Cranberries for preventing urinary tract infections - Jepson, RG ...

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Abstract
Background
Cranberries have been used widely for several decades for the prevention and treatment of urinary tract infections (UTIs). This is the third update of our review first published in 1998 and updated in 2004 and 2008.
Objectives
To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations.
Search methods
We searched the Cochrane Renal Group's Specialised Register (4 June 2013) through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.We contacted companies involved with the promotion and distribution of cranberry preparations and checked reference lists of review articles and relevant studies.
Date of search: July 2012
Selection criteria
All randomised controlled trials (RCTs) or quasi‐RCTs of cranberry products for the prevention of UTIs.
Data collection and analysis
Two authors independently assessed and extracted data. Information was collected on methods, participants, interventions and outcomes (incidence of symptomatic UTIs, positive culture results, side effects, adherence to therapy). Risk ratios (RR) were calculated where appropriate, otherwise a narrative synthesis was undertaken. Quality was assessed using the Cochrane risk of bias assessment tool.
Main results
This updated review includes a total of 24 studies (six cross‐over studies, 11 parallel group studies with two arms; five with three arms, and two studies with a factorial design) with a total of 4473 participants. Ten studies were included in the 2008 update, and 14 studies have been added to this update. Thirteen studies (2380 participants) evaluated cranberry juice/concentrate; nine studies (1032 participants) evaluated cranberry tablets or capsules; one study compared cranberry juice and tablets; and one study compared cranberry capsules and tablets. The comparison/control arms were placebo, no treatment, water, methenamine hippurate, antibiotics, or lactobacillus. Eleven studies were not included in the meta‐analyses because either the design was a cross‐over study and data were not reported separately for the first phase, or there was a lack of relevant data. Data included in the meta‐analyses showed that, compared with placebo, water or not treatment, cranberry products did not significantly reduce the occurrence of symptomatic UTI overall (RR 0.86, 95% CI 0.71 to 1.04) or for any the subgroups: women with recurrent UTIs (RR 0.74, 95% CI 0.42 to 1.31); older people (RR 0.75, 95% CI 0.39 to 1.44); pregnant women (RR 1.04, 95% CI 0.97 to 1.17); children with recurrent UTI (RR 0.48, 95% CI 0.19 to 1.22); cancer patients (RR 1.15 95% CI 0.75 to 1.77); or people with neuropathic bladder or spinal injury (RR 0.95, 95% CI: 0.75 to 1.20). Overall heterogeneity was moderate (I² = 55%). The effectiveness of cranberry was not significantly different to antibiotics for women (RR 1.31, 95% CI 0.85, 2.02) and children (RR 0.69 95% CI 0.32 to 1.51). There was no significant difference between gastrointestinal adverse effects from cranberry product compared to those of placebo/no treatment (RR 0.83, 95% CI 0.31 to 2.27). Many studies reported low compliance and high withdrawal/dropout problems which they attributed to palatability/acceptability of the products, primarily the cranberry juice. Most studies of other cranberry products (tablets and capsules) did not report how much of the 'active' ingredient the product contained, and therefore the products may not have had enough potency to be effective.
Authors' conclusions
Prior to the current update it appeared there was some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs. The addition of 14 further studies suggests that cranberry juice is less effective than previously indicated. Although some of small studies demonstrated a small benefit for women with recurrent UTIs, there were no statistically significant differences when the results of a much larger study were included. Cranberry products were not significantly different to antibiotics for preventing UTIs in three small studies. Given the large number of dropouts/withdrawals from studies (mainly attributed to the acceptability of consuming cranberry products particularly juice, over long periods), and the evidence that the benefit for preventing UTI is small, cranberry juice cannot currently be recommended for the prevention of UTIs. Other preparations (such as powders) need to be quantified using standardised methods to ensure the potency, and contain enough of the 'active' ingredient, before being evaluated in clinical studies or recommended for use.
PICOs
PICOs
Population
Intervention
Comparison
Outcome
The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.
Plain language summary
Cranberries for preventing urinary tract infections
Cranberries (usually as cranberry juice) have been used to prevent urinary tract infections (UTIs). Cranberries contain a substance that can prevent bacteria from sticking on the walls of the bladder. This may help prevent bladder and other UTIs. This review identified 24 studies (4473 participants) comparing cranberry products with control or alternative treatments. There was a small trend towards fewer UTIs in people taking cranberry product compared to placebo or no treatment but this was not a significant finding. Many people in the studies stopped drinking the juice, suggesting it may not be an acceptable intervention. Cranberry juice does not appear to have a significant benefit in preventing UTIs and may be unacceptable to consume in the long term. Cranberry products (such as tablets or capsules) were also ineffective (although had the same effect as taking antibiotics), possibly due to lack of potency of the 'active ingredient'.
Visual summary
Authors' conclusions
Implications for practice
The current body of evidence suggest that cranberry products (either in juice or as capsules/tablets) compared to placebo provides no benefits in most populations groups, and the benefit in some subgroups is likely to be very small. The large number of dropouts/withdrawals from some of the studies indicates that cranberry products, particularly in juice form, may not be acceptable over long periods of time. Cranberry capsules or tablets may overcome some issues with compliance, but from current evidence they do not appear to be any more effective than juice, although they may be as effective as antibiotics. One of the drawbacks of the studies of non‐juice products, such as capsules, is few of the triallists reported how much 'active' ingredients (if any) were in the tablets or capsules they used. Until there are more studies of products containing enough of the active ingredient, measured in a standardised way, cranberry products cannot be recommended for preventing UTIs.
Implications for research
A significant number of RCTs have now been conducted to assess the effectiveness of cranberry products for preventing UTIs, particularly in its juice form. Given the majority of studies indicate the benefit is likely to be small at best, and with poor adherence, further studies of cranberry juice are only likely to support this conclusion, and should not be undertaken without strong justification. More studies of cranberry products such as tablets and capsules may be justified, but only for women with recurrent UTIs, and only if they contain the recommended amount of PAC (at least 36 mg/d) which is quantified using standardised and validated measures.
Background
The term urinary tract infection (UTI) refers to the presence of a certain threshold number of bacteria in the urine (usually > 100,000/mL). It consists of cystitis (bacteria in the bladder), urethral syndrome and pyelonephritis (infection of the kidneys). Lower UTIs involve the bladder, whereas upper UTIs also involve the kidneys (pyelonephritis). Bacterial cystitis (also called acute cystitis) can occur in men and women and the signs and symptoms include dysuria (pain on passing urine), frequency, cloudy urine, occasionally haematuria (blood in the urine), and is often associated with pyuria (urine white cell count greater than 10,000/mL). Urethral syndrome (frequency and dysuria syndrome) is used to describe approximately 50% of women with these complaints who have either no bacterial growth or counts less than 100,000 colony‐forming units (cfu)/mL on repeated urine cultures. Pyelonephritis is thought to occur as a result of cystitis, particularly in the presence of transient (occasional) or persistent backflow of urine from the bladder into the ureters or kidney pelvis (vesicoureteric reflux). Signs and symptoms include flank pain or back pain, fever, chills with shaking, general ill feeling plus those symptoms of a lower UTI. Acute pyelonephritis can be severe in the elderly, in infants, and in people who are immunosuppressed (for example, those with cancer or AIDS). Although most people who present to the doctor or hospital have symptomatic UTIs, some can be asymptomatic and only those who are at high risk of developing further infections (pregnant women and the elderly) are considered to need treatment. Some people also have recurrent UTIs with an average of two to three episodes/year (Roberts 1979; Wong 1984). Children often present with a fever and non‐specific symptoms such as lethargy (tiredness), vomiting or poor feeding.
UTIs are one of the most common medical conditions requiring outpatient treatment, and complications resulting from persistent and repeated infections necessitate well over one million hospital admissions annually in the USA (Patton 1991). Specific subpopulations are at increased risk of developing a UTI. These groups include infants, pregnant women, the elderly, patients with spinal cord injuries and/or catheters, patients with diabetes or multiple sclerosis, patients with acquired immunodeficiency disease syndrome/human immunodeficiency virus, and patients with underlying urologic abnormalities (Foxman 2002). Although UTIs can occur in both men and women, they are about 50 times more common in adult women than adult men. This may be because women have a shorter urethra that may allow bacteria to ascend more easily into the bladder. Symptomatic infection of the bladder (lower UTI) has been estimated to occur in up to 30% of women at some stage during their lives (Kelly 1977). The annual incidence of acute uncomplicated UTI is 7% for all ages of women peaking at 15‐24 years and women older than 65 (Giesen 2010). Up to 25% of women who have a UTI are likely to have a reoccurrence within six months (Epp 2010). UTIs often occur in clusters with long periods (several months) where patients are symptom free (Stapleton 1997).
Most UTIs are thought to arise from the 'ascending' route of infection. The first step is colonisation of periurethral tissues with uropathogenic organisms, followed by the passage of bacteria through the urethra. Infection arises from bacterial proliferation (growth) within the otherwise sterile urinary tract. In children, UTI occurs more commonly in boys up to the age of 12 months, but overall occurs about three times more often in girls (1% to 3% in boys, 3% to 7% in girls) (Hellstrom 1991; Winberg 1974).
Cranberries (particularly in the form of cranberry juice) have been used widely for several decades to prevent and treat UTIs. Cranberries comprise nearly 90% water, but also contain various organic substances such as quinic acid, malic acid and citric acid as well as glucose and fructose. Until recently, it was suggested that the quinic acid caused large amounts of hippuric acid to be excreted in the urine which then acted as an antibacterial agent (Kinney 1979). Several studies, however, have shown no difference in the levels, or only a transient effect thus casting some doubt on this theory (Kahn 1967; McLeod 1978). No definitive mechanism of action has been established for cranberry in the prevention or treatment of UTIs. However, research suggests that cranberries prevent bacteria (particularly Escherichia coli) from adhering to uroepithelial cells that line the wall of the bladder (Schmidt 1988; Zafriri 1989). Without adhesion, E. coli cannot infect the mucosal surface of the urinary tract. In vitro, this adhesion is mediated by two components of cranberry; fructose, which inhibits adherence of type 1 (mannose specific) fimbriated E. coli (Foo 2000; Howell 2007), and substances called proanthocyanidins (PAC), which inhibit the adherence of p‐fimbriated (a‐galactose‐(1‐4) specific) E. coli (Zafriri 1989). PAC have A‐ and B‐ type linkages but It is only the PAC which contain the A‐type linkages (found in cranberry juice) which have been associated with preventing adhesion of the E.coli to (Howell 2002; Howell 2005). PAC with B‐type linkages are found in a number of sources including commercial apple and grape juice, dark chocolate but these do not appear to have any anti‐adhesion effects (Howell 2005).
Cranberry products include juice, syrup, capsules and tablets. A commonly recommended amount for UTI prevention is daily consumption of 300 mL of cranberry juice cocktail containing 36 mg PAC (Howell 2010). However, processing of cranberries into various products such as tablets or capsules can impact on the PAC composition (Howell 2010) which may result in products which contain little or no PAC ‐ the 'active' anti‐adhesion ingredient. In addition, the complexities of the PAC structures and A‐type linkages means that measurement of PAC content can often be erroneous and may not be reproducible (Prior 2010). To ensure potency in cranberry powders, levels of PAC must be quantified properly; and the 4‐dimethylaminocinnamaldehyde method is currently the most validated standard method for quantifying PAC in cranberry powders (Prior 2010). A randomised controlled trial (RCT) evaluating the dosage effect of cranberry powder found that to achieve a bacterial anti‐adhesion effect in urine, 36 mg of cranberry PAC equivalents/d is effective, but 72 mg may offer better protection in some cases. As the anti‐adhesion activity decreases over time, it is recommended that cranberries products should be consumed in the morning and in the evening (Howell 2010).
The aim of this review is to assess the effectiveness of cranberries in the prevention of UTIs in susceptible populations including children, women with recurrent UTIs, people with a neuropathic bladder, and older people.
The treatment of UTIs with cranberries is evaluated in another review by the same authors (New Reference).
Objectives
We wished to test the following hypotheses:
Cranberry juice/cranberry products are more effective than placebo/no treatment in the prevention of UTIs in susceptible populations.
Cranberry juice/ cranberry products are more effective than any other treatment in the prevention of UTIs in susceptible populations.
Different cranberry products (juice, capsules, tablets, concentrate) may differ in the effectiveness for preventing UTIs in susceptible populations
An attempt was also made to quantify the side effects of cranberry juice and the findings were taken into account in the discussion to determine the risk‐benefit of the treatment.
Methods
Criteria for considering studies for this review
Types of studies
All RCTs of cranberry juice (or derivatives) versus placebo, no treatment or any other treatment. Quasi‐RCTs (e.g. those studies which randomised participants by date of birth, or case record number) were included, but the quality of the studies was taken into account during the analysis and discussion. Both parallel group and cross‐over design were included.
Types of participants
Inclusion criteria
Studies of susceptible men, women or children as defined below. These categories were analysed separately.
Participants with a history of recurrent lower UTIs (more than two episodes in the previous 12 months)
Elderly men and women
Participants needing intermittent catheterization
Pregnant women
Participants with an in‐dwelling catheter
Participants with an abnormality of the urinary tract
Children with a first or subsequent UTI.
Exclusion criteria
Studies of the treatment of asymptomatic or symptomatic UTI (these are analysed in a separate review by the same authors New Reference).
Studies of any urinary tract condition not caused by bacterial infection (e.g. interstitial cystitis ‐ a chronic inflammation of the bladder wall).
Types of interventions
Cranberry juice or a cranberry product (e.g. cranberry capsules, tablets or extract) taken by participants for at least one month. The amount taken/d, concentration of the juice/cranberry product and length of treatment was also taken into account in subgroup analyses.
Types of outcome measures
Primary outcomes
Number (incidence) of UTIs in each group (confirmed by a catheter specimen of urine (CSU), midstream specimen of urine (MSU) if possible, or a 'clean catch' specimen).
The 'gold standard' bacteriological criteria for diagnosis of UTI includes microbiological confirmation from a MSU (or similar method) with greater than 100,000 bacterial cfu/mL, with some clinicians also requiring concurrent pyuria (white cells in the urine). In some situations a bacterial count < 100,000/mL is acceptable. For example, when a supra‐pubic bladder tap or a catheter urine specimen is obtained. If further studies become available for review, the method of collecting a specimen of urine, the causative organism (e.g. E. coli) and the presence of mixed organisms in the urine (which signifies contamination) will be subject to sensitivity analyses.
If further studies become available for review, this outcome will also be subgrouped into rate of symptomatic lower UTIs, rate of symptomatic upper UTIs (UTI plus fever) and rate of asymptomatic UTIs. Symptomatic is defined as having one or more or the following symptoms: dysuria, frequency, urgency or fever.
Methods used to diagnose upper and lower UTIs will also be subjected to sensitivity analysis if enough data is available.
Secondary outcomes
Adherence to therapy.
Side effects.
Search methods for identification of studies
Review update
We searched the Cochrane Renal Group's Specialised Register (4 June 2013) through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.
Studies contained in the Specialised register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies as well as a list of handsearched journals, conference proceedings and current awareness alerts are available in the 'Specialised Register' section of information about the Cochrane Renal Group.
(UTIs.sh. or cystitis.sh. or bacteriuria.sh. or pyelonephritis.sh. or UTI$.ti,ab. or urinary adj5 infection$.ti,ab. or bacter$.ti,ab. or pyelonephrit$.ti,ab. or cystitis.ti,ab.)
1 and 2
The following terms were searched to identify non‐English language studies:
Danish ‐ (Tranebaersaft.ti,ab. or tranebaer.ti,ab. or orkaempetranebaer.ti,ab. or store tranebaer.ti,ab. or cranberry.ti,ab.) and (urinvejsinfektion.ti,ab. or cystitis.ti,ab. or blaerebetaendelse.ti,ab. or pyelonephritis.ti,ab. or pyelonefrit.ti,ab.)
Dutch ‐ (veenbes.ti,ab. or lepeltjeheide.ti,ab. or lepeltjesheide.ti,ab. or Amerikaanse veenbes.ti,ab. or cranberry.ti,ab.) and (cystitis.ti,ab. or catarrhus.ti,ab. or vesicalis.ti,ab. or blaasontsteking.ti,ab. or urineweginfectie.ti,ab. or pyelonephritis.ti,ab. or nephropyelitis.ti,ab.)
French ‐ (canneberges ronce d'Amerique.ti,ab. or cranberry.ti,ab. or cranberrie.ti,ab.) and (cystite.ti,ab. or infection urinaire.ti,ab. or pyélonéphrite.ti,ab.)
German ‐ (moosbeere.ti,ab or kranbeere.ti,ab.) and (zystitis.ti,ab. or cystitis.ti,ab. or harnwegsinfektion.ti,ab. or harninfekt.ti,ab. or pyelonephritis.ti,ab.)
Reference lists of review articles and relevant studies were searched.
Conference abstracts from The Proceedings of the Urological Association (1990‐1998), and The Journal of the American Geriatrics Society (1990 ‐1998) were searched for relevant studies for the initial review. Handsearching was then undertaken by the Cochrane Renal Group.
The National Research Register was searched for studies currently underway.
Data collection and analysis
The search strategy described previously was employed to obtain titles and, where possible, abstracts of studies that were potentially relevant to the review. The titles and abstracts were screened by RJ and for the 2012 update, GW, who discarded studies that were clearly ineligible but aimed to be overly inclusive rather than risk losing relevant studies. Two authors independently assessed, using full copies of the papers, whether the studies met the inclusion criteria, with disagreements resolved by discussion. Further information was sought from the authors of those papers which contained insufficient information to make a decision about eligibility.
The quality of all studies which were deemed eligible for the review were then assessed independently by two authors, with discrepancies resolved by discussion. The 2012 update included Cochrane risk of bias assessments, these details were recorded by two authors (RJ and GW) and compared for discrepancies. Differences were resolved through discussion and a third author (JC) when necessary. Summary descriptors are provided in the additional tables (Table 1 ‐ Characteristics of studies;Table 2 ‐ Study design and quality of reporting).
Two authors independently extracted information using specially designed data extraction forms. For each included study, information was collected regarding the location of the study, methods of the study (as per quality assessment checklist), the participants (sex, age, eligibility criteria), the nature of the interventions, and data relating to the outcomes specified previously. Where possible, missing data (including side effects) were sought from the authors. All first authors were contacted for more data if necessary. Five authors replied (Kontiokari 2001; NAPRUTI Study 2011 I; Salo 2010; Stothers 2002; Walker 1997) but no additional information was obtained from three of these communications (Walker 1997; NAPRUTI Study 2011 I;Salo 2010). Discrepancies in the data extraction were resolved via discussion.
Studies with either parallel group or cross‐over design were included in the review. For cross‐over studies, only the period before the cross‐over is able to be synthesised in RevMan. However, this data were not available for any of the studies, so end of study data were reported descriptively along with the analysed studies (Table 3 ‐ Positive urine culture (bacteriuria); Table 4 ‐ Symptomatic UTIs). Risk ratio (RR) was used as the measure of effect for dichotomous outcomes, using a random effects model. Studies were sub‐grouped by population type (e.g. older people, women with recurrent UTIs). If enough data becomes available in the future, heterogeneity in the data will be noted and cautiously explored using previously identified characteristics of the studies, particularly assessments of quality. Sensitivity analyses will be undertaken to examine the stability of the results in relation to a number of factors including study quality, the source of the data (published or unpublished), the method used for confirming the presence of bacteria in the urine (e.g. CSU or MSU specimen of urine), the causative organism (e.g. E. coli) and the method of diagnosing upper or lower UTI.
Elderly men and women
Four studies evaluated cranberry juice for the prevention of UTIs in elderly populations (Avorn 1994; Haverkorn 1994; McMurdo 2005; PACS Study 2008). The largest and best quality study (McMurdo 2005) included 360 hospital patients aged 60 years or over who were randomised to daily ingestion of 300 mL of cranberry juice or matching placebo beverage using a parallel group design. Avorn 1994 was a quasi‐randomised, parallel group study of elderly women randomised to either cranberry juice or placebo juice. Although 192 women were initially randomised to treatment, only 153 provided enough data to be included in the final analysis. Haverkorn 1994 used a cross‐over design and included 38 men and women randomised to either cranberry juice or water. Only 17 completed treatment and seven were included in the final analysis. The fourth study was a small (59 participants), three‐armed study of a cranberry capsule, cranberry tablet or placebo (PACS Study 2008).
Six studies evaluated the effect of cranberry products in people needing either indwelling catheters or intermittent catheterisation (Foda 1995; Hess 2008; Lee 2007; Linsenmeyer 2004; Schlager 1999; Waites 2004). Four of the studies evaluated the effectiveness of cranberry capsules/tablets versus placebo in adults with spinal cord injuries (Hess 2008; Lee 2007; Linsenmeyer 2004; Waites 2004) of which two were cross‐over studies (Hess 2008; Linsenmeyer 2004), one was a parallel group study (Waites 2004), and one used a four‐arm factorial design comparing cranberry product with methenamine hippurate and placebo (Lee 2007). In the other two studies (Foda 1995; Schlager 1999), participants were children who had a paediatric neuropathic bladder and were managed by clean intermittent catheterisation. Both were cross‐over studies which compared cranberry juice to placebo/water and included 40 and 15 children respectively.
Children at risk of repeat UTI
Three studies enrolled children at risk of, or susceptible to, repeat UTI (Ferrara 2009; Salo 2010; Uberos 2010). Two studies (Ferrara 2009; Uberos 2010) included children who had experienced more than one UTI with and Salo 2010 enrolled children at their first UTI. All tested the effectiveness of different cranberry products. Salo 2010 compared cranberry juice with placebo; Uberos 2010 compared cranberry syrup versus trimethoprim syrup; and Ferrara 2009 compared cranberry plus lingonberry concentrate with lactobacillus.
Other populations
Cowan 2012 included patients undergoing radiation treatment for bladder or cervical cancer and compared two daily doses of cranberry juice with a placebo beverage. McGuiness 2002 compared cranberry capsules with placebo and included patients with multiple sclerosis, of which 72 voided naturally and 63 used intermittent self catheterisation.
Outcome measures
In all of the studies, symptomatic UTI and/or positive urine culture were reported as the primary outcome measures. The outcome reported in this review is the number of people experiencing at least one symptomatic UTI at the end of the follow‐up period.
Risk of bias in included studies
Figure 1 is a risk of bias graph showing the review authors' judgements about each risk of bias item, presented as percentages across all included studies. Figure 2 is a risk of bias summary showing the review authors' judgements about each risk of bias item for each included study.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Random sequence generation
Fourteen studies reported a method of random sequence generation that was judged to be at low risk of introducing bias, in eight studies the issue was unclear and for two studies (Avorn 1994; Haverkorn 1994) the method was considered at high risk of introducing bias (Figure 2)
Allocation concealment
Fifteen studies reported a method of allocation concealment considered to be at low risk of bias, in six studies this issue was unclear and for two studies the method reported was judged as being at high risk of introducing bias (Figure 2).
Blinding
Seventeen of the studies stated that participants and study personnel were blind to treatment allocation, five studies had no blinding, and for one study this issue was unclear (Essadi 2010). In 13 studies the outcome assessor was either stated as blinded (or assumed to be blinded based on study design) and in nine studies it was unclear whether the outcome assessor was blind to treatment allocation.
Incomplete outcome data
Twelve studies reported complete outcome data, eight studies had incomplete outcome data and for four studies this issue was unclear.
Selective reporting
Twenty studies reported the most appropriate outcomes for the study design, repeat symptomatic UTI or positive urine culture, while for three studies selective reporting issues were unclear.
Withdrawals, losses to follow‐up and intention‐to‐treat
The dropout rate varied considerably across the studies, from 0% to 55%. Six studies included all randomised participants in their analysis (Lee 2007; McMurdo 2009; PACS Study 2008; Schlager 1999; Stothers 2002; Wing 2008) whilst the remaining studies ‐ where this was able to be determined ‐ excluded between 5% and 55% of the randomised participants from the outcome analyses. One study (McGuiness 2002) reported that it used an intention‐to‐treat analysis, but the results do not concur with this assertion.
Several studies stated that palatability of the cranberry product (primarily cranberry juice) was assumed to be the reason for participants discontinuing or withdrawing from the study, but none provided actual data about this from participants.
At least one of the studies had serious flaws. In Avorn 1994 some of the baseline characteristics of the participants were markedly different in the cranberry and the placebo group. In particular, the rate of UTIs in the previous six months in the placebo group was over three times that of the cranberry juice group, and double for over 12 months. Two letters, published in JAMA, commented on these differences and inferred that the randomisation and/or blinding scheme had failed (Hopkins 1994; Katz 1994).
Effects of interventions
Cranberry product compared with placebo or no treatment
Overall
Across the combined population of patients, 13 studies (2462 participants) had data which were able to be analysed. The combined estimated RR of repeat UTI with cranberry treatment was not statistically significant (Analysis 1.1: RR 0.86, 95% CI 0.71 to 1.04). Twelve studies had data which could not be meta‐analysed. Of these, eight studies reported no effect, and two small studies reported a significant effect of cranberries compared to placebo (Hess 2008; Walker 1997). There was moderate overall heterogeneity (I² = 53%) but no significant between study heterogeneity (I² = 5.2%).
Women with a recurrent UTI
Four of the five studies (594 participants) which included a placebo group provided data that could be combined in a meta‐analysis (Kontiokari 2001; Barbosa‐Cesnik 2011; Stothers 2002; Sengupta 2011). Results showed a small, non‐significant reduction in risk of repeat symptomatic UTI with cranberry treatment compared to placebo or no treatment (Analysis 1.1.1: RR 0.74, 95% CI 0.42 to 1.31). However there was significant heterogeneity in the results, primarily with the addition of the newest largest study (Barbosa‐Cesnik 2011) (I² = 65%). When this study was omitted from the meta‐analysis, the RR was 0.58 (95% CI 0.39 to 0.86). There may be several reasons why Barbosa‐Cesnik 2011 showed different results to the other studies (i.e. no effect of cranberries). As they discuss, theirs was the only study which was powered sufficiently to detect a difference (it had a larger sample size than the other three put together). However, they do use a different (lower) threshold for defining a UTI than the other studies, although measurement of symptoms would have been similar.
The other study (Walker 1997) was published as a letter with no comparable data. In this study there were 21 incidents of UTIs amongst the 10 people who completed the study. Six were in the treatment group, and 15 were in the placebo group (P < 0.005) (see Table 4).
Older men and women
Overall the data from the studies in older men and women suggest that cranberries are not effective in preventing UTIs. Of the four studies evaluating the effectiveness of cranberry product(s) versus placebo in the population group, two studies were of high quality and had data available for analysis (McMurdo 2005; PACS Study 2008) (Analysis 1.1.2 (2 studies, 413 participants): RR 0.75, 95% CI 0.39 to 1.44). The other studies had significant flaws. Avorn 1994 reported 4% (20/473) of the urine samples in the treatment group and 7% (37/498) in the placebo group had bacteriuria and pyuria concurrent with the subjects reporting urinary tract symptoms (P = not significant). These figures, however, appear to include the baseline urine samples (i.e. before the participants began drinking either cranberry juice or placebo juice). Haverkorn 1994 gave no details about symptomatic UTIs. See Table 4 for more results from these two studies.
Overall the evidence from six studies suggest there is no benefit of cranberry juice in reducing UTIs in this population group. Only two of these studies had relevant data for a meta‐analysis (Lee 2007; Waites 2004). When we combined the results of these studies there was no difference between the cranberry and placebo groups (Analysis 1.1.3 (2 studies, 353 participants): RR 0.95, 95% CI 0.75 to 1.20). The other four studies were cross‐over studies. One (Hess 2008) found a significant effect, two reported a non‐significant effect (Foda 1995; Schlager 1999) and one only had asymptomatic UTIs as an outcome (Linsenmeyer 2004).
Pregnant women
Overall cranberry juice was found not to be effective in reducing UTIs in pregnant women. The two studies in pregnant women (Essadi 2010; Wing 2008) provided data that could be analysed, but these showed widely different results with combined RR of 1.04 (95% CI 0.93 to 1.16) (Analysis 1.1.4). Both studies evaluated relatively large quantities of cranberry juice (up to 1000 mL/d) and both had a high number of withdrawals (39% and 28% respectively). In one of the studies (Wing 2008), the number of withdrawals was so high that the dose was reduced from 720 mL/d to 540 mL/d.
Children with a susceptibility to UTIs
The overall evidence suggested that cranberry products are not effective for preventing UTIs in children. Two studies (Ferrara 2009; Salo 2010) in children showed a non‐significant reduction in risk of repeat symptomatic UTI with cranberry treatment compared to placebo (RR 0.48, 95% CI 0.19 to 1.22) (Analysis 1.1.5). The third study (Uberos 2010) was only published as an abstract and it was not clear whether the results were presented for symptomatic UTIs or just a positive culture.
Other populations
A single study (Cowan 2012) reported data in patients undergoing radiation treatment and showed a non‐significant increased risk of repeat UTI with cranberry product (RR 1.15, 95% CI 0.75 to 1.77) (Analysis 1.1.6). Another study of people with multiple sclerosis (either voiding naturally or using intermittent self catheterisation (McGuiness 2002) found no significant difference between the cranberry capsule or control group (34.6% of people versus 32.6%).
Cranberry product compared with antibiotic prophylaxis
Two studies in women with recurrent UTI (McMurdo 2009; NAPRUTI Study 2011 I) and one study in children (Uberos 2010), compared cranberry product with antibiotic prophylaxis. All three studies used either cranberry capsules or syrup, rather than cranberry juice. Analysis of the two studies in women showed that cranberry product compared to antibiotic were equally as effective in reducing the risk of repeat UTI in women (Analysis 2.1.1: RR 1.31, 95% CI 0.85 to 2.02) The study in children also showed that the cranberry product were equally as effective in reducing the risk of repeat symptomatic UTI compared to antibiotics (Analysis 2.1.2: RR 0.69, 95% CI 0.32 to 1.51).
High dose cranberry versus placebo
Three studies in different populations ‐ pregnant women (Wing 2008); elderly men and women (PACS Study 2008); and adult women (Sengupta 2011) ‐ compared high dose cranberry product to placebo. There was significant heterogeneity, both overall (I² = 55%) and between the subgroups (I² = 54.5%) and we therefore did not pool the results. The results ranged from RR 5.42 (95% CI 0.27 to 110.66) in pregnant women (Wing 2008) to RR 0.28 (95% CI 0.06 to 1.34) in adult women (Sengupta 2011) ( Analysis 4.1).
Cranberry versus complementary therapies
A single study (Lee 2007) compared cranberry product with methenamine hippurate in patients with spinal injury and showed no difference between the groups (Analysis 5.1: RR 1.02, 95% CI 0.79 to 1.31).
Two studies, one in children (Ferrara 2009) and one in adult women (Kontiokari 2001), compared cranberry with a probiotic treatment and showed a significant reduction in symptomatic UTI with cranberry compared to probiotic (Analysis 6.1 (2 studies, 152 participants): RR 0.42, 95% CI 0.24 to 0.74).
Cost effectiveness
One study (Stothers 2002) reported on the cost effectiveness of the intervention. The mean annual cost of prophylaxis was CAD 624 and CAD 1400 for cranberry tablets and juice respectively. Cost savings were greatest when patients experienced more than two symptomatic UTIs/year (assuming three days of antibiotic coverage) and had more than two days of missed work or required protective undergarments for urgency incontinence. Total antibiotic consumption was less annually in both treatment groups compared with placebo. The authors of the study reported that cost effectiveness ratios demonstrated cranberry tablets were twice as cost effective as organic juice for prevention.
Discussion
Summary of main results
In the last update of this review (Jepson 2008) we concluded that 'There was some evidence to show that cranberries (juice and capsules) can prevent recurrent infections in women. However, the evidence for elderly men and women was less clear, and there is evidence that is not effective in people who need catheterisation. In this update, with the addition of 14 new studies, it has become more evident that cranberry products do not significantly reduce the risk of repeat symptomatic UTI compared to placebo or no treatment in groups of people at risk of repeat UTI (overall RR 0.86, 95% CI 0.71 to 1.04) or for any of the subgroups analysed. There was however moderate heterogeneity (53%), which is largely unexplained. The two studies in children suggest the greatest effect (RR 0.48, 95% CI 0.19 to 1.22), however this result was not significant, reflecting the small sample size and infrequency of events. In adult women (RR 0.74, 95% CI 0.42 to 1.31) and the elderly (RR 0.75, 95% CI 0.39 to 1.44) the CIs were wide and do not reach not statistical significance. Studies in pregnant women, patients with spinal injury or neuropathic bladder, people with multiple sclerosis, and people receiving radiation therapy showed no significant benefit to cranberry product with RRs close to 1.
Three studies compared cranberry product with antibiotic treatment, two in adult women and one in children. When pooled, the two studies in women showed no significant difference in terms of risk of repeat UTI for women taking cranberry product while the study in children suggested the lower risk of repeat infection for those taking cranberry products compared with antibiotics.
Overall completeness and applicability of evidence
Several sub‐groups of the populations are at increased risk of repeat UTI and the majority of these groups are represented in studies included in this review. Adult women were most frequently studied (seven studies) and the range of other susceptible population groups ‐ children, the elderly, pregnant women, those with a spinal injury, neuropathic bladder, multiple sclerosis or undergoing radiotherapy ‐ were included.
From the evidence it is unlikely that cranberry in its juice form is going to be an acceptable and effective intervention, even if the anti‐adhesion can be demonstrated in vitro. Effectiveness of the cranberry juice in non‐research populations is likely to be dependant on high adherence to the amount and the timing. To maintain levels of cranberry PAC that are necessary to prevent anti‐adhesion, people would have to continuously drink the juice twice a day in serving of 150 mL for an indefinite period of time. If a woman only has two UTIs a year she would have to drink the juice twice a day for a year to potentially have one less UTI. Although for some women this regime may be acceptable (i.e. those who have a high rate of occurrence), others may find that the price, the calories in the juice, and the taste may make it less appealing.
Given the potential drawbacks of drinking cranberry juice for long periods, in recent years there have been an increasing number of studies evaluating the effectiveness of cranberry products such as tablets and capsules (Hess 2008; Lee 2007; Linsenmeyer 2004; McGuiness 2002; McMurdo 2009; NAPRUTI Study 2011 I; PACS Study 2008; Sengupta 2011; Stothers 2002; Waites 2004; Walker 1997). However, processing of cranberry into various products such as tablets or capsules can impact on the PAC composition (Howell 2010). Thus, proper standardization of cranberry products for PAC content, and correlation of the PAC level with anti‐adhesion bioactivity, may be important to ensure that particular cranberry products contain PAC that are efficacious(Howell 2010). Howell 2010 suggested that at least 36 mg of cranberry PAC equivalents/d is required to be effective, divided into two doses, one in the morning and one at night. Only three studies measured PAC content in non‐juice products (NAPRUTI Study 2011 I; Sengupta 2011; Uberos 2010). The PAC content reported in NAPRUTI Study 2011 I was 9.1 mg/g; 1.5% in Sengupta 2011; and in Uberos 2010 (of children) 5 mL of the syrup contained 36 mg. The other studies of non‐juice products did not report the PAC content, and thus it is not possible to ascertain whether the products used contained enough PAC content to be effective. There are currently three studies (Bonetta 2011; NCT00280592; NCT01033383) evaluating cranberry tablets or capsules which have not reported enough data to be included in this review update. More studies of cranberry capsules or tablets containing PAC amounting at least 36 mg/d, quantified using a standard measure, and taken twice daily may be warranted but potentially only for women with recurrent UTIs.
Quality of the evidence
Study design in most studies was relatively robust and free from significant bias. The biggest weakness of the evidence was in attrition bias due to the large number of participants who were randomised but not included in the outcome analysis (intention‐to‐treat). Not using an intention‐to‐treat analysis undermines the randomisation process and such an analysis was only undertaken in six studies. A further limitation to the findings is the small size of most studies; most studies lacked power to detect a realistic significant difference between treatment groups and even combining the few studies with similar populations and treatment, did not greatly improve this issue.
Potential biases in the review process
Data extraction was completed independently by two authors without financial interest in the outcome. Data compilation for the new studies in the current update was completed by an author uninvolved in the previous review and without expectations for results. In summary authors believe the review update was an unbiased process limited only by the adequacy of reporting in the included studies.
Agreements and disagreements with other studies or reviews
The most recent and robust systematic review that evaluated cranberry products versus placebo was published in 2012 (Wang 2012). Although the search strategy and inclusion/exclusion criteria were similar, the Wang 2012 only contained 13 studies (1616 participants) compare to this review with 24 studies (4473 participants). The main difference was that the authors did not include studies that compared cranberry products with another intervention (e.g. antibiotics). However, despite this difference, the review did not contain several placebo controlled studies that were included here (Cowan 2012; Essadi 2010; Lee 2007; Linsenmeyer 2004; NAPRUTI Study 2011 I; PACS Study 2008; Salo 2010; Sengupta 2011; Uberos 2010). Overall Wang 2012 reported similar results to this review. The main difference was their decision to exclude one of the studies with women with recurrent UTIs from their meta‐analysis (Barbosa‐Cesnik 2011). They excluded the study because there was significant heterogeneity in the results ‐ the Barbosa‐Cesnik 2011 study was the only one in the subgroup of women with recurrent UTIs which showed no effect of cranberry on the incidence of UTIs. Wang 2012 hypothesised that one of the reason for the different results in this study could be due to the threshold which Barbosa‐Cesnik 2011 used to define a UTI. It was the lowest at 10³ cfu/mL; most of the other studies used a threshold of 105 cfu/mL. However, since this threshold was used to define a UTI in both the control and intervention group in the study, this is unlikely to be the explanation. As the weighted prior probability of UTI varies across diagnostic threshold: 65.1% at ≥ 10² cfu/mL; 55.4% at ≥ 10³ cfu/mL; and 44.8% at ≥ 105 cfu/mL (Giesen 2010), you would expect to see more UTIs identified at a lower threshold, but this was not the case in this study. The incidence rate was 16.9%, almost half what would have been expected (27%), based on the literature (Foxman 2000). Therefore the study population may have been women who were less at risk of recurrent UTIs. We decided to include the study in our meta‐analysis because it was the largest study, the only one which used blinding, and did a power calculation, and therefore likely to have the most robust results. Wang 2012 also undertook subgroup analysis of cranberry juice versus tablets or capsule and found that juice was more effective but hypothesised that one reason for this could be that the participants who drank the cranberry juice were more hydrated.
Figures and Tables -
Figure 1
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.