if admitted on a neonatal ward or neonatal intensive care unit (NICU)], location (LMIC as defined by the 2021 World Bank classification6), language (articles written in English, German, French, Italian, Portu- guese and Spanish were included) and by relevant filters as per exclu- sion criteria (for a full list of terms and filters, see Supplemental Digital Content, http://links.lww.com/INF/E517). Our primary outcome was the effect of the interventions on (1) incidence of infection or (2) attrib- utable mortality, depending on study definitions. Fungal or bacterial hospital-acquired invasive infections in hospitalized neonates were the primary events for study. Secondary outcomes included impact on incidence of laboratory-confirmed urinary tract infection, throm- bophlebitis, necrotizing enterocolitis (NEC), device-associated infec- tions (clinically suspected or culture proven) and clinically suspected infection where laboratory cultures were negative or not available.

Inclusion Criteria Studies were eligible for full-text review if conducted in hos-

pitalized neonates, including neonatal ward and/or NICU settings, with a detailed description of the intervention. We included both single interventions [eg, probiotics, kangaroo mother care (KMC), breastfeeding, fluconazole prophylaxis] and bundled interventions (eg, vascular device care, hand hygiene and healthcare worker edu- cation combined). Studies conducted in several countries includ- ing both high-income countries and LMICs (as per the World Bank 2021 regions) could be included if possible, to extract data from the LMIC settings. Study designs included randomized controlled

trials, controlled and noncontrolled before-after, controlled and noncontrolled interrupted time series and cohort studies.

Exclusion Criteria We excluded letters, opinion articles and reviews that did

not report primary data. IPC interventions conducted during mater- nal care, in community-based settings and during outbreaks, were excluded. We also excluded studies conducted exclusively in high- income countries as per the World Bank 2021 regions.6 Interven- tions targeting viral infections (including HIV), infants older than 3 months or involving vaccination, diagnostic tools, infection predic- tion scores were excluded. We also excluded studies addressing IPC interventions on mixed neonatal/pediatric populations where extrac- tion of neonatal data was not possible and where only abstracts were available despite contacting the corresponding author. Finally, we excluded studies where bacterial colonization as opposed to invasive infection was the outcome, if BSI was not also included.

Study Selection Process The initial eligibility assessment of titles and abstracts identified

by our search was conducted independently by F.C.F. and A.D. using the predetermined inclusion and exclusion criteria. Disagreements on eligibility were resolved by consensus, if needed by consulting a third party. The reference lists of all eligible publications were screened for cross-referencing. After finalizing articles for full-text review, 2 authors evaluated the quality of each eligible publication using the Integrated Quality Criteria for the Review of Multiple Study Designs (ICROMS) tool,7 with disagreements resolved as explained above. The ICROMS tool was designed to allow the systematic integration and assessment of differing study types including both quantitative and qualitative designs for reviews of public health interventions such as those targeting IPC.7 The ICROMS tool provides a list of quality criteria with a set of require- ments specific for the study design. Studies are evaluated by a “decision matrix” where mandatory criteria must be met. The robustness of the study is measured by a score (see Tables, Supplemental Digital Content, http://links.lww.com/INF/E517, for criteria and scoring). To pass to the final analysis, studies must meet the minimum score and the mandatory ICROMS criteria, after duplicate review.

Data Abstraction We extracted data using a standardized data collection form

already independently piloted by F.C.F. and A.D. on a representa- tive sample of studies. Study details collected on the form included author(s), year of publication, country or countries where the study was performed, study design, study time frame, setting (neonatal ward, NICU or both), intervention type, intervention details and effect. We grouped studies by intervention type: IPC bundles, catheter care, skin integrity and bacterial colonization (umbilical cord care, skin cleansing, emollients and/or massage), fluconazole prophylaxis, hand hygiene, KMC, rooming-in/parental involvement in neonatal care and gastrointestinal integrity (probiotics and feeding practices). Data synthesis involved the collation and tabulation of results by interven- tion type, summarizing the key interventions and their effectiveness in IPC for hospitalized neonates (using either relative risk, odds ratios or hazard ratios as reported by each study). We did not undertake a meta- analysis due to diversity of study type, interventions and outcomes; although all studies targeted reduction of neonatal infections, each study had different modes of action for the intervention and/or major differences in study design that precluded combining data.

RESULTS We identified 5206 articles on initial searching, after

removal of duplicates (Fig.  1). Filter application (see Appendix,

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The Pediatric Infectious Disease Journal • Volume 41, Number 3S, March 2022

S28 | www.pidj.com © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Fitzgerald et al

Supplemental Digital Content, http://links.lww.com/INF/E517) reduced this to 1799 titles and abstracts then reviewed indepen- dently by 2 study authors (F.C.F. and A.D.) for relevance. Of these,

124 were selected for full-text review in duplicate and ICROMS scoring, leading to another 97 exclusions and 27 selected for inclu- sion in the final review (Tables 1 and 2). Forty studies were excluded

FIGURE 1. Search strategy for the identification and selection of publications reporting the effectiveness of interventions to prevent infections in neonatal wards and intensive care (January 2003–October 2020).

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The Pediatric Infectious Disease Journal • Volume 41, Number 3S, March 2022

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