Dry care versus chlorhexidine cord care for prevention of omphalitis. Systematic review with meta-analysis

ABSTRACT Objective: to compare the effect of dry care and the application of chlorhexidine to the umbilical cord of newborns at risk of developing omphalitis. Method: systematic review with meta-analysis. Clinical trials comparing dry care with the application of clorexidine to evaluate omphalitis were selected. Methodological quality was evaluated using the Consolidated Standards of Reporting Trials. Results: the joint analysis of the studies shows a significant decrease in the risk of omphalitis in the chlorhexidine group compared to the dry care group (RR=0.58, CI: 0.53-0.64). However, in the analysis by subgroups, chlorhexidine umbilical cord care did not reduce the risk of omphalitis in hospital births (RR=0.82, CI: 0.64-1.05), in countries with a low infant mortality rate (RR=0.8, CI: 0.5-1.28), or at chlorhexidine concentrations below 4% (RR=0.55, CI: 0.31-1). Chlorhexidine acted as a protective factor at a concentration of 4% (RR=0.58, CI: 0.53-0.64), when applied in cases of home births (RR=0.57, CI: 0.51-0.62), in countries with a high infant mortality rate (RR=0.57, CI: 0.52-0.63). Conclusion: dry cord care is effective in countries with low infant mortality rate and in hospital births. However, 4% chlorhexidine for umbilical cord care protects against omphalitis in home births, in countries with a high infant mortality rate.


Introduction
Omphalitis is an important cause of neonatal mortality and its prevention is of great importance for public health (1) . The incidence of omphalitis in newborns (NB) in developed countries is 0.7%, rising to 2.7% in developing countries (1)(2) , and it affects both sexes equally (1) .
It is defined as a periumbilical acute bacterial infection with induration, erythema, bad smell, pain, and presenting or not association with purulent exudate at the base of the navel (3) . It is peculiar at the neonatal period, and the average age for its incidence is the third or fourth day of life (2)(3) .
The strategies for prevention of omphalitis are: hygiene practices at delivery, aseptic material to cut the umbilical cord and hand washing every time the cord is handled (4) . In the 21st century there have been several studies on umbilical cord (UC) care comparing different antiseptics, and several studies have shown that the hygiene habits of bathing and drying it were not associated with an increased risk of omphalitis when compared to alcohol application (4)(5)(6) . Topical triple dye is a treatment used in the United States, and there are several studies comparing the topical triple dye with alcohol application for UC care, and the results of these studies show that there are no differences between the treatment groups of omphalitis (7)(8) .
There are no studies with adequate level of evidence to establish recommendations on the most effective UC care for prevention of omphalitis in NB.
Thus, a systematic review was performed to answer the question: Is the application of chlorhexidine more effective than dry cord care for prevention of omphalitis? The objective was: to compare the effect of dry care and the application of chlorhexidine to the umbilical cord of newborns at risk of developing omphalitis. prepare and publish the systematic review and metaanalysis, the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (9) were followed.

Method
For the selection of the studies, two authors independently assessed the inclusion of the studies identified by the search strategy. In the first phase, the articles were selected according to their title and, after reading the abstracts, those that met the inclusion criteria were selected. Subsequently, an in-depth reading was carried out and their methodological quality was assessed using the Consolidated Standards Of Reporting Trials (CONSORT) (10) .
Clinical trials comparing dry care with the application of chlorhexidine solutions at all concentrations available for UC care were used as inclusion criteria. All living NB were included, without restricting the weight at birth, sex, gestational age, geographical area, level of development and delivery setting.
Using a previously developed form, two authors independently extracted the data according to: type of study, population included, length of fieldwork period, duration of follow-up, type of intervention, procedure carried out with both the dry care and the chlorhexidine cord care, and results obtained. Those authors whose articles are the subject of this study were contacted so that they could provide the data necessary for performing the meta-analysis by subgroups. A third person evaluated the discrepancies found in order to decide on the inclusion of some articles and on data extraction.
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) (11) was used to evaluate the quality of the evidence, which was classified as: high, moderate, low or very low.
The results were expressed as relative risk (RR) with 95% confidence interval. The clinical heterogeneity and the homogeneity of the population were evaluated. The statistical heterogeneity and the consistency between the results of the studies were evaluated using I 2 as criterion measure. I 2 values of 25%, 50% and 75% were used to define heterogeneity as low, moderate and high. When this criterion was higher than 50%, a random effects model was applied to combine the results (12) . A sensitivity analysis of the results was carried out by performing  For the statistical analysis, Review Manager 5.3 (13) and Epidat 3.1 (14) softwares were used. Figure 1 shows the process of selecting studies.

Results
The literature search found 511 articles, of which 468 were discarded after a reading of their titles.
The analysis of the summaries led to exclusion of 28 through a complete reading of 15 articles, and 6 were eliminated for different reasons: chlorhexidine was not compared with dry cord care (15) ; be a research project (16) ; not be a clinical trial (17); exclusively measure the time until the umbilical cord stump falls off (18)(19)(20) .

Monitoring, procedure and results
Meberg et al (21) . Norway, 1985.          (30) was 0.4556 (p=0.6625), which indicates that there is no publication bias. The data with which the meta-analysis was carried out (Figure 4) come from studies in which chlorhexidine was applied multiple times. According to the GRADE system, this level of evidence is rated as moderate. It can be seen in the tree graph ( Figure 4) that four studies (21,(27)(28)(29) do not show a significant decrease in the risk of omphalitis with the use of chlorhexidine for cord care when compared with dry care.

Study Allocation concealment
Randomized sequence

Blinding of participants and practioners
Blinding of the evaluators Incomplete data Selective report of results and in this case, the statistical heterogeneity obtained is low (I 2 =23%). When sensitivity was analyzed by eliminating studies, it is observed that if a study is eliminated (22) , the resulting relative change is 6.18%, and this is the research whose confidence interval is more  studies also do not show differences in the incidence of omphalitis depending on the type of cord care, although they did not compare solely dry care with the application of chlorhexidine (32)(33) for UC care.

Sazawal
Several systematic reviews have shown similar results, in which chlorhexidine was found to reduce the risk of omphalitis (33)(34)(35) , especially in countries with high NMR. In this sense, our results support that UC care with the use of 4% chlorhexidine protects against omphalitis in home births in countries with high NMR. The application of chlorhexidine in concentrations lower than 4% did not act as a protection factor against omphalitis, although it must be emphasized that the studies using these concentrations of chlorhexidine evaluated hospital births.
Depending on where the birth takes place, the UC cutting technique is performed with the use of a new or boiled razor blade (35)(36) , and this, together with the lack of hand washing before the intervention (35) increases the risk of infection, especially in home deliveries.
Researchers are aware that efforts to promote hand washing, cut the umbilical cord with the use of clean instruments and avoid unclean domestic interventions can reduce exposure to infectious agents and improve neonatal outcomes (37) .
Limitations: This systematic review with metaanalysis needs to be interpreted with caution due to the included clinical trials and their own limitations. In at least 5 of these studies, it was not possible to mask the intervention of participants and professionals, although it is unlikely that the results were biased, as proven by the sensitivity analysis.
There is variation in the interventions carried out in the different studies such as: in 4 research studies (22,25,(27)(28) , training was provided to the mothers so that they could perform a correct hand hygiene. Regarding hygiene for cutting of the UC, 5 studies (22,(24)(25)(27)(28) specify that a delivery kit was given to achieving maximum cleanliness.
In 6 studies, the chlorhexidine concentration used for cord care was 4% (21)(22)(24)(25)(27)(28) , and the concentrations used in the remaining three studies (23,26,29) were 2.5% and 1% (23,26,29) . The sensitivity analysis performed considering the different chlorhexidine concentrations used, suggests that the use of chlorhexidine in concentrations lower than 4% is not associated with a greater protection against omphalitis than that provided by dry umbilical cord care.
Another limitation of the present analysis is that no data on low birth weight and premature babies are shown. The analysis only used data available from studies whose inclusion criteria specified NB at more than 36 weeks gestation.
The criteria used to perform the analysis on the studies classifying omphalitis into several categories were: Redness with pus or severe redness and severe redness with pus, which correspond to moderate and severe omphalitis.
There is no conflict of interest or funding in this study.

Conclusion
Application of 4% chlorhexidine in NB significantly There are no significant differences between dry cord care and the use of chlorhexidine in concentrations lower than 4% for UC care in countries with low NMR and in hospital births. It was evidenced that dry cord care is an effective intervention in these contexts and it may be recommended for prevention of omphalitis because it is less expensive. Therefore, it is convenient to expand the knowledge through double blind clinical trials in these contexts to evaluate both interventions and thus improve the care practice provided to the newborn.
In full term NB, there are no statistically significant differences between the two groups of UC care. It is necessary to carry out more studies according to the gestational age to know what proportion of preterm newborns have omphalitis regardless of the type of cord care.
It would be useful to conduct studies with qualitative methodology to know the experiences in the UC care and consider them for the development of more effective and efficient health strategies aiming at reducing the incidence of omphalitis.