Chlorhexidine skin or cord care for prevention of mortality and infections in neonates

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Authors

Anju Sinha1, Sunil Sazawal2, Alok Pradhan3, Siddarth Ramji4, Newton Opiyo5

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs


1Division of Reproductive and Child Health, Indian Council of Medical Research, Ansari Nagar, India [top]
2Johns Hopkins University, Baltimore, Maryland, USA [top]
3Kasturba Hospital, Delhi, India [top]
4Department of Neonatology, Maulana Azad Medical College, New Delhi, India [top]
5Cochrane Editorial Unit, Cochrane, London, UK [top]

Citation example: Sinha A, Sazawal S, Pradhan A, Ramji S, Opiyo N. Chlorhexidine skin or cord care for prevention of mortality and infections in neonates. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD007835. DOI: 10.1002/14651858.CD007835.pub2. [top]

Contact person

Anju Sinha

Division of Reproductive and Child Health
Indian Council of Medical Research
110029 Ansari Nagar
New Delhi
India

E-mail: apradhandr@gmail.com

Dates

Assessed as Up-to-date: 17 November 2013
Date of Search: 17 November 2013
Next Stage Expected: 17 November 2015
Protocol First Published: Issue 2, 2009
Review First Published: Issue 3, 2015
Last Citation Issue: Issue 3, 2015

Abstract

Background

Affordable, feasible and efficacious interventions to reduce neonatal infections and improve neonatal survival are needed. Chlorhexidine, a broad spectrum topical antiseptic agent, is active against aerobic and anaerobic organisms and reduces neonatal bacterial colonisation and may reduce infection.

Objectives

To evaluate the efficacy of neonatal skin or cord care with chlorhexidine versus routine care or no treatment for prevention of infections in late preterm or term newborn infants in hospital and community settings.

Search methods

We searched CENTRAL, latest issue of The Cochrane Library, MEDLINE (1966 to November 2013), EMBASE (1980 to November 2013), and CINAHL (1982 to November 2013). Ongoing trials were detected by searching the following databases: www.clinicaltrials.gov and www.controlled-trials.com External Web Site Policy.

Selection criteria

Cluster and individual patient randomised controlled trials of chlorhexidine use (for skin care, or cord care, or both) in term or late preterm neonates in hospital and community settings were eligible for inclusion. Three authors independently screened and selected studies for inclusion.

Data collection and analysis

Two review authors independently extracted data, and assessed study risk of bias. The quality of evidence for each outcome was assessed using GRADE. We calculated pooled risk ratios (RRs) and risk differences (RDs) with 95% confidence intervals (CIs), and presented results using GRADE 'Summary of findings' tables.

Main results

We included 12 trials in this review. There were seven hospital-based and five community-based studies. In four studies maternal vaginal wash with chlorhexidine was done in addition to neonatal skin and cord care.

Newborn skin or cord cleansing with chlorhexidine compared to usual care in hospitals

Low-quality evidence from one trial showed that chlorhexidine cord cleansing compared to dry cord care may lead to no difference in neonatal mortality (RR 0.11, 95% CI 0.01 to 2.04). Moderate-quality evidence from two trials showed that chlorhexidine cord cleansing compared to dry cord care probably reduces the risk of omphalitis/infections (RR 0.48, 95% CI 0.28 to 0.84).

Low-quality evidence from two trials showed that chlorhexidine skin cleansing compared to dry cord care may lead to no difference in omphalitis/infections (RR 0.88, 95% CI 0.56 to 1.39). None of the studies in this comparison reported effects of the treatments on neonatal mortality.

Newborn skin or cord cleansing with chlorhexidine compared to usual care in the community

High-quality evidence from three trials showed that chlorhexidine cord cleansing compared to dry cord care reduces neonatal mortality (RR 0.81, 95% CI 0.71 to 0.92) and omphalitis/infections (RR 0.48, 95% CI 0.40 to 0.57).

High-quality evidence from one trial showed no difference between chlorhexidine skin cleansing and usual skin care on neonatal mortality (RR 1.03, 95% CI 0.87 to 1.23). None of the studies in this comparison reported effects of the treatments on omphalitis/infections.

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution) in hospitals

Moderate-quality evidence from one trial showed no difference between maternal vaginal chlorhexidine in addition to total body cleansing and no intervention on neonatal mortality (RR 0.98, 95% CI 0.67 to 1.42). High-quality evidence from two trials showed no difference between maternal vaginal chlorhexidine in addition to total body cleansing and no intervention on the risk of infections (RR 0.93, 95% CI 0.82 to 1.16).

Findings from one trial showed that maternal vaginal cleansing in addition to total body cleansing results in increased risk of hypothermia (RR 1.33, 95% CI 1.19 to 1.49).

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution) in the community

Low-quality evidence from one trial showed no difference between maternal vaginal chlorhexidine in addition to total body cleansing and no intervention on neonatal mortality (RR 0.20, 95% CI 0.01 to 4.03). Moderate-quality evidence from one trial showed that maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention probably reduces the risk of neonatal infections (RR 0.69, 95% CI 0.49 to 0.95). These studies did not report effect on omphalitis.

Authors' conclusions

There is some uncertainty as to the effect of chlorhexidine applied to the umbilical cords of newborns in hospital settings on neonatal mortality. The quality of evidence for the effects on infection are moderate for cord application and low for application to skin. There is high-quality evidence that chlorhexidine skin or cord care in the community setting results in a 50% reduction in the incidence of omphalitis and a 12% reduction in neonatal mortality. Maternal vaginal chlorhexidine compared to usual care probably leads to no difference in neonatal mortality in hospital settings. Maternal vaginal chlorhexidine compared to usual care results in no difference in the risk of infections in hospital settings. The uncertainty over the effect of maternal vaginal chlorhexidine on mortality outcomes reflects small sample sizes and low event rates in the community settings.

Plain language summary

Chlorhexidine skin or cord care for prevention of mortality and infection in neonates

Background

Infections are the single most important cause of neonatal deaths worldwide and are responsible for almost a third of all neonatal mortality. Affordable, feasible and efficacious interventions to reduce neonatal infections and improved neonatal survival are needed. Chlorhexidine, a broad spectrum antiseptic agent, is active against common organisms causing perinatal infections. Use of chlorhexidine on neonatal skin or cord, or both, for prevention of infection is a possible strategy to improve neonatal survival. In this review we assessed the effects of neonatal skin or cord care with chlorhexidine compared to routine care or no treatment on neonatal survival and infections in newborn infants born in the hospital or community.

Study characteristics

We searched the medical literature for studies done in hospitals and communities that evaluated infections and deaths in newborns randomly assigned to receive either chlorhexidine care or the standard practice. Searches were done up to November 2013. There were 12 relevant studies found: there were seven hospital-based and five community-based studies. In four studies maternal vaginal wash with chlorhexidine was done in addition to neonatal skin and cord care. The durations of the included studies ranged from 6 months to 37 months. The number of participants in the included studies ranged from 112 to 29,760. None of the included studies declared any conflict of interest or were funded by pharmaceutical companies.

Key findings

Newborn skin or cord cleansing with chlorhexidine compared to usual care in hospitals

Chlorhexidine cord cleansing compared to dry cord care may lead to no difference in neonatal mortality. However, chlorhexidine cord cleansing probably reduces the risk of omphalitis or infections.

Chlorhexidine skin cleansing compared to dry cord care may lead to no difference in omphalitis or infections (none of the studies in this comparison reported effects of the treatments on neonatal mortality).

Newborn skin or cord cleansing with chlorhexidine compared to usual care in the community

Chlorhexidine cord cleansing compared to dry cord care reduces neonatal mortality and omphalitis or infections. There was no difference between chlorhexidine skin cleansing and usual skin care on neonatal mortality (none of the studies in this comparison reported effects of the treatments on omphalitis or infections).

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution) in hospitals

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no probably leads to no difference in neonatal mortality and infections. Maternal vaginal cleansing in addition to total body cleansing increases the risk of hypothermia.

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution) in the community

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention may lead to no difference in neonatal mortality. Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention probably reduces the risk of neonatal infections (none of the studies included in this comparison reported effects on omphalitis).

Quality of evidence

The confidence in estimate of effect (quality of evidence) for the effects of chlorhexidine on neonatal mortality and omphalitis or infections were varied (low, moderate and high). Main reasons for downgrading the quality of evidence were poorly conducted studies and lack of enough data.

Background

Description of the condition

Infections are the single most important cause of neonatal deaths worldwide and are responsible for almost 30% of all neonatal mortality (WHO 2001). Globally, 350,000 neonates die yearly because of septicaemia and meningitis. Major infectious causes of death include septicaemia, pneumonia, meningitis, omphalitis with sepsis, tetanus, and diarrhoea (Darmstadt 1998). In communities with high neonatal mortality rates, infections, including neonatal sepsis, account for approximately half of all newborn deaths (Lawn 2001).

Transmission of bacteria occurs vertically from the mother's genital tract during birth, or horizontally by organisms that have colonised the infant from the environment, and then enter through a breach in the muco-epithelium.

Bacterial colonisation of the skin precedes infection: this is the rationale for surface cultures used to predict systemic infections (Choi 2008). Although data for causes and risk factors of neonatal infections are scarce, the umbilical stump with its exposed blood vessels is regarded as a key entry point for systemic infections in newborn babies (Imdad 2013). In developing countries traditional practices involving application of potentially harmful substances to the umbilical stump are widespread, and are associated with high risk of infection (Zupan 2004).

There are reports suggesting a possible increase in the role of antibiotic resistance in the pathogens causing neonatal sepsis (Terrone 1999). The emerging problem of drug resistance is occurring at a faster pace than the development of new antibiotics. The World Health Organization (WHO) recommends a global programme to reduce the use of antibiotics in animals, plants, fish and in human medicine (WHO 1994).

Interventions that prevent morbidity during the neonatal period that are not centred on antibiotic use have the potential to be highly cost-effective and to affect health far beyond the neonatal period.

Continued efforts are required to describe optimal delivery of proven interventions and to identify and implement efficacious, affordable and feasible community-based interventions to reduce neonatal infections and mortality in order to meet the challenge of the Millennium Development Goal for child survival (United Nations 2001: http://www.un.org/millenniumgoals External Web Site Policy).

Description of the intervention

Chlorhexidine is a broad spectrum antiseptic agent that has been used extensively in hospital and other clinical settings for many decades. Of the numerous potential topical products (ethanol, silver sulphadiazine, triple dye, gentian violet, chlorhexidine, povidone iodine), chlorhexidine used as topical application has broad spectrum activity against gram positive (aerobic) and gram negative (anaerobic) organisms including those implicated in perinatal infections (Lumbiganon 2011).

Chlorhexidine has an extensive safety profile, is rarely associated with bacterial resistance, is easy to administer, and costs a few cents per application (Goldenberg 2006). It also has strong binding potential that results in residual effectiveness (Denton 2001; Mullany 2006).

Chlorhexidine is applied topically on neonatal skin as soon as possible after birth, preferably "within first six hours" of life. Researchers have used different formulations and doses of chlorhexidine. Its topical use has varied from a once a day to multiple applications, varying from 7 to 14 days in different studies.

Antibiotics are used for treating the infection after it has been established, whereas chlorhexidine application is a cost-effective intervention that presumably prevents bacterial colonisation from translating into bacteraemia.

There have been extensive studies of the safety of chlorhexidine in newborns. Reports have documented percutaneous absorption of chlorhexidine with both body wash and cord care wipe (Vorheer 1980; Mullany 2006); however, no adverse clinical consequences have been reported. Transient contact dermatitis in preterm very low birth-weight babies after long-term placement of chlorhexidine-impregnated dressings for a central venous catheter has been reported. Hypothermia has been identified as a potential neonatal risk following the application (McClure 2007). The data on the safety of chlorhexidine application are incomplete and the amount of exposure to chlorhexidine that can be considered safe is not known.

How the intervention might work

Chlorhexidine use substantially reduces bacterial colonisation of the cord stump and may be associated with reduced superficial skin infections (Belfrage 1985; Meberg 1985). Chlorhexidine rapidly reduces both skin flora and transient bacteria, such as gram-negative bacteria. In the 1970s, hand washing with chlorhexidine was shown to reduce skin flora by 86% to 92% (Lowbury 1973). In addition, it has residual activity on the skin that helps to prevent rapid regrowth of skin organisms and enhances the duration of skin antisepsis (Weinstein 2008). Chlorhexidine is currently included in the WHO Model List of Essential Medicines and can be maintained in non-alcohol aqueous solutions.

There is evidence that delivery of chlorhexidine solutions by vaginal lavage during labour and delivery, full-body newborn skin cleansing or umbilical cord cleansing or both reduces neonatal bacterial colonisation, infection and mortality (Taha 1997; Bakr 2005; Tielsch 2005; Mullany 2006). In technically-developed countries, research on chlorhexidine use in newborns has focused mainly on antisepsis of central venous catheters (Garland 1995; Garland 2001; Levy 2005).

Why it is important to do this review

There are two Cochrane reviews examining the role of chlorhexidine during labour for the prevention of maternal and neonatal infections (Stade 2008; Lumbiganon 2011). However, they have not included studies of neonatal skin cleansing with chlorhexidine solution to determine the effect of postdelivery treatment on neonatal morbidity and mortality as suggested by studies in Malawi (Taha 1997) and Egypt (Bakr 2005).

Use of chlorhexidine for topical antisepsis represents an important intervention with the potential for substantial effect on public health. There is a need to look separately at the role of neonatal skin cleansing with chlorhexidine to estimate the relative benefit of this intervention.

Objectives

To evaluate the efficacy of neonatal skin or cord care with chlorhexidine versus routine care or no treatment for prevention of infections in late preterm or term newborn infants in hospital and community settings.

Subgroup analyses are planned based on the following criteria in all primary comparisons:

  1. studies using cord cleansing with chlorhexidine exclusively;
  2. studies using total body cleansing with chlorhexidine.

Methods

Criteria for considering studies for this review

Types of studies

Cluster or individual patient randomised controlled trials of chlorhexidine use (for skin care, or cord care, or both) in neonates for prevention of infection.

Types of participants

  1. Term or late preterm newborn infants born in hospital settings up to 28 days (any weight);
  2. Term or late preterm newborn infants born in community settings (any weight) up to 28 days. We have included studies that enrolled late preterm infants. This is a deviation from our protocol. Late preterm is defined as 34 weeks 0 days to 36 weeks 6 days (ACOG 2008).

Types of interventions

  1. Preventive newborn skin or cord cleansing in hospital settings with chlorhexidine solution or powder in any dose compared with no intervention or standard practice, applied by health professionals or midwives or mothers.

    Subgroups:

    1. studies using cord cleansing with chlorhexidine;
    2. studies using total body cleansing with chlorhexidine.

  2. Preventive newborn skin or cord cleansing in community settings (including home deliveries) with chlorhexidine solution or powder in any dose compared with no intervention or standard practice of keeping the cord dry as recommended by the WHO.

    Subgroups:

    1. Studies using cord cleansing with chlorhexidine;
    2. Studies using total body cleansing with chlorhexidine.

  3. Preventive maternal vaginal chlorhexidine wash in addition to skin or cord care compared to no intervention or standard practice in hospital and community settings.

    Subgroups:

    1. studies using maternal vaginal chlorhexidine and cord cleansing with chlorhexidine;
    2. studies using maternal vaginal chlorhexidine and total body cleansing with chlorhexidine.

Types of outcome measures

Primary outcomes
  1. All-cause neonatal mortality.
  2. Incidence of infection (pneumonia, septicaemia, meningitis) in first 28 days (clinical signs/Integrated Management of Neonatal Childhood Illnesses (IMNCI)/WHO criteria/culture confirmed).
  3. Incidence of omphalitis.
Secondary outcomes
  1. Incidence of hypothermia (defined as an axillary temperature below 36.5 degrees Celsius).

Search methods for identification of studies

We used the standard search strategy for the Cochrane Neonatal Review Group (CNRG).

We performed searches using the following search strategy for The Cochrane Library, MEDLINE (via PubMed), CINAHL, and EMBASE.

We used the 'search terms' chlorhexidine AND ((infant, newborn[MeSH] OR newborn OR neon* OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh])) LIMITED to: Jan 2010 – Oct 3, 2012

Search strategy for controlled-trials.com External Web Site Policy AND clinicaltrials.gov:

We used the 'search terms' (infant OR newborn) AND chlorhexidine.

Electronic searches

We identified randomised controlled trials from the Cochrane Central Register of Controlled Trials (CENTRAL, latest issue of The Cochrane Library) and MEDLINE (1966 to November 2013) using the following subject headings (MeSH) and text word terms: 'Chlorhexidine' limiting to 'infants' AND 'pregnancy'. Other databases that were searched include EMBASE (1980 to November 2013); CINAHL (1982 to November 2013). Ongoing trials were detected by searching the following databases: www.clinicaltrials.gov and www.controlled-trials.com External Web Site Policy. We did not apply any language restriction. Two review authors performed the electronic database searches independently with help from the Trials Search Coordinator of the CNRG.

Searching other resources

We sought additional citations using references in articles retrieved from searches. We contacted subject experts to identify any unpublished and ongoing studies. We contacted authors of published trials to clarify or provide additional information related to their published study. Three review authors (AS, SR and AP) independently screened candidate articles to check their eligibility for inclusion in the review.

Data collection and analysis

GRADE approach was used in the post-protocol stage to assess the overall quality of evidence (Guyatt 2011). GRADE Profiler (GRADEpro) was used to import data from Review Manager and create 'Summary of findings' tables for all primary outcomes (neonatal mortality, infection, omphalitis) in each of the three comparisons. Five GRADE considerations (study limitation, consistency of effect, imprecision, indirectness, and publication bias) were used for assessment of quality of evidence. Justifications to downgrade quality of evidence from 'high quality' by one level for serious study limitations (risk of bias), or by two levels for (very serious) imprecision of effect estimates were provided using footnotes.

Meta-analysis of pooled data of studies using cluster randomised design was performed by using generic inverse variance method (GIVM) assuming a fixed-effect model. This uses the risk ratio (RR) and confidence interval (CI) (or an estimate of variance from the original study report). Review Manager Software (RevMan 2011) was used for statistical analysis.

The proportion of total statistical heterogeneity not explained by chance was estimated using the I² statistic. I² (calculated as I² = 100% x (Q-df)/Q; where Q is Cochran's heterogeneity statistic and df is the degrees of freedom) lies between 0% and 100%. Heterogeneity was explored by visual inspection of the forest plots, using the I² statistic, examining the trial characteristics (participants, design, intervention, outcome, and risk of bias).

Selection of studies

Three review authors (AS, SR and AP) independently screened candidate articles to check their eligibility for inclusion in the review. The review included cluster or individual patient randomised controlled trials of chlorhexidine use (for skin care, or cord care or both) in neonates for prevention of infection. In a deviation to our protocol, we included studies that enrolled preterm infants, since there was no weight restriction for inclusion. In case of disagreements a final decision was taken after discussions.

Data extraction and management

Two authors (AS, AP) independently extracted data using a data extraction form that was created and pilot tested before use. We extracted data on study design, participant characteristics, interventions, outcomes, and study settings. We present these findings in the 'Characteristics of included studies' table. The following quantitative data were extracted: for dichotomous data, we extracted the number of infants with the outcome and the total number analysed/randomised.

Assessment of risk of bias in included studies

We used the standard methods of the CNRG to assess the methodological quality (validity criteria) of the trials. Two review authors (AS, SR) independently evaluated included studies for data quality: blinding of allocation; blinding of intervention; completeness of follow-up; and blinding of outcome ascertainment and extracted data. Two review authors (AS, AP) who were not blinded to trial authors or institutions assessed the methodological quality of each study independently. The following issues were evaluated and entered into the 'Risk of bias' table:

  1. Selection bias (random sequence generation and allocation concealment): for each included study, we categorised the risk of selection bias as:
    1. low risk - adequate (any truly random process, e.g. random number table; computer random number generator);
    2. high risk - inadequate (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);
    3. unclear risk - no or unclear information provided.
  2. Allocation concealment: for each included study, we categorised the risk of bias regarding allocation concealment as:
    1. low risk - adequate (e.g. telephone or central randomisations; consecutively numbered, sealed, opaque envelopes);
    2. high risk - inadequate (open random allocation; unsealed or non-opaque envelope alternation; date of birth);
    3. unclear risk - no or unclear information provided.
  3. Performance bias: for each included study, we categorised the methods used to blind study personnel from knowledge of which intervention a participant received. As our study population consisted of neonates they would all be blinded to the study intervention:
    1. low risk - adequate for personnel (a placebo that could not be distinguished from the active drug was used in the control group);
    2. high risk - inadequate for personnel (aware of group assignment);
    3. unclear risk - no or unclear information provided.
  4. Detection bias: for each included study, we categorised the methods used to blind outcome assessors from knowledge of which intervention a participant received. (As our study population consisted of neonates, they would all be blinded to the study intervention.) Blinding was assessed separately for different outcomes or classes of outcome. We categorised the methods used with regards to detection bias as:
    1. low risk - adequate (follow-up was performed with assessors blinded to group assignment);
    2. high risk - inadequate (assessors at follow-up were aware of group assignment);
    3. unclear risk - no or unclear information provided.
  5. Attrition bias: for each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised the methods with respect to the risk attrition bias as:
    1. low risk - adequate (less than 10% missing data);
    2. high risk - inadequate (more than 10% missing data);
    3. unclear risk - no or unclear information provided.
  6. Reporting bias: for each included study, we described how we investigated the risk of selective outcome reporting bias and what we found. We assessed the methods as:
    1. low risk - adequate (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);
    2. high risk - inadequate (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
    3. unclear risk - no or unclear information provided (the study protocol was not available).
  7. Other bias: for each included study, we described any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias, as:
    1. low risk - no concerns of other bias raised;
    2. high risk - concerns raised about multiple looks at the data with the results made known to the investigators, difference in number of patients enrolled in abstract and final publications of the paper.
    3. unclear - concerns raised about potential sources of bias that could not be verified by contacting the authors.
      If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

For dichotomous outcomes risk ratio (RR) and its confidence interval, risk difference (RD) and its confidence interval, number needed to treat for benefit and harm (NNTB & NNTH) if risk difference was statistically significant were used. Meta-analysis of pooled data, using Mantel-Haenszel method was performed assuming a fixed-effect model. Meta-anlysis of pooled data from cluster randomised trials was performed using GIVM. Review Manager Software was used for statistical analysis (RevMan 2011).

Unit of analysis issues

There were four cluster randomised trials included in the review. Three of these (Mullany 2006; Tielsch 2007; Soofi 2012) reported adjustment of the standard error of risk ratio estimates using generalised estimating equations; one study reported using Huber-White sandwich estimator (Arifeen 2012) to account for the cluster design. We used the Generic Inverse Variance method in RevMan for the cluster randomised trials in order to preserve the corrections for clustering.

Three studies on cord cleansing with chlorhexidine (Mullany 2006; Arifeen 2012; Soofi 2012), used multiple cleansing (for 7 days in Mullany 2006 and Arifeen 2012, and 14 days in Soofi 2012). Arifeen 2012, in addition, included a single cleansing arm (in order to answer a question put up by an expert panel after the Nepal study by Mullany 2006). We used data from the multiple cleansing arm of Arifeen 2012 and pooled it with similar arms of the other two studies for comparison with the pooled data from the control arms of the three studies, for the purpose of meta-analysis, in this review. Data from the single cleansing arm of Arifeen 2012 were not included.

Dealing with missing data

Almost all studies reported intention-to-treat analyses for the outcomes measured; therefore, missing data did not affect this review. However, in Mullany 2006, outcome of neonatal mortality was not reported for 10 infants (probably lost to follow-up).

Assessment of heterogeneity

Heterogeneity between the trials was assessed using visual inspection of the forest plot. The proportion of total statistical heterogeneity not explained by chance was estimated using the I² statistic, (calculated as I² = 100% x (Q-df)/Q; where Q is Cochran's heterogeneity statistic and df is the degrees of freedom), which lies between 0% and 100%. Variability in the participants' intervention doses could amount to some clinical heterogeneity. There was methodological diversity present (eight parallel design, four cluster randomised studies).

We used the following categories for heterogeneity used by the neonatal review group:

  • less than 25%: no heterogeneity
  • 25% to 49%: low heterogeneity
  • 50% to 74%: moderate heterogeneity
  • 75% or greater: high heterogeneity

Assessment of reporting biases

As our meta-analyses included fewer than 10 studies, we did not assess publication bias with funnel plots. Due to the limited number of studies available, it is not possible to comment on publication bias for the review of subgroup analyses.

Data synthesis

We performed meta-analysis of pooled data using the Mantel-Haenszel method assuming a fixed-effect model. Meta-anlysis of pooled data from cluster randomised trials was performed using the generic inverse variance method (GIVM). Review Manager Software 5.1 (RevMan 2011) was used for statistical analysis.

Subgroup analysis and investigation of heterogeneity

We conducted subgroup analyses as prespecified in our protocol: within each of the three comparisons prespecified in the protocols, we analysed data for studies using cord cleansing with chlorhexidine and studies using total body cleansing. These subgroups were mutually exclusive.

We did not find any study of total body cleansing with chlorhexidine in the community setting that evaluated omphalitis as an outcome for inclusion in the prespecified subgroup. Similarly, no study using maternal vaginal chlorhexidine in addition to cord cleansing with chlorhexidine was identified for inclusion in the prespecified subgroup.

Sensitivity analysis

We planned sensitivity analysis using quality score of trials and dose of chlorhexidine. Sensitivity analysis was not conducted due to limited number of trials in subgroups. There was only one trial with low-quality scores among the hospital studies (Meberg 1985).

Results

Description of studies

See tables 'Characteristics of included studies'; 'Characteristics of excluded studies'; 'Characteristics of ongoing studies'. All the included trials were published in English.

Results of the search

After applying the search strategy, 226 records were retrieved from the databases and five other trials were found through additional searching. One hundred and seventy-seven records were excluded after reading the abstracts. The full text was obtained for 30 potentially-eligible trials. We found 18 of these trials to be ineligible on reading the full text. We finally included 12 trials in the systematic review (Figure 1).

Included studies

Twelve trials were included in this review: there were four cluster randomised trials, and eight randomised trials. There were 87,046 neonates (71,909 in cluster randomised and 15,137 in randomised trials) and 13,613 pregnant women enrolled in these trials.

Location/Setting:

There were seven hospital-based studies (Meberg 1985; Da Cunha 2008; Cutland 2009; Kapellen 2009; Saleem 2010; Pereira 2011; Gathwala 2013); and five community-based studies (Mullany 2006; Tielsch 2007; Saleem 2007; Arifeen 2012; Soofi 2012).

The studies were conducted in low-, middle- and high-income countries. There were seven studies reported from South-East Asia (Mullany 2006; Tielsch 2007; Saleem 2007; Saleem 2010; Arifeen 2012; Soofi 2012; Gathwala 2013); two reported from the African region (Cutland 2009; Pereira 2011); two from Europe (Kapellen 2009; Meberg 1985); and one study reported from South America (Da Cunha 2008).

Study designs:

Of the twelve included trials, four were cluster randomised community studies (Mullany 2006; Tielsch 2007; Arifeen 2012; Soofi 2012); the remaining eight were randomised trials (Meberg 1985; Saleem 2007; Da Cunha 2008; Cutland 2009; Kapellen 2009; Saleem 2010; Pereira 2011; Gathwala 2013). The study by Mullany 2006 was nested within the study by Tielsch 2007.

Sample size:

Arifeen 2012 included 29,760 participants in three study arms and was the largest cluster randomised study included in the meta-analysis. Sample sizes of other randomised studies ranged between 93 and 8070.

Interventions:

Chlorhexidine solution for neonatal skin/cord cleansing was used in different concentrations: 0.5% solution by Cutland 2009, 0.6% solution by Saleem 2007 and Saleem 2010, 0.25% baby wipes by Tielsch 2007, 0.25% solution by Da Cunha 2008, 4% solution by Soofi 2012, Arifeen 2012 and Mullany 2006. It was used as 1% powder in Kapellen 2009, 2.5% solution in Gathwala 2013 and 1% solution in Pereira 2011. Four studies used maternal vaginal wash with chlorhexidine in addition to neonatal total body cleansing with chlorhexidine (Saleem 2007; Cutland 2009; Saleem 2010; Pereira 2011).

Outcome:

Hospital-based studies (Meberg 1985; Da Cunha 2008; Kapellen 2009; Gathwala 2013) had infection, omphalitis and neonatal mortality as outcome. Four cluster randomised studies conducted in the community assessed omphalitis and neonatal mortality as outcomes (Mullany 2006; Tielsch 2007; Arifeen 2012; Soofi 2012). Four studies using maternal vaginal wash with chlorhexidine in addition to neonatal total body cleansing with chlorhexidine (Saleem 2007; Cutland 2009; Saleem 2010; Pereira 2011), used neonatal sepsis, a composite of neonatal sepsis or seven-day perinatal mortality or hypothermia as outcomes.

For this review, neonatal sepsis and skin infections reported in Saleem 2010, in addition to possible severe infection, skin infection, umbilical purulent discharge and neonatal antibiotics received, reported in Saleem 2007, have been entered under the outcome of infections. Similarly, probable sepsis, culture-proven sepsis and meningitis have been entered under the outcome of infection (Gathwala 2013).

Excluded studies

The reasons for excluding 18 studies were as follows: relevant outcomes not available (six trials); not a randomised trial (two trials); intervention with chlorhexidine conducted only in pregnant women (eight trials); studies compared different concentrations of chlorhexidine as comparison arms (two trials).

Risk of bias in included studies

The reasons for the risk of bias judgements in individual included studies are detailed in the table 'Characteristics of included studies' and the judgements are summarised in Figure 2 and Figure 3.

Allocation (selection bias)

Sequence generation:

Of 12 trials included in the review, the risk of bias for sequence generation was judged to be low in nine (Mullany 2006; Tielsch 2007; Saleem 2007; Da Cunha 2008; Cutland 2009; Pereira 2011; Arifeen 2012; Soofi 2012; Gathwala 2013). Risk of bias was unclear in three trials (Meberg 1985; Kapellen 2009; Saleem 2010).

Allocation concealment:

The allocation concealment was assessed to be as low risk of bias in nine trials (Mullany 2006; Tielsch 2007; Saleem 2007; Da Cunha 2008; Cutland 2009; Saleem 2010; Pereira 2011; Soofi 2012; Gathwala 2013); and as unclear risk of bias in three trials (Meberg 1985; Kapellen 2009; Arifeen 2012).

Blinding (performance bias and detection bias)

Blinding
Participants and personnel

Blinding of participants and personnel was assessed to be at low risk of bias in seven trials (Mullany 2006; Tielsch 2007; Saleem 2007; Da Cunha 2008; Saleem 2010; Soofi 2012; Gathwala 2013); it was unclear in two trials (Meberg 1985; Pereira 2011). Three trials were assessed to be at high risk of bias for blinding of participants and personnel (Cutland 2009; Kapellen 2009; Arifeen 2012).

Outcome assessment

The risk of bias for blinding of outcome assessment was judged low in nine trials (Mullany 2006; Tielsch 2007; Saleem 2007; Da Cunha 2008; Cutland 2009; Saleem 2010; Pereira 2011; Soofi 2012; Gathwala 2013); unclear in one trial (Meberg 1985); and high in two trials (Kapellen 2009; Arifeen 2012).

Incomplete outcome data (attrition bias)

Of the 12 trials included in the review, the risk of bias for incomplete outcome data was judged as low in all except one (Da Cunha 2008), in which it was assessed to be high.

Selective reporting (reporting bias)

The risk of bias due to selective reporting was assessed to be low in all 12 trials included in the review.

Other potential sources of bias

Studies were generally free of other potential sources of bias.

Effects of interventions

Comparison 1: Newborn skin or cord cleansing with chlorhexidine compared to usual care in hospitals

(a) Preventive newborn cord cleansing in hospitals
Neonatal mortality

One trial compared preventive cord cleansing to usual care (Gathwala 2013). The trial found no difference in the risk of neonatal mortality between the two groups (RR 0.11, 95% CI 0.01 to 2.04; RD -0.03, 95% CI -0.06 to 0.00; Analysis 1.1). The quality of evidence was rated low (downgraded by two levels due to very serious imprecision: wide 95% confidence interval and few deaths: N = 4 deaths (Summary of findings table 1).

Omphalitis/infections

Two studies (Gathwala 2013; Kapellen 2009) compared preventive chlorhexidine cord care versus dry cord care. Chlorhexidine cord care resulted in a reduction in the incidence of infections (RR 0.48, 95% CI 0.28 to 0.84; I² = 0%; RD -0.04, 95% CI -0.07 to -0.01; I² = 90%; NNTB 25; Figure 4, Analysis 1.2). The quality of evidence was downgraded by one level from high to moderate due to serious risk of selection bias, performance bias and detection bias in Kapellen 2009 (Summary of findings table 1).

(b) Preventive newborn skin cleansing in hospitals
Neonatal mortality

None of the included studies reported effects of treatments on neonatal mortality (Summary of findings table 2).

Omphalitis/infections

Two trials compared preventive chlorhexidine skin care with usual skin care (Meberg 1985; Da Cunha 2008). Pooled results from the two trials showed no difference between chlorhexidine skin cleansing and dry cord care groups in risks of omphalitis/infections: RR 0.88, 95% CI 0.56 to 1.39; test of heterogeneity not applicable (Da Cunha 2008 reported no events); RD -0.01, 95% CI -0.06 to 0.04; I² = 0%; Figure 4, Analysis 1.2). The quality of evidence was downgraded from high to moderate due to likely selection, performance and detection biases (sequence generation, allocation concealment, and blinding were unclear), and further from moderate to low due to serious imprecision (N = 71 events) (Summary of findings table 2).

Comparison 2: Newborn skin or cord cleansing with chlorhexidine compared to usual care in the community

(a) Preventive newborn cord cleansing in the community
Neonatal mortality

Three cluster-randomised trials compared multiple cord cleansing with chlorhexidine with dry cord care (Mullany 2006; Arifeen 2012; Soofi 2012). Pooled results from the three trials showed that chlorhexidine cord cleansing reduces neonatal mortality (RR 0.81, 95% CI 0.71 to 0.92, I² = 74%; RD -0.21, 95% CI -0.34 to -0.09, I² = 74%; NNTB 5) (Figure 5, Analysis 2.1). The quality of evidence was rated as high (Summary of findings table 3).

Omphalitis/infections

Three cluster-randomised trials compared multiple cord cleansing with chlorhexidine with dry cord care (Mullany 2006; Arifeen 2012; Soofi 2012). Pooled results from the three trials showed that showed that chlorhexidine cord cleansing reduces omphalitis/infections (RR 0.48, 95% CI 0.40 to 0.57, I² = 65%; RD -0.74; 95% CI -0.92 to -0.57, I² = 65%; NNTB 1) (Figure 6, Analysis 2.2). We did not downgrade for lack of blinding in Arifeen 2012 since the outcomes of mortality and omphalitis are fairly objective. The quality of evidence was rated as high (Summary of findings table 3).

Multiple versus single chlorhexidine cord cleansing

Arifeen 2012 also included a single chlorhexidine cleansing arm. This was included on recommendation of an expert panel after the Nepal study by Mullany 2006, to assess the role of single, soon after birth cleansing regimen. It showed benefit for neonatal mortality (RR 0.80, 95% CI 0.65 to 0.98) (discussed as a chance finding by Arifeen 2012), but not for omphalitis (RR 0.77, 95% CI 0.40 to 1.48).

(b) Preventive newborn skin cleansing in the community
Neonatal mortality

One trial compared preventive total body chlorhexidine skin cleansing with usual skin care (Tielsch 2007). The findings showed no difference between chlorhexidine skin cleansing and usual skin care groups in the risk of neonatal mortality (RR 1.03, 95% CI 0.87 to 1.23; RD 0.03; 95% CI -0.14, to 0.20) (Figure 5, Analysis 2.1). The quality of evidence was rated as high (Summary of findings table 4). This study reported significant effect only among low birth-weight infants (28% reduction in neonatal mortality); however, it was not reflected in this review as it was not a preplanned subgroup analysis.

Omphalitis/infections

We did not find any study of total body cleansing with chlorhexidine in the community setting that evaluated omphalitis as an outcome for inclusion in the prespecified subgroup (Figure 6, Analysis 2.2). (Summary of findings table 4).

Comparison 3: Maternal vaginal chlorhexidine in addition to total body cleansing (skin or cord care) compared to no intervention (sterile saline solution)

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution) in hospitals
Neonatal mortality

One trial compared the effect of maternal vaginal chlorhexidine in addition to total body cleansing to no intervention on neonatal mortality (Saleem 2010). The trial found no difference in the risk of neonatal mortality between the two groups (RR 0.98, 95% CI 0.67 to 1.42, I² = 7%; RD -0.00, 95% CI -0.01 to 0.01, I² = 91%) (Analysis 3.1). The quality of evidence was downgraded by one level from high to moderate due to serious imprecision (95% CI includes appreciable benefit and harm) (Summary of findings table 5).

Infections

Two trials compared the effect of maternal vaginal chlorhexidine to no intervention on neonatal infections (Cutland 2009; Saleem 2010). Pooled results from the two trials showed no difference in the risk of neonatal infections between the two groups (RR 0.98, 95% CI 0.82 to 1.16, I² = 45%; RD -0.00, 95% CI -0.01 to 0.01, I² = 0%) (Figure 7, Analysis 3.2) (Summary of findings table 5).

We did not find any study using maternal vaginal wash in addition to cord care with chlorhexidine for inclusion in this prespecified subgroup (Figure 7, Analysis 3.2).

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution) in the community
Neonatal mortality

One trial compared the effect of maternal vaginal chlorhexidine in addition to total body cleansing to no intervention on neonatal mortality (Saleem 2007). The trial found no difference in the risk of neonatal mortality between the two groups (RR 0.20, 95% CI 0.01 to 4.03; RD -0.02, 95% CI -0.05 to 0.01) (Analysis 4.1). The quality of evidence was downgraded by two levels from high to low due to very serious imprecision (wide 95% CI and few events, N = 2 deaths) (Summary of findings table 6).

Infections

One trial compared the effect of maternal vaginal chlorhexidine in addition to total body cleansing to no intervention on neonatal infections (Saleem 2007). Maternal vaginal chlorhexidine in addition to total body cleansing decreased the risk of neonatal infections (RR 0.69, 95% CI 0.49 to 0.95; RD -0.16, 95% CI -0.29 to -0.03) (Analysis 4.2). The quality of evidence was downgraded by one level from high to moderate due to serious imprecision (small sample size, N = 203 infants; few events, N = 87) (Summary of findings table 6).

Secondary outcomes
Incidence of hypothermia

One randomized control trial (Pereira 2011) was identified for this outcome. Hypothermia was defined as an axillary temperature below 36.5 degrees Celsius. Hypothermia occurred more frequently in the chlorhexidine group than in the usual care group (294 versus 114; RR 1.33, 95% CI 1.19 to 1.49; RD 0.22, 95% CI 0.14 to 0.30; NNTH = 5) (Analysis 3.3).

Discussion

Summary of main results

The meta-analyses performed by including four hospital based studies showed an overall significant effect of chlorhexidine cord and skin care on infections [typical RR 0.77, 95% CI 0.49 to 0.98 (test of heterogeneity I² = 35%); typical RD -0.03, 95% CI -0.05 to 0.00 (test of heterogeneity I² = 59%)].

The meta-analysis of four community-based studies (Mullany 2006; Tielsch 2007; Arifeen 2012; Soofi 2012) indicated that chlorhexidine skin or cord care intervention impacted on neonatal mortality significantly [typical RR 0.88, 95% CI 0.79 to 0.97 (test of heterogeneity I² = 74%); typical RD -0.13, 95% CI -0.23 to -0.03 (test of heterogeneity I² = 76%); NNTB 8].

The meta-analysis conducted by including three studies conducted in the community setting (Mullany 2006; Arifeen 2012; Soofi 2012) indicated that incidence of omphalitis was significantly reduced by chlorhexidine cord cleansing in the community setting; [typical RR 0.48, 95% CI 0.40 to 0.57 (test of heterogeneity I² = 65%); typical RD -0.74, 95% CI -0.92 to -0.57 (test of heterogeneity I² = 65%); NNTB 1].

We also analysed effect of chlorhexidine cleansing on neonatal mortality and incidence of infection in studies using maternal vaginal wash in addition to neonatal skin or cord care. Meta-analysis conducted by including two trials indicated a non-significant effect [typical RR 0.94, 95% CI 0.66 to 1.36 (test of heterogeneity I² = 7%); typical RD 0.00, 95% CI -0.01 to 0.01 (test of heterogeneity I² = 21%)]. Meta-analysis conducted by including three studies indicated a non-significant effect of maternal vaginal and neonatal chlorhexidine wipes on incidence of infection [typical RR 0.93, 95% CI 0.79 to 1.08 (test of heterogeneity I² = 45%); typical RD -0.00, 95% CI -0.01 to 0.00 (test of heterogeneity I² = 65%)].

Overall completeness and applicability of evidence

The objective of this review was to look at the role of neonatal skin/cord cleansing with chlorhexidine to estimate the relative benefit of this intervention. The studies included in the review were conducted in developed as well as developing countries. The statistically-significant evidence of a beneficial effect on the incidence of omphalitis and neonatal mortality achieved from our review may be considered important.

Our review also found a statistically significant evidence of a beneficial effect on neonatal mortality. Of the four studies included in the meta-analysis, Soofi 2012 reported a significant effect. The chlorhexidine-cleansing intervention was given for 14 days in this particular study, as compared to 7 days in Arifeen 2012 and Mullany 2006. Additional trials in the community settings are needed to determine the optimum frequency of chlorhexidine application (Saleem 2013).

The chlorhexidine intervention seems more suitable for births occurring in the community setting in developing countries where the need is clear, the possibilities attractive and risks low (Osrin 2012). Studies using chlorhexidine in 4% dose and repeated applications found statistically-significant evidence of a beneficial effect in our meta-analysis and individually on incidence of omphalitis: (Arifeen 2012) (RR 0.37, 95% CI 0.21 to 0.66); (Mullany 2006) (RR 0.25, 95% CI 0.14 to 0.47); and (Soofi 2012) (RR 0.54, 95% CI 0.45 to 0.65). The above-mentioned studies have been conducted in the South-East Asia region.

There were two studies from Africa included in our review: Cutland 2009 did not find a significant impact on infection; Pereira 2011 aimed to assess safety and acceptability. More evidence from high-mortality populations in Africa may be required (Osrin 2012). Recently studies have been initiated in Zambia and Tanzania (ongoing studies).

Quality of the evidence

For the main comparisons of interest our review has identified evidence of varying quality across the different outcomes. Studies conducted in hospital settings using chlorhexidine for skin or cord care provided low-quality evidence for reduction in neonatal mortality. Moderate-quality evidence was present for reduction of incidence of omphalitis (infections) by cord care intervention in hospitals. Gathwala 2013 was downgraded by two levels for very serious imprecision; Kapellen 2009 was downgraded due to serious risk of selection bias, performance bias and detection bias.

Our review findings indicate that there is high-quality evidence that the risk of omphalitis and neonatal mortality is lower with chlorhexidine intervention compared with usual care in the community setting. We observed moderate heterogeneity (65%) for risk ratio as well as risk difference for the reduction in incidence of omphalitis. Similarly, there is moderate heterogeneity (74%) for risk ratio and high (76%) for risk difference observed for the decline in neonatal mortality. The observed heterogeneity could be explained by the geographic variations in study settings, differences in baseline mortality rates of the control populations, differences in the underlying risk factors, cultural practices, duration of chlorhexidine intervention and method of outcome assessments between these three studies. We therefore did not downgrade for inconsistency since the magnitude and direction of effect was consistent across studies.

For the trials included in the meta-analysis, risk of bias for sequence generation was unclear in three trials (Meberg 1985; Kapellen 2009; Saleem 2010). Risk of bias for allocation concealment was unclear for three trials (Meberg 1985; Kapellen 2009; Arifeen 2012). The risk of blinding of participants and personnel was high in three trials (Cutland 2009; Kapellen 2009; Arifeen 2012), and risk for outcome assessment was high in two trials (Kapellen 2009; Arifeen 2012), unclear in one and low in nine trials. Risk of bias for incomplete outcome data was low in all trials except one where it was high. Trials were generally free of selective reporting and other biases.

In the Arifeen 2012 trial, blinding was not possible due to the nature of the intervention: the outcomes assessed were omphalitis and death, where blinding would not have mattered. In the Kapellen 2009 trial the risk of bias for blinding could be ignored as the event rates were quite low in both arms of the trial. Due to serious concern of unclear risk of biases in the trial by Meberg 1985, we contemplated sensitivity analysis by removing the trial: however it was not attempted due to lack of adequate numbers of hospital-based trials, and absence of the outcome of interest (infection) in Da Cunha 2008. The major conclusions from the review are based on the trials conducted in the community.

Potential biases in the review process

We identified and included all relevant studies in our review. We did not find any study of total body cleansing with chlorhexidine in the community setting that evaluated omphalitis as an outcome for inclusion in the prespecified subgroup. Similarly, no study using maternal vaginal chlorhexidine in addition to cord cleansing with chlorhexidine was identified.

The study by Arifeen 2012 included a single and a multiple chlorhexidine cleansing arm. (They reported including them on recommendation of an expert panel after the Nepal study by Mullany 2006, to assess the role of a single, soon-after-birth cleansing regimen). The single cleansing arm showed a benefit for neonatal mortality, (RR 0.80, 95% CI 0.65 to 0.98) but not for omphalitis (RR 0.77, 95% CI 0.40 to 1.48). The significant effect on neonatal mortality was discussed as a chance finding by Arifeen 2012.

In assessment of the role of chlorhexidine cleansing on neonatal mortality, we included data from the multiple intervention arm only from the trial by Arifeen 2012; we excluded the data available on single cleansing. This decision was taken in order to synthesise similar data (multiple intervention) available from other trials (Mullany 2006; Soofi 2012). There was moderate to high heterogeneity observed in our analysis. This could be explained by the difference in baseline mortality rates of the control populations (Imdad 2013).

Data on bacterial colonisation was provided in many trials; however, it was not included in this review. It is agreed that topical antimicrobials reduce bacterial colonisation; however, a firm relationship between colonisation and infection has not been established (Mullany 2003).

Agreements and disagreements with other studies or reviews

Two earlier Cochrane reviews examining the role of chlorhexidine during labour for the prevention of maternal and neonatal infections did not include studies of neonatal skin cleansing with chlorhexidine solution to determine the effect of post-delivery treatment on neonatal morbidity and mortality (Lumbiganon 2011; Stade 2008). This became the rationale for conducting the present review.

A literature review (Mullany 2003), covering studies on bacterial colonisation, mostly from developed but a few from developing countries, commented that cord antisepsis may decrease neonatal sepsis and death. It cautioned proper evaluation of the dry cord care practice before promoting it as the best practice, in the context of harmful applications on the cord being practised in developing countries.

A Cochrane review evaluating the effect of different antimicrobials on newborns' umbilical cord versus routine care for prevention of morbidity and mortality in hospital and community settings (Imdad 2013) concluded that there is significant evidence to suggest that topical application of chlorhexidine to the umbilical cord reduces neonatal mortality and omphalitis in community-care and primary-care settings in developing countries. Another review also indicated that cord cleansing with 4% chlorhexidine may reduce the risk of neonatal mortality and sepsis (omphalitis) in low-resource settings (Karumbi 2013). Methodological concerns (non-adjustment for cluster design, not using intension-to-treat analysis) have been raised regarding this review by Chandrasekaran 2013. Our results depicting benefit of 4% chlorhexidine intervention on neonatal mortality and omphalitis in the community setting are in agreement with the above reviews. Goldenberg 2013 has recommended considering adoption of this intervention wherever home births occur.

One earlier review (Zupan 2004) including studies conducted in developed countries has reported no benefit of cord care with antiseptics in hospital settings. We included a hospital-based study conducted in a developing country (Gathwala 2013). The result of our meta-analysis shows statistically significant effect for risk ratio (typical RR 0.77, 95% CI 0.49 to 0.98); but a borderline effect for risk difference (typical RD -0.03, 95% CI -0.05 to -0.00). However, the result of the subgroup analysis of chlorhexidine cord care on infections in hospital settings is significant; (typical RR 0.48, 95% CI 0.28 to 0.84); typical RD -0.04, 95% CI -0.07 to -0.01). About 25 newborns need to be treated to prevent infection in one.

A review of available evidence on 4% chlorhexidine solution for umbilical cord care for the WHO Model List of Essential Medicines has been proposed for consideration by the Subcommittee of the experts (Mario 2008).

Authors' conclusions

Implications for practice

There is some uncertainty as to the effect of chlorhexidine applied to the umbilical cords of newborns in hospital settings on neonatal mortality. The quality of evidence for the effects on infection are moderate for cord application and low for application to skin. There is high-quality evidence that chlorhexidine skin or cord care in the community setting results in a 50% reduction in the incidence of omphalitis and a 12% reduction in neonatal mortality. Maternal vaginal chlorhexidine compared to usual care probably leads to no difference in neonatal mortality in hospital settings. Maternal vaginal chlorhexidine compared to usual care results in no difference in the risk of infections in hospital settings. The uncertainty over the effect of maternal vaginal chlorhexidine on mortality outcomes reflects the low small sample sizes and low event rates in the community settings.

Results from presently ongoing studies in Africa would help substantiate this evidence. The WHO is considering including 4% Chlorhexidine solution in the list of essential medicines. (Mario 2008).

Implications for research

Our review concludes that there is evidence for a protective benefit of newborn skin and cord cleansing with chlorhexidine in the community in the South- East Asia region. Optimum frequency of applications of 4% chlorhexidine needs to be ascertained. More trials are required from low-resource settings in Africa (Osrin 2012).

Acknowledgements

We acknowledge Dr. Ambujam Nair, and Dr. Malabika Roy, ICMR Headquarters, New Delhi, for initiating the contact author in the science of Evidence Based Medicine; and Dr. Prathap Tharyan, Director, South East Asian Cochrane Network and Centre for providing necessary training and guidance. We thank Ms. Lee-Yee Chong, PhD, from the UK Cochrane centre for her advice on the analysis of cluster randomized trials.


We thank Toby Lasserson and Orla Ni Ogain from the Cochrane Editorial Unit for their suggestion to incorporate GRADE into the review and assistance in preparing the 'Summary of findings' tables. We also thank Dr. Roger Soll, Ms. Yolanda Montagne-Brosseau, Ms. Diane Haughton and Ms. Colleen Ovelman, from the Cochrane Neonatal Review Group (CNRG) for their support and guidance.

Contributions of authors

AS prepared the protocol. AS, SR, AP conducted the search. SS helped with additional search and information on ongoing studies. AS, SR, AP screened all the searched articles for inclusion. AS and SR extracted data independently. SS helped with data analyses. AS drafted the review. Newton Onyango Opiyo corrected the draft 'Summary of findings' tables and revised the draft review to incorporate the GRADE rating of evidence. All authors gave suggestions for refining the manuscript.

Declarations of interest

Dr. Anju Sinha was announced as the recipient of the "Aubrey Sheiham Primary care and Public Health Scholarship 2012" by the Cochrane Collaboration while working on this review. She received the scholarship during May to August 2013.

No other financial support was availed by any authors while working on the review.

Differences between protocol and review

We acknowledge inclusion of studies that enrolled late preterm and term infants in our analyses.This is a deviation from our published protocol entitled "Chlorhexidine skin care for prevention of infection in term neonates". The results of our review include effect of chlorhexidine intervention on neonatal mortality. We have therefore, changed the title of the review to "Chlorhexidine skin or cord care for prevention of mortality and infections in neonates".

Meta-analysis for the secondary outcome, 'hypothermia' could not be performed due to lack of studies.

We did not find any study of total body cleansing with chlorhexidine in the community setting that evaluated omphalitis as an outcome for inclusion in the prespecified sub-group. Similarly, no study using maternal vaginal chlorhexidine in addition to cord cleansing with chlorhexidine was identified for inclusion in the prespecified sub-group. We used GRADE approach for assessment of quality of evidence in the review as a post-protocol decision. We added Newton Opiyo as an author in the final stages of review preparation

Characteristics of studies

Characteristics of included studies

Arifeen 2012

Methods

A community-based, parallel cluster randomised trial was conducted during June 2007 to September 2009, in three rural sub-districts of Sylhet district in Bangladesh. The area was divided into 133 clusters on the basis of population size. In each cluster a female CHWa provided a basic package of community-based neonate care interventions. Four to five local female village health workers (VHW) were trained in each cluster to deliver the cord care intervention; each VHW served a population of about 1000 people

Participants

29,760 neonates were enrolled in three study groups

Inclusion: All live births visited within 7 days of birth by VHW

Exclusion: Died before VHW visit, not met within 7 days

Interventions

Group 1: 4% CHXb solution single cord cleansing after birth

Group 2: 4% CHX once daily cord cleansing for 7 days after birth

Group 3:  Dry cord care as per WHO

Outcomes

Neonatal mortality

Severe cord infection

Notes

Location: Rural Bangladesh, Sylhet District

Setting:   Rural sub-districts Beanibazar, Zakiganj, Kanaighat

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generated random allocation sequence (Stata version 9.2)

Allocation concealment (selection bias) Unclear risk

The CHW clusters (N = 133) were randomly allocated to 3 treatment regimens. Randomisation was stratified on the 3 groups of the previous Projahnmo project to achieve balance in underlying neonatal mortality risk

Blinding of participants and personnel (performance bias) High risk

Because of the nature of the interventions, intervention workers and study participants could not be masked

Blinding of outcome assessment (detection bias) High risk

Because of the nature of the interventions, intervention workers (VHWs and CHWs) and study participants could not be masked

Incomplete outcome data (attrition bias) Low risk

Outcome data on 100% of enrolled participants

Selective reporting (reporting bias) Low risk

Outcomes have been reported for all randomised participants

Other bias Low risk  

Cutland 2009

Methods

Hospital-based randomized controlled trial. Duration: April 2004 to Oct 2007

Generation of allocation sequence: computerised randomisation numbers generated using SAS ver.9.0 assigned in blocks of 50 participants

Inclusion of randomised participants in the analysis 8070/8129 = 99.2%

Participants

Pregnant women (aged 12 to 51 years) were screened for enrolment antenatally or in the labour ward and were reassessed for eligibility during active labour before randomisation and planned migration from study area in the first month after delivery. A total of 8103 mothers and 8070 neonates were enrolled

Inclusion criteria: pregnant women aged 12 to 51 years, who were planning to stay in study area after delivery

Exclusion criteria: planned caesarean section, Ante partum haemorrhage, severe congenital malformation, IUD before randomisation, known allergy to CHX, face presentation, many genital warts or ulcers, full cervical dilatation, age younger than 15 years

Interventions

Group 1: 0.5% CHX solution was used to wipe the cervix and vaginal walls of mothers during labour

Group 2: water was used for the control group to wipe only the external genitalia of mothers during labour

In Neonates CHX solution was used to wipe from head to toe avoiding face and ears. Neonates in the control group were given Chlorhexidine foot wipe

Outcomes

Early and late onset neonatal sepsis

Vertical transmission of group B streptococcus

Notes

Location: South Africa

Setting: Chris Hani Baragwanath Hospital, Soweto, South Africa

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computerised randomisation numbers generated using SAS version 9.0 assigned in blocks of 50 participants

Allocation concealment (selection bias) Low risk

Adequate. The forms were preprinted, sealed in opaque envelopes, and opened sequentially by study midwives when participants were randomly assigned

Blinding of participants and personnel (performance bias) High risk

Study midwives were aware of the intervention they were administering

Blinding of outcome assessment (detection bias) Low risk

The rest of the study team, including those gathering endpoint data, were unaware of the treatment allocations. Laboratory staff were also unaware of mother and neonate pairings. Study staff had no role in the management of the patient

Incomplete outcome data (attrition bias) Low risk

Inclusion of randomized participants in the analysis 8070/8129 = 99.2%

Selective reporting (reporting bias) Low risk  
Other bias Low risk  

Da Cunha 2008

Methods

A hospital-based masked randomised clinical trial was conducted with neonates born by vaginal delivery or caesarean section in a hospital in Porto Alegre, Brazil between 13 September 2005 and 14 March 2006. The primary objective was determination of skin colonisation 24 hrs. after first bath in healthy term newborn infants. The newborns were followed during the first month of life for clinical manifestations of sepsis or presence of positive blood/CSF culture

Participants

112 newborns were enrolled, 56 in each group

Inclusion criteria: normal term newborns with gestational age between 37 and 42 weeks, a appropriate for gestational age, with Apgar scores >= 7 in the first and fifth minutes, delivered between 13 September 2005 and 14 March 2006

Exclusion criteria: newborns with skin breakdown, congenital malformation, clinical suspicion of congenital infection, premature rupture of membranes for over 18 hrs., foetid amniotic  fluid, HIV+ve mothers, mothers with suspicion of or with bacterial infection before delivery or presenting axillary temperature > 37.8 degrees Celcius

Interventions

Group 1- Chlorhexidine digluconate at 0.4% liquid soap whole body bath

Group 2- Neutral liquid soap bath (prepared at the industrial pharmacy of Hospital de Clínicas de Porto Alegre consisting of Texapon SBN, Dehyton KB, Plantaren 2000, glycerin, Comperlan KDB, citric acid, deionised water, PH = 7

Outcomes

Skin colonisation 24 hrs after first bath. Infants were followed during the first month of life for clinical manifestations of infection (sepsis) or presence of positive blood cultures or CSF cultures or both

Notes

Location  Porto Alegre, Brazil

Setting: Obstetric centre of Hospital de Clínicas de Porto Alegre

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

List of random numbers

Allocation concealment (selection bias) Low risk

Randomisation was performed using sealed opaque envelopes

Blinding of participants and personnel (performance bias) Low risk

Nurses who bathed the newborns did not know the nature of soap that they were using

Blinding of outcome assessment (detection bias) Low risk

The collections were performed by a researcher who did not know the type of product that had been used in the bath. The researcher was absent during the randomisation and bath procedures

Incomplete outcome data (attrition bias) High risk

Outcome assessed in 93/112 infants (83%)

Selective reporting (reporting bias) Low risk  
Other bias Low risk  

Gathwala 2013

Methods

Hospital-based randomised controlled trial was carried out in the NICU of a tertiary level care teaching hospital in north India between June 2010 and November 2011

Blinded participants: yes

Blinded providers: yes

Inclusion of randomised participants in the analysis 100%: 140 randomized, 140 analyzed

Participants

146 newborns were screened for enrolment of which 140 were enrolled

Inclusion: newborns with gestational age > 32 weeks and weight > 1500 g at birth admitted to NICU

Exclusion: newborns with any anomalies involving umbilical cord, requiring umbilical catheterisation and those likely to get discharged within 5 days

Interventions

Group 1: chlorhexidine gluconate solution IP 2.5% SIRMAXO chemicals

Pvt. Ltd, Mumbai, India was applied on the umbilical cord (base and stump) 3 times a day for 3 days after cord separated out and fell off.

Group 2: dry cord care: umbilical cord was kept clean and dry and diapers were folded down under the umbilical stump so as not to irritate it.

Outcomes

Primary: cord separation time

Secondary: incidence of umbilical sepsis, neonatal sepsis (probable, culture proven, meningitis), and death.

Notes

A tertiary care level NICU in Rohtak India.

 

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

The newborns were assigned to either the chlorhexidine cord care or dry cord care groups as per the computer-generated random sequence.

Allocation concealment (selection bias) Low risk

The allocated group was mentioned in the sealed opaque envelopes. The envelopes were picked up serially at the time of enrolment of babies.

Blinding of participants and personnel (performance bias) Low risk

The allocated group was conveyed telephonically to the staff nurse involved in the care of these newborns.

Blinding of outcome assessment (detection bias) Low risk

The outcome measures were recorded by the clinician who was not aware of the group to which the baby had been allocated

Incomplete outcome data (attrition bias) Low risk

Inclusion of randomized participants in analysis 140/140 = 100%

Selective reporting (reporting bias) Low risk

All prespecified outcomes and all expected outcomes of interest to the review have been reported

Other bias Low risk  

Kapellen 2009

Methods

A hospital-based bi-centre randomised clinical trial was conducted in Leipzig, Germany from November 2003 to August 2005, to evaluate the efficacy of chlorhexidine powder versus dry cord care for umbilical care

Participants

Numbers: 669 enrolled; outcome presented for 669

Inclusion criteria: healthy newborns within the first 36 hours of life. Gestational age: 37 to 42 weeks; birth weight > 2500 g; informed consent given in a written form by both parents

Exclusion criteria: Current participation in another clinical trial 
Signs of clinically-relevant illnesses (excluding physiological neonatal hyperbilirubinaemia), evidence for HIV or hepatitis B/C-infection 
Evidence for infection of the newborn (also expected antibiotic therapy) 
Treatment of the subject with systemic antibiotics, treatment of the umbilical cord with local antimicrobial regimen before randomisation 
Twins or triplets

Delivery at home 

Interventions

Group1: Topical umbilical care with Chlorhexidine powder (1%) Riemser Arzneimittelwerke AG (Leipzig, Germany)                  

Group 2: Dry cord care

Outcomes

Time to separation of the umbilical cord stump, incidence of cord-related adverse events (erosion, lesion, irritation, omphalitis, redness of naval wall, weeping of the navel, pus, offensive smell or bleeding of the navel), Omphalitis (classification of Manson) and their signs (erythema, edema, secretion) or their complications (sepsis, umbilical phlegmona) and ulcers or umbilical granuloma. Parents acceptance and satisfaction with treatments

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk  
Allocation concealment (selection bias) Unclear risk  
Blinding of participants and personnel (performance bias) High risk  
Blinding of outcome assessment (detection bias) High risk

The cord stump was evaluated once a day by the trial personnel. After discharge the procedure was performed by the parents at home until 3 days after cord detachment. The observations of the parents (cord appearance, complications and date and time of cord detachment) were documented in a diary.

Incomplete outcome data (attrition bias) Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk  

Meberg 1985

Methods

In a prospective randomised hospital-based study different regimens for skin and umbilical disinfection in newborn infants were tested: daily whole body soap wash (control group); daily whole body soap wash and umbilical cleansing with 1) benzine solution, or 2) 0.05% chlorhexidine detergent solution (Hibiscrub). Bacterial cultures were taken from the nose and umbilical area at discharge. Clinical infections were registered in the nursery, and after discharge until 6 weeks of age. Study was conducted during Autumn 1982 (phase 1) and Autumn 1983 (phase 2)

Participants

549 newborns were enrolled; outcomes presented for 549

Inclusion criteria: healthy term (gestational age 37 weeks or more), vaginally delivered

Exclusion criteria: not stated

Interventions

Phase 1: daily whole body soap wash, (Baring soap solution, Sterisol AB, Sweden) (control group), and two test groups: 1) daily whole body soap wash and umbilical cleansing with 1) benzine solution (medical benzene, NAF, Norway), or 2) 0.05% chlorhexidine detergent solution (Hibiscrub)

Phase 2: control group (daily whole body soap wash) and one test group (daily whole body wash and umbilical cleansing with a 4% chlorhexidine detergent solution ( Hibiscrub ''ICI'')

Outcomes

Infections (pemphigus, paronychia, conjunctivitis, umbilical infection), colonisation rates

Notes

Location: Norway

Setting: maternity ward with modern facilities

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Not explicitly stated in the article

Allocation concealment (selection bias) Unclear risk

Not explicitly stated

Blinding of participants and personnel (performance bias) Unclear risk

Not explicitly stated

Blinding of outcome assessment (detection bias) Unclear risk

Not explicitly stated

Incomplete outcome data (attrition bias) Low risk

Outcomes assessed in all 549 infants included in the study

Selective reporting (reporting bias) Low risk

Not present. Results on infections and colonisation rates reported

Other bias Low risk  

Mullany 2006

Methods

Community-based cluster randomised trial, conducted from November 2002 to March 2005, in Sarlahi, Nepal. 413 communities were randomly assigned to one of three cord care regimens. 4934 infants were assigned to 4.0% chlorhexidine, 5107 to cleansing with soap and water, and 5082 to dry cord care. In intervention clusters, the newborn cord was cleansed in the home on days 1 to 4, 6,8, and 10. In all clusters the cord was examined for signs of infection (pus, redness or swelling) on these visits and in the follow-up visits on days 12, 14, 21 and 28.

Generation of allocation sequence: computerised random number generator

Inclusion of randomised participants in the analysis: 15102/15123 (99%)

Participants

15123 newborns were enrolled; outcomes were presented for 15102

Inclusion criteria: All alive infants at day 1 visit born after 17 November 2002, in the 413 actively-monitored sectors of Nepal Nutrition Intervention Project - Sarlahi (NNIPS) were eligible

Exclusion criteria: No consent; first visit after 10 days of life

Interventions

Group 1: Umbilical stump cleansing with 4.0% chlorhexidine (prepared by diluting 20% chlorhexidine digluconate (Medichem SA, Barcelona, Spain)

Group 2: Cleansing with soap and water (prepared by diluting Ivory Liqui-Gel (Procter & Gamble, Cincinnati, Ohio, USA)

Group 3: Dry cord care

Outcomes

1. Incidence of neonatal omphalitis

2. Neonatal mortality

Notes

Location: Sarlahi, Nepal

Setting : This cord cleansing trial was nested within a study of the effect of full-body skin cleansing with antiseptic on neonatal mortality

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Generated using computerised random number generator

Allocation concealment (selection bias) Low risk

Communities randomised with assignment blocked on terciles of sector-wise infant mortality risk estimated with data from a previous NNIPS study

Blinding of participants and personnel (performance bias) Low risk

The perfume used in the commercial cleanser was added to the chlorhexidine solution to make the smell of solutions indistinguishable. The intervention solutions were packaged in identical opaque plastic bottles. The study investigators, analysts, project field workers and participants were masked to the interventions

Blinding of outcome assessment (detection bias) Low risk

Yes

Incomplete outcome data (attrition bias) Low risk

15102/15123 (99%) of randomised participants were included in analysis

Selective reporting (reporting bias) Low risk

Results of primary and secondary objectives reported

Other bias Low risk  

Pereira 2011

Methods

Hospital-based randomised controlled trial to determine the safety, acceptability, and antimicrobial effect of 1% chlorhexidine vaginal washing compared with no washing in women in labour and their neonates. The pilot study was conducted between January and November 2005 at Harare Central Hospital, Zimbabwe. Mother-infant pairs were randomised in a 2:1 ratio in blocks of 6 to 10

Participants

Inclusion criteria included term pregnancy, planned vaginal delivery, lack of CHX allergy, and ability to attend follow-up appointments

Interventions

Group 1: 1% vaginal CHX washing and neonatal cleansing, at study entry and every 2 hour intervals with each vaginal examination

Group 2: Usual care

Neonates were cleansed immediately following birth with CHX-soaked cotton balls (excluding the head)

Outcomes

Incidence of maternal adverse effects, incidence of neonatal skin rash, the axillary temperature before and after neonatal wiping, and vaginal culture results

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Using a web-based random number generator

Allocation concealment (selection bias) Low risk

Randomization was done in 2:1 ratio in blocks of 6 to 10

Blinding of participants and personnel (performance bias) Unclear risk

Not stated, participants and personnel cannot be blinded since no placebo was used (usual care in control arm)

Blinding of outcome assessment (detection bias) Low risk

all neonates were observed daily for skin rash/irritation by a paediatrician blinded to the randomisation status

Incomplete outcome data (attrition bias) Low risk

Outcome reported in all 508 infants enrolled

Selective reporting (reporting bias) Low risk

data reported for all outcomes

Other bias Low risk  

Saleem 2007

Methods

A community-based randomised controlled trial was conducted during June 2005 to June 2008, after completion of a qualitative study assessing tolerance and safety of 0.6% chlorhexidine vaginal and neonatal wipes to improve perinatal outcomes in home deliveries in Pakistan and the ability of the traditional birth attendants and project staff to perform a randomised trial of this intervention was completed. After completion of focus groups and in-depth interventions, a study was performed: consenting women were randomly assigned to receive either 0.6% chlorhexidine or saline vaginal and neonatal wipes. Women and their infants were followed up on postpartum days 7, 14 and 28

Generation of allocation sequence: block randomisation scheme provided by data centre

Inclusion of randomised participants in the analysis: 199/200 = 99%

Participants

Inclusion criteria: gravidas with living fetus delivering at home in the care of identified study birth attendant (community) or admitted to the identified hospital (Civil Hospital Karachi) for delivery

Exclusion Criteria: contraindications to cervical exam (e.g. placenta praevia); active genital herpes or vulvovaginal ulceration; known or suspected allergy to chlorhexidine; fetus with face presentation; fetal death; nwilling/unable to give informed consent; less than 16 years of age

Interventions

Group 1: 0.6% chlorhexidine solution

Group 2: sterile saline solution

Outcomes

Primary outcome measures: neonatal death or severe sepsis at 7 days, safety of 0.6% chlorhexidine vaginal and neonatal wipes, feasibility of a randomised study in home-delivery setting

 

Secondary outcome measures:

Maternal: clinical chorioamnionitis, clinical endometritis, urinary tract infection, sepsis, length of hospitalisation, readmission to hospital, death. Neonatal: receipt of antibiotics, duration of hospitalisation, readmission to hospital

Notes

Location: Pakistan

Setting: home deliveries

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Block randomisation scheme provided by data centre (RTI, North Carolina)

Allocation concealment (selection bias) Low risk

Yes

Blinding of participants and personnel (performance bias) Low risk

All field study team members, including the traditional birth attendants, were blinded to the treatment assignments. Both solutions were clear and odourless, neither the study team members nor the subjects could differentiate between the two

Blinding of outcome assessment (detection bias) Low risk

Yes

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for 199/200 randomised participants

Selective reporting (reporting bias) Low risk

results provided for primary and secondary outcomes

Other bias Low risk  

Saleem 2010

Methods

A hospital-based placebo-controlled randomised controlled trial of chlorhexidine vaginal and neonatal wipes conducted in 3 hospitals in Pakistan from June 2005 to May 2008        

Participants

Number: 5008 pregnant women and neonates

Inclusion criteria: age 18 to 45 years, admitted to hospital

Exclusion criteria: contraindication to digital examination, active genital herpes, vulvovaginal ulceration, face presentation, known fetal death, allergy to CHX, planned caesarean delivery, full dilatation, follow-up risky or unwilling

Interventions

Group 1: 0.6% chlorhexidine solution prepared from chlorhexidine diacetate powder purchased from Degussa (Frankfurt, Germany) by adding sterile water (7.14 g/L), buffered to pH 8 with the addition of hydrochloric acid used as vaginal and neonatal wipes

Group 2: sterile saline solution

Outcomes

Primary: a composite of neonatal sepsis or 7-day perinatal mortality

Secondary: 28-day neonatal sepsis or mortality, mean number of neonatal hospital days, number of neonates remaining in hospital at day 7 or hospitalised before day 28 of life

Notes

Location: Aga Khan University, Karachi, Pakistan

Setting: 3 hospitals in Karachi

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Data centre prepared a randomisation list for each of the hospitals with treatment allocation generated in blocks of 4 and 8 computerised randomisation list

Allocation concealment (selection bias) Low risk

Adequate

Blinding of participants and personnel (performance bias) Low risk

The intervention and control solutions were packed in identical boxes in amber-coloured bottles. Study by teams of doctors and nurses were masked. Both solutions were clear and odourless, neither the study team members nor the participants could differentiate them.

Blinding of outcome assessment (detection bias) Low risk

The field teams examining mothers and neonates and collecting data were masked

Incomplete outcome data (attrition bias) Low risk

Inclusion of randomised participants in analysis (4947/5008 = 98.7%)

Selective reporting (reporting bias) Low risk

results reported for all outcomes

Other bias Low risk  

Soofi 2012

Methods

The community-based study used a two-by-two factorial, cluster randomised design. From October 2007 to June 2009, the study area was divided into clusters defined on the basis of the population covered by a functional Traditional Birth Attendant. 187 clusters were randomly allocated to 1 of the 4 groups (group A to D). Study interventions were delivered at the household level by TBAs working under the supervision of locally recruited community health workers (CHWs)

Participants

Number: 9741 infants

Inclusion: all newborn babies delivered by the participating TBAs in the study area were eligible for enrolment

Exclusion: birth defects; cord anomalies

Interventions

Group 1: clean birth kit, 4% CHX solution and a bar of soap used for cord care

Group 2: clean birth kit; bar of soap; standard dry cord care

Group 3: clean birth kits with 4% CHX      

Group 4: clean birth kits without CHX or soap. (control)

Outcomes

Incidence of omphalitis

Neonatal mortality

Notes

Location:  Rural district (Dadu District) in Sindh Province, Pakistan                       

Setting:     Health system of the Province

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer-generated random sequence, generated by a statistician not involved in the project

Allocation concealment (selection bias) Low risk

Adequate. Codes were available only to the pharmacy that prepared the CHX solution and included it in the birth kits. The birth kits were numbered and coded but otherwise identical. Implementation and data collection teams were masked to allocation

Blinding of participants and personnel (performance bias) Low risk

Yes

Blinding of outcome assessment (detection bias) Low risk

Yes

Incomplete outcome data (attrition bias) Low risk

9720/9741 (99.7%)

Selective reporting (reporting bias) Low risk

Data on all outcomes reported

Other bias Low risk  

Tielsch 2007

Methods

A community-based, placebo-controlled, cluster-randomised trial was conducted in Sarlahi, Nepal from September 2002 to March 2005. The area was divided into 413 sectors on the basis of population that a local female worker (ward distributor) could service (40 to 50 households). Pregnancies were identified by her during monthly visits, newborns were enrolled soon after birth and skin cleansing was conducted. Randomisation was conducted at the sector level, stratified by geographic area and terciles of infant mortality risk measured earlier

Participants

Number: 17306 (9519 in CHX , 8787 in placebo arm)

Inclusion: livebirth, in study area

Exclusion: stillbirth, refusal, other reasons, birth outside area

Interventions

Group1: Pampers infant wipes with  0.25% Chlorhexidine (Procter & Gamble Co, Cincinnati, OH)

Group2: Pampers infant wipes without chlorhexidine packed in sterile plastic sachets containing 6 wipes. Wiping of the total body excluding eyes and ears was conducted

Outcomes

All-cause neonatal mortality

Notes

Location: Nepal Newborn Washing Study

Setting: Sarlahi district, south-central Nepal

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computerised random number generator was used for random sequence generation. Randomisation was conducted at the sector level, stratified by geographic area and tertiles of infant mortality risk measured earlier

Allocation concealment (selection bias) Low risk

The allocation codes were kept at Procter & Gamble

Blinding of participants and personnel (performance bias) Low risk

Investigators and all study staff were masked to the treatment assignment

Blinding of outcome assessment (detection bias) Low risk

Investigators and all study staff were masked to the treatment assignment

Incomplete outcome data (attrition bias) Low risk

Outcome data presented for all randomised subjects (100%)

Selective reporting (reporting bias) Low risk

Data on all outcomes reported

Other bias Low risk  
Footnotes

aCHW = Community Health Worker

bCHX = chlorhexidine

Characteristics of excluded studies

Adriaanse 1995

Reason for exclusion

Chlorhexidine intervention used in women only, no intervention in newborns

Alder 1980

Reason for exclusion

Outcomes of interest not measured in the study

Bakr 2005

Reason for exclusion

Study is without random assignment, without concurrent controls

Burman 1992

Reason for exclusion

Chlorhexidine intervention used in women only, no intervention in newborns

Eriksen 1997

Reason for exclusion

Chlorhexidine intervention used in women only, no intervention in newborns

Gaillard 2001

Reason for exclusion

Chlorhexidine intervention used in women only, no intervention in newborns (outcome is mother-to-child transmission of HIV)

Henrichsen 1994

Reason for exclusion

Chlorhexidine intervention used in women only, no intervention in newborns

Hodgins 2010

Reason for exclusion

The study compares chlorhexidine gel versus chlorhexidine aqueous solution, outcome is colonisation

Mullany 2008

Reason for exclusion

Study compared different concentrations of chlorhexidine on bacterial colonisation

Mullany 2012

Reason for exclusion

Outcome was overall and organism-specific colonisation (not infection)

Mullany 2013

Reason for exclusion

Outcome is cord separation time

Nuntnarumit 2013

Reason for exclusion

Outcome is blood culture contamination rates

Oishi 2004

Reason for exclusion

Outcome was umbilical colonisation (not infection)

Pezzati 2003

Reason for exclusion

Study included preterm infants, outcome was cord separation time

Rouse 1997

Reason for exclusion

Chlorhexidine intervention used in women only, no intervention in newborns

Rouse 2003

Reason for exclusion

Chlorhexidine intervention used in women only, no intervention in newborns

Stray-Pedersen 1999

Reason for exclusion

Chlorhexidine intervention used in women only, no intervention in newborns

Taha 1997

Reason for exclusion

Study is without random assignment, without concurrent controls

Characteristics of studies awaiting classification

Abdeyazdan 2014

Methods  
Participants

98 hospitalised infants

Interventions

2 antiseptic solutions (povidone-iodine and chlorhexidine)

Outcomes

skin bacterial flora

Notes  

Gupta 2014

Methods  
Participants  
Interventions  
Outcomes  
Notes

Abstract Aim: The aim of this study was to evaluate the efficacy of skin cleansing with chlorhexidine (CHD) in the prevention of neonatal nosocomial sepsis - a randomized controlled trial. Methods: This study design was a randomized controlled trial carried out in a tertiary care center of north India. About 140 eligible neonates were randomly allocated to either the subject area group (wiped with CHD solution till day seven of life) or the control group (wiped with lukewarm water). The primary outcome studied was to determine the decrease in the incidence of neonatal nosocomial sepsis (blood culture proven) in the intervention group. Results: Out of 140 enrolled neonates, 70 were allocated to each group. The ratio of positive blood culture among the CHD group was 3.57%, while the ratio of positive blood culture among the control group was 6.85%. There was trending towards a reduction in blood culture proven sepsis in the intervention group, although the remainder was not statistically significant. A similar decreasing trend was observed in rates of skin colonization, duration of hospital stay, and duration of antibiotic treatment. Conclusion: CHD skin cleansing decreases the incidence of blood culture sepsis and could be an easy and cheap intervention for reducing the neonatal sepsis in countries where the neonatal mortality rate is high because of sepsis.

Sharma 2014

Methods  
Participants  
Interventions  
Outcomes  
Notes

Abstract Objective: To study the effect of chlorhexidine (CHD) application on umbilical cord and evaluate its impact on duration of NICU stay and antibiotic exposure days. Method: We enrolled 140 newborns in our study (70 in intervention group and 70 in control group), and their data were collected. Newborns in control group were given routine umbilical cord care, and intervention group received CHD spray on umbilical cord three times a day and for the next three days of cord fall. In this study, swabs were sent from umbilical cord at the age of three and seven days of life for culture. Data regarding culture-proven sepsis, duration of NICU stay and antibiotic days were recorded in the proforma for data collection. Results: This is a secondary analysis of the data of the randomized control trial. A significant reduction in duration of nursery stay was seen in CHD group in comparison with control group (12.4 ± 5.38 d versus 14.7 ± 6.62 d, p = 0.04, significant). Significant reduction was also seen in days of antibiotic exposure in the intervention group (9.74 ± 6.88 d versus 12.1 ± 7.78 d, p = 0.04, significant). Conclusion: Application of CHD to umbilical cord shortens duration of nursery stay and antibiotic days during nursery admission. This simple intervention may be used as mode in places where nursery facilities are limited, as aid in early discharge and shortening the exposure to antibiotic, which may help in reducing the prevalence of multidrug-resistance microbes. This cheap intervention may also be effective in reducing the economical burden on the health infrastructure of the country and parents.

Characteristics of ongoing studies

NCT01241318 Zambia

Study name

Impact of Chlorhexidine Cord Cleansing for Prevention of Neonatal Mortality in Zambia.

Methods

Randomised Controlled (open label) trial

Participants

Expected enrolments: 66300

Inclusion criteria: Pregnant women in the 2nd or 3rd trimester

Age 15 years and above

Pregnant women who plan to stay in the study area (catchment area of the health facility) for delivery and one month post partum

Willingness to provide cord care as per the protocol of their cluster

Willingness to provide informed consent

Exclusion Criteria: Pregnant women who are not willing to provide cord care as per the protocol of their cluster

Pregnant women who are not willing to provide informed consent

Pregnant women in the 1st trimester

Pregnant women under age 15 years 

Interventions

4% chlorhexidine gluconate, vs dry cord care

Outcomes

Primary:  all-cause mortality by day 28 of life among newborns who survive at  least the first day of life

Secondary: incidence of omphalitis

Starting date

January 2011

Contact information

Davidson H Hamer, MD

Notes

Location: Zambia

Setting:  Choma, Southern Province, Zambia 

NCT01528852, Pemba, Tanzania

Study name

"Efficacy of Use of Chlorhexidine to Clean Umbilical Cord of Neonates in First 10 Days for Reduction in Neonatal Mortality and Omphalitis - A Community Based Randomized, Double Masked Controlled Trial in Pemba Tanzania"

Methods

Randomised Controlled trial

Participants

Expected enrolments: 28000. Inclusion criteria: permanent resident of Pemba, consenting to participate, infants alive at first contact with Maternal and Child Health worker/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 hospitalisations and ICU care.

Interventions

Drug: chlorhexidine 4%
Other: control cord cleaning solution

Outcomes

Primary: neonatal mortality, Secondary: omphalitis

Starting date

October 2010

Contact information

Said M Ali, MS, Email:  

said@phlidc.org

Notes

Location: Pemba Tanzania, Registration Number: NCT01528852

Source of funding: Johns Hopkins Bloomberg School of Public Health

Summary of findings tables

1 Preventive newborn cord cleansing in hospitals

Preventive newborn cord cleansing with chlorhexidine compared with dry cord care in hospitals

Patient or population: Term or late preterm newborns born in hospitals
Settings: Hospitals (India, Germany)
Intervention: Chlorhexidine
Comparison: Dry cord care

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Dry cord care

Chlorhexidine

Neonatal mortality

Follow-up: 1.5 years

57 per 1000

6 per 1000

RR 0.11
(0.01 to 2.04)

140
(1 study)

⊕⊕⊝⊝
low 1

Gathwala 2013 (India)

Omphalitis (infections)
Follow-up: 1.5 to 1.8 years

77 per 1000

37 per 1000
(22 to 65)

RR 0.48
(0.28 to 0.84)

809
(2 studies)

⊕⊕⊕⊝
moderate 2

Gathwala 2013 (India)

Kapellen 2009 (Germany)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Footnotes

1 Downgraded by two levels due to very serious imprecision: wide 95% confidence interval (RR 0.11, 95% CI 0.01 to 2.04) and few events (N = 4 deaths);

2 Downgraded by one level because of risk of selection bias (allocation sequence generation and concealment were unclear); performance bias (inadequate blinding of research personnel); and detection bias (inadequate blinding of outcome assessors) in one trial (Kapellen 2009).

2 Preventive newborn skin cleansing in hospitals

Skin cleansing with chlorhexidine compared with usual skin care in hospitals

Patient or population: Term or late preterm newborns born in hospitals
Settings: Hospital (Brazil, Norway)
Intervention: Chlorhexidine
Comparison: Usual skin care

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Usual skin care

Chlorhexidine

Neonatal mortality

See comment

See comment

Not estimable

0 (0)

See comment

No study reported mortality outcome

Omphalitis

Follow-up: 4 to 6 weeks

118 per 1000

104 per 1000
(66 to 164)

RR 0.88
(0.56 to 1.39)

642
(2 studies)

⊕⊕⊝⊝
low 1,2

Meberg 1985 (Norway)

Da Cunha 2008 (Brazil)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Footnotes

1The quality of evidence was downgraded from high to moderate due to likely selection, performance and detection biases (sequence generation, allocation concealment, and blinding were unclear);

2The quality of evidence was downgraded from moderate to low due to serious imprecision (N = 71 events).

3 Preventive newborn cord cleansing in the community

Preventive cord cleansing with chlorhexidine compared with usual care in the community

Patient or population: Term or late preterm newborns born at home
Settings: Community settings (Bangladesh, Nepal, Pakistan)
Intervention: Chlorhexidine
Comparison: Dry cord care

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Dry cord care

Chlorhexidine

Neonatal mortality
Follow-up: 1.8 to 2.4 years

51 per 1000

41 per 1000
(36 to 47)

RR 0.81
(0.71 to 0.92)

31084
(3 studies)

⊕⊕⊕⊕
high

Arifeen 2012 (Bangladesh)

Mullany 2006 (Nepal)

Soofi 2012 (Pakistan)

Omphalitis
Follow-up: 1.8 to 2.4 years

20 per 1000

10 per 1000
(8 to 12)

RR 0.48
(0.4 to 0.57)

39925
(3 studies)

⊕⊕⊕⊕
high

Arifeen 2012 (Bangladesh)

Mullany 2006 (Nepal)

Soofi 2012 (Pakistan)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

4 Preventive newborn skin cleansing in the community

Preventive skin cleansing with chlorhexidine compared with usual skin care in the community

Patient or population: Term or late preterm newborns born at home
Settings: Community (Nepal)
Intervention: Chlorhexidine
Comparison: Usual care

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Usual skin care

Chlorhexidine

Neonatal mortality
Follow-up: mean 2.9 years

30 per 1000

31 per 1000
(26 to 36)

RR 1.03
(0.87 to 1.23)

17530
(1 study)

⊕⊕⊕⊕
high

Tielsch 2007 (Nepal)

Omphalitis

See comment

See comment

Not estimable

0 (0)

See comment

No study reported omphalitis outcome

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

5 Preventive maternal vaginal chlorhexidine in addition to total body cleansing in hospitals

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution)

Patient or population: Term or late preterm newborns born in hospitals
Settings: Hospital (Pakistan, South Africa)
Intervention: Chlorhexidine vaginal and neonatal wipes
Comparison: Placebo (sterile saline solution)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo (sterile saline solution)

Chlorhexidine vaginal and neonatal wipes

Neonatal mortality
Follow-up: 3 years

23 per 1000

22 per 1000
(15 to 32)

RR 0.98
(0.67 to 1.42)

4904
(1 study)

⊕⊕⊕⊝
moderate 1

Saleem 2010 (Pakistan)

Infections

Follow-up: 28 days to 3.6 years

39 per 1000

38 per 1000
(32 to 45)

RR 0.98
(0.82 to 1.16)

13033
(2 studies)

⊕⊕⊕⊕
high

Saleem 2007 (Pakistan)

Saleem 2010 (Pakistan)

Cutland 2009 (South Africa)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Footnotes

1 Downgraded by one level due to serious imprecision (95% CI includes appreciable benefit and harm).

6 Preventive maternal vaginal chlorhexidine in addition to total body cleansing in the community

Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution)

Patient or population: Term or late preterm newborns born at home
Settings: Hospital (Pakistan)
Intervention: Chlorhexidine vaginal and neonatal wipes
Comparison: Placebo (sterile saline solution)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Dry cord care

Chlorhexidine

Neonatal mortality

Follow-up: 28 days

2 per 100

0 per 100
(0 to 8)

RR 0.20

(0.01 to 4.03)

202
(1 study)

⊕⊕⊝⊝
low 1

Saleem 2007 (Pakistan)

Infections
Follow-up: 28 days

510 per 1000

352 per 1000
(250 to 484)

RR 0.69
(0.49 to 0.95)

203
(1 study)

⊕⊕⊕⊝
moderate 2

Saleem 2007 (Pakistan)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Footnotes

1Downgraded by two levels due to very serious imprecision: wide 95% CI (RR 0.20, 95% CI 0.01 to 4.03) and few events (N = 2 deaths).

2Downgraded by one level due to serious imprecision: small sample size (N = 203 infants) and few events (N = 87).

References to studies

Included studies

Arifeen 2012

Arifeen SE, Mullany LC, Shah R, Mannan I, Rahman, SM, Talukdar MR, et al. The effect of cord cleansing with chlorhexidine on neonatal mortality in rural Bangladesh: a community-based cluster-randomized trial. Lancet 2012;379(9820):1022-8.

Cutland 2009

Cutland CL, Madhi SA, Zell ER, Kuwanda L, Laque M, Groome M, et al. Chlorhexidine maternal-vaginal and neonate body wipes in sepsis and vertical transmission of pathogenic bacteria in South Africa: a randomized, controlled trial. Lancet 2009;374(9705):1909-16.

Da Cunha 2008

Da Cunha ML, Procianoy RS, Franceschini DT, Oliviera LL, Cunha ML. Effect of the first bath with chlorhexidine on skin colonization with Staphylococcus aureus in normal healthy term newborns. Scandinavian Journal of Infectious Diseases 2008;40(8):615-20.

Gathwala 2013

Gathwala G, Sharma D, Bhakri BK. Effect of topical application of Chlorhexidine for umbilical cord care in comparison with conventional dry cord care on the risk of neonatal sepsis: a randomized controlled trial. Journal of Tropical Pediatrics 2013;59(3):209-13.

Kapellen 2009

Kapellen TM, Gebauer CM, Brosteanu O, Labitzke B, Vogtmann C, Kiess W. Higher rate of cord-related adverse events in neonates with dry umbilical cord care compared to chlorhexidine powder. Results of a randomized controlled study to compare efficacy and safety of chlorhexidine powder versus dry care in umbilical cord care of the newborn. Neonatology 2009;96(1):13-8.

Meberg 1985

Meberg A, Schøyen R. Bacterial colonization and neonatal infections. Effects of skin and umbilical disinfection in the nursery. Acta Paediatrica Scandinavica 1985;74(3):366-71.

Mullany 2006

Mullany LC, Darmstadt GL, Khatry S, Katz J, LeClerg S, Shrestha S, et al. Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster-randomized trial [Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster-randomized trial]. Lancet 2006;367(9514):910-8.

Pereira 2011

Pereira L1, Chipato T, Mashu A, Mushangwe V, Rusakaniko S, Bangdiwala SI, et al. Randomized study of vaginal and neonatal cleansing with 1% chlorhexidine. International Journal of Gynecology and Obstetrics 2011;112:234-8. [Other: ; Other: ]

Saleem 2007

Saleem S, Reza T, McClure EM, Pasha O, Moss N, Rouse DJ, et al. Chlorhexidine Vaginal and Neonatal Wipes in Home Births in Pakistan. Obstetrics & Gynecology 2007;110(5):977-85.

Saleem 2010

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 & Gynecology 2010;115(6):1225-32.

Soofi 2012

Soofi S, Cousens S, Imdad A, Bhutto N, Ali N, Bhutta ZA. Topical application of chlorhexidine to neonatal umbilical cords for prevention of omphalitis and neonatal mortality in a rural district of Pakistan: a community-based, cluster-randomized trial. Lancet 2012;379:1029-36.

Tielsch 2007

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:e330-40.

Excluded studies

Adriaanse 1995

Adriaanse AH, Kollée LA, Muytjens HL, Nijhuis JG, de Haan AF, Eskes TK.. Randomized study of vaginal chlorhexidine disinfection during labor to prevent vertical transmission of group B streptococci. European Journal of Obstetrics & Gynecology and Reproductive Biology 1995;61(2):135-41.

Alder 1980

Alder VG, Burman D, Simpson RA, Fysh J, Gillespie WA. Comparison of hexachlorophane and chlorhexidine powders in prevention of neonatal infection. Archives of Diseases in Childhood 1980;55(4):277-80.

Bakr 2005

Bakr AF, Karkour T. Effect of Predelivery Vaginal Antisepsis on Maternal and Neonatal Morbidity and Mortality in Egypt. Journal of Women's Health 2005;14(6):496-501.

Burman 1992

Burman LG, Christensen P, Christensen K, Fryklund B, Helgesson AM, Svenningsen NW, et al. Prevention of excess neonatal morbidity associated with group B streptococci by vaginal chlorhexidine disinfection during labour. The Lancet 1992;340(8811):65-9.

Eriksen 1997

Eriksen NL, Sweeten KM, Blanco JD. Chlorhexidine vs. sterile vaginal wash during labour to prevent neonatal infection. Infectious Diseases in Obstetrics and Gynecology 1997;5(4):286-90.

Gaillard 2001

Gaillard P, Mwanyumba F, Verhofstede C, Claeys P, Chohan V, Goetghebeur E, et al. Vaginal Lavage with Clorhexidine during labour to reduce mother-to-child HIV transmission: clinical trial in Mombasa, Kenya. AIDS 2001;15(3):389-96.

Henrichsen 1994

Henrichsen T1, Lindemann R, Svenningsen L, Hjelle K. Prevention of neonatal infections by vaginal chlorhexidine disinfection during labour. Acta Paediatrica 1994;83(9):923-6.

Hodgins 2010

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

Mullany 2008

Mullany LC, Khatry SK, Sherchand JB, et al. A randomized controlled trial of the impact of chlorhexidine skin cleansing on bacterial colonization of hospital-born infants in Nepal. The Pediatric Infectious Disease Journal 2008;27(6):505-511.

Mullany 2012

Mullany LC, Saha SK, Shah R, Islam MS, Rahman M, Islam M, et al. Impact of 4.0% chlorhexidine cord cleansing on the bacteriologic profile of the newborn umbilical stump in rural Sylhet District, Bangladesh.. Pediatric Infectious Disease Journal 2012;31(5):444-50.

Mullany 2013

Mullany LC, Shah R, Arifeen S, Mannan I, Winch PJ, Hill A, et al. Chlorhexidine cleansing of the umbilical cord and separation time: a cluster-randomized trial. Pediatrics 2013;131(4):708-15.

Nuntnarumit 2013

Nuntnarumit P, Sangsuksawang N. A randomized controlled trial of 1% aqueous chlorhexidinegluconate compared with 10% povidine-iodine for topical antiseptic in neonates: effects on blood culture contamination rates. Infection control & Hospital Epidemiology: the official journal of the Society of Hospital Epidemilogists of America 2013;34(4):430-2.

Oishi 2004

Oishi T, Iwata S, Nonoyama M, Tsuji A, Sunakawa K. Double-blind comparative study on the care of the neonatal umbilical cord using 80% ethanol with or without chlorhexidine. Journal of Hospital infection 2004;58(1):34-7.

Pezzati 2003

Pezzati M1, Rossi S, Tronchin M, Dani C, Filippi L, Rubaltelli FF. Umbilical cord care in premature infants: the effect of two different cord-care regimens (salicylic sugar powder vs chlorhexidine) on cord separation time and other outcomes. Pediatrics 2003;112:e275-9.

Rouse 1997

Rouse DJ, Hauth JC, Andrews WW, Mills BB, Maher JE. Chlorhexidine vaginal irrigation for the prevention of peripheral infection: a placebo-controlled randomized clinical trial. American Journal of Obstetrics Gynecology 1997;176(3):617-22.

Rouse 2003

Rouse DJ, Cliver S, Lincoln TL, Andrews WW, Hauth JC. Clinical trial of chlorhexidine vaginal irrigation to prevent peripheral infection in nulliparous women. American Journal of Obstetrics Gynecology 2003;189(1):166-70.

Stray-Pedersen 1999

Stray-Pedersen B, Bergan T, Hafstad A, Normann E, Grøgaard J, Vangdal M.. Vaginal disinfection with chlorhexidine during childbirth. International Journal of Antimicrobial Agents 1999;12(3):245-51.

Taha 1997

Taha TE, Biggar RJ, Broadhead RL, Mtimavalye LA, Justesen AB, Liomba GN, et al. Effect of cleansing the birth canal with antiseptic solution on maternal and newborn morbidity and mortality in Malawi: Clinical trial. British Medical Journal 1997;315(7102):216-20.

Studies awaiting classification

Abdeyazdan 2014

Abdeyazdan Z, Majidipour N, Zargham-Boroujeni A. Comparison of the effects of povidone-iodine and chlorhexidine solutions on skin bacterial flora among hospitalized infants. Journal of Education and Health Promotion 2014;3:16. [PubMed: 24741656]

Gupta 2014

Gupta B, Vaswani ND, Sharma D, Chaudhary U, Lekhwani S. Evaluation of efficacy of skin cleansing with chlorhexidine in prevention of neonatal nosocomial sepsis - a randomized controlled trial. The Journal of Maternal-fetal & Neonatal Medicine 2014;1-6. [PubMed: 25483421]

Sharma 2014

Sharma D, Gathwala G, Shastri S. Chlorhexidine - a novel intervention to decrease the nursery stay and antibiotic exposure duration - randomized trial. The Journal of Maternal-fetal & Neonatal Medicine 2014;1-5. [PubMed: 25434645]

Ongoing studies

NCT01241318 Zambia

Unpublished data only

NCT01528852, Pemba, Tanzania

Unpublished data only

Additional references

ACOG 2008

Engle WA,Tomashek KM, Wallman C, MSN and the American Academy of Pediatrics Committee on Fetus and Newborn. Late preterm infants. ACOG Committee opinion 2008;404.

Belfrage 1985

Belfrage E, Enocksson E, Kalin M, Marland M. Comparative efficiency of chlorhexidine and ethanol in umbilical cord care. Scandinavian Journal of Infectious Diseases 1985;17(4):413-20.

Chandrasekaran 2013

Chandrasekaran A, Sankar MJ, Agarwal R, Paul VK. Topical umbilical cord care. The Pediatric Infections Disease Journal 2013.

Choi 2008

Choi Y, Saha SK, Ahmed AS, Law PA, Chowdhury MA, Islam M, et al. Routine skin cultures in predicting sepsis pathogens among hospitalized preterm neonates in Bangladesh. Neonatology 2008;94(2):123-31.

Darmstadt 1998

Darmstadt GL, Black RE, Santosham M. Research priorities and postpartum care strategies for the prevention and optimal management of neonatal infections in less developed countries. Pediatric Infectious Disease Journal 2000;19(8):739-50.

Denton 2001

Denton GW. Chlorhexidine. In: Block SS, editor(s). Disinfection, Sterilization, and Preservation. 5th edition. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001:321-6.

Garland 1995

Garland JS, Buck RK, Maloney P, Durkin DM, Toth-Lloyd S, Duffy M, et al. Comparison of 10% povidine-iodine and 0.5% chlorhexidine gluconate for the prevention of peripheral intravenous catheter colonization in neonates: a prospective trial. Pediatric Infectious Disease Journal 1995;14(6):510-6.

Garland 2001

Garland JS, Alex CP, Mueller CD, Otten D, Shivpuri C, Harris MC, et a. A randomized trial comparing povidine-iodine to a chlorhexidine gluconate-impregnated dressing for prevention of central venous catheter infections in neonates. Pediatrics 2001;107(6):1431-6.

Goldenberg 2006

Goldenberg RL, McClure M, Saleem S, Rouse D, Vermund S. Use of vaginally administered chlorhexidine during labour to improve pregnancy outcomes. Obstetrics and Gynecology 2006;107(5):1139-46.

Goldenberg 2013

Goldenberg RL, McClure EM, Saleem S. A review of studies with chlorhexidine applied directly to the umbilical cord. American Journal of Perinatology 2013;30(8):699-702.

GRADEpro

GRADEpro. [Computer program on www.gradepro.org] [Computer program]. McMaster University, 2014, 2009.

Guyatt 2011

Guyatt G, Oxman AD, AkI EL, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and Summary of Findings tables. Journal of Clinical Epidemiology 2011;64(4):383-94.

Imdad 2013

Imdad A, Bautista RM, Senen KA, Uy ME, Mantaring JB, Bhutta ZA. Umbilical cord antiseptics for preventing sepsis and death among newborns. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD008635. DOI: 10.1002/14651858.CD008635.pub2.

Karumbi 2013

Karumbi JK, Mulaku M, Aluvaala J, English M, Opiyo N. Topical umbilical cord care for prevention of infection and neonatal mortality. The Pediatric Infectious Disease Journal 2013;32(1):78-83.

Lawn 2001

Lawn J, McCarthy BJ, Ross SR. The healthy newborn: a reference manual for program managers. Atlanta, GA: The CARE/CDC Health Initiative, 2001.

Levy 2005

Levy I, Katz J, Solter E, Samra Z, Vidne B, Birk E, et al. Chlorhexidine-impregnated dressing for prevention of colonization of central venous catheters in infants and children: a randomized controlled study. Pediatric Infectious Disease Journal 2005;24(8):676-9.

Lowbury 1973

Lowbury E.J., Lilly H.A. Use of 4 per cent chlorhexidine detergent solution (Hibiscrub) and other methods of skin disinfection. British Medical Journal 1973;1(5852):510-5.

Lumbiganon 2011

Lumbiganon P, Thinkhamrop J, Thinkhamrop B, Tolosa JE. Vaginal chlorhexidine during labour for preventing maternal and neonatal infections (excluding Group B Streptococcal and HIV). Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004070. DOI: 10.1002/14651858.CD004070.pub2.

Mario 2008

Mario SD, Basevi V, Daya l, Magnano l, Magrini N. Review of the available evidence on 4% chlorhexidine solution for umbilical cord care. For the WHO model list of essential medicines. Second meeting of the subcommittee of the Expert Committee on the selection and use of Essential Medicines, Geneva, 29 September to 3 October 2008 June 2008.

McClure 2007

McClure EM, Goldenberg RL, Brandes N, Darmstadt GL, Wright LL; CHX Working Group. The use of chlorhexidine to reduce maternal and neonatal mortality and morbidity in low-resource settings. International Journal of Gynecology and Obstetrics 2007;97(2):89-94.

Mullany 2003

Mullany LC, Darmstadt GL, Tielsch JM. Role of antimicrobial applications to the umbilical cord in neonates to prevent bacterial colonization and infection: a review of the evidence. Pediatric Infectious Disease Journal 2003;22(11):996-1002.

Osrin 2012

Osrin, Hill ZE. Chlorhexidine cord cleansing to reduce neonatal mortality. Lancet 2012;379(9820):984-6.

RevMan 2011

Review Manager (RevMan) [Computer program]. Copenhagan: The Nordic Cochrane Centre. The Cochrane Collaboration, 2011.

Saleem 2013

Saleem S. Application of 4% chlorhexidine solution for cord cleansing after birth reduces neonatal mortality and omphalitis. Evidence-Based Medicine 2013;18(2):ebmed.18.2.e15.

Stade 2008

Stade BC, Shah VS, Ohlsson A. Vaginal chlorhexidine during labour to prevent early-onset neonatal group B streptococcal infection. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD003520. DOI: 10.1002/14651858.CD003520.pub2.

Terrone 1999

Terrone D, Rinehart BK, Einstein MH, Britt LB, Martin JN, Perry KG. Neonatal sepsis and deaths caused by resistant Escherichia coli:possible consequences of extended maternal ampicillin administration. American Journal of Obstetrics and Gynecology 1999;180(6 Pt 1):1345-8.

Tielsch 2005

Tielsch JM, Darmstadt GL, Mullany LC, et al. A community based, randomized trial of newborn washing with chlorhexidine on neonatal mortality in southern Nepal (abstract). In: Pediatric Academic Societies 2005 annual meeting. May 14 2005.

United Nations 2001

http://www.un.org/millenniumgoals. http://www.un.org/millenniumgoals.

Vorheer 1980

Vorherr H, Ulrich JA, Messer RH, Hurwitz EB. Antimicrobial effect of chlorhexidine and povidone-iodine on bacteria of groin, perineum and vagina. Journal of Reproductive Medicine 1980;24(4):153-7.

Weinstein 2008

Weinstein RA, Milstone AM, Passaretti CL, Perl TM. Chlorhexidine: Expanding the armamentarium for infection control and prevention. Clinical Infectious Diseases 2008;46(2):274-81.

WHO 1994

WHO. WHO Scientific Working Group on Monitoring and Management of Bacterial Resistance to Antimicrobial Agents. Geneva: WHO. WHO Scientific Working Group on Monitoring and Management of Bacterial Resistance to Antimicrobial Agents. Geneva: WHO 1994.

WHO 2001

World Health Organization. Estimates in saving newborn lives. In: State of the World's Newborns. Washington DC: Save the Children Federation-U.S., 2001:1-49.

Zupan 2004

Zupan J, Garner P, Omari AA. Topical umbilical cord care at birth. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD001057. DOI: 10.1002/14651858.CD001057.pub2.

Classification pending references

None noted.

Data and analyses

1 Newborn skin or cord cleansing in hospital with chlorhexidine compared to no intervention

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Neonatal mortality 1 280 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.01, 2.04]
1.2 Omphalitis, Infection 4 1451 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.49, 0.98]
  1.2.1 Cord cleansing with chlorhexidine 2 809 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.28, 0.84]
  1.2.2 Total body cleansing with chlorhexidine 2 642 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.56, 1.39]
 

2 Newborn skin or cord cleansing in the community

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Neonatal mortality 4 Risk Ratio (IV, Fixed, 95% CI) 0.88 [0.79, 0.97]
  2.1.1 Cord cleansing with chlorhexidine in the Community 3 Risk Ratio (IV, Fixed, 95% CI) 0.81 [0.71, 0.92]
  2.1.2 Total body cleansing with chlorhexidine in the community 1 Risk Ratio (IV, Fixed, 95% CI) 1.03 [0.87, 1.23]
2.2 Omphalitis 3 Risk Ratio (IV, Fixed, 95% CI) 0.48 [0.40, 0.57]
  2.2.1 Cord cleansing with chlorhexidineNew Subgroup 3 Risk Ratio (IV, Fixed, 95% CI) 0.48 [0.40, 0.57]
  2.2.2 Total body cleansing with chlorhexidine in the community 0 Risk Ratio (IV, Fixed, 95% CI) Not estimable
 

3 Maternal vaginal chlorhexidine in addition to skin or cord care compared to no intervention in hospitals

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Neonatal mortality 1 4904 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.68, 1.41]
3.2 Infections 2 13033 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.82, 1.16]
  3.2.1 Maternal Vaginal chlorhexidine in addition to total body cleansing 2 13033 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.82, 1.16]
  3.2.2 Maternal vaginal chlorhexidine and cord cleansing with CHX 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
3.3 Hypothermia defined as an axillary temperature below 36.5 degrees celsius 1 508 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [1.19, 1.49]
 

4 Maternal vaginal chlorhexidine in addition to skin or cord care compared to no intervention in the community

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
4.1 Neonatal mortality 1 202 Risk Ratio (M-H, Fixed, 95% CI) 0.20 [0.01, 4.03]
4.2 Infections 1 203 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.49, 0.95]
 

Figures

Figure 1

Refer to figure 1 caption below

Study flow diagram (Figure 1 description).

Figure 2

Refer to figure 2 caption below

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (Figure 2 description).

Figure 3

Refer to figure 3 caption below

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (Figure 3 description).

Figure 4 (Analysis 1.2)

Refer to figure 4 caption below

Forest plot of comparison: 1 Newborn skin or cord cleansing in hospital with chlorhexidine compared to no intervention, outcome: 1.2 Omphalitis, Infection (Figure 4 description).

Figure 5 (Analysis 2.1)

Refer to figure 5 caption below

Forest plot of comparison: 2 Newborn skin or cord cleansing in the community, outcome: 2.1 Neonatal mortality (Figure 5 description).

Figure 6 (Analysis 2.2)

Refer to figure 6 caption below

Forest plot of comparison: 2 Newborn skin or cord cleansing in the community, outcome: 2.2 Omphalitis (Figure 6 description).

Figure 7 (Analysis 3.2)

Refer to figure 7 caption below

Forest plot of comparison: 3 Maternal vaginal chlorhexidine in addition to skin or cord care compared to no intervention, outcome: 3.2 infections (Figure 7 description).

Sources of support

Internal sources

  • Indian Council of Medical Research, India. Johns Hopkins University, U.S.A. Maulana Azad Medical College, New Delhi, India. Municipal Corporation of Delhi, India, India

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

Appendices

1 Search Strategy and results PUBMED November 2013

Database Searched: Pubmed

Date Searched: November 17, 2013

Search Terms: chlorhexidine AND ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh])) AND ( ( "2012/04/01"[PDat] : "2013/12/31"[PDat] ) )

23 articles were retrieved.


This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2015 (see http://www.thecochranelibrary.com External Web Site Policy for information).  Cochrane reviews are regularly updated as new evidence emerges and in response to feedback.  The Cochrane Library should be consulted for the most recent version of the review.