Literature Review & Evidence Matrix of infection control in the NICUs

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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

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- NCND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commer- cially without permission from the journal.

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,

http://links.lww.com/INF/E517

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

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).

http://links.lww.com/INF/E517

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

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on tr

ol s

(9 /1

28 v

s. 2

7/ 13

0) , a

dj u

st ed

h az

ar d

of H

A I

6. 0

(9 5%

C I

2. 3–

16 )

in c

on tr

ol s;

in ci

de n

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f H

A I

40 v

s. 2

19 /1

00 0

pa ti

en t-

da ys

in t

h e

in te

rv en

ti on

ou p

vs . c

on tr

ol s.

I m

pr ov

ed w

ei gh

t ga

in a

n d

sk in

n di

ti on

in t

h e

in te

rv en

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u p,

n o

im pa

ct o

m or

ta li

ty o

r du

ra ti

on o

f ad

m is

si on

(C on

ti n

u ed

)

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

Fitzgerald et al

G at

h w

al a

a l17

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di a

1 N

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c or

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ni fic

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e to

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In di

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n =

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In ci

de n

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-n eo

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s ta

ke n

o n

d ay

s 1,

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7 of

li fe

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6/ 16

8 (3

.6 %

) bl

oo d

cu lt

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s am

pl es

p os

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e in

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e in

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vs . 1

2/ 17

5 (6

.9 %

) in

t h

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n tr

ol s

= 0

.1 95

)

B oo

a n

d Ja

m li

19 R

C T

M al

ay si

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ta bl

e n

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50 0

g bi

rt h

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1 N

N U

12 6

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C In

te rm

it te

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sk in

t o

sk in

n ta

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or m

in im

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h /d

( n

= 6

2) v

s. s

ta n

d - ar

d ca

re (

n =

6 4)

W ei

gh t

ga in

, o cc

ip it

of ro

n ta

l ci

rc u

m fe

re n

ce , b

re as

tf ee

d - in

g. I

n fe

ct io

n a

n d

N E

C a

s se

co n

da ry

o u

tc om

N o

si gn

ifi ca

n t

di ff

er en

ce in

c u

lt u

re -p

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n in

fe ct

io n

: 2 /6

4 n

eo n

at es

( in

te rv

en ti

on g

ro u

p) v

s. 1

/6 4

(c on

tr ol

P =

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f N

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it h

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p. C

h ar

pa k

a l20

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bi a

S ta

bl e,

n eo

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bi rt

h w

ei gh

t <2

00 0

g ad

m it

te d

to 1

N N

74 6

K M

C C

on ti

n u

ou s

K M

(n =

3 82

) vs

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di -

ti on

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em en

(n =

3 64

)

G ro

w th

a nd

m or

ta li

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o 40

/4 1

w ee

ks c

or re

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g es

ta ti

on al

e. S

ev er

e in

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re qu

ir -

in g

sy st

em ic

a nt

ib io

ti cs

d no

so co

m ia

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ec ti

on s

se co

nd ar

y ou

tc om

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il ar

n u

m be

rs o

f in

fe ct

io u

s ep

is od

es 4

9/ 38

2 (i

n te

rv en

- ti

on )

vs . 4

4/ 36

4 (c

on tr

ol s)

b u

t m

or e

m il

d/ m

od er

at e

in fe

ct io

u s

ep is

od es

( 7%

in te

rv en

ti on

s vs

3 %

c on

tr ol

s) ,

ab so

lu te

fi gu

re s

n ot

g iv

en . R

ed u

ct io

n in

n os

oc om

ia l

in fe

ct io

n s:

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v s.

4 %

in in

te rv

en ti

on s/

co n

tr ol

(P =

0 .0

26 )

ab so

lu te

fi gu

re s

n ot

g iv

en L

i e t

al 23

N C

B A

C h

in a

S ta

bl e

n eo

n at

>1 50

0 g

in 1

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U 14

46 R

oo m

in g-

in N

eo n

at es

m ov

ed t

o R

oo m

-i n

f ro

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IC U

= 1

01 8)

v s.

t h

os e

el ig

ib le

t o

m ov

e bu

t st

ay in

g in

N IC

(n =

4 28

). 62

9 ad

m it

te d

di re

ct ly

t o

R oo

m -i

M or

ta li

ty , g

ro w

th , d

u ra

ti on

a dm

is si

on . s

ec on

da ry

tc om

es : n

os oc

om ia

l i n

fe c -

ti on

a n

d N

E C

( u

n cl

ea r

h ow

fi n

ed )

N o

di ff

er en

ce in

n os

oc om

ia l i

n fe

ct io

n : 1

00 /1

08 1

vs . 4

8/ 42

8 in

in te

rv en

ti on

s vs

. c on

tr ol

s; P

= 0

.4 1;

f ew

er n

eo n

at es

t h

e in

te rv

en ti

on g

ro u

p w

it h

N E

C : 7

/1 08

1 vs

. 8 /4

(P =

0 .0

4) .

R ed

u ct

io n

in m

or ta

li ty

: 2 %

v s.

0 %

; P <

0 .0

P ar

ik h

a l25

R C

T In

di a

P re

te rm

n eo

n at

<1 50

0 g

ad m

it te

d to

te rt

ia ry

N N

12 0

F lu

co n

az ol

e pr

op h

y- la

xi s

F lu

co na

zo le

p ro

ph yl

ax is

it hi

n th

e fir

st 3

d t

o da

y 28

o r

di sc

ha rg

e/ de

at h

if s

oo ne

r (n

= 6

vs . p

la ce

bo (n

= 6

F u

n ga

l c ol

on iz

at io

n a

n d

in va

si ve

f u

n ga

l i n

fe ct

io n

lt u

re s

ta ke

n o

n d

ay s

1– 3,

1 4,

2 1

an d

N o

re du

ct io

n in

in va

si ve

c an

di da

in fe

ct io

n d

et ec

te d

bl oo

d cu

lt u

re s:

1 6/

60 e

pi so

de s

vs . 1

5/ 60

in in

te rv

en ti

vs . c

on tr

ol ; P

= 0

.8 35

; o f

n ot

e, 3

0/ 31

o f

in va

si ve

s pe

ci es

er e

n on

-a lb

ic an

s sp

ec ie

B ar

re ra

a l21

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or t

C ol

om bi

a A

ll n

eo n

at es

m it

te d

to 1

N N

U 66

55 H

an d

h yg

ie n

e In

tr od

u ct

io n

o f A

B H

di sp

en se

rs ; i

n it

ia l

ed u

ca ti

on ; d

ai ly

rv ei

ll an

ce , q

u ar

te rl

y fe

ed ba

H A

I, C

L A

B S

I, V

A P

a n

d U

T I

as p

er C

D C

d efi

n it

io n

s 12

60 p

at ie

n ts

w it

h H

A I,

7 24

/1 84

8 ep

is od

es c

on fi

rm ed

c u

lt u

re . T

re n

d in

r ed

u ct

io n

o f

M et

h ic

il li

n -r

es is

ta n

t S

ta ph

yl oc

oc cu

s au

re u

s, 2

.2 –0

.6 in

fe ct

io n

s/ 10

00 p

at ie

n t-

da ys

in f

ro m

2 00

1– 20

05 , −

30 %

, P =

0 .0

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o tr

en d

in r

ed u

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n o

f A

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ac te

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u m

an n

ii (

0. 6–

0. 2/

10 00

p at

ie n

t- da

ys ; P

v al

u e

n ot

g iv

en )

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n ifi

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t in

cr ea

se in

u se

o f

al co

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-b as

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ru b

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P ro

- ci

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T B

ra zi

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U , a

ll n

eo n

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≤3

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’ G A

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d 75

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sa ge

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as sa

ge t

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ap y

(t ac

ti le

- ki

n es

th et

ic s

ti m

u la

- ti

on , n

= 5

2) v

s. n

o in

te rv

en ti

(n =

5 2)

P ri

m ar

y ou

tc om

e: le

ng th

o f N

N U

ay ; s

ec on

da ry

o ut

co m

es :

w ei

gh t g

ai n,

ti m

e to

e nt

er al

ed s,

ti m

e to

o ra

l f ee

ds ,

in ci

de nc

e of

L O

S (c

lin ic

al ly

d bl

oo d

cu lt

ur e

co nfi

rm ed

), in

ci de

nc e

of N

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(c lin

ic al

a nd

di ol

og ic

c on

fir m

at io

L ow

er in

ci de

n ce

L O

S in

in te

rv en

ti on

v s.

c on

tr ol

s (5

/4 6

vs . 1

8/ 47

; P =

0 .0

05 );

8 vs

. 2 2

pa th

og en

s id

en ti

fi ed

cu lt

u re

s (u

n cl

ea r

h ow

m an

y cu

lt u

re s

h ad

m u

lt ip

pa th

og en

s) .

B ar

rí a

a l24

R C

T C

h il

e “h

ig h

-r is

k” n

eo n

at es

m it

te d

to 1

N U

74 In

tr av

en ou

s ca

th et

er i-

za ti

P er

ip h

er al

ly in

se rt

ce n

tr al

c at

h et

er s

= 3

7) v

s. s

ta n

da rd

ri ph

er al

in tr

av en

ou s

ca th

et er

s (n

= 3

L en

gt h

o f

n eo

n at

al in

te n

si ve

re u

n it

s ta

y an

d in

ci de

n ce

in fe

ct io

n a

n d

ph le

bi ti

N o

di ff

er en

ce in

in ci

de n

ce o

f su

sp ec

te d

in fe

ct io

n b

et w

ee n

ou ps

: 1 4/

37 v

s. 8

/3 7;

P =

0 .1

27 O

r cu

lt u

re -p

ro ve

n in

fe ct

io n

: 1 /3

7 vs

. 2 /3

7; P

= 0

.5 3.

R ed

u c -

ti on

in p

h le

bi ti

s: 4

/3 7

vs . 1

5/ 37

; P =

0 .0

07 . n

o di

ff er

en ce

t h

e le

n gt

h o

f st

ay : m

ed ia

n , 2

0 vs

. 1 7

d in

in te

rv en

- ti

on /c

on tr

ol g

ro u

ps ; P

= 0

.1 58

A B

H R

in di

ca te

s al

co h

ol -b

as ed

h an

d ru

b; C

A -B

S I,

c at

h et

er -a

ss oc

ia te

d bl

oo d

st re

am in

fe ct

io n

s; C

B A

, c on

tr ol

le d

be fo

re a

n d

af te

r; C

L A

B S

I, c

en tr

al li

n e–

as so

ci at

ed b

lo od

st re

am in

fe ct

io n

; C V

C , c

en tr

al v

en ou

s ca

th et

er s;

I T

S, in

te rr

u pt

ti m

e se

ri es

; I R

R , i

n ci

de n

t ra

te r

at io

; L O

S, la

te -o

n se

t in

fe ct

io n

; N C

B A

, n on

co n

tr ol

le d

be fo

re a

n d

af te

T A

B L

E 1

. (C

on ti

n u

ed ).

A u

th or

S tu

D es

ig n

* C

ou n

tr y

P op

u la

ti on

/S et

ti n

g S

am pl

e S

iz e

In te

rv en

ti on

pe In

te rv

en ti

on O

u tc

om e

K ey

F in

di n

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

Low-income Neonatal Units: Infection Prevention T

A B

L E

2 .

B u

n dl

ed I

n te

rv en

ti on

s fo

r th

e P

re ve

n ti

on o

f H

os pi

ta l-

A cq

u ir

ed N

eo n

at al

B lo

od st

re am

I n

fe ct

io n

s an

d C

li n

ic al

ly S

u sp

ec te

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fe ct

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L ow

-r es

ou rc

e S

et ti

n gs

( Ja

n u

ar y

20 03

t o

S ep

te m

be r

20 18

)

A u

th or

S tu

D es

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C ou

n tr

y P

op u

la ti

on /

S et

ti n

g S

am pl

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iz e

B u

n dl

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le m

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O u

tc om

e( s)

K ey

F in

di n

A za

b et

a l26

N C

B A

E gy

pt 1

N IC

U , a

N IC

ad m

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si on

s w

it h

ra ti

of in

va si

ve n

ti la

ti on

8 h

62 v

s. 8

1 V

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p re

ve n

ti on

b u

n dl

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ro u

ti n

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C m

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h ea

d- of

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ev at

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, h an

d h

yg ie

n e,

s te

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g, s

tr ic

t in

di ca

ti on

s fo

r in

tu ba

ti on

, r ei

n tu

ba ti

on a

n d

su c-

ti on

in g,

v en

ti la

to r

ci rc

u it

c h

an ge

v is

ib ly

s oi

le d

or m

al fu

n ct

io n

in g,

ou th

c ar

e, d

ai ly

e va

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f or

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fo r

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io n

ca ti

on s

V A

P e

pi so

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4 to

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( R

R 0

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; 9 5%

C I

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8– 0.

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d re

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in te

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ri od

( 21

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± 7.

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a n

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= 0

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)

L en

gt h

o f

st ay

in N

IC U

O ve

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be rt

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I T

S B

ra zi

l 5

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vs . 5

63 N

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in cl

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n g

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m ea

su re

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or ta

li ty

in V

L B

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eo -

n at

es (

pr im

ar y

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pi te

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ov em

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n ow

le dg

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t h

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ch an

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pr e-

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0% ; p

os t-

tr ai

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8. 2%

), se

ve re

R O

(1 .6

v s.

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% ),

la te

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in fe

ct io

n (

11 .3

v s.

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3 ca

se s/

10 00

in fa

n t

da ys

) or

o th

er o

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In ci

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t in

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io n

, N E

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n d

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al 31

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20 03

a n

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ph as

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; ph

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02 B

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h b

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lt u

re q

u al

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pr ov

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ro vi

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al co

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fe ct

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H s

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

Fitzgerald et al

for either missing mandatory ICROMS criteria or ICROMS scores below the cutoff for the particular study design. Of the included studies, 8 were conducted in lower middle-income countries and 19 in upper middle-income countries (only 2 studies were multicoun- try). None were conducted in low-income countries. Including mul- tisite studies and using the 2021 World Bank regions, 14 study sites were in Latin America/Caribbean, 14 in South-East Asia/Pacific, 5 in the Middle East/North Africa, 3 in Europe/Central Asia and 1 in Sub-Saharan Africa.6 Eighteen studies evaluated single interven- tions and 9 evaluated bundled interventions (two of which were conducted in multiple countries).

Single-Intervention Studies Of the single interventions (Table 1), probiotics/feeding

interventions were the most commonly evaluated (5), followed by emollients (4), chlorhexidine cord cleansing (2) and KMC (2).

Three of the 5 probiotic/feeding interventions evaluated oral bovine lactoferrin versus placebo in a total of 370 neonates with birth weights <2500 g.8–10 Varying bovine lactoferrin dosage (from 80 to 200 mg/kg/day) and weight/gestational age thresholds made data incomparable and meta-analysis inappropriate. Two studies showed reduction in HAI in the intervention groups, one document- ing 4.4 infections per 1000 patient-days in the intervention arm ver- sus 17.3 (P = 0.007), the other finding a risk ratio of 0.211 (95% CIs, 0.044–1.019; P = 0.036), in those receiving the intervention versus placebo.8,9 Two studies evaluated enteral supplements but neither reduced infection incidence [parenteral glutamine supplementation (P = 0.518)11 or mixed probiotic administration (P = 0.4)12].

For emollients, one group conducted 2 studies using sun- flower seed oil in 103 Egyptian and 497 Bangladeshi neonates <72 hours of age, born at <34 or <33 weeks’ gestational age, respec- tively.13,14 Both studies found that sunflower seed oil massage was associated with a significant decrease in the adjusted incidence rate ratio (aIRR, adjusted for weight on admission, gestational age and sex) of culture-proven BSI than control (aIRR 0.46; 95% CI 0.26–0.81 and aIRR 0.59; 95% CI 0.37–0.96). Notably, the Bangla- deshi study showed no difference in the rate of clinically suspected infection triggering taking of blood cultures or antibiotic treatment rates between groups, although culture-proven BSI decreased in the intervention arm. Topical coconut oil was used in a Pakistani study in 270 neonates (26–34 weeks gestational age), first in the neonatal unit (NNU) and then at home.15 Neonates randomized to the con- trol arm had an increased risk of hospital-acquired BSI (adjusted hazard ratio, 6.0; 95% CI 2.3–16). A Turkish study of 197 preterm neonates (<34 weeks’ gestation and <24 hours old) found no dif- ference in mortality, incidence of culture-proven or clinically sus- pected infection in patients randomized to receive aquaphor emol- lient versus standard skin care.16

Two studies from India examined the impact of topical application of chlorhexidine gluconate; one in 140 neonates ≥32 weeks’ gestational age and ≥1500 g using chlorhexidine 2.5% to clean the umbilical stump; the other in 140 neonates compar- ing whole-body cleansing with chlorhexidine 0.25% versus tepid water.17,18 The first demonstrated a significant decrease in culture- proven BSI with chlorhexidine cord care (2 vs. 15; P = 0.02; absolute risk, 21% vs. 3%; absolute risk reduction, 19%; CIs not shown), although clinically suspected infections increased in inter- vention versus control subjects (Table 1).17 The second study found a nonsignificant decrease in blood culture positivity with whole- body cleansing (6/168 blood cultures positive in the intervention group vs. 12/175; P = 0.195), possibly owing to a small sample size and that blood cultures were taken at set intervals regardless of clinical indication.18

Studies on KMC were carried out in Colombia and Malaysia, in 746 neonates <2000 g and 126 neonates <1500 g, respectively.19,20

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

Low-income Neonatal Units: Infection Prevention

These studies evaluated substantially different KMC interventions (≈24 hours per day of KMC vs. ≥1 hour per day of KMC; Table 1). The Colombian study found similar numbers of infectious epi- sodes [49/382 (intervention) vs. 44/364 (controls)], although they describe a milder phenotype in the intervention arm and a reduction in nosocomial infections (8% vs. 4% in interventions/controls; P = 0.026; absolute figures not given), without a clear distinction of the definition of “nosocomial” versus other infections. In the Malay- sian study, there were 2/64 infections in the intervention group ver- sus 1/64 controls (P = 1.0).

A large cohort study in Colombia (6655 neonates) evaluat- ing a hand hygiene intervention (alcohol-based hand rub dispens- ers, daily surveillance and quarterly feedback) found a decreased incidence density of neonatal methicillin-resistant Staphylococ- cus aureus BSIs (from 2.2 to 0.6 per 1000 patient-days; P = 0.01), although no decrease in Acinetobacter baumannii21 (0.6–0.2 per 1000 patient-days; P not given).

A small Brazilian study of massage therapy versus no inter- vention (n = 104) reported lower incidence of late-onset infections in the intervention versus control groups.22

No study evaluating “rooming-in” (defined as continuous presence of parent caregivers in the neonatal unit23), peripherally inserted central catheters versus standard intravenous catheters24 and fluconazole prophylaxis25 found differences in infection rates between the study arms (Table 1).

Bundled Interventions Five of the 9 studies reporting the impact of IPC bundles

(Table 2) focused on preventing device-associated infection.26–30 One small, single-center study in an Egyptian NICU achieved significant reduction in ventilator-associated pneumonia (VAP) rates and mechan- ical ventilation days, with a trend toward reduction in NICU length of stay and overall mortality.26 A multicountry study in 10 NICUs dem- onstrated significant reduction in VAP rates (RR 0.67; 95% CI 0.50– 0.91), after implementation of a multimodal strategy including hand hygiene, oral antiseptics, ventilator circuit management and enhanced infection surveillance.27 A tertiary hospital, 50-bed NICU in China, significantly reduced VAP rates, as well as overall mortality following implementation of a bundle including hand hygiene, ventilator disin- fection, education and rational antibiotic use.28

Two studies targeted prevention of central line–associated BSI. A multicountry study in 4 NICUs demonstrated significant reduction in central line–associated BSI rates following a multimodal intervention strategy including education, enhanced process and outcome surveil- lance and staff feedback (rate ratio, 0.45; 95% CI 0.33–0.63).29 A sin- gle-center Brazilian NICU significantly reduced central line–associated BSI rates (24 vs. 15 per 1000 catheter days; P = 0.04) following imple- mentation of a bundle including education, hand hygiene, chlorhexidine gluconate skin preparation and removal of unnecessary catheters.30

The first of two studies utilizing education/training inter- ventions was a noncontrolled “before-after” study conducted in 2 NICUs in the Philippines. The bundle focused on quality improve- ment in blood culture collection, hand hygiene compliance, use of infection control checklists and staff education. Although there was no change in the primary outcome (proportion of neonates newly colonized with resistant pathogens) or in the secondary outcome of bacteremia, the study achieved improved hand hygiene compli- ance rates and reduction in overall mortality.31 A Brazilian study in 5 neonatal units conducted an interrupted time series analysis following introduction of a nurse training package including IPC measures. Despite improvement in nurses’ knowledge and prac- tices, there was no change in mortality or rates of hospital-acquired BSI (11.3 vs. 12.3 cases/1000 infant days).32

A single-center cohort study at a large, academic center NICU in China enrolled outborn neonates <1500 g to assess the

impact of a hypothermia prevention bundle on admission tem- perature, rates of NEC and neonatal infection. Mean axillary tem- perature on arrival increased, and overall mortality rates decreased significantly; however, there was no difference in either NEC or infection incidence following the intervention.33

A recent, large cohort study in a Zambian neonatal unit evaluated the impact of IPC training, text message reminders for staff, hand hygiene promotion with alcohol-based hand rub, enhanced environmental cleaning and weekly whole-body bathing of neonates ≥1.5 kg with 2% chlorhexidine gluconate. The bundle achieved significant reduction in overall mortality, clinically sus- pected infection and culture-proven BSI for all birth weight groups except those <1 kg.34 In a subsequent subanalysis of the interven- tion group data, chlorhexidine gluconate bathing reduced the haz- ard rate of BSI among inborn babies ≥1.5 kg by a factor of 0.58 (P = 0.10; 95% CI 0.31–1.11).35

DISCUSSION Although infection is the most frequent complication of hos-

pitalization in LMIC neonates, the most effective IPC interventions remain unknown. We, therefore, conducted a systematic review of published studies describing the impact of various IPC inter- ventions on healthcare-associated infection rates in LMIC NNUs. We identified 27 eligible publications that assessed single (n = 18) and bundled IPC interventions (n = 9). None were carried out in low-income countries, only 1 in Sub-Saharan Africa and just 2 had sites in multiple countries. We found considerable heterogeneity of study design, analysis and outcomes selected, as well as diversity in the modes of infection prevention targeted (skin and gastroin- testinal mucosal integrity, promotion of normal flora acquisition and reduction of bacterial pathogen colonization). The evidence base we have identified for the effectiveness of IPC interventions in LMIC neonatal units is limited but appears most promising for bundled interventions targeting device-associated infections.

Limitations of this review include the paucity of published research on neonatal IPC from LMIC, the lack of multicenter stud- ies or large sample sizes and the failure to use optimal study inter- ventional study designs. Although we endeavored to be as inclusive as possible in our search terms, we only searched 4 databases and in 6 languages, so it is possible that we missed some relevant studies. It was not appropriate to do meta-analyses due to heterogeneity of both interventions and outcomes. Most studies were carried out in tertiary or academic neonatal units, which further limits the gener- alizability of the findings. Of note, although our initial search cap- tured a large number of potentially eligible studies, full-text review led to 40/120 (33%) papers being excluded due to not including mandatory criteria required by ICROMS or having a low score for study design/analysis quality. Thus, some geographic areas were not well represented, in particular, Sub-Saharan Africa with only one study included.34 This highlights the challenges for clinicians in LMIC settings to identify and implement contextually appropri- ate evidence-based guidelines. It also demonstrates the difficulties of designing and analyzing high-quality IPC studies where facility, laboratory and statistical support may be lacking.

IPC studies are notoriously complex to design and imple- ment, with issues of contamination between arms, the need for large-scale randomization (eg, cluster randomization of hospitals) and use of study designs unfamiliar to many academic clinicians, for example, interrupted time series analysis. IPC interventions also frequently involve behavior change, which does not lend itself to RCT evaluation. In recognition of the importance of evaluating effective behavior change in interventions in fields such as IPC, the UK Medical Research Council has developed guidance on how these studies should be designed and implemented.36 Similarly, the

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

Fitzgerald et al

ICROMS score was developed to allow the inclusion of studies such as controlled before-after studies, noncontrolled before-after studies and qualitative studies in assessing evidence, the exclusion of which from standard systematic reviews undermines their poten- tial contribution to the evidence base.7

A major challenge in selecting the primary end point for neonatal IPC studies is the very low yield of blood cultures (the current gold standard for confirmation of BSI) in both high- and low-income settings. This necessitates recruitment of large num- bers of neonates to conclusively demonstrate an intervention’s impact, which is often particularly challenging in LMIC owing to budgetary and logistic constraints. Sensitive and specific neo- natal infection diagnostic tools that are accessible and affordable in LMIC settings are needed. In addition, standardized and vali- dated definitions for clinically suspected, culture-negative neona- tal infections are required, to allow for comparison of findings across study sites. Use of multiple study outcomes (proven infec- tion, clinically suspected infection and mortality) may compli- cate interpretation of findings, particularly where the results are discrepant.14 Until there is consensus on definitions of clinically suspected neonatal infection, particularly in settings where cul- tures have limited availability, the issue of quantifying reduction in infection rates will persist.

Despite these inherent limitations in the available data, end point definitions and study methodologies used, we have conducted the first systematic review of IPC interventions for LMIC NNUs. We used a robust search strategy, long inclusion time frame and ICROMS quality assessment to ensure we have identified all rel- evant and rigorously conducted research on this topic.

Among the single-intervention studies, emollient therapy (sunflower oil) in low-birth-weight babies had the strongest evidence supporting its use, demonstrating reduced healthcare-associated infection rates in both studies.13,14 There was also evidence to support the use of oral bovine lactoferrin, although the studies were small and there was inconsistency in dosage used. This finding is echoed in a recent Cochrane review of studies in high- and low-resource settings, which concluded there was low-certainty evidence that lactoferrin supplementation could reduce late-onset sepsis, though not NEC or all-cause mortality.37 Contrary to another previous Cochrane review, we did not find strong evidence for KMC as an intervention to reduce BSI in LMICs—only 2 studies fulfilled the ICROMS criteria and only 1 had some evidence of impact on BSI.20,38 For studies that ana- lyzed the impact of bundled interventions, the strongest evidence was generated from studies aiming to prevent device-associated infec- tion. Bundles incorporating other interventions (education, infection surveillance with feedback, hand hygiene promotion and chlorhex- idine gluconate bathing) were also effective, but the evidence was generated from single-center or small studies.

Particular areas that appear promising for future research on neonatal IPC in LMIC are the use of chlorhexidine gluconate body washing and/or emollient therapy. Bundles that target neonatal BSI (the most common neonatal HAI) should be developed, utilizing les- sons learned from the success of bundles targeting device-associated infections. The ideal bundled intervention should target all portals of entry for pathogenic bacteria causing neonatal BSI. It could include avoidance of hospitalization and/or invasive procedures, promotion of mucosal integrity (gut and skin), promotion of colonization with normal flora and reduced colonization with pathogenic bacteria.

Future studies in LMICs should utilize multinational col- laborations, standardize definitions (or at least clearly elucidate what criteria have been used) and use robust study designs, for example, individual randomized or cluster-randomized con- trolled trials and interrupted time series analysis to generate evidence for IPC interventions that can be adopted in neonatal practice. Wherever possible, guidelines such as Strengthening

the Reporting of Observational Studies in Epidemiology for Newborn Infection should be followed to allow for future com- parisons between studies.1

CONCLUSIONS There is a limited evidence base for IPC interventions in

LMIC neonatal units. Overall, bundled interventions targeting pre- vention of device-associated infection are supported by the strong- est evidence to date. More multisite studies using standardized neonatal infection definitions and robust study designs are needed to inform IPC interventions for use in low-resource neonatal units.

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