Chen Hong-Lin (Orcid ID: 0000-0003-0169-3286)

Pozzilli Paolo (Orcid ID: 0000-0001-5090-636X)

Raz Itamar (Orcid ID: 0000-0003-0209-4453)

Global recurrence rates in diabetic foot ulcers: a

systematic review and meta-analysis

Manuscript number: # DMRR-18-REV-442

Short running title: Recurrence in diabetic foot ulcers

Authors:

Xue-Lei Fu1; Hui Ding2; Wei-Wei Miao3; Chun-Xing Mao4; Min-Qi Zhan5; Hong-Lin Chen6.

1-5. Bachelor Student. School of Nursing, Nantong University, Nantong, Jiangsu, PR China

6. Ph.D. School of Nursing, Nantong University, Nantong, Jiangsu, PR China

Correspondence:

Hong-Lin Chen, School of Nursing, Nantong University, Nantong, Jiangsu, PR China

Address: Qixiu Road 19#

E-mail: zhongchuangnt@126.com Tel: +86-513-85051856 Fax: +86-513-85051780

Word count for the abstract: 214

Word count for the main body of the text: 3097

References: 88 Figures: 4

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/dmrr.3160

This article is protected by copyright. All rights reserved.

Funding:

It was supported by Innovation Training Program Project of Nantong University (Project Number 2018169).

Abstract

Recurrence rates of diabetic foot ulcers vary widely in the published literature. The aim of this systematic

review is to estimate recurrence rates of diabetic foot ulcers. We did a PubMed search, and performed a

review of reference lists for studies reporting recurrence of diabetic foot ulcers. The weighted relative risk

(RR) and corresponding 95% confidence interval (CI) for recurrence was estimated. 49 studies reporting

recurrence of diabetic foot ulcers were included. A pooled estimate for recurrence rate was 22.1% per

person-year (py) (95% CI, 19.0-25.2%). Recurrence rate was 24.9% per py in Europe (95% CI, 20.0%-29.7%),

17.8% per py in North America (95% CI, 12.7%-22.9%), 16.9% per py in Africa (95% CI, 4.7%-29.0%) and

17.0% per py in Asia (95% CI, 11.1%-23.0%). Turkey had the highest recurrence rate of 44.4% per py (95%

CI, 24.9%-63.9%), and Bangladesh had the lowest of 4.3% per py (95% CI, 2.3%-6.3%). Recurrence rates of

diabetic foot ulcers before 2002, between 2002 and 2008, and after 2008 were 22.2% per py (95% CI, 17.6%-

26.8%), 21.9% per py (95% CI, 17.0%-26.8%), and 21.8% per py (95% CI, 16.3%-27.2%), respectively.

Recurrence rates of diabetic foot ulcers are high. Recurrence rates vary widely in different regions and have

decreased recently. More attention towards recurrence of diabetic foot ulcers is urgently required.

Key Words: Diabetic foot ulcers; Meta-analysis; Recurrence rate

This article is protected by copyright. All rights reserved.

Introduction

Diabetic foot ulcers occur due to neuropathy (sensory, motor, and autonomic deficits), ischaemia, or

both 1. It is a serious complication of diabetes, which frequently results in amputation 2,3. It is reported that

the prevalence of diabetic foot ulcers in patients is 4– 10%, and the lifetime incidence is as high as 25% 4.

According to 2015 prevalence data from the International Diabetes Federation, foot ulcers annually develop

in 9.1 million to 26.1 million people with diabetes all over the world 5. Mobility limitation, pain and

discomfort feelings are problems that disturb patients with diabetic foot ulcers, which lead to poor overall

health-related quality of life 6. Diabetic foot ulcers not only influence the quality of life, but also reduce life

expectancy 7,8. In addition, expenses for treating diabetic patients with ulcers are 1.5 to 2.4 times that of

those without ulcers 9. With the presence of peripheral arterial disease, the expenses may increase to

nearly 4 times that of purely neuropathic wounds 10. Previous studies estimated that the average cost for

each ulceration was nearly $13 000, imposing great financial burden on patients 11,12.

Recurrence of a diabetic foot ulcer is a common problem even after the resolution of a foot ulcer 5.

However, recurrence rate of diabetic foot ulcers is unknown. Recurrence rates of diabetic foot were rather

different in the published literature. Overall recurrence rates ranged from 28% at 12 months to 100% at 40

months 13. In addition, recurrence of foot ulcers ranges from 30% to 87% after conventional non-surgical

measures 14. Those scattered data may make difficult in counselling about future risk and create uncertainty

to the optimal management. What’s more, previous study reported that recurrence rates varied at different

time periods. Roughly 40% of patients with healed ulcers have a recurrence within 1 year, almost 60% within

3 years, and 65% within 5 years. Armstrong DG held the view that it was more useful to regard patients who

have achieved wound closure as being in remission rather than being healed 5.

This article is protected by copyright. All rights reserved.

 A systematic review and meta-analysis published in 2016 has investigated global epidemiology of

diabetic foot ulcers and revealed the prevalence in each continent and country, which may provide public

health planning and management of diabetic foot ulcers with suggestive information 15. Mauro Rigato

reported the characteristics of patients with diabetic foot in Africa, with great attention to prevalence,

amputation, and mortality of ulcers 16. Mairghani M et al also performed a systematic review to reveal

prevalence and incidence of diabetic foot ulcers in the Arab world 17. However, the recurrence of diabetic

foot has been neglected. Although recurrence rates of diabetic foot ulcers have been described in several

published studies, they varied widely in different studies and the sample sizes of those studies were small.

Global recurrence rates of foot ulcers have not been systematically summarized to provide

recommendations and suggestions for future studies.

Given the increasing number of published studies of recurrence of diabetic foot ulcers, we performed

an updated systematic review and meta-analysis by appraising and synthesizing the existing literature. This

study aimed to obtain a current estimate of recurrence rates of diabetic foot ulcers, providing a basis for

public advocacy efforts and future studies of epidemiology.

Methods

Data sources and searches

This study was performed according to the Preferred Reporting Items for Systematic Reviews and

Meta-analyses (PRISMA) checklist 18. A comprehensive search of the PubMed for studies investigating the

recurrence of diabetic foot ulcers was carried out. The electronic search was performed for articles

published on or before July 20, 2018. The full search strategy was outlined in detail in Supplementary Table

1, and included MeSH headings and keyword searches of “recurrence”, “recrudesce”, “re-ulceration”,

“relapse”, “recurrent ulcers”, “ulcer recurrence”, “diabetic foot”, “diabetes foot” and “epidemiology”.

This article is protected by copyright. All rights reserved.

Language in publications was limited to English. Reference lists of relevant articles were also hand searched.

Study selection

A screening of identified abstracts and titles were independently performed by two reviewers to

produce a shortlist of potentially relevant sources. After initial screening, eligible studies were obtained in

full-text format and assessed independently by two reviewers. Disagreement was resolved by discussion.

Studies were eligible for inclusion in this meta-analysis if they met the following four categories. Type

of study: published research articles that separately reported data of recurrence were included, including

case-control studies, cohort studies, case series and randomised controlled trials (RCT); review papers,

meta-analyses, editorial or comment papers, and case reports were excluded. Patient characteristics:

studies of patients with diabetic foot ulcers or healed diabetic foot ulcers were included. Outcome: studies

that examined patients with first occurrence of recurrence or subsequent occurrence were included.

Recurrent foot ulcer was defined as an ulcer appearing at the same site as a previously healed ulcer. Other

new foot ulcer was regard as a foot ulcer developing after healing of a previous foot ulcer, located at any

other site than previous healed foot ulcer. Studies that only documented recurrence rates of other new

foot ulcers were not eligible. Time period: follow-up period must be reported in the studies. Studies that

only reported median of follow-up period were excluded. What’s more, studies with follow-up period over

3 years were excluded because recurrence rates in each year may uneven. Large time span may result in

great bias.

Data extraction and quality assessment

A data abstraction sheet was developed to collect information. Sample characteristics for each study

were extracted. From each included study, two reviewers independently extracted baseline data for first

authors, publish year, study location, study period, study design, age, the population of males and females,

This article is protected by copyright. All rights reserved.

duration of diabetes, HbA1c. Data including sample size, number of patient-years of follow-up, cases of

recurrence, recurrence rate were also extracted and calculated. For those studies that number of person-

years of follow-up was not provided and cannot be calculated, number of person-years of follow-up was

approximated from follow-up duration and sample size.

Risk of bias in included studies was independently examined by two reviewers using suitable tools. A

new risk of bias tool for prevalence studies based on modifying the Leboeuf-Yde and Lauritsen tool was

used in our study. This tool comprises 10 items addressing four domains of bias (selection, nonresponse

bias, measurement bias and bias related to the analysis) plus a summary assessment 19.

Data synthesis and analysis

Stata v.12 (StataCorp, College Station, TX) was used to perform data analysis. When the counts of

patients with ulcer recurrence were zero, a correction of 0.5 was added to the number of recurrent cases

of diabetic foot ulcers and person-years of follow-up, prior to calculation 20. Heterogeneity between studies

was assessed by Cochran Q (p <0.05 was considered significant) and I² statistics (>50% reflecting

heterogeneity). Meta-analysis model was chosen by heterogeneity. Where no statistically significant

heterogeneity was detected, a fixed-effect model was used. If statistically significant heterogeneity was

found, a random-effects model was chosen 21.

Recurrence rates were shown as the number of recurrent cases per py. The outcomes of interest for

analysis were recurrence rates of diabetic foot ulcers, which were abstracted from published studies; exact

95% CIs were calculated subsequently. Publication bias was evaluated by visual inspection of funnel plot,

as well as Egger’s test and Begg-Mazumdar’s test 22,23. Leave-one-out sensitivity analysis was carried out,

which assessed the influence of each study by removing one study at a time.

This article is protected by copyright. All rights reserved.

 Subgroup analyses were performed according to the continents and countries. If study locations were

more than one in a study, they were divided into different studies by continents and countries. Since only

one study conducted in Oceania, its continent was classified as Asia.

In analysis according to year, meta-regression analysis was conducted. Year was defined as the median

of study period. If study period was more than one or was not reported in the study, publish year was used.

Years were also divided into before 2002, between 2002 and 2008 and after 2008 three groups for subgroup

analysis.

In analysis regarding to age, meta-regression analysis and subgroup analysis for means of age were

carried out. Ages were stratified into younger than 60, between 60 and 65 years old, and older than 65.

In analysis on gender, proportions of male population were used for meta-regression and were divided

into three groups (less than 50%, between 50% and 70%, and over 70%).

In analysis respecting to duration of diabetes, means of duration were used for meta-regression

analysis and subgroup analysis. Duration was stratified into less than 13 years, between 13 and 18 years

and over 18 years.

In analysis concerning HbA1c, meta-regression analysis and subgroup analysis for means of HbA1c

were performed. Means of HbA1c were stratified into less than 7.85%, between 7.85% and 9.05% and over

9.05% for subgroup analysis.

Results

Literature search

A flow diagram of our search strategy was shown in Figure 1. The PubMed search and the review of

reference lists retrieved a total of 759 studies. After initial screening of all titles and abstracts, 577 of these

articles were excluded. 182 full-text articles were assessed for eligibility, and 133 (65 reviews, 8 studies of

This article is protected by copyright. All rights reserved.

duplicated population and 60 studies with data that cannot be extracted) of them were removed since they

did not meet our selection criteria. Finally, 49 articles were included in our meta-analysis after full-text

review 24-72.

Study characteristics

The publication year ranged from 1995 to 2018. Of the articles we selected, 33 were prospective

studies and 16 were retrospective studies. Combined, these 49 studies accounted for 9670.6 patient-years

of follow-up. Supplementary Table 2 showed a summary of included studies. Risk of bias in 14 studies was

low, in 30 studies were moderate and in 5 studies was high.

Main meta-analysis

Overall recurrence rate

Recurrence rates of diabetic foot ulcers ranged from 0.0 to 83.8% per py. Random-effects model was

used due to high heterogeneity (I²= 94.9%; p= 0.000). We estimated that recurrence rate was 22.1% per py

(95% CI, 19.0%-25.2%; z= 13.97; p= 0.000) (Figure 2). Funnel plot graphics indicated publication bias in this

meta-analysis (Supplementary Figure 1). Egger’s test (t= 5.52; p= 0.000) and Begg-Mazumdar’s test (z= 2.08;

p= 0.038) also showed publication bias. Leave-one-out sensitivity analysis was robust in our meta-analysis

(Supplementary Figure 2).

Recurrence rates in regional distribution

Recurrence rates varied in different continents. The lowest recurrence rate was 16.9% per py in Africa

(95% CI, 4.7%-29.0%), while the highest was 24.9% per py in Europe (95% CI, 20.0%-29.7%). In addition,

recurrence rate in North America was 17.8% per py (95% CI, 12.7%-22.9%), and 17.0% per py in Asia (95%

CI, 11.1%-23.0%) (Figure 3A).

Recurrence rates varied widely in different countries. Turkey had the highest recurrence rate of 44.4%

This article is protected by copyright. All rights reserved.

per py (95% CI, 24.9%-63.9%), and Bangladesh had the lowest recurrence rate of 4.3% per py (95% CI, 2.3%-

6.3%). Recurrence rates in United Kingdom, United States, Italy, Sweden, Egypt, China, Norway, Spain,

Netherlands, India, Australia, Tanzania, Sudan, Switzerland and Lithuania were 23.1% per py (95% CI, 8.3%-

37.9%), 21.0% per py (95% CI, 15.1%-26.9%), 28.1% per py (95% CI, 15.2%-41.1%), 20.8% per py (95% CI,

13.3%-28.4%), 30.6% per py (95% CI, 24.0%-37.2%), 27.1% per py (95% CI, 2.6%-51.5%), 41.5% per py (95%

CI, 26.4%-56.6%), 38.5% per py (95% CI, 28.5%-48.5%), 27.3% per py (95% CI, 23.2%-31.5%), 8.6% per py

(95% CI, 0.5%-16.7%), 41.4% per py (95% CI, 23.5%-59.3%), 12.1% per py (95% CI, 8.9%-15.3%), 8.0% per

py (95% CI, 0.5%-15.5%), 20.4% per py (95% CI, 11.5%-29.3%) and 23.8% per py (95% CI, 18.5%-29.1%),

respectively. No statistical significance was in Germany, Canada and Cuba (Figure 3B).

Recurrence rates in temporal variations

Year was not the source of heterogeneity (t= 0.56, p= 0.578), but the recurrence rates showed a

downward trend over time in meta-regression analysis (Supplementary Figure 3A). The pooled recurrence

rates of diabetic foot ulcers were 22.2% per py before 2002 (95% CI, 17.6%-26.8%), 21.9% per py from 2002

to 2008 (95% CI, 17.0%-26.8%), and 21.8% per py after 2008 (95% CI, 16.3%-27.2%). Supplementary Figure

3B showed the subgroup analysis by years.

Recurrence rates in variations of age

Mean age was not the source of heterogeneity (t=0.53; p= 0.602) (Supplementary Figure 4A).

Recurrence rates were 23.4% per py in patients younger than 60 (95% CI, 18.3%-28.5%), 17.0% per py in

patients between 60 and 65 years old (95% CI, 12.4%-21.6%) and 30.7% per py in patients older than 65

(95% CI, 19.7%-41.6%) (Supplementary Figure 4B).

Recurrence rates in distribution of gender

Proportion of male population was the source of heterogeneity (t= 2.27; p= 0.028) and adjusted R-

This article is protected by copyright. All rights reserved.

squared was -2.18% (Supplementary Figure 5A). Recurrence rates were 31.5% per py in patients with

proportion of male population less than 50% (95% CI, 14.0%-49.0%), 21.0% per py in patients with

proportion of male population between 50% and 70% (95% CI, 16.6%-25.5%), and 20.7% per py in patients

with proportion of male population over 70% (95% CI, 16.1%-25.2%) (Supplementary Figure 5B).

Recurrence rates in variations of duration of diabetes

While duration of diabetes was not the source of heterogeneity (t= 0.31; p= 0.762), recurrence rates

increased with the duration of diabetes (Supplementary Figure 6A). Recurrence rates were 15.9% per py in

patients with duration less than 13 years (95% CI, 5.2%-26.5%), 28.3% per py in those with duration

between 13 and 18 years (95% CI, 22.6%-34.1%) and 29.2% per py in those with duration over 18 years (95%

CI, 11.7%-46.8%) (Supplementary Figure 6B).

Recurrence rates in variations of HbA1c

HbA1c was not the source of heterogeneity (t= 0.71; p=0.484), but recurrence rates rose with the level

of HbA1c (Supplementary Figure 7A). In group with HbA1c less than 7.85%, recurrence rate was 24.6% per

py (95% CI, 11.1%-38.0%); In group with HbA1c between 7.85% and 9.05%, recurrence rate was 25.8% per

py (95% CI, 18.4%-33.2%); In group with HbA1c over 9.05%, recurrence rate was 32.0% per py (95% CI,

12.2%-51.9%) (Supplementary Figure 7B).

The data of the second panel in Supplementary Figures 3-7 were integrated. Figure 4 can concisely

show the risk of recurrence according to risk factors (year, age, gender, duration of diabetes and HbA1c).

Discussion

The systematic review and meta-analysis of 49 studies identified the recurrence rate of diabetic foot

ulcers was 22.1% per py (95% CI, 19.0%-25.2%). In addition, recurrence rates showed a downtrend over

time, which meant that the management of the diabetic foot may have made progress 73. Although duration

This article is protected by copyright. All rights reserved.

of diabetes and HbA1c were not the source of heterogeneity, recurrence rates increased with duration of

diabetes and levels of HbA1c in our meta-regression. Diabetic foot ulcer was most likely to occur in diabetic

patients with long duration of diabetes mellitus and poor glycemic control 74. Compared with those without

recurrent foot ulcer, HbA1c increased significantly in patients who developed recurrent foot ulceration.

Hence, good glycemic control plays an important role in preventing diabetic foot ulcers75.

Ulcer recurrence is regarded as a result of unrecognized repetitive trauma 68. Previous foot ulcers are

76, 77.
associated with peripheral arterial disease which might lead to the loss of sensitivity Moreover,

although previous ulcer has epithelialized, intact skin and underlying tissue might not be recovered,

increasing the risk of additional injury 68. Minor lesions greatly increase the probability of ulcer recurrence

68. Abundant callus, blistering, or hemorrhage are early symptoms of skin damage that strongly predict ulcer

recurrence 5. If these signs are noticed in time, it is likely to prevent recurrence of ulcers. Lamola, G reported

that peripheral neuropathy combined with tissue changes and deformity leads to the increase of plantar

pressures, which outlines a biomechanical pathway to ulceration 78. The actual load on the foot can be well

shown by combining in-shoe and barefoot pressure, footwear adherence, and step activity data, which is

an important factor to predict recurrence 79. It can be improved by footwear and offloading interventions

80.
In addition, increased local skin temperature is an early sign of foot ulcers, which is a result of

inflammation and enzymatic autolysis of tissue. So, home monitoring of foot temperatures is an effective

approach for early recognition and treatment of pre-signs of ulceration 81.

Global recurrence rates of diabetic foot ulcers calculated in our study provided a reference for the

whole world. Preventative measures such as a collective refocusing on prevention and a reallocation of

resources should be taken into consideration 5. More attention should be paid on the long-term cost rather

than the short-term cost until healing, as foot ulcer and amputation are usually associated with increased

This article is protected by copyright. All rights reserved.

re-ulceration rate and lifelong disability 78,82. It is crucial to master the treatment time correctly, and manage

wounds scientifically 83. Treatment during active disease along with great education and a focus on

improving care after ulcer healing can lead to fewer inpatient and outpatient visits, and improve the quality

of life 5. Multidimensional care models can improve treatment compliance 84 and regular nursing care may

decrease the occurrence of ulcers 85. Theoretical and practical training programs should be launched for

nurses since knowledge regarding foot management is not well used during care 86. Meanwhile, the

International Working Group on the Diabetic Foot also has provided clinicians with all kinds of evidence-

based recommendations and suggestions for prevention, which may reduce the risk of ulcer recurrence

and burden of this disease on patients and society to some extent 87,88. But recurrence of this disease is still

a challenging problem. Prevention strategies targeting the high-risk individuals are urgently required to

avoid ulcer recurrence. Optimized management and integrated care are promising and effective methods

for further prevention.

However, there are many limitations in this study. First, heterogeneities were high in this study.

According to meta-regression analyses, we just found that proportion of male population was the source

of heterogeneity in meta-analysis for recurrence. The original literature did not provide more data for

identifying the source of heterogeneity. Second, significant publication bias was present in this study since

the included literature was limited to English-language publications. But English-language literature

accounting for the majority of all literature. Third, number of person-years of follow-up was exaggerated in

some included studies, making the recurrence rates lower. More studies with precise number of person-

years of follow-up should be conducted to reveal recurrence rates. Fourth, due to the lack of data provided

by each study for comprehensively exploring the time trends of the recurrence in each year, secondary

calculations were needed.

This article is protected by copyright. All rights reserved.

Conclusions

In conclusion, our review and meta-analysis demonstrated that global recurrence rate of diabetic foot

ulcers was high, with 22.1% per py. The estimate can aid management decisions and counseling related to

recurrence of diabetic foot ulcers. They also warn patients and society to pay more attention to recurrence

of diabetic foot ulcers. Further studies could be devoted to perfecting foot ulcers prevention program and

reducing recurrence.

Funding

It was supported by Innovation Training Program Project of Nantong University (Project Number

2018169).

Conflict of Interest

No potential conflicts of interest relevant to this article were reported.

Acknowledgments

We thank all staff members involved in this study.

Reference

1. Cavanagh PR, Lipsky BA, Bradbury AW, Botek G. Treatment for diabetic foot ulcers. Lancet.
2005;366(9498):1725-1735.
2. Khaodhiar L, Dinh T, Schomacker KT, et al. The use of medical hyperspectral technology to evaluate
microcirculatory changes in diabetic foot ulcers and to predict clinical outcomes. Diabetes Care.
2007;30(4):903-910.
3. Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet. 2003;361(9368):1545-1551.
4. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA.
2005;293(2):217-228.
5. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med.
2017;376(24):2367-2375.
6. Siersma V, Thorsen H, Holstein PE, et al. Importance of factors determining the low health-related
quality of life in people presenting with a diabetic foot ulcer: the Eurodiale study. Diabet Med.

This article is protected by copyright. All rights reserved.

 2013;30(11):1382-1387.
7. Moulik PK, Mtonga R, Gill GV. Amputation and mortality in new-onset diabetic foot ulcers stratified by
etiology. Diabetes Care. 2003;26(2):491-494.
8. Fortington LV, Geertzen JH, van Netten JJ, Postema K, Rommers GM, Dijkstra PU. Short and long term
mortality rates after a lower limb amputation. Eur J Vasc Endovasc Surg. 2013;46(1):124-131.
9. Ramsey SD, Newton K, Blough D, et al. Incidence, outcomes, and cost of foot ulcers in patients with
diabetes. Diabetes Care. 1999;22(3):382-387.
10. Economic Burden of Diabetic Foot Ulcers and Amputations: Data Points #3 -- Data Points Publication
Series. 2011.
11. Stockl K, Vanderplas A, Tafesse E, Chang E. Costs of Lower-Extremity Ulcers Among Patients With
Diabetes. Diabetes Care. 2004;27(9):2129-2134.
12. Rogers LC, Lavery LA, Armstrong DG. The right to bear legs--an amendment to healthcare: how
preventing amputations can save billions for the US Health-care System. Journal of the American
Podiatric Medical Association. 2008;98(98):166-168.
13. Cavanagh PR, Lipsky BA, Bradbury AW, Botek G. Treatment for diabetic foot ulcers. Lancet.
2006;366(9498):1725-1735.
14. Lavery LA. Effectiveness and safety of elective surgical procedures to improve wound healing and reduce
re-ulceration in diabetic patients with foot ulcers. Diabetes Metab Res Rev. 2012;28 Suppl 1:60-63.
15. Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic foot ulceration: a systematic
review and meta-analysis. Ann Med. 2017;49(2):106-116.
16. Rigato M, Pizzol D, Tiago A, Putoto G, Avogaro A, Fadini GP. Characteristics, prevalence, and outcomes
of diabetic foot ulcers in Africa. A systemic review and meta-analysis. Diabetes Res Clin Pract.
2018;142:63-73.
17. Mairghani M, Elmusharaf K, Patton D, et al. The prevalence and incidence of diabetic foot ulcers among
five countries in the Arab world: a systematic review. J Wound Care. 2017;26(Sup9):S27-S34.
18. Moher D, Liberati A, Tetzlaff J, Altman D. Preferred reporting items for systematic reviews and meta-
analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.
19. Brooks P, Woolf A, Blyth F, et al. Assessing risk of bias in prevalence studies: modification of an existing
tool and evidence of interrater agreement.%A Hoy D. Journal of clinical epidemiology. 2012;65(9):934-
939.
20. Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song, Fujian. Methods for Meta-Analysis in Medical
Research. John Wiley Sons. 2000.
21. Dersimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials. 1986;7(3):177.
22. Begg C, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics.
1994;50(4):1088-1101.
23. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical
test. BMJ. 1997;315(7109):629-634.
24. Acosta JB, Savigne W, Valdez C, et al. Epidermal growth factor intralesional infiltrations can prevent
amputation in patients with advanced diabetic foot wounds. Int Wound J. 2006;3(3):232-239.
25. Ahmad I, Akhtar S, Masoodi Z. Role of early radical debridement and skin cover in diabetic foot
ulceration. J Wound Care. 2012;21(9):442-444, 446-447.
26. Apelqvist J, Ragnarson-Tennvall G, Larsson J, Persson U. Long-term costs for foot ulcers in diabetic
patients in a multidisciplinary setting. Foot Ankle Int. 1995;16(7):388-394.
27. Armenio A, Cutrignelli D, Nardulli M, et al. Bio-Engineering tissue and V.A.C. therapy: A new method for

This article is protected by copyright. All rights reserved.

 the treatment of extensive necrotizing infection in the diabetic foot. Ann Ital Chir. 2017;88:268-274.
28. Armstrong DG, Fiorito JL, Leykum BJ, Mills JL. Clinical efficacy of the pan metatarsal head resection as a
curative procedure in patients with diabetes mellitus and neuropathic forefoot wounds. Foot Ankle Spec.
2012;5(4):235-240.
29. Atway S, Nerone VS, Springer KD, Woodruff DM. Rate of residual osteomyelitis after partial foot
amputation in diabetic patients: a standardized method for evaluating bone margins with intraoperative
culture. J Foot Ankle Surg. 2012;51(6):749-752.
30. Blackman E, Moore C, Hyatt J, Railton R, Frye C. Topical wound oxygen therapy in the treatment of severe
diabetic foot ulcers: a prospective controlled study. Ostomy Wound Manage. 2010;56(6):24-31.
31. Ciccone MM, Marchese A, Generali A, et al. Interventional therapy in diabetic foot: risk factors, clinical
events and prognosis at one year follow-up (a study of 103 cases). Pak J Biol Sci. 2012;15(16):789-794.
32. Colen LB, Kim CJ, Grant WP, Yeh JT, Hind B. Achilles tendon lengthening: friend or foe in the diabetic
foot? Plast Reconstr Surg. 2013;131(1):37e-43e.
33. Dalla Paola L, Carone A, Morisi C, Cardillo S, Pattavina M. Conservative Surgical Treatment of Infected
Ulceration of the First Metatarsophalangeal Joint With Osteomyelitis in Diabetic Patients. J Foot Ankle
Surg. 2015;54(4):536-540.
34. Dalla Paola L, Faglia E, Caminiti M, Clerici G, Ninkovic S, Deanesi V. Ulcer recurrence following first ray
amputation in diabetic patients: a cohort prospective study. Diabetes Care. 2003;26(6):1874-1878.
35. Dargis V, Pantelejeva O, Jonushaite A, Vileikyte L, Boulton AJ. Benefits of a multidisciplinary approach in
the management of recurrent diabetic foot ulceration in Lithuania: a prospective study. Diabetes Care.
1999;22(9):1428-1431.
36. Dubský M, Jirkovská A, Bem R, et al. Risk factors for recurrence of diabetic foot ulcers: prospective
follow-up analysis in the Eurodiale subgroup. Int Wound J. 2013;10(5):555-561.
37. Faglia E, Clerici G, Frykberg R, et al. Outcomes of Chopart Amputation in a Tertiary Referral Diabetic Foot
Clinic: Data From a Consecutive Series of 83 Hospitalized Patients. J Foot Ankle Surg. 2016;55(2):230-
234.
38. Fernández-Montequín JI, Betancourt BY, Leyva-Gonzalez G, et al. Intralesional administration of
epidermal growth factor-based formulation (Heberprot-P) in chronic diabetic foot ulcer: treatment up
to complete wound closure. Int Wound J. 2009;6(1):67-72.
39. Frigg A, Pagenstert G, Schäfer D, Valderrabano V, Hintermann B. Recurrence and prevention of diabetic
foot ulcers after total contact casting. Foot Ankle Int. 2007;28(1):64-69.
40. Günal Ö, Tuncel U, Turan A, Barut S, Kostakoglu N. The Use of Vacuum-Assisted Closure and GranuFoam
Silver® Dressing in the Management of Diabetic Foot Ulcer. Surg Infect (Larchmt). 2015;16(5):558-565.
41. Hu Z, Zhu J, Cao X, et al. Composite Skin Grafting with Human Acellular Dermal Matrix Scaffold for
Treatment of Diabetic Foot Ulcers: A Randomized Controlled Trial. J Am Coll Surg. 2016;222(6):1171-
1179.
42. Khalifa WA. Risk factors for diabetic foot ulcer recurrence: A prospective 2-year follow-up study in Egypt.
Foot (Edinb). 2018;35:11-15.
43. Kloos C, Hagen F, Lindloh C, et al. Cognitive function is not associated with recurrent foot ulcers in
patients with diabetes and neuropathy. Diabetes Care. 2009;32(5):894-896.
44. Lemaster JW, Reiber GE, Smith DG, Heagerty PJ, Wallace C. Daily weight-bearing activity does not
increase the risk of diabetic foot ulcers. Med Sci Sports Exerc. 2003;35(7):1093-1099.
45. Lesens O, Desbiez F, Theïs C, et al. Staphylococcus aureus-Related Diabetic Osteomyelitis: Medical or
Surgical Management? A French and Spanish Retrospective Cohort. Int J Low Extrem Wounds.

This article is protected by copyright. All rights reserved.

 2015;14(3):284-290.
46. Mahmoud SM, Mohamed AA, Mahdi SE, Ahmed ME. Split-skin graft in the management of diabetic foot
ulcers. J Wound Care. 2008;17(7):303-306.
47. Molines-Barroso RJ, Lázaro-Martínez JL, Aragón-Sánchez J, García-Morales E, Carabantes-Alarcón D,
Álvaro-Afonso FJ. The influence of the length of the first metatarsal on the risk of reulceration in the
feet of patients with diabetes. Int J Low Extrem Wounds. 2014;13(1):27-32.
48. Monami M, Longo R, Desideri CM, Masotti G, Marchionni N, Mannucci E. The diabetic person beyond a
foot ulcer: healing, recurrence, and depressive symptoms. J Am Podiatr Med Assoc. 2008;98(2):130-136.
49. Mueller MJ, Sinacore DR, Hastings MK, Strube MJ, Johnson JE. Effect of Achilles tendon lengthening on
neuropathic plantar ulcers. A randomized clinical trial. J Bone Joint Surg Am. 2003;85-A(8):1436-1445.
50. Ndosi M, Wright-Hughes A, Brown S, et al. Prognosis of the infected diabetic foot ulcer: a 12-month
prospective observational study. Diabet Med. 2018;35(1):78-88.
51. Oliver N, Attinger C, Steinberg J, Evans K, Vieweger D, Kim P. Influence of Hallux Rigidus on Reamputation
in Patients With Diabetes Mellitus After Partial Hallux Amputation. J Foot Ankle Surg. 2015;54(6):1076-
1080.
52. Örneholm H, Apelqvist J, Larsson J, Eneroth M. Recurrent and other new foot ulcers after healed plantar
forefoot diabetic ulcer. Wound Repair Regen. 2017;25(2):309-315.
53. Peters EJ, Armstrong DG, Lavery LA. Risk factors for recurrent diabetic foot ulcers: site matters. Diabetes
Care. 2007;30(8):2077-2079.
54. Pua BB, Muhs BE, Maldonado T, Ben-Arie E, Sheehan P, Gagne PJ. Total-contact casting as an adjunct to
promote healing of pressure ulcers in amputees. Vasc Endovascular Surg. 2006;40(2):135-140.
55. Quebedeaux TL, Lavery LA, Lavery DC. The development of foot deformities and ulcers after great toe
amputation in diabetes. Diabetes Care. 1996;19(2):165-167.
56. Richter M, Zech S. Four-stage regimen for operative treatment of diabetic foot ulcer with deformity - a
results of 300 patients. Foot Ankle Surg. 2012;18(4):247-254.
57. Saltoglu N, Dalkiran A, Tetiker T, et al. Piperacillin/tazobactam versus imipenem/cilastatin for severe
diabetic foot infections: a prospective, randomized clinical trial in a university hospital. Clin Microbiol
Infect. 2010;16(8):1252-1257.
58. Scatena A, Petruzzi P, Ferrari M, et al. Outcomes of three years of teamwork on critical limb ischemia in
patients with diabetes and foot lesions. Int J Low Extrem Wounds. 2012;11(2):113-119.
59. Shaikh N, Vaughan P, Varty K, Coll AP, Robinson AH. Outcome of limited forefoot amputation with
primary closure in patients with diabetes. Bone Joint J. 2013;95-B(8):1083-1087.
60. Skafjeld A, Iversen MM, Holme I, Ribu L, Hvaal K, Kilhovd BK. A pilot study testing the feasibility of skin
temperature monitoring to reduce recurrent foot ulcers in patients with diabetes--a randomized
controlled trial. BMC Endocr Disord. 2015;15:55.
61. Tajaddini A, Scoffone HM, Botek G, Davis BL. Laser-induced auto-fluorescence (LIAF) as a method for
assessing skin stiffness preceding diabetic ulcer formation. J Biomech. 2007;40(4):736-741.
62. Uccioli L, Faglia E, Monticone G, et al. Manufactured shoes in the prevention of diabetic foot ulcers.
Diabetes Care. 1995;18(10):1376-1378.
63. Ulbrecht JS, Hurley T, Mauger DT, Cavanagh PR. Prevention of recurrent foot ulcers with plantar
pressure-based in-shoe orthoses: the CareFUL prevention multicenter randomized controlled trial.
Diabetes Care. 2014;37(7):1982-1989.
64. van Asten S, Mithani M, Peters E, La Fontaine J, Kim P, Lavery L. Complications during the treatment of
diabetic foot osteomyelitis. Diabetes Res Clin Pract. 2018;135:58-64.

This article is protected by copyright. All rights reserved.

65. Veves A, Falanga V, Armstrong DG, Sabolinski ML. Graftskin, a human skin equivalent, is effective in the
management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter
clinical trial. Diabetes Care. 2001;24(2):290-295.
66. Viswanathan V, Madhavan S, Gnanasundaram S, et al. Effectiveness of different types of footwear
insoles for the diabetic neuropathic foot: a follow-up study. Diabetes Care. 2004;27(2):474-477.
67. Viswanathan V, Wadud JR, Madhavan S, et al. Comparison of post amputation outcome in patients with
type 2 diabetes from specialized foot care centres in three developing countries. Diabetes Res Clin Pract.
2010;88(2):146-150.
68. Waaijman R, de Haart M, Arts ML, et al. Risk factors for plantar foot ulcer recurrence in neuropathic
diabetic patients. Diabetes Care. 2014;37(6):1697-1705.
69. Wang Y, Zhou J, Yan F, et al. Comparison of Arthrodesis with Total Contact Casting for Midfoot
Ulcerations Associated with Charcot Neuroarthropathy. Med Sci Monit. 2015;21:2141-2148.
70. Westphal C, Neame IM, Harrison JC, Bower VM, Gurr JM. A diabetic foot ulcer pilot study: does silicone
gel sheeting reduce the incidence of reulceration? J Am Podiatr Med Assoc. 2011;101(2):116-123.
71. Winkley K, Stahl D, Chalder T, Edmonds ME, Ismail K. Risk factors associated with adverse outcomes in
a population-based prospective cohort study of people with their first diabetic foot ulcer. J Diabetes
Complicat. 2007;21(6):341-349.
72. Xu L, Qian H, Gu J, Shi J, Gu X, Tang Z. Heart failure in hospitalized patients with diabetic foot ulcers:
clinical characteristics and their relationship with prognosis. J Diabetes. 2013;5(4):429-438.
73. H VD, R. L. [The diabetic foot]. Revue medicale de Liege. 2005;60(null):516-525.
74. Nima M, Ozra TM, Mohammad P, Ramin H, Bagher L, Mohammad-Reza MT. Who are diabetic foot
patients? A descriptive study on 873 patients. Journal of Diabetes & Metabolic Disorders. 2013;12(1):36-
36.
75. Mantey I, Foster AV, Spencer S, Edmonds ME. Why do foot ulcers recur in diabetic patients? Diabet Med.
1999;16(3):245-249.
76. Lazzarini PA, Hurn SE, Kuys SS, et al. Foot Complications in a Representative Australian Inpatient
Population. J Diabetes Res. 2017;2017:4138095.
77. Peter-Riesch B. The Diabetic Foot: The Never-Ending Challenge. Endocr Dev. 2016;31:108-134.
78. Lamola G, Venturi M, Martelli D, et al. Quantitative assessment of early biomechanical modifications in
diabetic foot patients: the role of foot kinematics and step width. J Neuroeng Rehabil. 2015;12:98.
79. Bus SA. Priorities in offloading the diabetic foot. Diabetes Metab Res Rev. 2012;28 Suppl 1:54-59.
80. Bus SA, van Deursen RW, Armstrong DG, Lewis JE, Caravaggi CF, Cavanagh PR. Footwear and offloading
interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a
systematic review. Diabetes Metab Res Rev. 2016;32 Suppl 1:99-118.
81. Aan de Stegge WB, Mejaiti N, van Netten JJ, et al. The cost-effectiveness and cost-utility of at-home
infrared temperature monitoring in reducing the incidence of foot ulcer recurrence in patients with
diabetes (DIATEMP): study protocol for a randomized controlled trial. Trials. 2018;19(1):520.
82. Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic
foot? Diabetes Metab Res Rev. 2000;16 Suppl 1:S75-83.
83. Liu XL, Wang L. A review of the development and current status of wound ostomy continence nurses in
the mainland of China. International Journal of Nursing Sciences. 2018:S2352013217303575.
84. Demirtaş A, Akbayrak N. Development of an assessment scale for treatment compliance in type 2
diabetes mellitus in Turkish population: Psychometric evaluation. International Journal of Nursing
Sciences. 2017;4(3):S2352013216302332.

This article is protected by copyright. All rights reserved.

85. Ji L, Bai JJ, Sun J, Wang Z. Nursing care for diabetic toe ulcers: A case series report and literature review.
International Journal of Nursing Sciences. 2016;3(3):332-336.
86. Kaya Z, Karaca A. Evaluation of Nurses' Knowledge Levels of Diabetic Foot Care Management. Nurs Res
Pract. 2018;2018:8549567.
87. Bus SA, van Netten JJ, Lavery LA, et al. IWGDF guidance on the prevention of foot ulcers in at-risk
patients with diabetes. Diabetes Metab Res Rev. 2016;32 Suppl 1:16-24.
88. Bus SA, Armstrong DG, van Deursen RW, Lewis JE, Caravaggi CF, Cavanagh PR. IWGDF guidance on
footwear and offloading interventions to prevent and heal foot ulcers in patients with diabetes.
Diabetes Metab Res Rev. 2016;32 Suppl 1:25-36.

Authors' Contribution Statement:

Xue-Lei Fu had full access to all the data in the study and wrote article.

Hui Ding and Wei-Wei Miao independently extracted the related data information.

Chun-Xing Mao and Min-Qi Zhan checked the related data information again.

Hong-Lin Chen conceived the study concept and design, drafted the manuscript, and contributed to

the critical revision of the manuscript. Chen HL is the guarantor of this work and, as such, have full access

to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data

analysis.

All authors have read and approved the final manuscript.

This article is protected by copyright. All rights reserved.

Figures
Figure 1. A. Flow diagram of the assessment of the studies identified in the systematic review of global
diabetic foot ulcer recurrence.

Records identified through Additional records identified

database searching through other sources
(n = 759) (n = 0)

Records after duplicates removed

(n = 759)

Records excluded
(n = 577)
Records screened
-irrelevant title (n= 508)
(n = 759)
-irrelevant abstract (n= 69)

Full-text articles assessed Full-text articles excluded,

for eligibility with reasons (n = 133)
(n = 182) - reviews (n = 65)
-duplicated populations (n=
8)
-cannot extract data (n= 60)

Studies included in
qualitative synthesis
(n = 49)

Studies included in
quantitative synthesis
(meta-analysis)
(n = 49)

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.