Abbreviations

and Acronyms

PAC ¼ proanthocyanidin

RCT ¼ randomized controlled trial

rUTI ¼ recurrent UTI

TSA ¼ trial sequential analysis

UTI ¼ urinary tract infection

WRR ¼ weighted risk ratio

Accepted for publication March 14, 2017.No direct or indirect commercial incentive

associated with publishing this article.The corresponding author certifies that, when

applicable, a statement(s) has been included inthe manuscript documenting institutional reviewboard, ethics committee or ethical review boardstudy approval; principles of Helsinki Declarationwere followed in lieu of formal ethics committeeapproval; institutional animal care and usecommittee approval; all human subjects providedwritten informed consent with guarantees ofconfidentiality; IRB approved protocol number;animal approved project number.

Supported by Universidade da Beira Interiorand bank Santander/Totta protocol post-doctoralresearch fellowship BIPD/ICI-FC-BST-UBI 2016(AL).

* Correspondence: Centro de Matem�atica eAplicac~oes, Universidade da Beira Interior, RuaMarques d’�Avila e Bolama, 6201-001 Covilh~a,Portugal (telephone: þ351 275 319 700; FAX:þ351 275 329 183; e-mail: lpereira@ubi.pt).

614 j www.jurology.com

00

T

�

Infection/Inflammation

Can Cranberries Contribute to Reduce the Incidence of UrinaryTract Infections? A Systematic Review with Meta-Analysis andTrial Sequential Analysis of Clinical Trials

Angelo Luıs, Fernanda Domingues and Luısa Pereira*

From the Centro de Investigacao em Ciencias da Sa�ude and Centro de Matem�atica e Aplicac~oes (LP), Universidade da Beira Interior,

Covilha, Portugal

Purpose: We sought to clarify the association between cranberry intake and theprevention of urinary tract infections.

Materials and Methods: This systematic review, which complies with thePRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis)statement, was done as a meta-analysis and trial sequential analysis of clinicaltrials.

Results: The findings clearly showed the potential use of cranberries for theclinical condition of urinary tract infection. Cranberry products significantlyreduced the incidence of urinary tract infections as indicated by the weightedrisk ratio (0.6750, 95% CI 0.5516e0.7965, p <0.0001). The results of subgroupanalysis demonstrated that patients at some risk for urinary tract infectionswere more susceptible to the effects of cranberry ingestion.

Conclusions: The results of the current study could be used by physicians torecommend cranberry ingestion to decrease the incidence of urinary tract in-fections, particularly in individuals with recurrent urinary tract infections. Thiswould also reduce the administration of antibiotics, which could be beneficialsince antibiotics can lead to the worldwide emergence of antibiotic resistantmicroorganisms.

Key Words: urinary tract infections, fruit and vegetable juices, disease

susceptibility, proanthocyanidins, study publication bias

URINARY tract infections are commonand among the most frequent medicalconditions requiring outpatienttreatment.1 Approximately 80% of allUTIs occur in women and 20% to 30%of women with a UTI will experiencerecurrence.1 rUTIs, defined as atleast 3 UTI episodes in the last 12months or 2 episodes in the last 6months, can develop in susceptibleindividuals and they are a significantsource of patient morbidity andhealth care costs.2 In individuals withrUTIs low dose antibiotic prophylaxis

22-5347/17/1983-0614/0

HE JOURNAL OF UROLOGY®

2017 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARC

for several months can be recom-mended.1 However, antibiotics arethe main cause of the development ofantibiotic resistance and such pro-longed treatments can lead toincreased resistance.1 The increasingprevalence of Escherichia coli isolatesresistant to antimicrobial agents hasstimulated interest in nonantibioticmethods to prevent UTIs.1

Prophylaxis with cranberries is apotential prevention strategy withhealth benefits associated with thehigh concentrations of polyphenols

H, INC.

http://dx.doi.org/10.1016/j.juro.2017.03.078

Vol. 198, 614-621, September 2017

Printed in U.S.A.

CRANBERRIES AND URINARY TRACT INFECTIONS 615

such as PACs in these berries.3,4 PACs are stablephenolics with antiadhesion activity againstE. coli.3 They act as receptor analogues and inhibitE. coli adhesion to cells by binding to the fimbrialtips.3

The effects of cranberry ingestion in the preven-tion of UTIs were systematized in 2 previous re-views with meta-analyses.5,6 The most recent onesuggested that there is insufficient evidence thatcranberries decrease the number of UTIs since thepooled findings were based on a small number ofstudies.5 Considering this together with the resultsof recent clinical trials evaluating cranberries toprevent UTIs we performed this systematic review,which complies with the PRISMA (PreferredReporting Items for Systematic Review and Meta-Analysis) statement. The review was followed bymeta-analysis and TSA (http://www.ctu.dk/tsa/), anewer approach that can assist in decreasing thelikelihood of a type I error, to clarify the associationbetween cranberry intake and the preventionof UTIs.

METHODS

Search StrategyThe search was performed in September 2016 in severalelectronic databases, including PubMed�, Scopus�,

Figure 1. Results of review author judgments of risk of bias assess

summary of each risk of bias item for each included study.2e4,7e1

included studies.

SciELO (Scientific Electronic Library Online), CochraneLibrary and Web of Science� using the terms (cranberr*OR Vaccinium) AND (urinary tract infections OR UTI)AND clinical trial AND human. According to the PRISMAstatement, titles and abstracts of the records retrievedwere screened and the full texts of those considered rele-vant were analyzed. Two of us independently performedthe literature search with disagreements resolved byconsensus with another of us. To be included in this workstudies had to be clinical trials in humans, present a truecontrol group and report the number of patients whoexperienced at least 1 UTI at the end of followup period(outcome of interest).

Data ExtractionTwo of us independently assessed and extracted thedata. Information was collected on the proportion of pa-tients with at least 1 UTI and on study characteristics(supplementary table 1, http://jurology.com/). The RRserved as the measure of effect for the outcome ofinterest.

Bias Assessment RiskThe bias risk of each included RCT was assessed with theCochrane Library tool. This risk, which was classifiedaccording to 7 domains, was independently assigned by 2of us with discrepancies resolved through discussions(fig. 1). Results were presented as a risk of bias summaryand a risk of bias graph, which were sketched with Rev-Man, version 5.3.5 (http://community.cochrane.org/).

ment regarding methodological quality of included studies. A,0,13e30 B, each risk of bias item shown as percent across all

616 CRANBERRIES AND URINARY TRACT INFECTIONS

Statistical AnalysisData statistical analysis was performed using Comprehen-sive Meta-Analysis, version 2.0 (https://www.meta-analysis.com/). A forest plot was generated to illustratestudy specific RRs and the WRR estimate along with the95% CIs using the random effects model. The I2 statisticserved as a measure of inconsistency across the findings ofthe studies.

Three analyses were performed to assess the potentialimpact of publication bias on the meta-analysis. Oneanalysis was a funnel plot in which the log of RR wasplotted against the corresponding SE. In the absence ofpublication bias the studies would have been symmetri-cally distributed about the WRR. Since interpretation islargely subjective, the Egger regression test was alsoperformed. Finally the trim and fill approach was applied,which uses an iterative procedure to remove the mostextreme small studies from the positive or negative side ofthe funnel plot and recalculate the RRs to yield an unbi-ased estimate of WRR.

Sensitivity analysis was performed by removing 1study at a time to evaluate result stability. Further-more, subgroup analysis was done according to patientmean age and gender, and intervention durationand type.

Records identified through database searching(n=157)

Records after duplica

Records scree

Full-text articleeligib

(n=5

Studies includesynth(n=2

Studies includedsynthesis (me

(n=2

Identification

Screening

Eligibility

Included

Figure 2. Flow diagram of database search, trial selection and artic

indicates that studies by Caljouw et al,3 Stothers7 and Wing et al8 we

Trial Sequential AnalysisTSA is a methodology in which the evidence required isquantified, providing a value for the required informationsize. To adjust CIs due to sparse data and repeat testing onthe cumulativemeta-analysis we used TSA, version 0.9.5.5beta. If the cumulative Z-curve crosses the trial sequentialmonitoring boundary or enters the futility area, it can beconcluded that a sufficient level of evidence for the antici-pated intervention effect may have been reached and nofurther trials are needed. TSAwas performed at the level ofan overall 5% risk of a type I error and with 80% power.

RESULTS

Included Studies

In compliance with the PRISMA statement theinitial search identified 157 articles with the po-tential to be included in this meta-analysis. Figure 2shows the progression of the database searchregarding the effects of cranberries to prevent UTIs.After all steps 25 studies were considered suitablefor qualitative and quantitative analyses. Amongthe reasons to exclude studies were an absent

Additional records identified through other sources

(n=18)

tes removed (n=138)

ned (n=138) Records excluded (n=86)

s assessed for ility2)

d in qualitative esis5)

Full-text articles excluded, with reasons(n=27)

in quantitative ta-analysis)8)*

les included in systematic review with meta-analysis. Asterisk

re each divided into 2 trials.

Randommodel effects of cranberry ingestion on UTI incidence

Outcome UTI Incidence

No. trials 28No. pts 4,947Required information size 4,875WRR (95% CI):Observed 0.6750 (0.5516e0.7965)Adjusted 0.8334 (0.6976e0.9956)

p Value <0.0001 (significant)% I2 58.1740

CRANBERRIES AND URINARY TRACT INFECTIONS 617

control group and lack of results in terms of theoutcome of interest.

Three of the 25 included studies were divided into2 trials for a total of 28 studies in 4,947 patientsincluded in this meta-analysis. The study byCaljouw et al was divided since it presents patientsat high and low UTI risk.3 Stothers described 2ways of orally administering cranberry products,that is tablets of concentrated cranberry juice andpure unsweetened cranberry juice.7 Wing et aladministered 2 doses of PACs, including a high dose(240 mg PACs per day) and a low dose (80 mg PACsper day).8

During the search 2 previous meta-analyses werealso found on the prevention of UTIs by cran-berries.5,6 The 2012 study by Jepson et al, whichfocused on the effectiveness of cranberry and blue-berry products to prevent symptomatic UTIs,included 13 trials in the meta-analysis.5 In 2012

Study name Statistics for each study

Risk Lower Upper ratio limit limit p-Value

Caljouw, et al. (2014) a) High UTI Risk1,017 0,700 1,477 0,930Caljouw, et al. (2014) b) Low UTI Risk 1,073 0,557 2,065 0,833Schlager et al. (1999) 0,667 0,129 3,436 0,628Kontiokari et al. (2001) 0,444 0,213 0,927 0,031Maki et al. (2016) 0,671 0,454 0,991 0,045Pagonas et.al. (2012) 0,531 0,388 0,725 0,000Burleigh et al. (2013) 0,483 0,295 0,791 0,004Ledda et al. (2015) 0,182 0,045 0,727 0,016Foxman et al. (2015) 0,522 0,279 0,975 0,041Vostalova et al. (2015) 0,420 0,207 0,852 0,016Stothers et al. (2002) a) (tablet) 0,563 0,275 1,151 0,115Stothers et al. (2002) a) (juice) 0,625 0,315 1,241 0,179McMurdo et al. (2005) 0,505 0,209 1,224 0,130Hess et al. (2008) 0,375 0,161 0,874 0,023Bonetta et al. (2012) 0,359 0,211 0,612 0,000Takahashi et al. (2013) 0,834 0,567 1,227 0,357Salo et al. (2011) 0,731 0,435 1,228 0,237Barbosa-Cesnick et al. (2011) 1,426 0,871 2,334 0,158Cowan et al. (2012) 1,150 0,747 1,769 0,526Wing et al. (2008) a) HD 0,621 0,192 2,011 0,427Wing et al. (2008) a) LD 0,940 0,350 2,529 0,903Afshar et al. (2012) 0,625 0,271 1,443 0,271Waites et al. (2003) 1,058 0,507 2,208 0,881Ferrara et al. (2009) 0,278 0,121 0,640 0,003McGuiness et al. (2002) 1,075 0,662 1,746 0,770Singh et al. (2016) 0,375 0,233 0,604 0,000Bianco et al. (2012) 1,033 0,626 1,707 0,898Lee et al. (2007) 0,924 0,723 1,182 0,531

0,675 0,572 0,797 0,000

UTI

Meta Analysis

Figure 3. Forest plot of comparisons of cranberry ingestion effects

Wang et al evaluated products containing cranberryto prevent UTI and examined the factors influ-encing effectiveness in 10 clinical trials.6 The cur-rent meta-analysis includes 28 clinical trials, whichstrengthened the statistical analysis to allow forbetter understanding of the effects of cranberryingestion in the prevention of UTIs.

Supplementary table 1 (http://jurology.com/) liststhe studies included and their characteristics. Allrepresented individuals at certain risk for repeatUTIs, including children and elderly patients, long-term care facility residents, patients with cancer orspinal cord injury, and patients on clean intermit-tent catheterization. Followup in the included trialsvaried from 2 weeks to 12 months. Patients enrolledin the intervention groups ingested cranberries inseveral oral forms ranging from juices, capsules,tablets and extracts for different PAC doses per day.

Bias Risk

Figure 1 shows the results of the assessment of biasrisk in the included RCTs. The nonrandomizedstudy by Bonetta and Di Pierro,9 the observationalstudy by Burleigh et al,2 and the registry, supple-ment and pilot study by Ledda et al10 were notclassified by bias risk since the Cochrane tool canonly be applied to RCTs. In general the includedRCTs satisfied the 7 domains of bias. The RCTsclaimed to be randomized but only 13 trials detailedthe randomization process and were classified as

Risk ratio and 95% CI

Relative weight

5,223,370,892,975,105,664,361,193,533,103,053,212,352,494,105,134,194,364,801,552,012,532,962,544,424,484,306,14

0,1 0,2 0,5 1 2 5 10

Cranberry group Placebo group

on UTI incidence.2e4,7e10,13e30 HD, high dose. LD, low dose.

618 CRANBERRIES AND URINARY TRACT INFECTIONS

low risk in the random sequence generation domain.Concerning the performance and detection types ofbias, which are related to blinding of participantsand personnel, and blinding to outcome assessment,respectively, 3 studies were classified as high risksince the investigators were not clear about theblinding process. Other sources of bias were alsoidentified, namely the payment of a stipend to trialparticipants or sponsorship and financial support,which are factors that can skew the results.

Cranberry Ingestion Effects

The table summarizes meta-analysis results andfigure 3 shows a forest plot of the results. Overallthe estimated WRR showed a significant reductionin the risk of repeat UTIs with cranberry treatmentcompared to placebo (WRR ¼ 0.6750, 95% CI0.5516e0.7965, p <0.0001). There was a moderatedegree of heterogeneity (I2 ¼ 58.1740%). TSAresulted in a required information size of 4,875,which was reached, and the cumulative Z-curvecrossed the boundaries (fig. 4). Therefore, it was

Figure 4. Trial sequential analysis of pooled result of effects

possible to reach a conclusion with no need foradditional trials. To our knowledge the TSA ofcranberry ingestion on the incidence of UTIs wasapplied for the first time, strengthening the con-clusions achieved.

Subgroup and Sensitivity Analyses

To evaluate the influence of mean patient age,intervention duration and type, and patient genderon the effectiveness of cranberries in the preventionof UTIs a subgroup analysis was performed(supplementary table 2, http://jurology.com/).Although there was evidence of the benefit of cran-berries in reducing UTIs overall, the subgroupanalysis showed that compared with placebo cran-berries did not significantly decrease repeat UTIs inany of the subgroups, including clean intermittentcatheterization (WRR ¼ 0.887, 95% CI 0.676e1.165,p ¼ 0.384), young and older adults (WRR ¼ 0.824,95% CI 0.443e1.533, p ¼ 0.542 and WRR ¼ 0.833,95% CI 0.697e1.119, p ¼ 0.304, respectively), preg-nant women (WRR ¼ 0.792, 95% CI 0.371e1.687,

of cranberry ingestion on UTI incidence.2e4,7e10,13e30

CRANBERRIES AND URINARY TRACT INFECTIONS 619

p ¼ 0.545) and patients with bladder or cervicalcancer (WRR ¼ 1.150, 95% CI 0.747e1.796,p ¼ 0.526).

The sensitivity analysis was performed byexcluding 1 or more studies from analysis to deter-mine how this would affect the results (fig. 5). Thisanalysis showed that the pooled effects of cranberryingestion on the incidence of UTIs did not changesubstantially whether a single study or a fewstudies were omitted. Overall the sensitivity anal-ysis demonstrated that the findings of the currentmeta-analysis were robust.

Publication Bias

The funnel plot, which was generated for thedefined outcome and considered the trim and filladjustment, included observed studies and theimputed studies necessary to achieve the absenceof bias (fig. 6). Because there were more studies onthe left side than on the right side, 9 studies wereimputed on the right to adjust the funnel plotfor the absence of publication bias. The key findingthat the RR had substantive importance did notchange (adjusted WRR ¼ 0.8334, 95% CI 0.6976e0.9956).

Study name Statistics with study removed

Lower Upper Point limit limit p-Value

Caljouw, et al. (2014) a) High UTI Risk 0,660 0,556 0,782 0,000Caljouw, et al. (2014) b) Low UTI Risk 0,664 0,560 0,786 0,000Schlager et al. (1999) 0,674 0,570 0,798 0,000Kontiokari et al. (2001) 0,683 0,577 0,809 0,000Maki et al. (2016) 0,673 0,565 0,802 0,000Pagonas et.al. (2012) 0,684 0,576 0,812 0,000Burleigh et al. (2013) 0,685 0,578 0,812 0,000Ledda et al. (2015) 0,687 0,583 0,809 0,000Foxman et al. (2015) 0,681 0,574 0,807 0,000Vostalova et al. (2015) 0,685 0,579 0,811 0,000Stothers et al. (2002) a) (tablet) 0,678 0,572 0,804 0,000Stothers et al. (2002) a) (juice) 0,676 0,570 0,801 0,000McMurdo et al. (2005) 0,679 0,573 0,804 0,000Hess et al. (2008) 0,685 0,580 0,810 0,000Bonetta et al. (2012) 0,696 0,591 0,819 0,000Takahashi et al. (2013) 0,666 0,559 0,792 0,000Salo et al. (2011) 0,671 0,565 0,798 0,000Barbosa-Cesnick et al. (2011) 0,655 0,557 0,771 0,000Cowan et al. (2012) 0,658 0,556 0,778 0,000Wing et al. (2008) a) HD 0,675 0,570 0,799 0,000Wing et al. (2008) a) LD 0,670 0,565 0,793 0,000Afshar et al. (2012) 0,675 0,570 0,800 0,000Waites et al. (2003) 0,665 0,562 0,788 0,000Ferrara et al. (2009) 0,692 0,588 0,815 0,000McGuiness et al. (2002) 0,660 0,557 0,783 0,000Singh et al. (2016) 0,697 0,592 0,820 0,000Bianco et al. (2012) 0,662 0,558 0,785 0,000Lee et al. (2007) 0,660 0,555 0,786 0,000

0,675 0,572 0,797 0,000

Sensitivity An

Meta Analysis

Figure 5. Sensitivity analysis results.2e4,7e

In addition to visual inspection of the funnel plot,publication bias for the impact of cranberry inges-tion on the UTI incidence was explored using theEgger regression test (95% CI �2.81222e0.07500,t ¼ 1.94874, df ¼ 25, p ¼ 0.0623). Results did notindicate evidence of publication bias.

DISCUSSIONSeveral studies have presented the effects of cran-berries in subgroups of the population at increasedrisk for UTIs. The current systematic review withmeta-analysis demonstrates the effectiveness ofcranberry products in the prevention of UTIs. Theaddition of further studies to previous meta-analyses allows us to conclude that there existsstrong evidence that cranberries decrease thenumber of UTIs, particularly in patients withrUTIs.

Single UTI episodes are common, especially inwomen, with a 50-fold higher rate of infection thanmen.11 Subgroup analysis of patient gender wasperformed to verify whether the effects of cranberryingestion are gender dependent. It was observedthat for both genders the incidence of UTIs was

Risk ratio (95% CI) with study removed

0,5 1 2

Cranberry group Placebo group

alysis - UTI

10,13e30 HD, high dose. LD, low dose.

-2,0 -1,5 -1,0 -0,5 0,0 0,5 1,0 1,5 2,0

0,0

0,2

0,4

0,6

0,8

1,0

Stan

dard

Err

or

Log risk ratio

Funnel Plot of Standard Error by Log risk ratio

Figure 6. Funnel plot of SE by log RR for publication bias tests of cranberry ingestion effects on UTI incidence. Blue symbols represent

observed studies. Red circles represent imputed studies necessary to achieve absent bias.

620 CRANBERRIES AND URINARY TRACT INFECTIONS

significantly decreased in the cranberry treatedgroup.

It is known that the prevalence of UTIs is alsoage dependent.11 During the first year of life therate of UTIs is less than 2%. The incidence amongmales remains relatively low after age 1 year toapproximately age 60 years, when prostateenlargement interferes with bladder emptying.11 Totake this into consideration a subgroup analysisconcerning mean patient age was performed. Re-sults enabled us to conclude that in children 2 to 17years old and in middle-aged adults 36 to 55 yearsold cranberry ingestion significantly decreases theincidence of UTIs.

The results of subgroup analysis of patient typerevealed that those with rUTIs and those who hadundergone gynecologic surgery were more protectedby cranberry intake with a significant reduction inthe incidence of UTIs in those groups. This inter-esting result reinforces the importance of theingestion of cranberries by patients at some riskfor UTIs.

Although EAU (European Association of Urology)recommends continuous use of cranberries as analternative method to prevent UTIs, the data arenot conclusive because the available studies wereperformed for periods of up to a year. Thus, there isno evidence to support the efficacy of cranberryproducts for chronic use. Future trials may need tocover much longer periods.

The effectiveness of cranberry products is likelyto depend on the concentration of PACs, which arethe polyphenols associated with the amelioration of

UTIs. The most accepted mechanism of action forpreventing UTIs by cranberries is based on itsinterference with bacterial adhesion in the urinarytract.12 An antiadhesion response is caused in urineafter cranberry consumption, preventing uropatho-genic P-fimbriated E. coli from adhering to bladdercell receptors.12 If the bacteria are not able toadhere to cells, they cannot grow and cause infec-tion.12 The daily recommended amount of PACs todecrease the number of UTIs is at least 36 mg. Alimitation of the findings is the lack of consistencyamong the administered doses of PACs in theconsidered studies.

Another limitation found during the preparationof this report was the absence of uniformity in thedefinition of UTI among the included trials. All tri-als used the term UTI while in fact some referredspecifically to E. coli UTI. The differentiation be-tween UTI and E. coli UTI makes a clinical differ-ence. For example, cranberry would likely not beeffective in patients with other uropathogens but itwould be expected to be effective in patients withE. coli UTI since cranberry inhibits the adhesion ofE. coli pili.

CONCLUSIONSThe current systematic review with meta-analysiscould be used by physicians to recommend theingestion of cranberries to decrease the incidence ofUTIs, particularly in patients with recurrent UTIs.This alternative treatment could also help reducethe widespread use of antibiotics, which is leading

CRANBERRIES AND URINARY TRACT INFECTIONS 621

to the worldwide emergence of antibiotic resistantmicroorganisms. Future research should focus onclarifying the underlying mechanisms thatcontribute to the efficacy of cranberry PACs in

decreasing UTIs and the standardization of quan-tities of cranberries and/or doses of ingested cran-berry PACs along with the duration of thetreatment required to be effective.

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