Wang CH, Fang CC, Chen NC, et al. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: A systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(13):988-996.

Urinary tract infections (UTIs) are the most common bacterial infections, causing approximately 7,000,000 office visits each year in the United States and approximately 100,000 hospitalizations. Twenty to thirty percent of women who have a UTI will have a recurrence. Cranberry (Vaccinium macrocarpon) has been a traditional remedy for UTIs for decades. Its mechanism of action was originally thought to be acidification of the urine, but it was later found that A-type proanthocyanidins prevented the adhesion of the bacteria to the urinary epithelium, preventing infection. This paper is a review and meta-analysis of the factors affecting the effectiveness of cranberry for UTI. It goes beyond the recent Cochrane meta-analysis¹ by including some new studies and providing a more thorough analysis.

The meta-analysis was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Two authors independently searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2011. Studies were not excluded because of language, population, or year of publication; however, conference proceedings and registered clinical trials were not included. Inclusion criteria were: (1) randomized controlled trials (RCTs), (2) comparison of cranberry-containing products vs. placebo or non-placebo control for prevention of UTI, and (3) outcomes reported as incidence of UTIs.

Information gathered from each suitable trial included: (1) type of study and study design, (2) characteristics of the study population, (3) types of intervention and controls, (4) definitions of UTI, (5) types of outcomes measured, and (6) number and reasons of participants lost to follow-up. The primary outcome was incidence of UTI.

Thirteen trials were included, consisting of 9 parallel and 4 crossover studies; none of the latter had washout periods. The total population was 1616 subjects. Eight trials were conducted according to the intention-to-treat principle, and 5 trials used per-protocol analysis. All trials but 1 were done in the free-living community. Each study population was sub-divided into the following categories: women with recurrent UTIs, elderly patients, patients with neuropathic bladder, pregnant women, and children.

The forms of cranberry used included cranberry juice (9 trials) or cranberry capsules/tablets (4 trials). Cranberry-containing products provided by the manufacturer Ocean Spray (Lakeville-Middleboro, Massachusetts) were used in 6 trials. The dose ranged from 0.4 g to 194.4 g and was given for 6 months in most trials. A formulated placebo was employed in 10 trials, placebo was not used in 2 trials, and water was used as the placebo in 1 trial. Compliance was measured indirectly in most trials; methods included periodic interviews, self-reported questionnaires, and pill counting of remaining study medication.

The definition of UTI varied widely among the studies. In most trials (10), UTI was reported as a cumulative incidence rate. These trials were used in the quantitative data synthesis (n=1494; 794 in the cranberry group and 700 in the control group). There was significant heterogeneity among included trials (relative risk [RR]: 0.68; 95% confidence interval [CI]: 0.47-1.00) (I²=59%). Several analyses showed that 1 trial was a source of heterogeneity with a large impact on the pooled summary estimate, and so it was excluded, which improved heterogeneity. Following this, cranberry was shown to be effective in preventing UTIs (RR: 0.62; 95% CI: 0.49-0.80) (I²=43%). It was also effective in women with recurrent UTIs (RR: 0.53; 95% CI: 0.33-0.83) (I²=0%), female populations (RR: 0.49; 95% CI: 0.34-0.73) (I²=34%), children (RR: 0.33; 95% CI: 0.16-0.69) (I²=0%), cranberry juice users (RR: 0.47; 95% CI: 0.30-0.72) (I²=2%), and people using cranberry-containing products more than twice daily (RR: 0.58; 95% CI: 0.40-0.84) (I²=18%), although the P values were not significant in meta-regression.

A funnel plot did not show evidence of publication bias.

Results of the effectiveness of cranberry for UTI were similar to those of the Cochrane review once the trial with heterogeneity was excluded (when included, the results were non-significant). The excluded study did not show effectiveness, but had the most stringent definition of UTI (the lowest bacterial threshold) and a placebo that included ascorbic acid, which is also known to counteract UTIs.

Sensitivity analysis showed that there was greater effectiveness in non-controlled trials, suggesting that an expectation of efficacy may have biased the results. Other analyses showed that sub-populations with certain characteristics were more likely to benefit, including those of younger age, female sex, and individuals with recurrent UTI history. Cranberry juice was shown to be more effective than capsules or tablets, which may be because it provides better hydration or because there are other substances in the juice that contribute to efficacy that may not be present in capsules or tablets. On the other hand, juice has the drawbacks that it is high in sugar and may cause gastrointestinal or other adverse side effects. A dosing frequency of twice a day was shown to have a better preventive effect.

Only 1 trial addressed dose response, and most trials did not explain their choice of dosage. There is an ongoing study currently examining this aspect. More recent trials (3 total) measured the concentration of proanthocyanidins in the dose given, but it was not possible to determine an effective dose from these data. Further studies should include declaration of the concentration of proanthocyanidins so that their effect can be elucidated.

The authors conclude that while the results of the meta-analysis showed that cranberry is effective for UTIs, the results should be interpreted with great caution, because of study heterogeneity. Cranberry may be most beneficial in a twice daily dose in the form of juice, in women with recurrent UTIs, female populations generally, and in children specifically.

—Risa Schulman, PhD

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