Interventions for treating umbilical granuloma: a protocol for a systematic review and meta-analysis of randomised controlled trials
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* Fumihiko Namba
* Naoyuki Miyahara
* Mitsuhiro Haga
* Erika Ota
* Yasuhisa Ikuta
* Citra Gabriella Mamahit

## Abstract

**Introduction** The most frequent umbilical abnormality in infancy period is umbilical granuloma. Although umbilical granuloma treatment with silver nitrate is practised worldwide, silver nitrate cauterisation is high in cost and if silver nitrate comes into contact with healthy tissues, it might cause injury. This systematic review aims to look for evidence concerning the safety and efficacy of all interventions for treating umbilical granuloma in neonates.

**Methods and analysis** Individual and cluster randomised controlled trials will be included in our study. The direct comparisons between two of any interventions for treating umbilical granuloma, including silver nitrate cauterisation, dry care, common salt, alcoholic wipes, topical doxycycline, topical steroid ointment, ligatures, cryosurgery, electrocautery, surgical excision and no intervention will be investigated. Primary outcomes will be the healing rate after 2 weeks of treatment and the incidence of cord-related adverse events. We will search CENTRAL, Embase and MEDLINE.

**Ethics and dissemination** Ethical approval is not applicable in this study since we will retrieve and analyse data from previous published studies. The results of this systematic review are expected to be published in a scientific journal and presented at medical conferences.

**PROSPERO registration number** CRD42022369915.

*   neonatal intensive & critical care
*   systematic review
*   neonatology

### STRENGTHS AND LIMITATIONS OF THIS STUDY

*   This systematic review aims to create the most comprehensive review of the effects of any interventions for the treatment of umbilical granuloma.

*   Although systematic review provides the best available evidence, limitations could be due to selection of studies and relevant outcomes, methods of analysis, interpretation of heterogeneity and application of results.

*   There is potential for a low certainty of the evidence of the included studies in this systematic review.

## Introduction

Umbilical granuloma (UG) is one of the most common umbilical abnormalities in the infancy period with a prevalence estimated at in 500 newborn infants. With a careful medical history and physical examination, most UG can be easily diagnosed. The granulation tissue near the umbilicus is usually pink, soft, composed of fibroblasts and capillaries, with a diameter of 3–10 mm in size, and may secrete seropurulent fluid.1 Within 1–2 weeks after birth, the umbilical chord stump normally dries and separates.2 On the closure of the umbilicus fibromuscular ring and the fall of the cord stump, the ring is normally covered by the skin. Inadequate epithelialisation over the ring and granulation tissue may be present after cord separation. Granulation tissue production is a natural part of wound healing, but it can cause UG when it occurs in the umbilicus. The primary cause of UG formation is delayed and uneven stump separation caused by inflammation in response to subclinical infection.3 This excessive granulation tissue fails epithelialisation of the normal process, resulting in infections, such as omphalitis and necrotising fasciitis, which are life-threatening complications and may result in death.4 The mortality risk is 46% higher among infants with cord infection compared with those without in a developing country.5 Untreated UG spontaneous regression is not well documented. Therefore, UG is considered pathological and needs treatment.6

Conventional treatment of UG with silver nitrate is a worldwide practice. In textbooks of paediatrics and neonatology, SNC (silver nitrate cauterisation) is advocated as a first-line treatment option, and other non-invasive and invasive approaches almost are not mentioned. However, SNC is high in cost and adjacent healthy tissues may be damaged to skin burning and ulceration if silver nitrate is contacted.7–9 Therefore, the main objective of this systematic review is to look for evidence concerning the safety and efficacy of any interventions for treating UG in neonates, including SNC, dry care, common salt, alcoholic wipes, topical doxycycline, topical steroid ointment, double ligatures, cryosurgery, electrocautery and surgical excision.

## Methods and analysis

### Study aim

To evaluate the effectiveness of any interventions for the treatment of UG in neonates.

### Study design

Individual and cluster randomised controlled trials (RCTs) will be included. Studies based on language or publication status, such as conference abstracts and PhD theses will not be excluded.

### Types of participants

Neonates with UG.

### Types of interventions

Direct comparisons between two of any interventions for treating UG will be conducted.

Intervention

1.  SNC.

2.  Dry care, the procedure in which the umbilical stump is kept ‘clean and dry without applying anything’.

3.  Common salt
    
    *   1 Table salt placed for a long period (≥30 min).
    
    *   2 Table salt placed for a short period (<30 min).
    
    *   3 Hypertonic NaCl solution.

4.  Alcoholic wipes.

5.  Topical doxycycline.

6.  Topical steroid ointment.

7.  Ligatures.

8.  Cryosurgery.

9.  Electrocautery.

10. Surgical excision.

11. No intervention, not receiving any interventions.

### Outcome measures

Primary outcomes

1.  Healing rate after 2 weeks of treatment.

2.  Incidence of cord-related adverse events.

Secondary outcomes

1.  The time to healing.

2.  Incidence of not cord-related adverse events.

3.  Parents’ acceptance of treatment.

4.  Parents’ satisfaction with treatment.

### Electronic searches

Relevant trials will be searched in the following databases from the inception to January 2023: CENTRAL (Cochrane Central Register of Controlled Trials), Embase and MEDLINE (see online supplemental material). All relevant RCTs will be identified regardless of the status of publication (published, unpublished, in progress or in press) or language.

### Supplementary data

[[bmjopen-2023-076931supp001.pdf]](pending:yes)

### Data collection and analysis

### Selection of studies

Two authors (YI and CGM) will independently screen the retrieved articles based on the title and abstract to identify which study should be evaluated. All potentially relevant full-text articles will be investigated. Any disagreements will be resolved through consensus or by involving the third author (EO). If the issue is unable to be resolved, the article will be added to the ‘awaiting assessment’ list, and study authors will be contacted for clarification. An adapted Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols flow chart will be presented.

### Data extraction and management

Studies that meet the inclusion criteria will be abstracted independently by two authors (YI and CGM). Data about efficacy outcomes and adverse events will also be reported. Disagreements will be resolved through discussion or, if necessary, by a third author (EO), using standard data extraction templates.

In the table ‘study characteristics’ and ‘matrix of study endpoints’ online supplemental appendix, information about possibly relevant ongoing studies, including trial identifiers, will be provided. The protocol of the included study will be located in ongoing trial databases or in study design publications. The data in the ‘matrix of study endpoints’ (protocol/trial documents) appendix will be specified.

In order to see if the authors are available to address questions about their trials, an email will be sent to all authors. Following that, if necessary, the primary author of the article will be contacted to obtain any missing trial information.

### Assessment of risk of bias

The risk of bias will be assessed by two authors (YI and CGM) independently. Disagreements will be resolved with a third author (EO) by consensus, or by consultation.

The risk of bias will be assessed using the Cochrane Risk of Bias 2.0 tool. We will assess the following criteria in this assessment:

*   Randomisation process.

*   Deviations from intended interventions.

*   Missing outcome data.

*   Measurement of the outcome.

*   Selection of the reported results.

Risk of bias criteria will be judged as ’low risk’, ’high risk’ or ‘some concerns’. Individual bias items will be evaluated.10 A figure of ’risk of bias’ graph and ’risk of bias summary’ will be presented.

### Measures of treatment effect

Dichotomous data will be presented as risk ratios or ORs with 95% CIs. Continuous data will be presented as mean differences with 95% CIs.

### Unit of analysis issues

The randomisation level, such as cluster RCTS, cross-over RCTs and multiple observations, will be considered.

### Dealing with missing data

Missing data will be obtained from authors, if possible, and thoroughly evaluate important numerical data such as screened, intention-to-treat and per-protocol populations. Attrition rates, such as drop-outs, withdrawals, lost to follow-up will be evaluated.

In the absence of SD for outcomes, values will be imputed by assuming that the missing outcome’s SD is the average of the SD from the studies that disclosed this information. The robustness of the overall findings will be examined using sensitivity analysis.

### Assessment of heterogeneity

If there is significant statistical heterogeneity, the results will not be reported in a meta-analysis. Due to the low power of the test, the heterogeneity will be assessed visually by inspecting the forest plots and by using a standard χ2 test with a significance level of α=0.1.To analyse the influence of heterogeneity on the meta-analysis, heterogeneity will be examined using the I2 statistic, which measures inconsistency; an I2 value of 75% or greater indicates a significant inconsistency level. An examination of the characteristics of individuals and subgroups will be conducted when heterogeneity is found.

### Assessment of reporting biases

An assessment of the effects of small studies will be conducted using funnel plots if there are more that 10 studies included that investigate a particular outcome. The results will be interpreted carefully due to the possibility of several explanations for the asymmetry of funnel plot.

### Data synthesis

In the absence of strong evidence for homogeneous effects across trials, a random-effects model will be used to summarise a low risk of bias data. Random-effects meta-analysis will be interpreted by considering the whole distribution of effects. In addition, we will perform statistical analyses in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Where statistical pooling is not possible, or heterogeneity is found, we will present the findings in narrative form.

### Subgroup analysis and heterogeneity

We intend to conduct subgroup analysis and examine the interaction.

Meta-analysis will be performed within study subgroups and across all trials, regardless of subgroup membership.

*   Neonates (<28 days of age) versus others.

*   Developing countries versus developed countries.

### Sensitivity analysis

We will conduct sensitivity analyses to investigate the impact of these factors on effect sizes.

*   Analysing only to study that are published.

*   Limiting the analysis by considering the risk of bias.

*   Identify the extent to which the results are dominated by limiting the analysis to large/long trials.

*   Limiting the analysis based on the publication language, country, diagnostic criteria, imputation and source of funding.

The analyses will be repeated to determine the robustness of the results using a variety of effect size measures and different statistical models.

### Summary of findings and assessment of the certainty of the evidence

We plan to create ‘summary of finding’ tables for the following comparisons.

*   SNC versus dry care.

*   SNC versus common salt.

*   SNC versus alcoholic wipes.

*   SNC versus topical doxycycline.

*   SNC versus topical steroid ointment.

*   SNC versus ligatures.

*   SNC versus cryosurgery.

*   SNC versus electrocautery

*   SNC versus surgical excision.

We will include the following outcomes to assess the certainty of the evidence.

*   Healing rate after 2 weeks of treatment.

*   Incidence of cord-related adverse events.

*   The time to healing.

*   Incidence of not cord-related adverse events.

*   Parents’ acceptance of treatment.

*   Parents’ satisfaction with treatment.

One review author (YI) will do the Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments of each outcome. Disagreements will be resolved through consensus or by involving the third author (EO).

The certainty of the body of evidence will be assessed for each outcome using GRADE with five considerations (risk of bias, consistency of effect, imprecision, indirectness and publication bias). According to the GRADE approach, evidence is classified as ‘high’, ‘moderate’, ‘low’ or ‘very low’ depending on the outcome. For example, if the summary included numerous randomised trials with a low risk of bias, the rating of certainty would be high, but if there were concerns about the risk of bias, inconsistency, indirectness, imprecision or publication bias, the rating of certainty would be lower. Explanations should be provided in the footnotes or in the comment column in the summary of findings table for judgements that are not of high certainty. GRADEpro GDT software will be used to adhere to GRADE guidance.

### Patient and public involvement

Patients and the public will not be involved in the design, reporting, interpretation or dissemination of this research since it is based on previously published data.

## Ethics and dissemination

No ethical approval is required. There will be no involvement of human subjects in this study. We will retrieve and analyse data from previous published studies. The results of this systematic review are expected to be published in a scientific journal and presented at medical conferences.

## Ethics statements

### Patient consent for publication

Not applicable.

## Footnotes

*   Twitter @nambaf1107

*   Contributors FN, NM and MH performed the protocol of this study. YI and CGM are responsible for literature searches, screening and data analysis. EO will be responsible to resolve the disagreement and assist in data analysis. All authors read and approved the final protocol. We are grateful to all authors for their support of this study.

*   Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

*   Competing interests None declared.

*   Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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## References

1.  Nagar H. Umbilical Granuloma: a new approach to an old problem. Pediatr Surg Int 2001;17:513–4. [doi:10.1007/s003830100584](http://dx.doi.org/10.1007/s003830100584)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s003830100584&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=11666047&link_type=MED&atom=%2Fbmjopen%2F13%2F10%2Fe076931.atom) 

2.  Farhat AS, Mohammadzadeh A. Comparison between two and twenty-four hours salt powder in treatment of infant umbilical Granuloma. Iran Red Crescent Med J 2008;10:267–9.
    
    

3.  Kesaree N, Babu PS, Banapurmath CR, et al. Umbilical Granuloma. Indian Pediatr 1983;20:690–2.
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=6676326&link_type=MED&atom=%2Fbmjopen%2F13%2F10%2Fe076931.atom) 

4.  Hegazy AA. Anatomy and Embryology of Umbilicus in newborns: a review and clinical correlations. Front Med 2016;10:271–7. [doi:10.1007/s11684-016-0457-8](http://dx.doi.org/10.1007/s11684-016-0457-8)
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F13%2F10%2Fe076931.atom) 

5.  Mullany LC, Darmstadt GL, Katz J, et al. Risk of mortality subsequent to umbilical cord infection among newborns of Southern Nepal: cord infection and mortality. Pediatr Infect Dis J 2009;28:17–20. [doi:10.1097/INF.0b013e318181fb4c](http://dx.doi.org/10.1097/INF.0b013e318181fb4c)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/INF.0b013e318181fb4c&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=19034065&link_type=MED&atom=%2Fbmjopen%2F13%2F10%2Fe076931.atom) 

6.  Wang H, Gao Y, Duan Y, et al. Dramatic response of topical Doxycycline in umbilical Granuloma: report of 84 cases. Glob Pediatr Health 2015;2:2333794X15607315. [doi:10.1177/2333794X15607315](http://dx.doi.org/10.1177/2333794X15607315)
    
    

7.  Spencer N, Blackburn C, Bonas S, et al. Et al parent reported home smoking bans and toddler (18–30 month) smoke exposure: a cross-sectional survey. Arch Dis Child 2005;90:670–4. [doi:10.1136/adc.2004.054684](http://dx.doi.org/10.1136/adc.2004.054684)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImFyY2hkaXNjaGlsZCI7czo1OiJyZXNpZCI7czo4OiI5MC83LzY3MCI7czo0OiJhdG9tIjtzOjI3OiIvYm1qb3Blbi8xMy8xMC9lMDc2OTMxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

8.  Chamberlain JM, Gorman RL, Young GM. Silver nitrate burns following treatment for umbilical Granuloma. Pediatr Emerg Care 1992;8:29–30. [doi:10.1097/00006565-199202000-00008](http://dx.doi.org/10.1097/00006565-199202000-00008)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/00006565-199202000-00008&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=1603685&link_type=MED&atom=%2Fbmjopen%2F13%2F10%2Fe076931.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=A1992HG92600007&link_type=ISI) 

9.  Daniels J. Is silver nitrate the best agent for management of umbilical Granulomas Arch Dis Child 2001;85:432. [doi:10.1136/adc.85.5.431](http://dx.doi.org/10.1136/adc.85.5.431)
    
    

10. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions, 2nd edn. Chichester: John Wiley & Sons, 2019. [doi:10.1002/9781119536604](http://dx.doi.org/10.1002/9781119536604)