Cochrane Database of Systematic Reviews (Reviews) || Umbilical cord antiseptics for preventing sepsis and death among newborns

Umbilical cord antiseptics for preventing sepsis and death

among newborns (Review)

Imdad A, Bautista RMM, Senen KAA, Uy MEV, Mantaring III JB, Bhutta ZA

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2013, Issue 5

http://www.thecochranelibrary.com

Umbilical cord antiseptics for preventing sepsis and death among newborns (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

16DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

19AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

69SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

69DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

69INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iUmbilical cord antiseptics for preventing sepsis and death among newborns (Review)


[Intervention Review]

Umbilical cord antiseptics for preventing sepsis and deathamong newborns

Aamer Imdad1, Resti Ma M Bautista2 , Kathlynne Anne A Senen2, Ma Esterlita V Uy3, Jacinto Blas Mantaring III2, Zulfiqar A Bhutta4

1Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York, USA. 2Section of Newborn Medicine, Department

of Pediatrics, University of the Philippines, Manila, Philippines. 3National Institutes of Health, Manila, University of the Philippines,

Manila, Philippines. 4Division of Women and Child Health, Aga Khan University Hospital, Karachi, Pakistan

Contact address: Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box

3500, Karachi, 74800, Pakistan. [email protected].

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 11, 2013.

Review content assessed as up-to-date: 25 March 2013.

Citation: Imdad A, Bautista RMM, Senen KAA, Uy MEV, Mantaring III JB, Bhutta ZA. Umbilical cord antiseptics for pre-

venting sepsis and death among newborns. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD008635. DOI:

10.1002/14651858.CD008635.pub2.


A B S T R A C T

Background

The umbilical cord is a structure made of blood vessels and connective tissue that connects the baby and placenta in utero. The umbilical

cord is cut after birth, which separates the mother and her baby both physically and symbolically. Omphalitis is defined as infection of

the umbilical cord stump. Tracking of bacteria along the umbilical vessels may lead to septicaemia that can result in neonatal morbidity

and mortality, especially in developing countries.

Objectives

To determine the effect of application of antimicrobials on newborn’s umbilical cord versus routine care for prevention of morbidity

and mortality in hospital and community settings.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (1 October 2012). In addition, we also searched LILACS

(1982 to 11 October 2012) and HERDIN NeON (October 2012)

Selection criteria

We included randomized, cluster-randomized and quasi-randomized controlled trials of topical cord care compared with no topical

care, and comparisons between different forms of care.

Data collection and analysis

Two review authors independently assessed trials for inclusion, trial quality and subsequently extracted data. Data were checked for

accuracy.

1Umbilical cord antiseptics for preventing sepsis and death among newborns (Review)


mailto:[email protected]

http://www.herdin.ph/index.php


Main results

The search identified 77 trials. We included 34 trials in the review involving 69,338 babies, five studies are awaiting classification and

there are two ongoing community trials. Included studies were conducted in both developed and developing countries. Among the

34 included trials, three were large, cluster-randomized trials conducted in community settings in developing countries and 31 studies

were conducted in hospital settings mostly in developed countries. Data for community and hospital studies were analyzed separately.

The three trials conducted in community settings contributed 78% of the total number of children included in this review. Of the trials

conducted in hospital settings, the majority had small sample sizes. There were 22 different interventions studied across the included

trials and the most commonly studied antiseptics were 70% alcohol, triple dye and chlorhexidine.

Only one antiseptic, chlorhexidine was studied in community settings for umbilical cord care. Three community trials reported data

on all-cause mortality that comprised 1325 deaths in 54,624 participants and combined results showed a reduction of 23% (average

risk ratio (RR) 0.77, 95% confidence interval (CI) 0.63 to 0.94, random-effects, T² = 0.02, I² = 50%) in the chlorhexidine group

compared with control. The reduction in omphalitis ranged from 27% to 56% depending on the severity of infection. Cord separation

time was increased by 1.7 days in the chlorhexidine group compared with dry cord care (mean difference (MD) 1.75 days, 95% CI

0.44 to 3.05, random-effects, T² = 0.88, I² = 100%). Washing of umbilical cord with soap and water was not advantageous compared

with dry cord care in community settings.

Among studies conducted in hospital settings, no study reported data for mortality or tetanus. No antiseptic was advantageous to

reduce the incidence of omphalitis compared with dry cord care in hospital settings. Topical triple dye application reduced bacterial

colonization with Staphylococcus aureus compared with dry cord care (average RR 0.15, 95% CI 0.10 to 0.22, four studies, n = 1319,

random-effects, T² = 0.04, I² = 24%) or alcohol application (average RR 0.45, 95% CI 0.25 to 0.80, two studies, n = 487, random-

effects, T² = 0.00, I² = 0%). There was no advantage of application of alcohol and triple dye for reduction of colonization with

streptococcus. Topical alcohol application was advantageous in reduction of colonization with Enterococcus coli compared with dry cord

care (average RR 0.73, 95% CI 0.58 to 0.92, two studies, n = 432, random-effects, T² = 0.00, I² = 0%) and in a separate analysis, triple

dye increased the risk of colonization compared with alcohol (RR 3.44, 95% CI 2.10 to 5.64, one study, n = 373). Cord separation

time was significantly increased with topical application of alcohol (MD 1.76 days, 95% CI 0.03 to 3.48, nine studies, n = 2921,

random-effects, T² = 6.54, I² = 97%) and triple dye (MD 4.10 days, 95% CI 3.07 to 5.13, one study, n = 372) compared with dry

cord care in hospital settings. The number of studies was insufficient to make any inference about the efficacy of other antiseptics.

Authors’ conclusions

There is significant evidence to suggest that topical application of chlorhexidine to umbilical cord reduces neonatal mortality and

omphalitis in community and primary care settings in developing countries. It may increase cord separation time however, there is no

evidence that it increases risk of subsequent morbidity or infection.

There is insufficient evidence to support the application of an antiseptic to umbilical cord in hospital settings compared with dry cord

care in developed countries.

P L A I N L A N G U A G E S U M M A R Y

Umbilical cord antiseptics for preventing sepsis and death among newborns

The umbilical cord connects the baby and mother during pregnancy. The cord is cut after birth. The cord stump then dries and falls

off, generally within five to 15 days. Infection of the umbilical cord stump (omphalitis), caused by skin bacteria, is a significant cause of

illness and death in newborn babies in developing countries. This review evaluated all studies that assessed antiseptics applied topically

to the umbilical cord to determine if they reduce the risk of cord infection and death. Thirty-four randomised controlled studies

were included involving 69,338 babies. There were 22 different interventions studied. The most commonly studied antiseptics in the

included studies were 70% alcohol, triple dye and chlorhexidine. Three studies were conducted in community settings in developing

countries; the remainder were conducted in hospital settings, mostly in developed countries. Studies conducted in community settings

were large and contributed about 78% of all the participants included in this review. Hospital-based studies were small and had

limitations.

Studies conducted in community settings evaluated the effectiveness of topical application of chlorhexidine and combined results

showed that chlorhexidine reduced risk of death by 23% and the risk of cord infection ranging from 27% to 56%, depending on the



severity of infection. Topical application of chlorhexidine may increase cord separation time by about 1.7 days, however, this does not

increase subsequent risk of cord infection or death.

None of the studies conducted in hospital settings reported data for risk of death or tetanus. No antiseptic was found to be advantageous

for the prevention of cord infection compared with dry cord care in hospital settings. Topical triple dye application reduced bacterial

colonization with Staphylococcus aureus compared to both dry cord care and alcohol application. There was no advantage of application

of alcohol and triple dye for reduction of colonization with streptococcus. Topical alcohol application was advantageous in the reduction

of colonization with Enterococcus coli compared with dry cord care and triple dye application. Cord separation time was increased

with topical application of alcohol and triple dye compared with dry cord care in hospital settings. There were insufficient studies to

determine the efficacy of other antiseptics.

B A C K G R O U N D

Description of the condition

The umbilical cord is a structure made of blood vessels and con-

nective tissue that connects the baby and placenta in utero. Its

outer surface is a membrane that is bathed in amniotic fluid. The

umbilical cord is cut after birth, which separates the mother and

her baby, both physically and symbolically. The cord stump then

dries, falls off and the wound heals. The natural process of the

umbilical cord falling off involves the formation of an area of sep-

aration between the drying cord and the abdominal wall in which

polymorphonuclear leucocytes (a type of white blood cells) are

present (Oudesluys-Murphy 1990). During this process, material

may collect at this junction that sometimes looks like pus and is

often wrongly identified as an infection. The cord usually separates

between five and 15 days after birth (Oudesluys-Murphy 1987).

Before the separation, the remaining stump can be considered to

be a healing wound and thus a possible route for infection through

the vessels into the baby’s blood stream.

Infection of an umbilical cord may be clinically obvious, but is

also sometimes not apparent. In case of frank infections the cord

may be swollen, the surrounding skin inflamed, or the cord may

be ’smelly’ if infected with anaerobic bacteria (Mullany 2006a).

Tracking of bacteria along the umbilical vessels is not obvious to

the eye, but can cause septicaemia, or result in other focal infections

as a result of blood-borne spread such as septic arthritis (Forshall

1957). In such cases, affected babies may also present with fever,

lethargy or poor feeding, collectively called sepsis, in the neonatal

period.

Description of the intervention

As described above, the umbilical cord stump can be the potential

source of entry of pathogenic microorganisms causing morbidity

and mortality. There are two important considerations in this re-

gard; first, is the colonization of newborn skin and umbilical cord

stump with potential pathogenic microorganisms and second is

the application of harmful substances to the umbilical cord. It is

well known that the skin of the newborn, including the umbilical

stump, is colonized by microorganisms soon after birth (Mir 2011;

Mullany 2012). These microorganisms include both pathogenic

and non-pathogenic species. The profile of organisms colonizing

the cord stump varies according to hygenic conditions at the time

of birth and immediate postpartum period. In high-resource set-

tings, the likely organisms are gram positive ones while in low re-

source, community settings, gram negative organisms seem more

prevalent. A study from US showed that 210 of 211 (99.7%) in-

fants studied were found positive for Staphylococcus aureus at least

once in the first six days of life (Fairchild 1958). A recent study

from community settings from Bangladesh showed that predom-

inant flora that colonize the newborn umbilical stump were gram

negative (Escherichia coli, Klebsiella pneumoniae, and Pseudomonasspp) (Mullany 2012). Pathogenic bacteria such as Escherichia coli,Klebsiella pneumoniae, and Pseudomonas spp and streptococci can

track up the umbilical stump causing infection. It is therefore es-

sential to keep the cord clean.

The practice of cord cutting at birth and care of the umbilical

stump afterwards varies according to local practice and culture

(Elhassani 1984; Mullany 2006; Mullany 2007). In many parts

of the world, deliveries occur at home and the cord is cut with

unsterile tools such as used razors or scissors after which various

substances are applied including mustard oil, turmeric, charcoal,

grease, cow dung or dried banana to speed up cord separation (Mir

2011; Mullany 2007; Mullany 2009; Smith 2009). This combi-

nation of unhygienic cutting of cord and application of poten-

tial harmful substances is an important sources of bacterial infec-

tion and neonatal tetanus (Bennett 1997; Mullany 2007; Mullany

2009). Up to this point, there is a general agreement about the

’clean’ technique for cutting the cord using a sterile cutting in-

strument (blade or scissors) and clean hands to avoid infection



(Blencowe 2011), however, there is less agreement on what is the

best care of the cord stump (Blencowe 2011; Zupan 2004).

The most frequent modern practice of umbilical cord care is ap-

plying antimicrobials to the cord stump. These include antisep-

tics (such as alcohol, silver sulphadiazine, iodine, chlorhexidine

(CHX); and dyes such as triple dye, gentian violet, acriflavine and

eosin) and/or topical application of antibiotics (for example, bac-

itracin, neomycin, nitrofurazone, or tetracycline, or moisture ab-

sorbing powders). These substances may be used as solutions in

water, alcohol, detergent or ointments. Another approach is to

keep the cord clean and dry without applying anything and this is

recommended by the World Health Oraganization (WHO 1999).

A previous approach was to bath the baby soon after birth with

an antimicrobial solution such as hexachlorophene, however, hex-

achlorophene is no longer recommended in newborn babies as it is

absorbed through the skin and is neurotoxic (WHO 1999). One

potential side effect of topical antimicrobials is the delay in cord

separation time, which can potentially increase the risk of bacterial

entry (Novack 1988). However, it has been shown that it does not

increase the risk of mortality (Mullany 2006b).

How the intervention might work

Studies from developed countries have shown that use of an anti-

septic on umbilical cord stump in hospital nurseries significantly

reduced umbilical colonization rates (Barrett 1979; Pezzati 2002;

Speck 1977). Seventy per cent alcohol has been used since the

1900s for routine cord care along with antimicrobial solutions such

as triple dye, tincture of iodine, iodophors, antibiotic ointments,

silver sulphadiazine and CHX. Soaking the umbilical stump in

70% alcohol rapidly kills gram positive and gram negative bac-

teria. However, it has been shown in several hospital studies to

be less effective in controlling umbilical colonization than other

antimicrobials such as triple dye or CHX (Panyavudhikrai 2002;

Pezzati 2002). Despite its limitations, its low cost and availabil-

ity have led to widespread use, especially in low-resource settings

(WHO 1999).

Recently, CHX has been studied for cord care in community set-

tings (Arifeen 2012; Mullany 2006). CHX is a broad spectrum

antiseptic that is extensively used in dental, obstetric and surgical

scrub. It has also been used in obstetrics, peripartum, perineal and

vaginal washes in concentrations as high as 4% (McClure 2007).

Safety studies in newborn infants exposed to CHX washes in var-

ious concentrations found no evidence of toxicity even in babies

in which percutaneous absorption may have taken place (Aggett

1981; Johnsson 1987). CHX is currently included in WHO’s Es-

sential Drugs List (WHO 2011).

Why it is important to do this review

According to a recent estimate about 40.3% (3.1 million) of all

deaths in children less than five years occurred in the neonatal

period (Liu 2012). Most of these deaths occurred in developing

countries and infections, along with complications of prematurity

are the most important cause of mortality in the neonatal period

(Liu 2012). In populations with high neonatal mortality rates,

infections account for approximately half of all newborn deaths

(Lawn 2005). Infection of the cord stump, called omphalitis, is a

significant cause of mortality and morbidity in developing coun-

tries (Agrawal 2012; Lehmann 1999; Mir 2011; Mullany 2007;

Mullany 2009; Sawardekar 2004; Thaver 2009). The infection

typically presents as a superficial cellulitis that may progress to

involve the abdominal wall and eventually to necrotizing fasci-

itis, myonecrosis, or systemic disease (Gallagher 2010). The risk

is greatest in situations where deliveries take place at home, often

with unskilled traditional birth attendants who do not employ

clean delivery practices (Darmstadt 2009; Mullany 2009). Om-

phalitis is relatively rare in developed countries with an overall in-

cidence rate which varies from 0.2% to 0.7% (McKenna 1977).

Incidence of omphalitis in developing countries in community

settings may range up to 21% (Mir 2011). In these settings, the

mortality rate among all infants with omphalitis, including those

who develop complications, is estimated at up to 46% (Mullany

2009). The mortality rate is significantly higher (about 71%) af-

ter the development of necrotizing fasciitis or myonecrosis (Sawin

1994). Suggested risk factors for poor prognosis include male sex,

prematurity or being small-for-gestational age, and septic delivery

(Faridi 1993; Gallagher 2010; Mullany 2007).

The WHO and American Academy of Pediatrics recommend good

hygiene at delivery, and promote dry cord care practice after birth

(AAP 2003; WHO 1999). These recommendations however, are

based on insufficient evidence in favour of or against an antiseptic

(McClure 2007; Zupan 2004). The aim of this review is to provide

data useful for identifying good practice in both high- and low-

income countries.

O B J E C T I V E S

To determine the effect of application of antimicrobials on the

umbilical cord of newborns versus routine care for prevention of

morbidity and mortality in hospital and community settings.

M E T H O D S

Criteria for considering studies for this review

Types of studies



Randomized, cluster-randomized and quasi-randomized con-

trolled trials.

Types of participants

Live newborns born to mothers with or without risk factors for the

development of infection (for example, chorioamnionitis, preterm

rupture of membranes, urinary tract infection), regardless of place

of delivery (home, hospital, non-institutional birth, etc) and ges-

tational age and birthweight.

Types of interventions

We evaluated the following interventions.

1. Antiseptic versus no antiseptic or placebo/dry cord care.

2. Antibiotics versus no antibiotic.

3. Antiseptic versus antibiotic.

4. Antiseptic versus antiseptic.

5. Single versus multiple application.

6. Washing umbilical cord with soap/water versus dry cord

care.

Those studies were excluded where a combination of antiseptic

and antibiotic was used. Studies that evaluated hexachlorophene

were excluded as the antiseptic had been removed from the market

because of central nervous toxicity.

Types of outcome measures

Primary outcomes

• All-cause mortality

• Confirmed or suspected sepsis

• Omphalitis

• Tetanus

Confirmed sepsis is defined as clinical signs and symptoms consis-

tent with infection and microbiologically proven with a positive

blood culture, cerebrospinal fluid culture, urine culture or culture

from a normally sterile site (e.g. pleural fluid, peritoneal fluid or

autopsy specimens) for bacteria or fungi.

Suspected sepsis is defined as clinical signs and symptoms consis-

tent with sepsis without isolation of a causative organism.

Tetanus is defined as trismus (spasm of the muscles involved in

opening of the jaws) and severe generalized muscular spasms not

attributable to other causes (i.e. hypocalcaemia, phenothiazine re-

action, strychnine poisoning) (AAP 2003).

Omphalitis is defined as clinical signs and symptoms of umbilical

stump infection which include the following.

Localized infection:

1. purulent or malodorous discharge from the umbilical

stump;

2. periumbilical erythema;

3. oedema;

4. tenderness.

Three case definitions have been described by Mullany 2006a to

describe the severity of omphalitis and had been used wherever

data were available. The three definitions are described below.

Algorithm 1: Moderate or severe redness.

Algorithm 2: Moderate redness with pus, or severe redness (with-

out regard to pus).

Algorithm 3: Severe redness with pus.

Extensive local disease that includes conditions such as necrotizing

fasciitis or myonecrosis, which are typically found in a perium-

bilical location but may spread across the abdominal wall, onto

the flanks and back, and into the scrotum. These signs may also

suggest infection by both aerobic and anaerobic organisms and

include the following:

1. ecchymoses, violaceous discolorations;

2. bullae;

3. peau d’orange appearance (the skin looks like orange peel);

4. crepitus;

5. petechiae;

6. progression of cellulitis despite antimicrobial therapy

(Gallagher 2010).

Secondary outcomes

• Bacterial colonization

• Time to cord separation

Search methods for identification of studies

Electronic searches

We contacted the Trials Search Co-ordinator to search the

Cochrane Pregnancy and Childbirth Group’s Trials Register (1

October 2012).

The Cochrane Pregnancy and Childbirth Group’s Trials Register

is maintained by the Trials Search Co-ordinator and contains trials

identified from:

1. monthly searches of the Cochrane Central Register of

Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. weekly searches of EMBASE;

4. handsearches of 30 journals and the proceedings of major

conferences;

5. weekly current awareness alerts for a further 44 journals

plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and

EMBASE, the list of handsearched journals and conference pro-

ceedings, and the list of journals reviewed via the current aware-

ness service can be found in the ‘Specialized Register’ section



within the editorial information about the Cochrane Pregnancy

and Childbirth Group.

Trials identified through the searching activities described above

are each assigned to a review topic (or topics). The Trials Search

Co-ordinator searches the register for each review using the topic

list rather than keywords.

In addition, we searched LILACS (1982 to 11 October 2012)

using the search strategy detailed in Appendix 1, and HERDIN

NeON, the Philippine database of local science journals (October

2012).

We did not apply any language restrictions.

Data collection and analysis

Selection of studies

Two review authors independently assessed for inclusion potential

studies identified as a result of the search strategy. We resolved any

disagreement through discussion or, if required, we consulted a

third person.

Data extraction and management

For eligible studies, at least two review authors extracted the data.

We resolved discrepancies through discussion or, if required, we

consulted a third person. We entered data into Review Manager

software (RevMan 2011) and checked for accuracy.

When information regarding any of the above was unclear, we

attempted to contact authors of the original reports to provide

further details.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each

study using the criteria outlined in the Cochrane Handbook forSystematic Reviews of Interventions (Higgins 2011). We resolved

any disagreement by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible

selection bias)

We described for each included study the method used to generate

the allocation sequence in sufficient detail to allow an assessment

of whether it should produce comparable groups.

We assessed the method as:

• low risk of bias (any truly random process, e.g. random

number table; computer random number generator);

• high risk of bias (any non-random process, e.g. odd or even

date of birth; hospital or clinic record number);

• unclear risk of bias.

(2) Allocation concealment (checking for possible selection

bias)

We described for each included study the method used to conceal

the allocation sequence and determine whether intervention allo-

cation could have been foreseen in advance of, or during recruit-

ment, or changed after assignment.

We assessed the methods as:

• low risk of bias (e.g. telephone or central randomization;

consecutively numbered sealed opaque envelopes);

• high risk of bias (open random allocation; unsealed or non-

opaque envelopes, alternation; date of birth);


(3) Blinding (checking for possible performance bias)

We described for each included study the methods used, if any, to

blind study participants and personnel from knowledge of which

intervention a participant received. We considered that studies

were at low risk of bias if they were blinded, or if we judged that the

lack of blinding could not have affected the results. We assessed

blinding separately for different outcomes or classes of outcomes.


• low, high or unclear risk of bias for participants;

• low, high or unclear risk of bias for personnel;

• low, high or unclear risk of bias for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition

bias through withdrawals, dropouts, protocol deviations)

We described for each included study, and for each outcome or

class of outcomes, the completeness of data including attrition

and exclusions from the analysis. We stated whether attrition and

exclusions were reported, the numbers included in the analysis at

each stage (compared with the total randomized participants), rea-

sons for attrition or exclusion where reported, and whether miss-

ing data were balanced across groups or were related to outcomes.

Where sufficient information was reported, or could be supplied

by the trial authors, we included the missing data in the analyses.

We assessed methods as:

• low risk of bias (e.g. less than 10% missing data);

• high risk of bias (e.g. numbers or reasons for missing data

imbalanced across groups; ‘as treated’ analysis done with

substantial departure of intervention received from that assigned

at randomization);


If missing data could not be supplied by the trial authors, we

carried out subgroup analysis for groups with sufficient outcome

data.

(5) Selective reporting (checking for reporting bias)



http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/PREG/frame.html







We described for each included study how we investigated the

possibility of selective outcome reporting bias and what we found.


• low risk of bias (where it was clear that all of the study’s pre-

specified outcomes and all expected outcomes of interest to the

review had been reported);

• high risk of bias (where not all the study’s pre-specified

outcomes had been reported; one or more reported primary

outcomes were not pre-specified; outcomes of interest were

reported incompletely and so could not be used; study failed to

include results of a key outcome that would have been expected

to have been reported);


(6) Other sources of bias

We described for each included study any important concerns we

had about other possible sources of bias.

We assessed whether each study was free of other problems that

could put it at risk of bias (e.g. study design, imbalance in baseline

data):

• low risk of other bias;

• high risk of other bias;

• unclear whether there is risk of other bias.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high

risk of bias, according to the criteria given in the Cochrane Hand-book (Higgins 2011). With reference to (1) to (6) above, we as-

sessed the likely magnitude and direction of the bias and whether

we considered it likely to impact on the findings. We explored

the impact of the level of bias through sensitivity analyses - seeSensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio

with 95% confidence intervals. For the three included cluster-ran-

domized trials, data were entered using the generic inverse vari-

ance option in RevMan 2011 to allow adjustment of the variance

for cluster effect (Higgins 2011).

Continuous data

For continuous data, we used the mean difference with 95% con-

fidence intervals. For studies with multiple groups, comparison

groups were combined into a single pair-wise comparison. Stan-

dard deviations were adjusted using the formula in the CochraneHandbook (Higgins 2011).

Unit of analysis issues

We included cluster-randomized trials in the analyses along with

individual-randomized trials. We used cluster-adjusted values

from the trials, irrespective of the method used. In case a trial was

not adjusted for cluster design, results were adjusting by inflating

the standard error of the effect size by quare root of design effect

given in the study.

Dealing with missing data

For included studies, we took note of levels of attrition. We ex-

plored the impact of including studies with high levels of missing

data in the overall assessment of treatment effect by using sensi-

tivity analysis.

For all outcomes, we carried out analyses, as far as possible, on an

intention-to-treat basis, i.e. we included all participants random-

ized to each group in the analyses, and analyzed all participants in

the group to which they were allocated, regardless of whether or

not they received the allocated intervention.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using

the T², I² and Chi² statistics. We considered heterogeneity as sub-

stantial if an I² was greater than 50% and either the T² was greater

than zero, or the P value was less than 0.10 in the Chi² test for

heterogeneity.

Assessment of reporting biases

We planned that, if there were 10 or more studies in the meta-

analysis, we would investigate reporting biases (such as publication

bias) using funnel plots. We intended to assess funnel plot asym-

metry visually. If asymmetry was suggested by a visual assessment,

we planned to perform exploratory analyses to investigate it.

Data synthesis

We performed statistical analysis using the Review Manager soft-

ware (RevMan 2011). We used the random-effects analysis to pro-

duce an overall summary of the average treatment effect across

trials considering the different interventions across different eco-

nomic settings. We have presented the results as the average treat-

ment effect with its 95% confidence interval, and the estimates of

T² and I².

Subgroup analysis and investigation of heterogeneity

We planned to the following subgroup analyses:

1. preterm (gestational age less than 37 weeks) versus term

(gestational age 37 weeks or more);

2. hospital setting; community-based studies; settings mixed

or undefined;



3. trials carried out in Europe-Americas; Western Pacific;

Eastern Mediterranean; South-East Asia; Africa.

Gestational age and birthweight are relevant subgroups since the

incidence of sepsis is high among low birthweight and preterm

infants. Causative organisms, corresponding susceptibility to an-

tiseptics and severity of disease, may differ in hospital versus com-

munity settings. We therefore analyzed hospital and community-

based studies separately. Baseline neonatal mortality rate varies

with region: Europe-America (11-12/1000 livebirths); Western

Pacific (19/1000 livebirths); Eastern Mediterranean (40/1000 live-

births); Southeast Asia (38/1000 livebirths); Africa (44/1000 live-

births) (WHO 2006).

We included all primary outcomes in the subgroup analysis (mor-

tality, confirmed or suspected sepsis, tetanus and omphalitis).

Sensitivity analysis

We carried out sensitivity analysis removing studies of low quality.

We also carried out sensitivity analyses to investigate the effect of

missing data:

• less than 5% missing data;

• 5% to 10% missing data;

• 10% to 20% missing data;

• 20% or more missing data.

R E S U L T S

Description of studies

See Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

Results of the search

The search identified 77 trials; we included 34 studies in the review,

involving 69,338 babies (See Characteristics of included studies).

Thirty-six studies were excluded (see Characteristics of excluded

studies). Five studies are awaiting classification (see Characteristics

of studies awaiting classification) while there are two ongoing com-

munity trials (see Ongoing studies).

Included studies

Thirty-four trials reported in 46 papers met the inclusion cri-

teria. More than one report was available for six (17%) trials

(Arifeen 2012; Evens 2004; Mullany 2006; Speck 1977; Soofi

2012; Suliman 2010). When results of an included trial were re-

ported in more than one publication, we extracted data from all

reports but counted it as one trial. All included trials reported data

that could be included in a meta-analysis.

There were three large, cluster-randomized trials conducted in

community settings (Arifeen 2012; Mullany 2006; Soofi 2012).

These three trials contributed 78% of the total number of children

included in this review. The two ongoing studies are also com-

munity trials that assess effect of topical application of chlorhexi-

dine to umbilical cord. One study is being conducted in Zambia

(Hamer 2010) and other in Pemba (Sazawal 2012).

Of the trials conducted in hospital settings, the majority had small

sample sizes. Sample size of these 31 (91%) trials ranged between

71 and 2241.

Seventeen (50%) of the included studies had a ’dry cord care’ group

and 16 (47%) studies comprised more than two study groups.

The studies were conducted in both developing and developed

countries. All three community studies were conducted in devel-

oping countries and most of the hospital-based studies were con-

ducted in developed countries. There were eight studies conducted

in USA (Barrett 1979; Evens 2004; Gladstone 1988; Golombek

2002; Rosenfeld 1989; Schuman 1985; Speck 1977; Suliman

2010), four in Canada (Dore 1998; Janssen 2003; Medves 1997;

Rush 1986), three in Taiwan (Hsu 1999; Hsu 2010; Huang 2001),

two each in Iran (Ahmadpour-Kacho 2006; Nourian 2009), Nor-

way (Meberg 1985; Meberg 1990), Italy (Pezzati 2002; Pezzati

2003), and Pakistan (Shafique 2006; Soofi 2012) and one each in

Saudi Arabia (Al-Binali 2006), Palestine (Arad 1981), Bangladesh

(Arifeen 2012), Scotland (Bain 1994), Peru (Davila 2007), Ger-

many (Kapellen 2009), England (Mugford 1986), Nepal (Mullany

2006), Japan (Oishi 2004), Thailand (Panyavudhikrai 2002), and

Spain (Perapoch 1993).

There were 18 (52%) studies that included full-term babies, five

(15%) included preterm babies (Bain 1994; Gladstone 1988;

Pezzati 2002; Pezzati 2003; Rosenfeld 1989), seven (20%) in-

cluded both term and preterm babies (Ahmadpour-Kacho 2006;

Arifeen 2012; Davila 2007; Janssen 2003; Mullany 2006; Oishi

2004; Soofi 2012) and gestational age was not mentioned in

four (12%) studies (Al-Binali 2006; Barrett 1979; Mugford 1986;

Schuman 1985).

There were 22 different interventions studied across the included

trials. These included topical antiseptics, antibiotics and measures

such as washing the cord with soap and water. There were 20 stud-

ies (58%) that evaluated topical alcohol application, 10 (29%)

triple dye, nine (26%) chlorhexidine, five (14%) Silver Sulfadi-

azine, three (8%) Povidine and two (5%) salicylic powder. There

was one study each for Beniktol, neomycin, bismuth, breastmilk,

bacitracin, benzine, hydrophobic gauze, mercurochrome, green

clay powder, katoxin, fuschine, and citrane.

Of the primary outcomes considered, three trials (Arifeen 2012;

Mullany 2006; Soofi 2012) evaluated the effect of cord care on

mortality. Thirteen studies reported data on omphalitis. One study

reported data on sepsis (Pezzati 2003) and one study reported sep-

sis-related mortality (Mullany 2006). No study reported tetanus.

Of the secondary outcomes, 26 studies reported cord separation

time, 12 reported bacterial colonization.



Excluded studies

Thirty-six studies were excluded (See Characteristics of excluded

studies). Reasons for exclusion were: 1) not a randomized con-

trolled trial, 2) not a cord care study or, 3) effect of individual

intervention was not established due to co-interventions.

Risk of bias in included studies

See Figure 1 for summary of assessment of risk of bias.



Figure 1. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included

study.



Allocation

Twelve (35%) studies had adequate methods of sequence genera-

tion, eight (24%) had inadequate methods or were quasi-random-

ized trials while in 14 (41%) studies, methods were inadequately

described to make a complete assessment.

Allocation was adequately concealed in seven (21%) studies while

in 22 (65%) studies it was not mentioned or unclear. Five (15%)

studies had inadequate methods of allocation concealment.

Blinding

Method of blinding was not done, not feasible, or not mentioned

in 30 (88%) studies. Three studies had “adequate” methods of

blinding. The study of Mullany 2006 mentioned that investiga-

tors, field workers and participants were masked to chlorhexidine

and soap and water but not to the dry cord care.

Incomplete outcome data

Seventeen (50%) studies reported data on attrition and exclusion

while 14 studies (41%) did not describe enough details on follow-

up. There was insufficient information in three (9%) studies to

make a complete assessment.

Selective reporting

It is difficult to assess true selective reporting bias when proto-

cols of the included studies are not available. Review authors had

access to the protocols of three studies to make an assessment

(Arifeen 2012; Mullany 2006; Soofi 2012) and they were con-

sidered to be adequate. In the rest of the studies, the judgment

was made based on variables mentioned in the methods section

compared to those reported in the results section of the study.

Based on this assessment, 13 studies had adequate descriptions

of outcomes in the results section for the outcomes mentioned

in the methods section (Ahmadpour-Kacho 2006; Arifeen 2012;

Bain 1994; Barrett 1979; Dore 1998; Hsu 2010; Medves 1997;

Mugford 1986; Mullany 2006; Nourian 2009; Rosenfeld 1989;

Soofi 2012; Suliman 2010).

Other potential sources of bias

In the study of (Ahmadpour-Kacho 2006), baseline characteristics

showed more vaginal deliveries in the dry care, alcohol and silver

groups compared with the breastmilk group. Arad 1981 included

the outcome of sepsis but no bacterial cultures were obtained

to prove the condition. The community trial from Bangladesh

(Arifeen 2012), showed that there was no effect of multiple cleans-

ing with chlorhexidine on neonatal mortality. This may be due to

the fact that the study was not powered enough to detect a sig-

nificant difference in this arm, as pointed out by authors (Arifeen

2012). In the study of Bain 1994, there was a higher rate of rupture

of membranes in the dry care group. In Davila 2007, there was

no table of baseline characteristics. In the study of Evens 2004,

there was a higher rate of vaginal delivery in the alcohol group.

The studies by Golombek 2002 and Shafique 2006 gathered data

on the incidence of omphalitis by telephone calls and no home

visits were made to make an assessment. This could have resulted

in false positives or negatives as symptoms were reported by moth-

ers. Kapellen 2009 had no table of baseline characteristics but the

text mentioned that the groups were comparable in terms of sex,

ethnicity, birthweight, birth length, gestational age, model of de-

livery and Apgar score. No description of baseline characteristics

of study participants was given in five studies (Al-Binali 2006;

Meberg 1985; Meberg 1990; Perapoch 1993; Speck 1977). The

study of Medves 1997 had no table of baseline characteristics.

Mugford 1986 mentioned in the text that the groups were com-

parable in terms of sex, birthweight and mode of delivery. The

study of Oishi 2004 states that the babies in the alcohol group

had low birthweights but the proportion was not mentioned. The

desired sample size in Soofi 2012was not achieved due to a security

situation in the study area.

Effects of interventions

Antiseptics versus dry cord care/placebo

There were 18 studies that had a comparison group between ’dry

cord care’ and ’an antiseptic’. Fifteen of these studies were con-

ducted in hospital settings while three were conducted in commu-

nity settings (Arifeen 2012; Mullany 2006; Soofi 2012).

The antiseptics included in this comparison were: alcohol, triple

dye, chlorhexidine, salicylic sugar powder, green clay powder, silver

sulphadiazine, benzine, katoxin powder, fuschine, zinc powder and

breastmilk.

Community studies

Primary outcomes

Mortality

Only one antiseptic, i.e. chlorhexidine was studied in community

settings for umbilical cord care. Three community trials reported

data on all-cause mortality (Arifeen 2012; Mullany 2006; Soofi



2012). There were 1325 deaths in 54,624 participants of three

studies and combined results showed a reduction of 23% in the

intervention group compared with control (average risk ratio (RR)

0.77, 95% confidence interval (CI) 0.63 to 0.94; random-effects,

T² = 0.02, I² = 50% (Analysis 1.1)).

Sepsis

No community-based study reported data on the incidence of

sepsis, however, one trial (Mullany 2006) from Nepal reported data

on sepsis-specific mortality and showed a 31% reduction in the

chlorhexidine group compared with dry cord care but the results

were not statistically significant (RR 0.69, 95% CI 0.40 to 1.18).

Omphalitis

Antiseptics were associated with a significant reduction in om-

phalitis ranging from 27% to 56% depending on the severity of

infection: redness extending to skin: average RR 0.73, 95% CI

0.64 to 0.83; three studies, random-effects, T² = 0.00, I² = 34%

(Analysis 1.2); redness with pus or severe redness: average RR 0.69,

95% CI 0.60 to 0.79; three studies, random-effects, T² = 0.00,

I² = 0% (Analysis 1.3); severe redness with pus: average RR 0.44,

95% CI 0.28 to 0.69; three studies, random-effects, T² = 0.03,

I² = 19% (Analysis 1.4), with the most significant reduction in

severe cases.

Secondary outcomes

Bacterial colonization

One study (Arifeen 2012) reported data on bacterial colonization

and showed a significant reduction in bacterial colonization of

Staphylococcus aureus (RR 0.27, 95% CI 0.23 to 0.31 (Analysis

1.5)); Enterococcus coli (RR 0.50, 95% CI 0.46 to 0.54 (Analysis

1.6)) and streptococci (RR 0.28, 95% CI 0.22 to 0.37 (Analysis

1.7)) with topical chlorhexidine application compared with con-

trol.

Cord separation time

Data for cord separation time was available from two studies

(Arifeen 2012; Mullany 2006), carried out in Bangladesh and

Nepal respectively. In the study by Mullany 2006, cord separa-

tion time was longer in the chlorhexidine group (5.32 ± 2.4 days)

compared with the dry cord care group (4.24 ± 1.6 days). There

was no increased risk of mortality in children who had increased

cord separation time (Mullany 2006). In Arifeen 2012, separation

time in the combined chlorhexidine group (7.20 ± 3.0 days) was

2.40 (95% CI 2.17 to 2.64) days longer than among babies not

exposed to chlorhexidine (4.79 ± 1.8 days) (Unpublished data).

The combined data for both of these studies showed that cord sep-

aration time was 1.7 days longer in the chlorhexidine group com-

pared with the non-chlorhexidine group (mean difference (MD)

1.75, 95% CI 0.44, to 3.05, random-effects, T² = 0.88, I² = 100%

(Analysis 1.8)).

Hospital studies

Primary outcomes

Mortality/sepsis/tetanus

Among studies conducted in hospital settings, no study reported

data on mortality, sepsis or tetanus for the comparison of antisep-

tics versus dry cord care/placebo.

Omphalitis

Five studies reported data for incidence of omphalitis (Bain 1994;

Janssen 2003; Kapellen 2009; Nourian 2009; Pezzati 2002). There

was no significant difference for the incidence of omphalitis when

alcohol (three studies) (average RR 0.92, 95% CI 0.62 to 1.39),

triple dye (two studies) (average RR 0.71, 95% CI 0.13 to 3.73),

chlorhexidine (one study) (RR 0.28, 95% CI 0.06 to 1.35), sali-

cylic sugar powder (one study) (RR 0.21, 95% CI 0.01 to 4.38)

and green clay powder (one study) (RR 0.48, 95% CI 0.04 to

5.26) were compared with dry cord care/placebo (Analysis 2.1).

Secondary outcomes


Compared with dry cord care/placebo, bacterial colonization of

umbilical cord with Staphylococcus aureus was significantly reduced

with application of triple dye (four studies) (average RR 0.15,

95% CI 0.10 to 0.22, random-effects, T² = 0.04, I² = 24%), silver

sulphadiazine (two studies) (average RR 0.72, 95% CI 0.60 to

0.87, random-effects, T² = 0.00, I² = 0%), chlorhexidine (one

study) (RR 0.65, 95% CI 0.55 to 0.77), salicylic sugar powder (one

study) (RR 0.32, 95% CI 0.17 to 0.58), green clay powder (one

study) (RR 0.51, 95% CI 0.31 to 0.82) and fuschine (one study)

(RR 0.52, 95% CI 0.32 to 0.84). For the same control group, there

was no significant difference for alcohol (two studies) (average RR

0.61, 95% CI 0.11 to 3.36), benzine (one study) (RR 0.99, 95%



CI 0.90 to 1.09). Compared with dry cord care/placebo, there was

a significantly increased risk of bacterial colonization of umbilical

cord with Staphylococcus aureus associated with use of katoxin (one

study) (RR 1.43, 95% CI 1.02 to 2.00). See Analysis 2.2.

For the outcome of colonization with streptococci, there was a

significant reduction with application of silver sulphadiazine (two

studies) (average RR 0.62, 95% CI 0.43 to 0.89, random-effects,

T² = 0.00, I² = 0%) and fuschine (one study) (RR 0.19, 95%

CI 0.04 to 0.85) compared with dry cord care/placebo. For the

same comparison group, there was no difference in colonization

of streptococci with the application of alcohol (two studies) (RR

0.42, 95% CI 0.15 to 1.19, random-effects, T² = 0.33, I² = 50%),

triple dye (three studies) (average RR 0.57, 95% CI 0.28 to 1.18,

random-effects, T² = 0.31, I² = 79%), chlorhexidine (one study)

(RR 0.53, 95% CI 0.27 to 1.04), salicylic sugar powder (one study)

(RR 0.74, 95% CI 0.29 to 1.90). However, there was an increased

risk of streptococcal bacterial colonization associated with the use

of green clay powder (one study) (RR 4.62, 95% CI 2.41 to 8.84)

and katoxin powder (one study) (RR 5.87, 95% CI 3.12 to 11.05).

See Analysis 2.3.

Compared with dry cord care/placebo, there was a significant re-

duction in the colonization of Enterococcus coli with topical appli-

cation of alcohol (two studies) (average RR 0.73, 95% CI 0.58

to 0.92, random-effects, T² = 0.00, I² = 0%), silver sulphadiazine

(one study) (RR 0.70, 95% CI 0.53 to 0.93) and chlorhexidine

(one study) (RR 0.59, 95% CI 0.39 to 0.90). In contrast, there

was no significant difference with application of triple dye (two


T² = 0.06, I² = 79%), salicylic sugar powder (one study) (RR 0.59,

95% CI 0.32 to 1.10), green clay powder (one study) (RR 1.27,

95% CI 0.79 to 2.05) and katoxin powder (one study) (RR 1.12,

95% CI 0.70 to 1.81). There was increased risk of Enterococcus colicolonization associated with application of fuschine (one study)

(RR 2.04, 95% CI 1.33 to 3.13). See Analysis 2.4.


There was a significant increase in cord separation time when

alcohol was applied to umbilical cord compared with dry cord

care/placebo (nine studies) (MD 1.76 days, 95% CI 0.03 to 3.48,

random-effects, T² = 6.54, I² = 97%). There was one study each

for triple dye (MD 4.10 days, 95% CI 3.07 to 5.13), katoxin

powder (MD 0.80 days, 95% CI 0.18 to 1.42), fuschine (MD 2.80

days, 95% CI 2.01 to 3.59) and silver sulphadiazine (MD 3.60

days, 95% CI 2.66 to 4.54) and these antiseptics were associated

with a significant increase in cord separation time compared with

dry cord care/placebo. One study each for zinc powder (MD -

1.82 days, 95% CI -2.23 to -1.41), salicylic sugar powder (MD -

1.90 days, 95% CI -2.47 to -1.33), green clay powder (MD -0.80

days, 95% CI -1.36 to -0.24), breastmilk (MD -1.69 days, 95%

CI -2.31 to -1.07) and chlorhexidine (MD -0.80 days, 95% CI -

1.21 to -0.39) were associated with decreased cord separation time

compared with dry cord care. See Analysis 2.6.

Antibiotics versus no antibiotic

There were no studies in community or hospital settings that in-

vestigated this comparison.

Antiseptics versus antibiotics

Community studies

There was no study that was conducted in community settings for

this comparison.

Hospital studies

Primary outcomes

Mortality/sepsis/tetanus/omphalitis

Among studies conducted in hospital settings, no data were re-

ported on mortality, sepsis, tetanus or omphalitis for this compar-

ison.

Secondary outcomes


One study compared triple dye (RR 0.65, 95% CI 0.03 to 12.87),

silver sulphadiazine (RR 2.18, 95% CI 0.42 to 11.33) and povi-

done (RR 2.18, 95% CI 0.42 to 11.33) with bacitracin and there

were no differences in bacterial colonization rates for Staphylococ-cus aureus (Analysis 3.1). No data were reported for colonization

with streptococcus and enterococcus.


Cord separation time was significantly reduced when umbilical

cord was treated with triple dye compared with bacitracin (one

study) (MD -5.60 days, 95% CI -9.36 to -1.84) and neomycin

(one study) (MD -4.30, 95% CI -6.27 to -2.33). There was no

difference in cord separation time when silver sulphadiazine was

compared with neomycin (one study) (MD -1.40 days, 95% CI

-3.65 to 0.85). Cord separation time was significantly reduced

when umbilical cord was treated with povidone versus bacitracin



(one study) (MD -2.00 days, 95% CI -3.67 to -0.33). Similarly,

alcohol was associated with a significantly reduced cord separation

time compared with beniktol (MD -2.33 days, 95% CI -3.77 to

-0.89). See Analysis 3.2.

Antiseptics versus antiseptics

Community studies

There was no study that was conducted in community settings for

this comparison.

Hospital studies

Primary outcomes

Sepsis and mortality

Among studies conducted in hospital settings, no study reported

data on mortality or tetanus. One study compared chlorhexidine

with salicylic acid powder and reported no difference in the inci-

dence of sepsis between the two groups (RR 1.11, 95% CI 0.07

to 17.50 (Analysis 4.1)).

Omphalitis

Three studies evaluated triple dye versus alcohol and reported no

significant reduction in the incidence of omphalitis in the triple dye

group compared with the alcohol-treated group (average RR 0.48,

95% CI 0.14 to 1.63, random-effects, T² = 0.54, I² = 41%). There

was no difference when triple dye was compared with salicylic

sugar powder (one study) (RR 4.29, 95% CI 0.21 to 88.65) and

katoxin (one study) (RR 2.13, 95% CI 0.19 to 23.34).

Similarly, there was no difference in the incidence of omphalitis

for the comparisons of alcohol versus povidone (RR 0.84, 95%

CI 0.62 to 1.16, one study), alcohol versus salicylic powder (RR

4.69, 95% CI 0.23 to 97.03, one study), alcohol versus green clay

powder (RR 2.07, 95% CI 0.19 to 22.60, one study), alcohol ver-

sus katoxin (RR 2.10, 95% CI 0.19 to 22.97, one study), alcohol

versus fuschine (RR 2.10, 95% CI 0.19 to 22.97, one study) and

alcohol versus chlorhexidine (RR 2.77, 95% CI 0.12 to 66.49, one

study). One study also compared chlorhexidine with hydrophobic

gauze and reported no significant difference in the incidence of

omphalitis (RR 1.36, 95% CI 0.55 to 3.36).

In contrast, triple dye was associated with a significant reduction

in the incidence of omphalitis compared with povidone-iodine

(RR 0.15, 95% CI 0.07 to 0.32, one study). See Analysis 4.2.

Secondary outcomes


Bacterial colonization with Staphylococcus aureus was significantly

reduced when umbilical cord was treated with triple dye compared

with alcohol (two studies) (average RR 0.45, 95% CI 0.25 to 0.80,

random-effects, T² = 0.00, I² = 0%), silver sulphadiazine (three


T² = 0.00, I² = 0%), green clay powder (one study) (RR 0.27,

95% CI 0.11 to 0.65) and katoxin powder (one study) (RR 0.26,

95% CI 0.11 to 0.63) (Analysis 4.3). There was no significant dif-

ference in Staphylococcus aureus colonization rates for comparisons

of triple dye versus povidone (RR 0.65, 95% CI 0.03 to 12.87),

triple dye versus salicylic sugar powder (one study) (RR 0.43, 95%

CI 0.16 to 1.12) or triple dye versus fuschine (one study) (RR

1.92, 95% CI 0.18 to 20.97). One trial (Pezzati 2002) studied

alcohol in comparison with green clay powder (RR 0.59, 95% CI

0.30 to 1.16), fuschine (RR 0.57, 95% CI 0.29 to 1.12), salicylic

powder (RR 0.94, 95% CI 0.43 to 2.03) and povidone (RR 0.84,

95% CI 0.62 to 1.16) and found no significant difference in the

colonization of umbilical cord with Staphylococcus aureus.However, treating the umbilical cord with alcohol was associated

with a significant reduction in bacterial colonization with Staphy-lococcus aureus compared with the use of katoxin powder (RR

0.21, 95% CI 0.12 to 0.37, one study). One study each evaluated

chlorhexidine in comparison with hydrophobic gauze (RR 0.90,

95% CI 0.70 to 1.15) and mercurochrome (RR 0.11, 95% CI

0.01 to 2.04) and found no significant difference in colonization

rates for Staphylococcus aureus. There was however, a significant

difference when chlorhexidine was compared with alcohol (two

studies) (RR 0.41, 95% CI 0.24 to 0.71). See (Analysis 4.3).

One study each compared triple dye with alcohol (RR 0.46, 95%

CI 0.04 to 4.94), silver sulphadiazine (RR 1.26, 95% CI 0.71

to 2.25), and fuschine (RR 0.48, 95% CI 0.04 to 5.24) and re-

ported no significant difference between the groups for coloniza-

tion of streptococcus (Analysis 4.4). However, for the same out-

come, there was a significant effect of triple dye compared with

green clay powder (one study) (RR 0.02, 95% CI 0.00 to 0.14),

salicylic sugar powder (one study) (RR 0.12, 95% CI 0.02 to 0.98)

and katoxin powder (one study) (RR 0.02, 95% CI 0.00 to 0.11).

Application of alcohol to the umbilical cord was also associated

with a reduction in colonization of streptococcus compared with

green clay powder (one study) (RR 0.04, 95% CI 0.01 to 0.17)

and katoxin powder (one study) (RR 0.03, 95% CI 0.01 to 0.14)

but there was no difference when alcohol was compared with fus-

chine (one study) (RR 1.05, 95% CI 0.15 to 7.38) or salicylic

powder (one study) (RR 0.94, 95% CI 0.43 to 2.03). See Analysis

4.4.

Triple dye led to an increased risk of colonization of Enterococcuscoli compared with alcohol (one study) (RR 3.44, 95% CI 2.10 to



5.64), silver sulphadiazine (one study) (RR 1.36, 95% CI 1.02 to

1.81), green clay powder (one study) (RR 1.83, 95% CI 1.27 to

2.65) and salicylic sugar powder (one study) (RR 3.92, 95% CI

2.28 to 6.72) and katoxin powder (one study) (RR 2.07, 95% CI

1.43 to 3.00) (Analysis 4.5). For the same outcomes, alcohol had a

significant preventive effect compared with green clay powder (RR

0.53, 95% CI 0.31 to 0.92) and fuschine (RR 0.33, 95% CI 0.20

to 0.55). However, there was no difference in colonization rates

of Enterococcus coli for the comparison of alcohol with salicylic

powder (one study) (RR 1.14, 95% CI 0.58 to 2.4) and katoxin

powder (one study) (RR 0.60, 95% CI 0.35 to 1.04). Similarly,

there were no differences in colonization rates when comparing

chlorhexidine with hydrophobic gauze (one study) (RR 0.79, 95%

CI 0.31 to 2.00) or mercurochrome (one study) (RR 0.21, 95%

CI 0.01 to 4.13). See Analysis 4.5.


Cord separation time was not significantly different when triple

dye was compared with alcohol (two studies) (MD 0.43 days, 95%

CI -8.49 to 9.35, random-effects, T² = 40.92, I² = 99%) or when

triple dye was compared with silver sulphadiazine (two studies)

(MD 0.15 days, 95% CI -6.20 to 6.51, random-effects, T² =

18.82, I² = 89%). Cord separation time was increased when triple

dye was compared with salicylic sugar powder (one study) (MD

6.00 days, 95% CI 5.01 to 6.99), povidone-iodine (one study)

(MD 7.60 days, 95% CI 3.96 to 11.24), green clay powder (one

study) (MD 4.90 days, 95% CI 3.92 to 5.88), katoxin powder

(one study) (MD 3.30 days, 95% CI 2.28 to 4.32) and fuschine

(one study) (MD 1.30 days, 95% CI 0.17 to 2.43) (Analysis 4.6).

There was also a significant increase in cord separation time when

the umbilical cord was treated with alcohol compared with green

clay powder (one study) (MD 10.20 days, 95% CI 9.05 to 11.35),

katoxin powder (one study) (MD 8.60 days, 95% CI 7.42 to

9.78), salicylic powder (one study) (MD 11.30 days, 95% CI

10.14 to 12.46) or fuschine (one study) (MD 6.60 days, 95%

CI 5.32 to 7.88) (Analysis 4.6). Chlorhexidine decreased cord

separation time compared with hydrophobic gauze (one study)

(MD -0.40 days, 95% CI -0.57 to -0.23), however, chlorhexidine

significantly increased cord separation time compared with either

salicylic powder (one study) (MD 3.00 days, 95% CI 2.46 to

3.54) or mercurochrome (one study) (MD 6.40 days, 95% CI

5.25 to 7.55) (Analysis 4.6). One study showed that application

of povidone resulted in a shorter cord separation time compared

with silver sulphadiazine (MD -4.00 days, 95% CI -5.53 to -2.47).

However, there was no significant difference in cord separation

time when a combination of triple dye and alcohol was compared

with triple dye alone (MD 1.00 day, 95% CI -0.45 to 2.45). See

Analysis 4.6.

Single versus multiple application of antiseptic

Community studies

There was one study from community settings that compared sin-

gle versus multiple application of chlorhexidine and reported all-

cause mortality, incidence of omphalitis and bacterial coloniza-

tion (Arifeen 2012). No study reported sepsis and tetanus for this

comparison.

Primary outcomes

Mortality

One study (Arifeen 2012) reported data on mortality and there

was no significant difference in all-cause mortality between the

two groups (RR 0.85, 95% CI 0.70 to 1.03] (Analysis 5.1).

Omphalitis

The effect on the incidence of omphalitis varied according to the

severity of omphalitis. Single application was associated with an

increased incidence of moderate (RR 1.53, 95% CI 1.22 to 1.92)

and severe episodes (RR 2.12, 95% CI 1.10 to 4.11) of omphalitis

(Analysis 5.3; Analysis 5.4) compared with multiple applications.

There was no difference between single application and multiple

application groups for mild omphalitis (RR 1.14, 95% CI 0.97 to

1.34 (Analysis 5.2)).

Secondary outcomes


Compared with multiple applications, single application of

chlorhexidine increased the risk of bacterial colonization with

Staphylococcus aureus in one study (RR 3.63, 95% CI 2.74 to 4.82

(Analysis 5.5)) and Enterococcus coli (RR 1.17, 95% CI 1.03 to

1.32 (Analysis 5.7)). For bacterial colonization with streptococcus,

there was no difference between single and multiple application

of chlorhexidine groups in one study (RR 1.01, 95% CI 0.67 to

1.53 (Analysis 5.6)).

Hospital-based studies

Among studies conducted in hospitals settings, no study reported

data for mortality, sepsis, tetanus, omphalitis or bacterial coloniza-

tion.



Secondary outcomes


Four studies reported data for cord separation time. Among these

studies, three studied triple dye and reported a significant reduc-

tion with single application compared with multiple application

(MD -4.24 days, 95% CI -4.41 to -4.07, random-effects, T² =

0.00, I² = 0% (Analysis 6.1). One study evaluated zinc powder

and showed no difference in cord separation time for single appli-

cation compared with multiple application (MD -0.02 days, 95%

CI -0.31 to 0.27 (Analysis 6.1)).

Washing umbilical cord versus dry cord care

Community studies

One large cluster-randomized community trial (Mullany 2006)

evaluated washing the umbilical cord with soap and water com-

pared with dry cord care. No study reported data on the incidence

of sepsis or tetanus.

Primary outcomes

Mortality

There was no significant difference in all-cause mortality between

the group washing the umbilical cord with soap and water and

the dry cord care group (RR 1.00, 95% CI 0.76 to 1.32 (Analysis

7.1)).

Omphalitis

There was no differential effect of cord washing with soap/water

compared with dry cord care for the incidence of mild (RR 1.03,

95% CI 0.87 to 1.22 (Analysis 7.2)), moderate (RR 0.88, 95%

CI 0.69 to 1.12 (Analysis 7.3)) and severe omphalitis (RR 1.01,

95% CI 0.58 to 1.76 (Analysis 7.4)).

Secondary outcomes


Cord separation times were similar between the group washing the

umbilical cord with soap and water and the dry cord care group

(MD 0.01 day, 95% CI -0.05 to 0.07 (Analysis 7.5)).

Hospital-based studies

No study reported data for mortality, sepsis, tetanus, omphalitis

and cord separation time.

Secondary outcomes


One study (Rush 1986), was conducted in hospital settings and

reported no significant difference in colonization rates of Staphy-lococcus aureus between the cord washing and dry cord care groups

(RR 0.93, 95% CI 0.65 to 1.34 (Analysis 8.1)).

D I S C U S S I O N

Summary of main results

This review included 34 studies, involving 69,338 babies. Five

further studies are awaiting classification and there are two ongo-

ing community trials. Included studies were conducted in both

developed and developing countries. Among the 34 included tri-

als, three were large, cluster-randomized trials conducted in com-

munity settings in developing countries and 31 studies were con-

ducted in hospital settings mostly in developed countries. Data for

community and hospital studies were analyzed separately. There

were 22 different interventions studied across the included trials;

70% alcohol, triple dye and chlorhexidine were the most com-

monly studied antiseptics in included studies.

Studies conducted in community settings

Combined results of three large, community-based, cluster-ran-

domized trials showed that topical application of chlorhexidine to

umbilical cord stump reduced neonatal mortality and incidence

of omphalitis (Arifeen 2012; Mullany 2006; Soofi 2012). One

study carried out in community-based settings reported microbi-

ologic data and showed that topical application of chlorhexidine

reduces colonization of common pathologic bacteria, which corre-

lates with a reduction in mortality and omphalitis (Arifeen 2012).

There was no difference in mortality reduction with single ver-

sus multiple application of chlorhexidine to umbilical cord, how-

ever, multiple application seems advantageous for the reduction

of omphalitis and bacterial colonization compared with single ap-

plication.Topical application of chlorhexidine may increase cord

separation time by about 1.7 days based on the combined results

of two trials from community settings (Arifeen 2012; Mullany

2006). There was no beneficial effect of washing the umbilical



cord with soap and water compared with dry cord care for reduc-

tion of mortality, omphalitis and cord separation time (Mullany

2006). Results of one trial showed that there was no advantage of

the promotion of handwashing among caretakers for prevention

of omphalitis and mortality in community settings compared with

control (Soofi 2012).

Studies conducted in hospital settings

Studies conducted in hospital setting were small and had limita-

tions. No study reported data for mortality or tetanus. Triple dye

and alcohol were the most commonly studied antiseptics in hospi-

tal settings. When compared with dry cord care, no antiseptic was

convincingly advantageous to reduce the incidence of omphalitis.

Topical triple dye application reduced bacterial colonization with

Staphylococcus aureus compared with dry cord care and that of alco-

hol application (two separate analyses). There was no advantage of

application of alcohol and triple dye for reduction of colonization

with streptococcus. Topical alcohol application was advantageous

for the reduction of colonization with Enterococcus coli compared

with dry cord care and triple dye application (two separate anal-

yses). Topical application of alcohol and triple dye increased cord

separation time compared with dry cord care in hospital settings.

When triple dye was compared with alcohol, no significant dif-

ference was noticed in the incidence of omphalitis and cord sep-

aration time. Single application of triple dye was associated with

a decrease in cord separation time compared with multiple appli-

cation. Washing the cord was not advantageous compared with

dry cord care. The number of studies was insufficient to make an

inference about the efficacy of other antiseptics.

Overall completeness and applicability ofevidence

Studies conducted in community settings

Three large, well-conducted, cluster-randomized, community tri-

als reported data on the effectiveness of topical application of

chlorhexidine for prevention of mortality and omphalitis. The ag-

gregated sample size of these trials involved 78% of the 69,338

babies included in this review. Pooled results for all-cause mor-

tality showed a significant reduction of 23% in the intervention

group compared with control. The statistical heterogeneity for this

comparison was significant (I2 = 50%). The likely reasons for this

statistical heterogeneity could be the difference in mortality rates

in control populations of included studies and the diversity in

topical application of materials other than antiseptics such as ash,

surma (a lead-based preparation Soofi 2012), mud, mustard oil

and even cow dung. The mortality in the control group was 36.1/

1000 in Soofi 2012, 28.3/1000 in Arifeen 2012 and 19.3/1000 in

Mullany 2006. The reduction in the incidence of omphalitis was

also significant and was more prominent for severe cases. Data on

reduction of bacterial colonization reported by one trial (Arifeen

2012) correlated with the reduction in mortality and omphalitis.

Cord separation time may be slightly increased with application

of chlorhexidine, however, there was no increased risk of mortal-

ity or omphalitis as discussed by authors in the study by Mullany

2006.These findings suggest that there is significant evidence to

recommend topical application of chlorhexidine in community

settings for prevention of mortality and omphalitis.

Studies conducted in hospital settings

Most of the studies conducted in hospital settings were small and

had limitations. The sample size ranged between 71 and 2241.

There were no studies conducted in hospital settings that reported

mortality or tetanus. Compared with dry cord care, no antisep-

tic was advantageous to prevent omphalitis. The most commonly

studied antiseptics were alcohol and triple dye. Both of them re-

duced bacterial colonization but there are no data to show that

this decrease in bacterial colonization converts into prevention

of clinical outcomes of mortality, sepsis, tetanus or omphalitis.

Cord separation time may increase with application of alcohol and

triple dye. In summary, there is no convincing evidence to recom-

mend an antiseptic in hospital settings compared with dry cord

care. Most of the hospital-based studies were conducted in devel-

oped countries. The lack of protective effect of antiseptics may be

correlated with better hygiene at the time of birth and later care

of babies in newborn nurseries. It is also likely that most of the

hospital-based deliveries were planned and mothers were getting

regular prenatal care. The chances of getting therapeutic care for

perinatal infections are also greater with hospital-based deliveries.

It may thus be correlated that the overall risk of infection is low

in hospital-based deliveries in developed countries compared with

community-based deliveries in developing countries and thus the

apparent protective effect of chlorhexidine in community studies.

Quality of the evidence

Figure 1 summarizes the risk of bias in the studies. Most of the

studies included in this review had a moderate risk of bias. The

overall risk of bias is summarized in Figure 2.



Figure 2. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.

Studies conducted in community settings were large and were at

low risk of bias. Pooled data showed a moderate amount of statis-

tical heterogeneity that could be expected because of the baseline

difference in study settings, topical application of other substances

and baseline mortality.

Studies conducted in hospital settings were small and had out-

comes that did not have clinical significance. No study reported

data on mortality or tetanus.

Potential biases in the review process

This review used clearly specified inclusion and exclusion crite-

ria and a comprehensive search strategy for the identification of

relevant studies. The post-hoc decision to include studies on all

antiseptics for umbilical cord care is noted in Differences between

protocol and review. This decision was made to include all avail-

able evidence on umbilical cord care. Studies conducted in hospital

and community studies were analysed separately because the risk

factors for umbilical cord infection may differ between hospital

and community settings. The comprehensive search strategy was

devised to minimize publication bias by searching for both pub-

lished and unpublished studies. While studies with positive results

are more likely to be published than studies with negative results,

studies large enough to make a difference in this review are very

likely to be published. Pre-specified subgroup analyses for gesta-

tional age and geographic location were not performed because

there were insufficient studies to make a conclusive comparison.

The three community trials involved 10 individual study groups

that tested different frequencies and durations of chlorhexidine

application along with other interventions such as washing the

cord with soap and water (Mullany 2006) and promotion of hand-

washing among caretakers (Soofi 2012). There was no differential

effect of interventions other than topical chlorhexidine applica-

tion. In order to examine whether chlorhexidine has any protec-

tive effect, all the chlorhexidine groups were combined and com-

pared with non-chlorhexidine groups. This combination of study

groups is not expected to bias the results as the soap/water group

in Mullany 2006 had an effect size very similar to control, i.e. dry

cord care. Soofi 2012 was a factorial design trial and we included

the factorial analyses in which handwashing groups were balanced

between the two study groups (chlorhexidine + handwashing plus

chlorhexidine only versus handwashing only plus dry cord care).

Arifeen 2012 had two chlorhexidine groups, i.e. seven-day and

one-day application. These were combined to include chlorhexi-

dine groups in one arm and compared it with dry cord care.

Random-effects models were used for all meta-analyses. There are

no comprehensive rules on when to use random-effects or fixed-

effect models for meta-analysis (Higgins 2011). The difference

between two models is that a fixed-effect model assumes that ob-

served differences between results of trials is due to sampling vari-

ation of individual studies only whereas a random-effects model

assumes that outcomes of trials might differ both because of sam-

pling variation of individual studies and true diversity in effects.

Both models can be appropriately applied for pooling data but a

random-effects model is usually preferred with heterogeneity. We

used random-effects models because there was substantial hetero-

geneity across studies in study design, settings, and package of in-

terventions and/or intensity of delivery of those interventions.

Agreements and disagreements with otherstudies or reviews

The only comprehensive review on umbilical cord care was by Zu-

pan et al that was first published in 1998. The most updated ver-



sion (Zupan 2004) came to conclusion that there are not enough

data to recommend in favour of or against an antiseptic for um-

bilical cord care. Most of the included studies were small and con-

ducted in hospital settings. Results of our review are in agreement

with those of Zupan 2004 for studies conducted in hospital set-

tings with the addition of the effectiveness of chlorhexidine to

reduce mortality and morbidity in community settings. We have

not only included studies from community settings but have also

included more studies from hospital settings. The updated analy-

ses did not change the results for hospital-based studies.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

There is significant evidence to suggest that topical application of

chlorhexidine to umbilical cord reduces neonatal mortality and

omphalitis in community and primary care settings in developing

countries. It may increase cord separation time however there is no

evidence that it increases subsequent risk of mortality or infection.

There is not sufficient evidence to support the application of an

antiseptic to umbilical cord in hospital settings compared with dry

cord care in developed countries.

Implications for research

More studies are needed to explore the effects of antiseptics in

hospital settings with clinically important outcomes of mortality,

sepsis, tetanus and omphalitis. Studies should be undertaken in a

range of settings and should account for differences in outcomes

among different gestational ages.

Three community trials were conducted in South Asia. Further

trials should be conducted in other parts of the world to replicate

the results. Further evaluation of the effectiveness of chlorhexi-

dine should be performed in the context of interventions pack-

aged to facilitate their delivery by health systems. Such packages

may include a wide range of interventions to reduce perinatal and

neonatal mortality, such as clean delivery practices, breastfeeding,

mother/infant skin-to-skin care, and delayed bathing.

A C K N O W L E D G E M E N T S

We would like to acknowledge Professor Lourdes Amarillo and

Professor Cynthia Cordero for their statistical contributions.

We also thank Sara Roden-Scott for her translation of Davila 2007.

We would like to give special thanks to Sonja Henderson from

Pregnancy and Childbirth Cochrane Review Group for her con-

tinuous support and co-ordination during the conduct of this re-

view.

The National Institute for Health Research (NIHR) is the largest

single funder of the Cochrane Pregnancy and Childbirth Group.

The views and opinions expressed therein are those of the authors

and do not necessarily reflect those of the NIHR, NHS or the

Department of Health.

R E F E R E N C E S

References to studies included in this review

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KR, Jordan FR, et al.Umbilical cord care: effect of three

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Societies Annual Meeting; 2007 May 5-8; Toronto, Canada.

2007.

References to studies excluded from this review

Alda 2000 {published data only}

Alda ER, Covas MC, Ventura SS, Baeza AM. Umbilical

cord bacterial growth in healthy newborn with two different

antiseptics. Pediatric Research 2000;47:385A.

Aldar 1980 {published data only}

Alder VG, Burman D, Simpson RA, Fysh J, Gillespie

WA. Comparison of hexachlorophane and chlorhexidine

powders in prevention of neonatal infection. Archives of

Disease in Childhood 1980;55:277–80.

Barclay 1994 {published data only}

Barclay L, Harrington A, Conroy R, Royal R, LaForgia J. A

comparative study of neonates’ umbilical cord management.

Australian Journal of Advanced Nursing 1994;11:34–40.

Bhakoo 1969 {published data only}

Bhakoo ON, Lall JC, Agarwal KC. Prevention of hospital

infections in neonates: an evaluation of no bath regimen.

Indian Pediatrics 1969;6:697–700.

Birenbaum 1990 {published data only}

Birenbaum HJ, Glorioso L, Rosenberger C, Arshad C,

Edwards K. Gowning on a postpartum ward fails to decrease

colonization in the newborn infant. American Journal of

Diseases of Children 1990;144:1031–3.



Bourke 1989 {published data only}

Bourke E. Cord care: too much or too little. Australian

Journal of Advanced Nursing 1990;7(2):19–22.

Bradshaw 1993 {published data only}

Bradshaw C. An experimental study to compare treatment vs

non treatment of the umbilical cord. National Conference

on Research in Midwifery; 1993 Sept 14; Birmingham, UK.

1993.

Chamnanvanakij 2005 {published data only}

Chamnanvanakij S, Decharachakul K, Rasamimaree P,

Vanprapar N. A randomised study of 3 umbilical cord care

regimens at home in Thai neonates: comparison of time to

umbilical cord separation, parental satisfaction and bacterial

colonization. Journal of the Medical Association of Thailand

2005;88(7):967–72.

Coyer 1975 {published data only}

Coyer WF. Neonatal skin care and the prevention of

staphylococcus aureus (staph) colonization. Pediatric

Research 1975;9:339.

Darmstadt 2007 {published data only}

Darmstadt GL, Hossain MM, Choi Y, Shirin M, Mullany

LC, Islam M, et al.Safety and effect of chlorhexidine skin

cleansing on skin flora of neonates in Bangladesh. Pediatric

Infectious Disease Journal 2007;26(6):492–5.

Erenel 2010 {published data only}

Erenel AS, Vural G, Efe SY, Ozkan S, Ozgen S, Erenoglu R.

Comparison of olive oil and dry-clean keeping methods in

umbilical cord care as microbiological. Maternal & Child

Health Journal 2010;14(6):999–1004.

Gezon 1964 {published data only}

Gezon HM, Thompson DJ, Rogers KD, Hatch TF, Taylor

PM. Hexachlorophene bathing in early infancy. New

England Journal of Medicine 1964;270(8):379–6.

Gluck 1963 {published data only}

Gluck L, Wood HF. Staphylococcal colonization in

newborn infants with and without antiseptic skin care. A

consideration of epidemiologic routes. New England Journal

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Guala 2003 {published data only}

Guala A, Pastore G, Garipoli V, Agosti M, Vitali M, Bona

G. The time of umbilical cord separation in healthy full-

term newborns: a controlled clinical trial of different cord

care practices. European Journal of Pediatrics 2003;162(5):

350–1.

Guinsburg 1991 {published data only}

Guinsburg R, Ikezawa MK, Fogliano RRF, Reichert

MCF, Carvalho ES, Cardo DM, et al.Umbilical bacterial

colonization (UBC) of normal newborn (NB) infants:

effect of four antiseptic regimens. Pediatric Research 1991;

29:282A.

Healey 1991 {published data only}

Healey E, Greenish K, Armstrong C, Ayers S. A study of the

relationship between the delivery to cord clamping interval

and the time of cord separation. Midwifery 1991;7:167–76.

Henningsson 1981 {published data only}

Henningsson A, Nystrom B, Tunnell R. Bathing or washing

babies after birth?. Lancet 1981;2:1401–3.

Hnatko 1977 {published data only}

Hnatko SI. Alternatives to hexachlorophene bathing of

newborn infants. Canadian Medical Association Journal

1977;117:223–6.

Hodgins 2010 {published data only}

Hodgins S, Thapa K, Khanal L, Aryal S, Suvedi BK, Baidya

U, et al.Chlorhexidine gel versus aqueous for preventive

use on umbilical stump: a randomized noninferiority trial.

Pediatric Infectious Disease Journal 2010;29(11):999–1003.

Jellard 1957 {published data only}

Jellard J. Umbilical cord as reservoir of infection in a

maternity hospital. BMJ 1977;1(5024):925–8.

Kumar 2008 {published data only}

Kumar V, Mohanty S, Kumar A, Misra RP, Santosham

M, Awasthi S, et al.Effect of community-based behaviour

change management on neonatal mortality in Shivgarh,

Uttar Pradesh, India: a cluster-randomised controlled trial.

Lancet 2008;372(9644):1151–62.

Kwong 1973 {published data only}

Kwong MS, Loew AD, Anthony BF, Oh W. The effect of

hexachlorophene on staphylococcal colonization rates in

the newborn infant: a controlled study using a single-bath

method. Journal of Pediatrics 1973;82:982–6.

Olowe 1980 {published data only}

Olowe SA, Ransome-Kuti O. The risk of jaundice in

glucose-6-phosphate dehydrogenase deficient babies

exposed to menthol. Acta Paediatrica Scandinavica 1980;

69:341–5.

Pildes 1973 {published data only}

Pildes RS, Ramamurthy RS, Vidyasagar D. Effect of triple

dye on staphylococcal colonization in the newborn infant.

Journal of Pediatrics 1973;82:987–90.

Pyati 1977 {published data only}

Pyati SP, Ramamurthy RS, Krauss MT, Pildes RS.

Absorption of iodine in the neonate following topical use of

povidone iodine. Journal of Pediatrics 1977;91(5):825–8.

Ronchera-Oms 1994 {published data only}

Ronchera-Oms C, Hernandez C, Jimenez NV. Antiseptic

cord care reduces bacterial colonisation but delays cord

detachment. Archives of Disease in Childhood. Fetal and

Neonatal Edition 1994;70:F70.

Saleem 2007 {published data only}

Saleem S, Reza T, McClure EM, Pasha O, Moss N, Rouse

DJ, et al.Chlorhexidine vaginal and neonatal wipes in home

births in Pakistan: a randomized controlled trial. Obstetrics

and Gynecology 2007;110(5):977–85.

Saleem 2010 {published data only}

Saleem S, Rouse DJ, McClure EM, Zaidi A, Reza T, Yahya

Y, et al.Chlorhexidine vaginal and infant wipes to reduce

perinatal mortality and morbidity: a randomized controlled

trial. Obstetrics and Gynecology 2010;115(6):1225–32.



Shah 2010 {published data only}

Shah R, Munos MK, Winch PJ, Mullany LC, Mannan

I, Rahman SM, et al.Community-based health workers

achieve high coverage in neonatal intervention trials: a case

study from Sylhet, Bangladesh. Journal of Health, Population

& Nutrition 2010;28(6):610–8.

Smales 1988 {published data only}

Smales O. A comparison of umbilical cord treatment in

the control of superficial infection. New Zealand Medical

Journal 1988;101:453–5.

Tielsch 2006 {published data only}

Tielsch JM. Community trial of newborn skin and

umbilical cord cleansing on neonatal mortality in Nepal.

ClinicalTrials.gov (http://clinicaltrials.gov/) (accessed 2006)

2006.

Tielsch 2007 {published data only}

Tielsch JM, Darmstadt GL, Mullany LC, Khatry SK, Katz

J, LeClerq SC, et al.Impact of newborn skin-cleansing with

chlorhexidine on neonatal mortality in Southern Nepal:

a community-based, cluster-randomized trial. Pediatrics

2007;119(2):e330–e340.

Wade 2006 {published data only}

Wade A, Osrin D, Shrestha BP, Sen A, Morrison J,

Tumbahangphe KM, et al.Behaviour change in perinatal

care practices among rural women exposed to a women’s

group intervention in Nepal. BMC Pregnancy and

Childbirth 2006;6:20.

Wald 1977 {published data only}

Wald ER, Snyder MJ, Gutberlet RL. Group B beta-

hemolytic streptococcal colonization. Acquisition,

persistence, and effect of umbilical cord treatment with

triple dye. American Journal of Diseases of Children 1977;

131:178–80.

Watkinson 1992 {published data only}

Watkinson M, Dyas A. Staphylococcus aureus still colonizes

the untreated neonatal umbilicus. Journal of Hospital

Infection 1992;21:131–6.

Wojciechowska 1989 {published data only}

Wojciechowska L. Trial to assess the effects of different

treatments of the umbilical cord in newborn infants.

Personal communication 1989.

References to studies awaiting assessment

Covas 2011 {published data only}

Covas MC, Alda ER, Medina MS, Ventura S, Esandi ME,

Pezutti O, et al.Alcohol versus bath and natural drying

for term newborns’ umbilical cord care: a prospective

randomized clinical trial. Pediatric Academic Societies

Annual Meeting; 2010 May 1-4; Vancouver, Canada. 2010.∗ Covas Mdel C, Alda E, Medina MS, Ventura S, Pezutti

O, Paris de Baeza A, et al.Alcohol versus bath and

natural drying for term newborns’ umbilical cord care: A

prospective randomized clinical trial [Spanish]. Archivos

Argentinos de Pediatria 2011;109(4):305–13.

Nasrallah 2003 {published data only}

Nasrallah BK, Rox AK, Mazer B, Richards L, Chuachingco

J, Naqvi M. Comparison of two methods of umbilical cord

care: application of 70% isopropyl alcohol vs. natural

drying. Pediatric Academic Societies Annual Meeting; 2003

May 1-4; Seattle Washington, USA. 2003.

Sellares Casas 2002 {published data only}

Sellares Casas E, Yanez Juan A, Lopez de Aguileta Ibisate A,

Peix Sambola MA, Esteva Nuto N, Domenech Terricabras

P. Efficacy of one versus three applications of merbromin in

achieving umbilical cord detachment [Spanish] [Efficacia

de una aplicacion frente a tres de merbromina en el tiempo

de caida del cordon]. Acta Pediatrica Espanola 2002;60(9):

521–5.

Srinivasan 2003 {published data only}

Srinivasan H, Luayon M, Barrios F, Geraldo V, Poladian A,

Reyes J, et al.Prospective randomized controlled trial to

study the effect of daily application of triple dye to umbilical

cord of very low birth weight (VLBW) infants. Pediatric

Academic Societies Annual Meeting; 2003 May 1-4; Seattle,

Washington. 2003.

Taffazoli 2008 {published data only}

Taffazoli M, Farahani LA, Mohammadzadeh A, Esmaeeli H,

Ghazvini K. Does topical application of breast milk affect

on bacterial colonization in umbilical cord?. Koomesh 2008;

10(1):29–35.

References to ongoing studies

Hamer 2010 {published data only}∗ Hamer DH. Zambia Chlorhexidine Application Trial

(ZamCAT). Clinicaltrials.gov (http://clinicaltrials.gov)

(accessed 2010) 2010.

Herlihy JM, Semrau K, Mazimba A, Yeboah-Antwi K,

Grogan C, Banda B, et al.Chlorhexidine 4% umbilical

wash lengthens time to cord separation. Pediatric Academic

Societies Annual Meeting 2012 April 29-May 1; Boston,

USA. 2012.

Sazawal 2012 {published data only}

Sazawal S. Chlorhexidine cordcare for reduction in neonatal

mortality and omphalitis (CHX-Pemba). ClinicalTrials.gov

2012.

Additional references

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Agrawal 2012

Agrawal PK, Agrawal S, Mullany LC, Darmstadt GL,

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Zupan 2004

Zupan J, Garner P, Omari AAA. Topical umbilical cord care

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Ahmadpour-Kacho 2006

Methods Randomized, non-blinded, conducted in hospital settings.

Participants Infants 36-42 weeks, appropriate for gestational age, no disease/congenital anomalies,

mother without significant complication (N = 312)

Interventions (1) Dry care (n = 78).

(2) Breastmilk (n = 79).

(3) 95% ethyl alcohol (n = 78).

(4) Silver sulphadiazine (n = 77).

Outcomes Time to cord separation.

Notes Preterm and term.

Non-low birthweight.

Hospital setting.

Eastern Mediterranean (Iran).

All fed with own mother’s milk.

All roomed in.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Method not mentioned.

Allocation concealment (selection bias) Unclear risk Method not mentioned.

Blinding (performance bias and detection

bias)

All outcomes

High risk Not feasible.

Incomplete outcome data (attrition bias)

All outcomes

High risk No ITT analysis. Outcome of 61 (19.6%)

neonates (16 in dry care, 15 in breastmilk,

15 in alcohol, 15 in silver sulphadiazine)

were excluded because of concurrent use of

2 topical agents for cord care, the need for

admission in the neonatal ward for treat-

ment with antibiotics and for not reporting

time/date of cord separation

Selective reporting (reporting bias) Low risk Outcomes were reported as mentioned in

the method’s section.



Ahmadpour-Kacho 2006 (Continued)

Other bias High risk Baseline characteristics showed more ce-

sarean deliveries in the dry care, alcohol and

silver groups compared with the breastmilk

group

Al-Binali 2006

Methods Randomized study conducted in Saudi Arbia in hospital setting

Participants Healthy newborn admitted to nursery. Total sample size was 76 in which there were 38

babies in the alcohol group and 38 in Beniktol spray group

Interventions 1) 70% alcohol.

2) Beniktol spray (Nebacetin with Neomycin sulphate and Bacitracin)

Outcomes Cord separation time, omphalitis.

Notes No particular definition was used for omphalitis. Gestational ages of the newborns were

not mentioned in the study

Risk of bias



bias)

High risk Comment, “Sequence generation was

based on month of delivery”



bias)

All outcomes



All outcomes

High risk Attrition and exclusion were not described.

Selective reporting (reporting bias) Unclear risk Insufficent information to make an assess-

ment.

Other bias High risk Baseline characteristics were not compared

at the baseline.



Arad 1981

Methods Randomized but method not mentioned, conducted in hospital settings at Jerusalem

Participants Healthy, appropriate-for-gestational age, term infants admitted to nursery. Total sample

size 121

Interventions Initial bath.

Daily application during hospital stay.

1. Triple dye (n = 36).

2. Neomycin ointment (n = 26).

3. Sulphadiazine ointment (n = 25).

4. Bismuth powder (n = 34).

Daily alcohol applied at home.

Outcomes Cord separation time, sepsis.

Notes No control group with dry cord care.

Risk of bias



bias)

Unclear risk “..... were each randomly assigned to one

of four treatment regimens.”

Comment: Probably not done.

Allocation concealment (selection bias) Unclear risk Not mentioned.


bias)

All outcomes

Unclear risk Not mentioned.


All outcomes

High risk No account of attrition or exclusion was

given in the text or tables

Selective reporting (reporting bias) Unclear risk Insufficent information to permit a judge-

ment.

Other bias High risk Bacteriological data were not obtained.

Arifeen 2012

Methods Cluster-randomized trial conducted in community settings in Bangladesh

Participants Neonates whose parents were enrolled in study.

Babies whose parents were not enrolled in parent trial and who were first visited after 48

hours of life, were excluded. Total sample size 29, 760



Arifeen 2012 (Continued)

Interventions 1. Dry care (n = 10,008).

2. 4.0% chlorhexidine single application (n = 9423).

3.4.0% chlorhexidine multiple application (n = 10329).

Outcomes Omphalitis and all-cause mortality.

Notes Single and multiple application CHX groups were combined for the analysis mortality

and omphalitis analysis

Risk of bias



bias)

Low risk Quote: “A random allocation sequence for

each stratum was done using a computer-

generated procedure”

Allocation concealment (selection bias) Low risk Comment: As this was a cluster-random-

ized trial allocation concealment is not an

issue


bias)

All outcomes

High risk This study was not blinded.


All outcomes

Low risk Attrition and exclusion was adequately ad-

dressed.

Selective reporting (reporting bias) Low risk Study protocol was available to make an

assessment and authors reported the out-

comes mentioned in the protocol

Other bias High risk There was no effect of multiple cleansing

with CHX on neonatal mortality. This may

be due to the fact that the study was not

powered enough to detect a significant dif-

ference in this arm, as pointed out by au-

thors

Bain 1994

Methods Randomized but method not mentioned, non-blinded, non-ITT, conducted in hospital

settings

Participants Newborn with weight > 1 kg, gestational age < 37 weeks, no umbilical lines, no abdominal

surgery (N = 102)



Bain 1994 (Continued)

Interventions (1) Dry care (no treatment; “cleaning only with water when necessary”) (n = 28)

(2) 0.33% Hexachlorophene + 3% zinc oxide powder (Sterzac) (n = 24)

(3) 70% isopropyl alcohol (Steret) (n = 24).

(4) 70% isopropyl alcohol (Steret) + 0.33% hexachlorophene + 3% zinc oxide powder

(Sterzac) (n = 26)


Notes Preterm only.

Low birthweight.

Hospital setting.

Europe (Scotland).

None roomed in.

Group 2 and 4 was excluded from the analysis as it included hexachlorophene, which is

neurotoxic

Risk of bias



bias)

Unclear risk “Randomization method.”



bias)

All outcomes



All outcomes

High risk No ITT analysis. 18 babies (17.6%) were

subsequently excluded due to the insertion

of umbilical lines or transferred back to

their mothers before completion of trial

Selective reporting (reporting bias) Low risk This study seems to report the outcomes

mentioned in the methods section

Other bias High risk Higher rate of rupture of membranes > 24

hours in dry care.

Barrett 1979

Methods Randomized study conducted in USA.

Participants Infants were assigned to the normal newborn nursery, received routine general care. Total

sample size was 300

Infants who received antibiotics or developed complications precluding their assignment

to the normal newborn nursery, or who were subsequently transferred from this nursery,



Barrett 1979 (Continued)

were excluded

Interventions 1. Silver sulphadiazine, single application (n = 100).

2. Triple dye, single application (n = 100).

3. Dry cord care (n = 100).

Outcomes Colonization of periumbilical area and anterior nares at 48 hours

Notes Cultures of the periumbilical area and the anterior nares were obtained at 48 hours of

age

Gestational ages of newborns were not described in the study

Risk of bias



bias)

Low risk “Cord-care regimens were assigned by a com-

puter-generated table of random numbers.”

Allocation concealment (selection bias) Unclear risk Insufficent information to permit a judge-

ment.


bias)

All outcomes

Low risk “Laboratory personnel were not aware of the

cord-care regimen the subjects had received.”


All outcomes

Low risk A complete account of attrition and exclusion

was given in the result’s section

Selective reporting (reporting bias) Low risk The study reported the outcomes mentioned

in the methods section

Other bias Low risk No other form of bias was found.

Davila 2007

Methods Randomized but method not mentioned (unclear), non-blinded, non-ITT, conducted

in hospital settings

Participants Healthy newborns, birthweight > 2000 g and < 4000 g, gestational age 34-41 weeks,

Apgar > or equal to 7, vaginal or abdominal delivery (N = 162)

Interventions (1) 70% alcohol (n = 57).

(2) 5% povidone iodine (n = 55).

(3) 4% chlorhexidine (n = 50).

Outcomes Time to cord separation, bacterial colonization.



Davila 2007 (Continued)

Notes Preterm and term.

Low birthweight and non-low birthweight.

Latin Americas (Peru).

Paper in Spanish.

Unable to include data on time to cord separation as no SDs were reported

Risk of bias



bias)




bias)

All outcomes

High risk Method not mentioned, blinding not fea-

sible.


All outcomes

High risk No ITT analysis. Some mothers refused for

samples to be taken because they were dis-

charged outside of hospital hours


ment.

Other bias Unclear risk No table of baseline characteristics.

Dore 1998

Methods Randomized, non-blinded, non-ITT, conducted in hospital settings

Participants Admitted at postpartum unit, > or equal to 36 weeks’ gestation, not receiving antibiotics,

fewer than 8 hours of age at randomizations, spent no time in NICU, mother spoke and

read English, mother had telephone, mother planned to keep newborn (N = 1811)

Interventions (1) Dry care; “natural drying” (n = 909).

(2) 70% isopropyl alcohol (n = 902).

Outcomes Omphalitis; time to cord separation.

Notes Term.


Hospital setting.

Americas (Canada).

Sponge bath 52.9% vs 52.8%, tub bath 44% vs 44%.

Intention to breastfeed 87% vs 86.4%.

All roomed in (“admitted to postpartum unit”).



Dore 1998 (Continued)

Risk of bias



bias)

Low risk Table of random numbers.

Allocation concealment (selection bias) Low risk Opaque envelopes.


bias)

All outcomes

High risk “A coloured dot for the newborn’s

bassinette indicates group assignment.”


All outcomes

High risk No ITT analysis. 65 newborns (3.6%) did

not complete the study (27 were admit-

ted to the NICU, 25 families could not be

reached for telephone interview, 7 families

changed their mind, 6 gave mixed reason

for not participating)

Selective reporting (reporting bias) Low risk Study reported all the outcomes mentioned

in the methods section

Other bias Low risk Baseline characteristics comparable.

Evens 2004


Participants Infants < 34 weeks, no umbilical vessel catheterization, no umbilical cord anomalies (N

= 103)

Interventions (1) Dry care, “natural drying” (n = 50).

(2) 70% isopropyl alcohol (n = 53).

Outcomes Omphalitis; cord separation time; bacterial colonization.

Notes Preterm.

Low birthweight.

Hospital setting.

Americas (USA).

Initial bath at > 12 hours of life.

None roomed in.

Risk of bias




Evens 2004 (Continued)


bias)

Unclear risk Insufficent information to make an assess-

ment.

Allocation concealment (selection bias) Unclear risk Insufficent information to make an assess-

ment.


bias)

All outcomes



All outcomes

High risk No ITT analysis. 7 infants (6.4%) were ex-

cluded from the final analyses because of

incomplete data due to transfer or need

for umbilical vessel catheterization. (It was

mentioned from which group were the ex-

cluded.)


ment.

Other bias High risk Higher rate of cesarean delivery in alcohol

group (83% vs 69%)

Gladstone 1988

Methods Randomized study conducted in hospital settings in USA.

Participants Inborn healthy term infants > 2500 g. A total of 249 participants were included (53, 48,

44, 42, 14, and 48 in each group)

Interventions 6 study groups

1. Triple dye once daily until separation.

2. Triple dye once then alcohol until separation.

3. Triple dye once only.

4. Povidone iodine daily until separation.

5. Silver sulphadiazine daily until separation.

6. Bacitracin ointment until cord separation.

Outcomes Colonization at discharge from hospital.

Separation time.

Maternal satisfaction.

Local or other infections.

Nursing staff satisfaction.

Notes Infants were excluded from the study for any of the following reasons: birthweight less

than 2500 g, gestational age less than 37 weeks, refusal to give consent, non-routine

treatments such as phototherapy or systemic antibiotics, or follow-up care planned at a

different medical facility



Gladstone 1988 (Continued)

Risk of bias



bias)

Low risk Quote: “by use of a table of random num-

bers”.


ment.


bias)

All outcomes

Unclear risk Insufficent information to make an assess-

ment.


All outcomes

Low risk Attrition and excluded participants were

adequately described in the result’s section


ment.


Golombek 2002

Methods Randomized trial conducted in hospital settings in USA.

Participants Infants admitted to the well-baby nursery. A total of 634 infants were enrolled and 599

completed the study

Interventions 1. Alcohol (n = 292).


Outcomes Cord infection.

Cord separation.

Nursing staff satisfaction.

Notes Data for cord separation time were not included as means and SDs were not given

Risk of bias



bias)

High risk Comment: Triple dye was applied to in-

fants admitted to newborn nursery during

month of January and March while alcohol

was applied during months of December

and February



Golombek 2002 (Continued)

Allocation concealment (selection bias) High risk Comment: Methods of randomizations

were not adequate and no effort was made

to conceal the allocation


bias)

All outcomes

High risk Comment: Intervention was known to

house staff, parents and assessors


All outcomes

Low risk Attrition and exclusion was adequately de-

scribed in the result’s section


ment.

Other bias High risk Data on incidence of omphalitis were gath-

ered by telephone calls. No home visits were

made to make an assessment

Hsu 1999

Methods A randomized study conducted in hospital settings in Taiwan.

Participants Healthy term newborn, 101 in experimental group and 79 in control group

Interventions 1. Triple dye, single application.

2. Triple dye, daily application.

Single application group was later treated with 70% alcohol until discharge from hospital

while the second group was continued to be treated with triple dye

Outcomes Cord separation time.

Omphalitis.

Notes Daily whole body wash with soap for both the groups.

Risk of bias



bias)

Unclear risk Randomization methods were not de-

scribed.

Allocation concealment (selection bias) Unclear risk Randomization methods were not de-

scribed.


bias)

All outcomes

Unclear risk No information was provided about blind-

ing.



Hsu 1999 (Continued)


All outcomes

Low risk Exclusion and attrition was described.


ment.

Other bias Unclear risk Single application group was treated with

another antiseptic(i.e. 70% alcohol) that

may interfere with cord separation time

Hsu 2010

Methods Randomized trial.

Participants Newborn delivered at Tri-Service Heneral Hospital, Taiwan. Total sample size 142

Interventions 1) Dry cord care (n = 71).

2) 95% isopropyl alcohol (n = 71).

Outcomes Cord separation time

Notes Following newborns were excluded:

1) low birthweight < 2500 g;

2) gestational age < 36 weeks;

3) those receiving phototherapy;

4) being treated with systemic antibiotics;

5) those with umbilical catheters;

6) diagnosed with any disease before discharge;

7) who transgressed study protocols;

8) or were lost to follow-up.

Risk of bias



bias)

Unclear risk “They were then randomly assigned to one of two groups for

cord management”. No more details were provided for sequence

generation

Allocation concealment (selection bias) Unclear risk Insufficent information to make an assessment.


bias)

All outcomes

Unclear risk Insufficent information to make an assessment.


All outcomes

Unclear risk Reason for exclusion and attrition were given.



Hsu 2010 (Continued)

Selective reporting (reporting bias) Low risk Study reported all the outcomes mentioned in the methods sec-

tion

Other bias Unclear risk None noticed.

Huang 2001

Methods “Randomly assigned” but method not mentioned (unclear), open label, non-ITT, con-

ducted in hospital settings

Participants Healthy term newborns (N = 150).


(2) 95% alcohol (n = 75).

Outcomes Omphalitis and umbilical cord separation time.

Notes Term.


Hospital setting.

Western Pacific (Taiwan).

Daily bath with ordinary soap.

None roomed in.

Only abstract available for evaluation.

No data were included as the means and SDs were not given.

Risk of bias



bias)




bias)

All outcomes

High risk Not mentioned; not feasible.


All outcomes

High risk No ITT. 8 neonates (5.3%) were excluded:

dry care (3 protocol breach and 1 lost to

follow-up) and alcohol (4 lost to follow-up)


ment.

Other bias Low risk Comparable baseline characteristics.



Janssen 2003

Methods Randomized, non-blinded, ITT conducted in hospital settings.

Participants Hospital born, no antibiotics since birth, Vancouver address, fluent in English, Can-

tonese or Mandarin, not admitted to level III nursery (N = 766)


(2) Triple dye on day of birth then alcohol until cord separation (n = 384)

Outcomes Omphalitis; bacterial colonization.

Notes No mention of gestational age or birthweight.

Hospital setting with community follow-up.

Americas (Canada).

Daily bath with mild soap.

Breastfeeding at discharge 95% vs 95.6%.

Exclusive breastfeeding at home visit 69.9% vs 72.4%.

Mixed feeding at home visit 24.9% vs 24.2%.

“Omphalitis was defined as erythema (redness, swelling and/or warmth) of the abdominal

skin in the periumbilical region, extending beyond 5mm from the umbilicus.”

Risk of bias



bias)

Low risk Randomization was stratified on the clin-

ical area; consecutively numbered opaque

envelopes

Allocation concealment (selection bias) Low risk Sealed opaque envelopes.


bias)

All outcomes



All outcomes

Low risk ITT analysis.


ment.




Kapellen 2009


Participants Healthy newborn within the 1st 36 hours of life, 37-42 weeks’ gestation, birthweight >

2500 g, with consent (N = 669)


(2) Chlorhexidine powder (n = 337).

Outcomes Omphalitis, time to cord separation.

Notes Term.


Hospital setting.

Europe (Germany).

Admitted to nursery then roomed in.

Omphalitis was defined the classification of (Mason 1989).

Risk of bias



bias)

Low risk Randomized by sealed envelope, random-

izations was stratified in neonates delivered

normally or by caesarean section because

of the expected differences in time to cord

detachment

Allocation concealment (selection bias) Low risk Sealed envelope.


bias)

All outcomes



All outcomes

High risk No ITT analysis. 669 neonates were en-

rolled but cord separation time was only

documented in 578 neonates (13.6% miss-

ing); no mention of breakdown of dropouts


ment.

Other bias Low risk “Neonates randomized to either group did

not differ in sex, ethnicity, birthweight or

length, gestational age, mode of delivery or

Apgar score.” (No table of baseline charac-

teristics.)



Meberg 1985

Methods Hospital-based randomized study conducted in Norway.

Participants Healthy term newborn admitted to nursery. A total of 547 infants were included

Interventions 1. Benzine daily (n = 113).

2. Chlorhexidine (0.05%) daily (n = 217).

3. Total body wash with soap (n = 217).

Outcomes Colonization of stump at discharge.

Infection (umbilical and severe) within 6 weeks.

Notes Phase 1: 1982; Phase 2: 1983.

Roomed in with mothers.

Data were give for all kind of infection (pemphigus, conjunctivitis, paronychia, and

umbilical infection) and no separate data were available for omphalitis (cord infection)

Risk of bias



bias)

High risk Quote: “infants were consecutively and

randomly selected to 1 of the following

groups”. There was no description of exact

methods of sequence generation


ment.


bias)

All outcomes

Unclear risk Insufficent information to permit a judge-

ment.


All outcomes

Low risk Attrition and exclusion were adequately de-

scribed in result’s section


ment.

Other bias High risk No description of baseline characteristics of

study participants was given

Meberg 1990

Methods Prospective randomized study conducted in hospital setting in Norway

Participants Healthy term infants admitted to newborn nursery. A total of 2441 infants were registered



Meberg 1990 (Continued)

Interventions 1. Hydrophobic gauze material bandage, applied daily (n = 1213).

2. Chlorhexidine in alcohol, applied daily (n = 1228).

Outcomes Infections of skin, cord, eyes during stay and at 6 weeks.

Cord separation time.

Notes Methods of statistical analyses were not described in adequate details

Risk of bias



bias)

Low risk Quote: “Births were consecutively num-

bered, and infants with even and uneven

numbers enlisted into the two groups re-

spectively.”


ment.


bias)

All outcomes

Unclear risk Insufficent information to permit a judge-

ment.


All outcomes


scribed in results section

Selective reporting (reporting bias) Unclear risk Insufficent information to permit a judge-

ment.

Other bias High risk No description of baseline characteristics of

study participants were given

Medves 1997

Methods Randomized, non-blinded, ITT, conducted in hospital settings

Participants Term infants (except 1 born 36 weeks and 5 days), born at a tertiary care hospital in

Western Canada (N = 148)

Interventions (1) Alcohol (n = 74).

(2) Sterile water (n = 74).

Outcomes Bacterial colonization; time to cord separation.

Notes Preterm (1 participant), term.

No mention of birthweight.

Hospital setting.



Medves 1997 (Continued)

Americas (Canada).

Initial bath with chlorhexidine gluconate 2% within first 6 hours of life

Risk of bias



bias)

Low risk Blocked randomizations.



bias)

All outcomes

Low risk Only outcome assessors were blinded.


All outcomes

Low risk ITT analysis for bacterial colonization. “In-

fants remained in the treatment group to

which they were assigned, even if the par-

ents did not follow the treatment”

Selective reporting (reporting bias) Low risk Study reported the outcomes mentioned in

the method’s section

Other bias Unclear risk No table of baseline characteristics.

Mugford 1986

Methods Randomized, blinded, non-ITT, conducted in hospital settings

Participants Babies born in the labour ward, normal postnatal care, singleton, mother resident of

West Berkshire District. (N = 815)

Interventions It was a factorial design trial that compared different forms of antiseptics, cleansing

method and frequency of application. The trial studied powders (zinc and baby talcum

powder = 203, Sterzac = 204, Cordocel = 202, no powder = 203), Cleansing method

(water = 272, spirit = 271, and no routine cleansing = 272) and frequency of application

(daily = 407 and once only = 408)


Notes Hospital setting.

Europe (England).

All rooming in (“admitted to postnatal ward”).

There was no mention of gestational age or birthweight of the babies

Data for group 5 and 6 were excluded.

Risk of bias



Mugford 1986 (Continued)



bias)

Unclear risk “Randomized”. Method not mentioned.

Allocation concealment (selection bias) Low risk Sealed envelope. Use of “blind” packaging

so that it was not possible to guess the al-

location before entry of a baby to the trial


bias)

All outcomes



All outcomes

High risk No ITT analysis.


the method’s section

Other bias Low risk “Groups are comparable in respect in dis-

tributions of sex, birthweight and mode of

delivery.” Cannot extrapolate data from in-

cluded table of results

Mullany 2006

Methods Cluster-randomized, double-blind (for chlorhexidine and soap and water), study con-

ducted in community settings

Participants All infants born after November 17, 2002, in 413 actively monitored enters in Southern

Nepal, with consent, alive at first visit, first visit within first 10 days of life


(2) 4% chlorhexidine (n = 4924).

(3) Soap and water (n = 5107).

Outcomes Time to cord separation; neonatal mortality and omphalitis.

Notes No mention of gestational age.

Low birthweight and non-low birthweight.

Community-based.

South-East Asia (Nepal).

Initial cleansing full body wipe with 0.25% chlorhexidine or placebo

No breastfeeding < 1% all groups.

Breastfeeding initiated at < 11.9 hours 46% vs 52% vs 47%.

Facility birth 8% vs 8% vs 9%.

Data on omphalitis have been taken from table 3 for the category of “moderate or sever

redness”



Mullany 2006 (Continued)

Risk of bias



bias)

Low risk Computer-generated random sequence.



bias)

All outcomes

Low risk “Investigators, field workers, and partic-

ipants were masked with respect to the

chlorhexidine and soap/water treatment

groups”. Not blinded to dry care


All outcomes

Low risk No ITT analysis. A total of 15,113 infants

were enrolled in the trial but analyses were

restricted to 14,887 (98.4%) of those in-

fants, for whom specific information on

time to cord separation was collected (1.

5% missing)

Selective reporting (reporting bias) Low risk This study appears to be free of selective re-

porting. Outcomes are described in 2 dif-

ferent papers

Other bias Low risk Comparable baseline characteristics.

Nourian 2009

Methods A quasi-randomized study conducted in Iran.

Participants Healthy term Newborn, 36 in group 1 and 41 in group 2.

Interventions 1) Dry cord care.

2) 70 alcohol.

Outcomes Omphalitis.

Bacterial colonization.


Notes Hospital-based study

Newborns with gestational age < 37 weeks, birthweight < 2500 g, Apgar score < 8 and

the twins were excluded and so were infants receiving antibiotics or developing any

complications requiring hospitalization

SDs for mean cord separation time were not given in the study. They were derived from

other studies with similar settings and sample size

Omphalitis data were taken from table 2. Redness, exudates, foul odor, tenderness and



Nourian 2009 (Continued)

inflammation were taken as signs of omphalitis

Risk of bias



bias)

High risk A quasi-randomized study.

Allocation concealment (selection bias) High risk A quasi-randomized study.


bias)

All outcomes

Unclear risk Blinding methods were not described in the

study.


All outcomes

Low risk Attrition was described in the results sec-

tion.

Selective reporting (reporting bias) Low risk Study reports all the outcomes mentioned

in the method’s section

Other bias Low risk None noticed.

Oishi 2004

Methods Randomized, double-blind, no ITT, conducted in hospital settings

Participants Neonates born at National Tokyo Medical Centre from March to May 2000, nursed at

a maternity ward from birth to discharge, with consent (N = 100)

Interventions (1) 80% ethanol (n = 52).

(2) 80% ethanol with 0.5% chlorhexidine (n = 48).

Outcomes Omphalitis, bacterial colonization.

Notes Preterm, term.

Low birthweight, non-low birthweight.

Hospital setting.

Western Pacific (Japan).

Daily bath.

All roomed in (“admitted to maternity ward from birth”).

Reports omphalitis but does not state which group.

Risk of bias




Oishi 2004 (Continued)


bias)

Low risk Table of random numbers.



bias)

All outcomes

Low risk The mothers of the neonates and the nurs-

ing staff were unaware as to which disinfec-

tant was being used


All outcomes

High risk For colonization, complete outcomes re-

ported for all participants for omphalitis,

no ITT analysis. 1 case of omphalitis but

not stated in which group; no loss of par-

ticipants


ment.

Other bias High risk Alcohol group had low birthweight babies

but the proportion is not specified

Panyavudhikrai 2002

Methods Randomized trial, conducted in hospital settings.

Participants Neonates born at department of obstetrics and gynaecology, Siriraj hospital, Thialand.

Mean gestational age of included babies was 38 weeks. Total n = 272

Interventions 1) Povidine-iodine (n = 93).

2) Triple dye (n = 90).

3) 70% alcohol (n = 89).

Outcomes Incidence of omphalitis, cord separation time.

Notes Data have been included for 70% alcohol vs triple dye only, as the data for Povidine

group were incomplete

Risk of bias



bias)

Unclear risk “Simple randomisation was used”, No fur-

ther description of the sequence generation

procedure was described

Allocation concealment (selection bias) Unclear risk Insufficent information to permit judge-

ment.



Panyavudhikrai 2002 (Continued)


bias)

All outcomes

Unclear risk Insufficent information to permit judge-

ment.


All outcomes


ment.

Selective reporting (reporting bias) Unclear risk Insufficent information to permit judge-

ment.

Other bias Unclear risk Insufficent information to permit judge-

ment.

Perapoch 1993

Methods Randomized study conducted in hospital settings in Spain.

Participants Healthy term newborns admitted to nursery. A total of 311 infants were included in the

study

Interventions 1. Alcohol (70%) (n = 75).

2. Alcohol + mercurochrome (n = 78).

3. Mercurochrome (n = 84).

4. Chlorhexidine (1%) (n = 74).

Outcomes Cord infection.

Cord separation.


Notes

Risk of bias



bias)

High risk Quote: “They were randomly assigned to

one of the four assessed methods”. No fur-

ther details of methods of randomization

were given


ment.


bias)

All outcomes


ment.



Perapoch 1993 (Continued)


All outcomes

High risk No details of exclusion or attrition were

given.


ment.

Other bias High risk Baseline characteristics of study partici-

pants were not given

Pezzati 2002

Methods Randomized study conducted in hospital settings

Participants Healthy term newborns admitted to nursery. A total of 1470 infants were included

Interventions 1. Salicylic sugar powder (n = 167).

2. Green clay powder (n = 184).

3. Natural drying (n = 177).

4. Katoxin (n = 208).

5. Cicatrene (n = 174).

6. 1% basic fuschine (n = 187).


8. 70% alcohol (n = 178).

Outcomes Sepsis.

Death.

Cord infection.

Cord separation.

Cord bleeding.

Compliance.

Parental satisfaction.


Notes Preterm (gestational age < 37 weeks) and low birthweight (< 2500 g) infants were excluded

from the study, as well as infants who were receiving phototherapy, antibiotics or who

developed complications of any kind requiring hospitalization in our neonatal pathology

unit

Risk of bias



bias)

High risk Quote: ”It was deemed unnecessary to

make use of a stricter randomization since

the type of treatment was recognizable both

by the nursery staff and parents.”



Pezzati 2002 (Continued)

Allocation concealment (selection bias) High risk Quote: ”It was deemed unnecessary to



by the nursery staff and parents.“


bias)

All outcomes

High risk Quote: ”It was deemed unnecessary to



by the nursery staff and parents.”


All outcomes


scribed in result’s section


ment.

Other bias Low risk Baseline characteristics were comparable at

the baseline.

Pezzati 2003

Methods A prospective randomized trial conducted in Italy in hospital settings

Participants Premature neonates. Total sample size was 213.

Interventions 1) 4% Cchlorhexidine solution (n = 101).

2) Salicylic sugar powder (n = 112).

Outcomes Mortality.

Sepsis.



Notes

Risk of bias



bias)

Unclear risk Quote: “A prospective, randomised study

was conducted on all premature infants”

Exact methods of sequence generation were

not described.

Allocation concealment (selection bias) Low risk Quote: “The patients were selected to enter

either of the 2 groups randomly by means

of the sealed envelope technique”



Pezzati 2003 (Continued)


bias)

All outcomes

High risk Quote: “The caregivers were not blinded

as to allocation because the cord stumps

looked different depending on which treat-

ment group the infant was in”


All outcomes

Low risk Exlusion and attrition was described in the

result section.


ment.

Other bias Unclear risk None noticed.

Rosenfeld 1989

Methods Randomized study conducted in hospital settings in USA.

Participants Premature babies < 2200 g. A total of 114 babies were included in the study

Interventions 1. Triple dye, single application (n = 54).

2. Isopropyl alcohol each diaper change (n = 60).

Outcomes Colonization on day 4 and at discharge.

Notes Only Abstract available.

Risk of bias



bias)

High risk Alternate allocation.

Allocation concealment (selection bias) High risk Inadequate methods of randomization.


bias)

All outcomes


ment.


All outcomes

High risk No details of exclusion or attrition were

given.


the methods section

Other bias Low risk Baseline characteristics were comparable

between the 2 groups



Rush 1986

Methods Randomized study conducted in hospital settings in Canada.

Participants Heathy term newborns admitted to nursery. A total of 181 infants were included in the

study

Interventions 1. Routine daily bath with water and soap (n = 95).

2. Initial bath only(n = 86).

Outcomes Colonization on day 4 in the nose and umbilicus.

Notes

Risk of bias



bias)


ment.


ment.


bias)

All outcomes


ment.


All outcomes

Low risk Details of exclusion and attrition were ad-

equately described


ment.

Other bias Low risk Baseline characteristics were comparable

between the 2 groups

Schuman 1985

Methods Randomized trial conducted in hospital settings.

Participants Newborns delivered at USAF hospital, Grand forks, USA (N = 71)

Interventions 1) Triple dye (n = 35).

2) Isopropyle alcohol (n = 36).


Notes The following infants were excluded from the analysis:

1) infants receiving phototherapy;



Schuman 1985 (Continued)

2) had insertion of umbilical catheter;

3) during hospitalizations developed complications.

Risk of bias



bias)

Low risk “.....infants were randomly assigned by

computer to one of two treatment regi-

mens.”


ment.


bias)

All outcomes


ment.


All outcomes


ment.


ment.

Other bias Unclear risk Insufficent information to permit judge-

ment.

Shafique 2006

Methods A quasi-randomized study conducted in Pakistan.

Participants Full term newborn, 50 in group A and 50 in group B.

Interventions A) 70% alcohol.

B) Dry cord care.


Notes Study conducted in hospital settings.

The exclusion criteria were maternal pyrexia (temperature more than 38°C) during

labour, premature rupture of membrane for greater than 18 hours, low birthweight

newborns (weight < 2.5 kg), newborns being given oral or systemic antibiotic, admission

in nursery within 48 hours after birth and presence of open congenital anomalies in the

newborn

Risk of bias




Shafique 2006 (Continued)


bias)

High risk A quasi-randomized study.

Allocation concealment (selection bias) High risk A quasi-randomized al study.


bias)

All outcomes

High risk No methods described for blindings.


All outcomes

High risk No reasons for loss to follow-up were de-

scribed.


ment..

Other bias High risk Data on umbilical cord infections and sep-

sis were collected by telephone and no

physician examined the child for surveil-

lance

Soofi 2012

Methods 2 x 2 cluster-randomized community trial conducted in Pakistan

Participants Newborn whose parents were enrolled in the study (N = 9741).

Interventions 1) Chlorhexidine (n = 2214).

2) Chlorhexidine + handwashing (n = 2475).

3) Handwashing alone (n = 2653).

4) Control (n = 2399).

Outcomes Omphalitis, all-cause mortality, cord separation time.

Notes Intervention was delivered by TBAs. Factorial analysis (chlorhexidine vs no chlorhexi-

dine) was included in this review

Risk of bias



bias)

Low risk Quote: “.........randomly allocated to one

of four groups (groups A to D) with a

computer-generated random number se-

quence”

Allocation concealment (selection bias) Low risk Comment: As this was a cluster-random-

ized trial allocation concealment is not an

issue



Soofi 2012 (Continued)


bias)

All outcomes

High risk Comment: Particiants were not blinded to

the intervention however, Implementation

and data collection teams were masked to

allocation


All outcomes


scribed. ITT analysis

Selective reporting (reporting bias) Low risk This study was free of selective reporting.

Other bias High risk The desired sample size was not achieved

due to security situation in the study area

Speck 1977

Methods Randomized trial conducted in hospital settings.

Participants Term healthy newborn. A total of 240 newborn babies were included in the study

Interventions 1. Daily wash with Castile soap (n = 78).


3. Silver sulphadiazine (n = 82).

Routine daily sponge bath with tap water.

After discharge, daily application of isopropanol.

Outcomes Bacterial culture from the nose day 3, 14.

Cord infection. Conjunctivitis. Impetigo.

Notes Data were taken from table II. Percentages were converted into number of events

Risk of bias



bias)


ment.


ment.


bias)

All outcomes


ment.


All outcomes

Low risk Attrition and exclusion were described in

the results section



Speck 1977 (Continued)


ment.

Other bias High risk Baseline characteristics of study partici-

pants were not given

Suliman 2010

Methods A prospective, randomized clinical trial conducted in US in hospital settings

Participants Healthy full term newborn, 90 babies completed the study.

Interventions 1) Alcohol rub plus triple dye application (n = 46).

2) Triple dye application alone (n = 44).



Notes Data were described for different appearances of cord but no definition was used to

define omphalitis

SDs were not given for cord separation time. We used the SDs from similar settings with

similar sample size

Risk of bias



bias)

Unclear risk Quote: “.......newborns were randomised to

receive either no further preventive treat-

ment to their umbilical cord or twice daily

rubbing alcohol application”


ment.


bias)

All outcomes

Unclear risk Methods of blinding were not described.


All outcomes

Unclear risk Attrition and exclusion was described.

Selective reporting (reporting bias) Low risk Study reported all the outcomes mentioned

in the method’s section

Other bias Unclear risk No physical surveillance was done to make

an assessment for cord infection



CHX: chlorhexidine

ITT: Intention-to-treat (analysis)

NICU: neonatal intensive care unit

SD: standard deviation

TBAs: traditional birth attendants

vs: versus

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Alda 2000 Comparison between hexachlorophene and chlorhexidine. Hexachlorophene not recommended anymore

because of central nervous toxicity

Aldar 1980 Comparison between hexachlorophene, which is not recommended anymore due to neural toxicity, and

chlorhexidine

Barclay 1994 This study is not a randomized trial. 890 babies in comparison between chlorhexidine and no specific

treatment to cord

Bhakoo 1969 Non-randomized, no alcohol or dry care in treatment, comparison between bathing and non-bathing

Birenbaum 1990 Not cord care.

Bourke 1989 This study was not a randomized trial. All babies born in 2 designated wards were entered into study. The

treatment groups included dry cord care and alcohol (70%)

Bradshaw 1993 Independent effect of alcohol cannot be assessed; alcohol was administered with hexachlorophene powder.

Hexachlorophene not recommended anymore because of central nervous toxicity

Chamnanvanakij 2005 Triple dye applied to all participants before randomization.

Coyer 1975 Not cord care.

Darmstadt 2007 Not cord care.

Erenel 2010 A quasi-experimental study.

Gezon 1964 Not cord care.

Gluck 1963 Non-randomized, total body skin care including cord.

Guala 2003 6 study groups. Allocation was in groups of 50. No randomization was done

Guinsburg 1991 4 study groups. Only abstract available. Non-randomized.

Healey 1991 Not cord care.



(Continued)

Henningsson 1981 Not cord care.

Hnatko 1977 Intervention included hexachlorophene which is not recommended because of central nervous toxicity.

Allocation to groups was according to predetermined schedule

Hodgins 2010 No dry cord care group, comparison between gel and aqueous chlorhexidine

Jellard 1957 All received surgical spirit so effect of treatment with antiseptics could not be assessed

Kumar 2008 Not cord care.

Kwong 1973 Non-randomized, total body bathing.

Olowe 1980 Not cord care.

Pildes 1973 Non-randomized, no alcohol or dry care in treatment.

Pyati 1977 Controlled trial in which multiple applications of povidone iodine were compared with a single application

Ronchera-Oms 1994 Non-randomized.

Saleem 2007 Not cord care.

Saleem 2010 Not a cord care study.

Shah 2010 Not a cord care study.

Smales 1988 No alcohol or dry care in treatment. 2 hospitals with different regimens reversed after 2 months

Tielsch 2006 Not cord care.

Tielsch 2007 Not cord care.

Wade 2006 Not cord care.

Wald 1977 1 of the treatment arms used Hexachlorophene which is not recommended because of central nervous

toxicity

Watkinson 1992 Comparison between alcohol and hexachlorophane with no antiseptic. Hexachlorophene not recommended

because of central nervous toxicity

Wojciechowska 1989 Study completed but not analyzed. No data available.



Characteristics of studies awaiting assessment [ordered by study ID]

Covas 2011

Methods Open prospective controlled clinical trial.

Participants Newborns.

Interventions Study group-body bath with neutral soap in the first 2 days of life and natural drying of the umbilical cord without

special treatment

Control group -umbilical cord hygiene with alcohol 70% at each diaper change until its separation and bath 2 days

later


Notes Need full text for further assessment.

Nasrallah 2003


Participants Newborn.

Interventions Intervention: 70% isopropyl alcohol application.

Control: natural drying of the cord.



Sellares Casas 2002

Methods Experimental study.

Participants Newborn, total sample size 285.

Interventions 1) 1 application of Merbromin.

2) 3 application of Merbromin.






Srinivasan 2003


Participants Very low birthweight infants admitted to Mount Sinai hospital

Interventions Intervention: umbilical cord cleaned with alcohol swab, followed by application of triple dye daily

Control: umbilical cord cleaned with alcohol swab.

Outcomes Bacterial colonization.


Taffazoli 2008

Methods Randomized clinical trial conducted in Iran.

Participants Newborn, total sample size 118.

Interventions 1) Mothers milk.

2) Dry cord care.




Characteristics of ongoing studies [ordered by study ID]

Hamer 2010

Trial name or title Zambia Chlorhexidine Application Trial (ZamCAT).

Methods Cluster-randomized community trial.

Participants Newborn whose parents are enrolled in the study.

Interventions Chlorhexidine cord care: experimental.

Control group: dry cord care.

Outcomes All-cause neonatal mortality and neonatal omphalitis.

Starting date November 12 2010.

Contact information Principal Investigator: Davidson H Hamer, MD: Boston University Center for Global Health and Develop-

ment

Notes Currently the trial is in recruitment phase.



Sazawal 2012

Trial name or title Chlorhexidine Cordcare for Reduction in Neonatal Mortality and Omphalitis (CHX-Pemba)

Methods Community-based controlled trial.

Participants Inclusion criteria

• Permanent resident of Pemba.

• Consenting to participate, infants alive at first contact with MCH/TBA/Hospital staff.

• First contact within 48 hours of delivery.

Exclusion criteria

• Congenital malformations where application of intervention is not possible.

• Very sick child needing hospitalization and ICU care.

Interventions 1. Experimental: 4% chlorhexidine cord application for 10 days

2. Active comparator: control: same liquid as intervention without the chlorhexidine used for cord cleaning

for 10 days once daily

3. No intervention: dry cord care use current recommended keep cord dry

Outcomes Neonatal mortality.

Omphalitis.

Starting date October 2010.

Contact information Contact: Said M Ali, MS.

Notes

ICU: intensive care unit



D A T A A N D A N A L Y S E S

Comparison 1. Antispetics vs dry cord care/placebo. Studies conducted in community settings

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 All-cause mortality 3 Risk Ratio (Random, 95% CI) Subtotals only

1.1 Chlorhexidine versus dry

cord care/placebo

3 Risk Ratio (Random, 95% CI) 0.77 [0.63, 0.94]

2 Omphalitis: Algorithm 1:

Redness extending to skin


3 Omphalitis: Algorithm 2:

Redness with pus or severe

redness


4 Omphalitis: Algorithm 3: severe

redness with pus


5 Bacterial colonization:

Staphyococcus aureus1 5234 Risk Ratio (M-H, Random, 95% CI) 0.27 [0.23, 0.31]

6 Bacterial colonization: E.coli 1 5234 Risk Ratio (M-H, Random, 95% CI) 0.50 [0.46, 0.54]


Streptococcus

1 5234 Risk Ratio (M-H, Random, 95% CI) 0.28 [0.22, 0.37]

8 Cord separation time (days) 2 37233 Mean Difference (IV, Random, 95% CI) 1.75 [0.44, 3.05]

8.1 Chlorhexidine 2 37233 Mean Difference (IV, Random, 95% CI) 1.75 [0.44, 3.05]

Comparison 2. Antiseptics vs dry cord care/placebo. Studies conducted in hospital settings


studies

No. of


1 Omphalitis 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Alcohol 3 484 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.62, 1.39]

1.2 Triple dye 2 968 Risk Ratio (M-H, Random, 95% CI) 0.71 [0.13, 3.73]

1.3 Chlorhexidine 1 669 Risk Ratio (M-H, Random, 95% CI) 0.28 [0.06, 1.35]

1.4 Salicylic sugar powder 1 344 Risk Ratio (M-H, Random, 95% CI) 0.21 [0.01, 4.38]

1.5 Green clay powder 1 361 Risk Ratio (M-H, Random, 95% CI) 0.48 [0.04, 5.26]


Staphylococcus aureus6 Risk Ratio (M-H, Random, 95% CI) Subtotals only



2.3 Silver sulphadiazine 2 360 Risk Ratio (M-H, Random, 95% CI) 0.72 [0.60, 0.87]


2.5 Benzine 1 221 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.90, 1.09]

2.6 Salicyclic sugar powder 1 344 Risk Ratio (M-H, Random, 95% CI) 0.32 [0.17, 0.58]


2.8 Katoxin powder 1 385 Risk Ratio (M-H, Random, 95% CI) 1.43 [1.02, 2.00]

2.9 Fuschine 1 364 Risk Ratio (M-H, Random, 95% CI) 0.52 [0.32, 0.84]




Streptococcus

6 Risk Ratio (M-H, Random, 95% CI) Subtotals only









4 Bacterial colonization: E. coli 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only









5 Parental satisfaction 1 355 Risk Ratio (M-H, Random, 95% CI) 0.55 [0.45, 0.66]

6 Time to cord separation (days) 11 Mean Difference (IV, Random, 95% CI) Subtotals only

6.1 Alcohol 9 2921 Mean Difference (IV, Random, 95% CI) 1.76 [0.03, 3.48]

6.2 Zinc powder 1 401 Mean Difference (IV, Random, 95% CI) -1.82 [-2.23, -1.41]

6.3 Triple dye 1 372 Mean Difference (IV, Random, 95% CI) 4.1 [3.07, 5.13]

6.4 Salicylic sugar powder 1 344 Mean Difference (IV, Random, 95% CI) -1.90 [-2.47, -1.33]

6.5 Green clay powder 1 361 Mean Difference (IV, Random, 95% CI) -0.80 [-1.36, -0.24]

6.6 Katoxin powder 1 385 Mean Difference (IV, Random, 95% CI) 0.80 [0.18, 1.42]

6.7 Fuschine 1 364 Mean Difference (IV, Random, 95% CI) 2.80 [2.01, 3.59]

6.8 Silver sulphadiazine 1 155 Mean Difference (IV, Random, 95% CI) 3.60 [2.66, 4.54]

6.9 Breastmilk 1 157 Mean Difference (IV, Random, 95% CI) -1.69 [-2.31, -1.07]

6.10 Chlorhexidine 1 669 Mean Difference (IV, Random, 95% CI) -0.80 [-1.21, -0.39]

Comparison 3. Antiseptic vs antibiotic. Studies conducted in hospital settings


studies

No. of




1.1 Triple dye vs bacitracin 1 62 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.03, 12.87]

1.2 Silve sulphadiazine vs

bacitracin


1.3 Povidine vs bacitracin 1 92 Risk Ratio (M-H, Random, 95% CI) 2.18 [0.42, 11.33]


2.1 Triple dye vs bacitracin 1 62 Mean Difference (IV, Random, 95% CI) -5.60 [-9.36, -1.84]

2.2 Triple dye vs neomycin 1 62 Mean Difference (IV, Random, 95% CI) -4.3 [-6.27, -2.33]

2.3 Silve sulphadiazene vs

neomycin

1 51 Mean Difference (IV, Random, 95% CI) -1.40 [-3.65, 0.85]

2.4 Povidine vs bacitracin 1 92 Mean Difference (IV, Random, 95% CI) -2.0 [-3.67, -0.33]



2.5 Alcohol vs beniktol 1 76 Mean Difference (IV, Random, 95% CI) -2.33 [-3.77, -0.89]

Comparison 4. Antiseptic vs antiseptic. Studies conducted in hospital settings


studies

No. of


1 Sepsis 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Chlorhexidine vs salicylic

powder


2 Omphalitis 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only

2.1 Triple dye vs alcohol 3 1560 Risk Ratio (M-H, Random, 95% CI) 0.48 [0.14, 1.63]

2.2 Triple dye vs povidone-

iodine


2.3 Triple dye vs salicylic sugar

powder


2.4 Triple dye vs katoxin 1 403 Risk Ratio (M-H, Random, 95% CI) 2.13 [0.19, 23.34]

2.5 Triple dye vs fuchsine 1 382 Risk Ratio (M-H, Random, 95% CI) 1.92 [0.18, 20.97]

2.6 Alcohol vs povidone-

iodine


2.7 Alcohol vs salicylic powder 1 345 Risk Ratio (M-H, Random, 95% CI) 4.69 [0.23, 97.03]

2.8 Alcohol vs green clay

powder


2.9 Alcohol vs katoxin 1 365 Risk Ratio (M-H, Random, 95% CI) 2.10 [0.19, 22.97]

2.10 Alcohol vs fuchsine 1 365 Risk Ratio (M-H, Random, 95% CI) 2.10 [0.19, 22.97]

2.11 Alcohol vs chlorhexidine 1 100 Risk Ratio (M-H, Random, 95% CI) 2.77 [0.12, 66.49]

2.12 Chlorhexidine vs

hydrophobic gauze





3.2 Triple dye vs silver

sulphadiazene



powder



iodine


3.5 Triple dye vs green clay

powder


3.6 Triple dye vs katoxin

powder




powder




3.11 Alcohol vs salicylic

powder




3.12 Alcohol vs povidine-

iodine



hydrophobic gauze


3.14 Chlorhexidine vs alcohol 2 165 Risk Ratio (M-H, Random, 95% CI) 0.41 [0.24, 0.71]


mercurochrome



Streptococcus




sulphadiazene



powder



powder



powder




powder





powder





sulphadiazene



powder



powder



powder




powder


5.8 Alcohol vs salicylic powder 1 345 Risk Ratio (M-H, Random, 95% CI) 1.14 [0.58, 2.24]




hydrophobic gauze



mercurochrome



6.1 Triple dye vs alcohol 2 444 Mean Difference (IV, Random, 95% CI) 0.43 [-8.49, 9.35]


sulphadiazene

2 117 Mean Difference (IV, Random, 95% CI) 0.15 [-6.20, 6.51]


powder

1 362 Mean Difference (IV, Random, 95% CI) 6.0 [5.01, 6.99]




iodine



powder



powder


6.7 Triple dye vs fuchsine 1 382 Mean Difference (IV, Random, 95% CI) 1.30 [0.17, 2.43]


powder


6.9 Alcohol vs katoxin 1 386 Mean Difference (IV, Random, 95% CI) 8.60 [7.42, 9.78]


powder


6.11 Alcohol vs fuchsine 1 365 Mean Difference (IV, Random, 95% CI) 6.60 [5.32, 7.88]

6.12 Alcohol vs silver

sulphadiazine

1 155 Mean Difference (IV, Random, 95% CI) -4.04 [-4.96, -3.12]

6.13 Chlorhexidine vs salicylic

powder



hydrophobic gauze



mercurochrome


6.16 Povidine-iodine vs silver

sulphadiazene


6.17 Triple dye plus alcohol vs

triple dye alone

1 90 Mean Difference (IV, Random, 95% CI) 1.00 [-0.45, 2.45]

Comparison 5. Single vs multiple application. Studies conducted in community settings


studies

No. of


1 All-cause mortality 1 (Random, 95% CI) 0.85 [0.70, 1.03]

1.1 Chlorhexidine 1 (Random, 95% CI) 0.85 [0.70, 1.03]

2 Omphalitis: Algorithem 1 1 (Fixed, 95% CI) 1.14 [0.97, 1.34]

2.1 Chlorhexidine 1 (Fixed, 95% CI) 1.14 [0.97, 1.34]









Streptococcus







Comparison 6. Single vs multiple application. Studies conducted in hospital settings


studies

No. of


1 Cord separation time (days) 4 Mean Difference (IV, Random, 95% CI) Subtotals only

1.1 Triple dye 3 408 Mean Difference (IV, Random, 95% CI) -4.24 [-4.41, -4.07]

1.2 Zinc powder 1 800 Mean Difference (IV, Random, 95% CI) -0.02 [-0.31, 0.27]

Comparison 7. Washing cord vs dry cord care. Studies conducted in community settings


studies

No. of


1 All-cause mortality 1 Risk Ratio (Fixed, 95% CI) 1.0 [0.76, 1.32]




5 Cord separation time (days) 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

Comparison 8. Washing cord vs dry cord care. Studies conducted in hospital settings


studies

No. of



Staphylococcus aureus1 181 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.65, 1.34]



F E E D B A C K

Aydin, 27 July 2013

Summary

Chlorhexidine gluconate is a widely used topical antiseptic that is recommended by the Center for Disease Control and Prevention for

skin cleansing before central venous catheter insertion in adults and children. But, because of limited safety data, infection prevention

guidelines do not recommend its use in babies who are less than two months old. There are many reports on the potential toxicity

of chlorhexidine gluconate, for example genotoxic and cytotoxic effects (1). Chlorhexidine gluconate contact may cause corneal

damage, ototoxicity, and neurotoxicity (2). In one study chlorhexidine gluconate was detected in the blood of preterm infants receiving

chlorhexidine gluconate skin antisepsis for peripherally central catheter insertion (3). Further investigation is required to determine the

safety of this use for newborn infants, especially preterm infants.

References

1. Arabaci T, et al. Assessment of cytogenetic and cytotoxic effects of chlorhexidine digluconate on cultured human lymphocytes. Acta

Odontol Scand 2013 71: 1255-60.

2. Zinn J, Jenkins JB,et al. Intraoperative patient skin prep agents: is there a difference. AORN J 2012 92: 662-74.

3. Chapman AK, et al. Absorption and tolerability of aqueous chlorhexidine gluconate used for skin antisepsis prior to catheter insertion

in preterm neonates. J Perinatol 2013 33):768-71. doi: 10.1038/jp.2013.61. Epub 2013 May 23.

Comment submitted by Mustafa Aydin, July 2013

W H A T ’ S N E W

Last assessed as up-to-date: 25 March 2013.

Date Event Description

27 July 2013 Feedback has been incorporated Feedback 1 received from Mustafa Aydin.

C O N T R I B U T I O N S O F A U T H O R S

Aamer Imdad contributed to the background. Aamer Imdad and Jacinto Blas V Mantaring were primarily responsible for the methods.

Jacinto Blas V Mantaring carried out the additional searches listed in the methods section. Aamer Imdad, Jacinto Blas V Mantaring,

Resti Ma M Bautista, Ma Esterlita V Uy and Kathlynne Anne Abat-Senen reviewed citations for inclusion, extracted data and formulated

the ’Characteristics of included study’ table along with ’Risk of bias’ table. Aamer Imdad, Jacinto Blas V Mantaring, Resti Ma M

Bautista, Ma Esterlita V Uy and Kathlynne Anne Abat-Senen entered outcome data into RevMan, analyzed the data and wrote the

results. Jacinto Blas V Mantaring, Resti Ma M Bautista, Ma Esterlita V Uy and Kathlynne Anne Abat-Senen drafted the discussion

text, which Aamer Imdad and Zulfiqar Ahmed Bhutta subsequently revised. Zulfiqar Ahmed Bhutta provided supervision and is the

guarantor for the review.



D E C L A R A T I O N S O F I N T E R E S T

Aamer Imdad and Zulfiqar Ahmed Bhutta were authors for study Soofi 2012. Data for Soofi 2012 were not extracted by these two

authors.

S O U R C E S O F S U P P O R T

Internal sources

• Effective Health Care Research Programme Consortium, Philippines.

External sources

• SEA-ORCHID Project (South-East Asia - Optimising Reproductive and Child Health Outcomes in Developing Countries),

Australia.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

1. It was decided post-hoc to include studies on all antiseptics rather than just alcohol. This was to include all possible evidence on

umbilical cord care.

2. Comparison of dry cord care with other antiseptics was not performed as there was too much clinical heterogeneity in the

comparison group.

3. It was decided not to pool community and hospital-based studies together because of significant clinical heterogeneity of

population of patients in hospitals and community settings.

4. Subgroup analyses based on gestational age and that of geographical regions were not performed as the number of studies were

not sufficient.

I N D E X T E R M S

Medical Subject Headings (MeSH)

∗Umbilical Cord [microbiology]; Anti-Infective Agents, Local [∗administration & dosage]; Chlorhexidine [administration & dosage];

Infant, Newborn; Inflammation [mortality; prevention & control]; Randomized Controlled Trials as Topic; Sepsis [mortality;∗prevention & control]

MeSH check words

Humans



Documents

Cochrane Database of Systematic Reviews (Reviews) || Umbilical cord antiseptics for preventing sepsis and death among newborns