HerbalEGram: Volume 9, Issue 12, December 2012

Experts, researchers clarify results of most recent meta-analysis

Urinary tract infections (UTI) are among the most common type of infection in adults and result in more than 8 million visits to healthcare providers annually. UTIs — which are 50 times more likely to occur in women — can arise in any part of the urinary tract, including the kidneys, bladder, or urethra, and are most frequently caused by bacteria such as E. coli. Currently, antibiotics are considered the most effective treatment for the infection, and some women who experience frequent UTIs are prescribed low-dose antibiotics as a preventative measure.¹ With antibiotic resistance a growing concern in recent years, however, researchers are studying plant-based UTI prevention strategies, including formulations of American cranberry (Vaccinium macrocarpon).

Cranberry has been a popular prophylactic for urinary tract infections for decades and has been used by indigenous North American peoples for centuries to treat certain urinary conditions.² Since 1998, cranberry has been the focus of four major reviews from the Cochrane Collaboration, an independent research organization that advocates evidence-based decision-making in healthcare.^3,4 Its popularity as a urinary tract health supplement, in part, helped make cranberry the best-selling single herb supplement in the US Food, Drug, and Mass Market retail channel in 2011, commanding sales of more than $40 million.⁵

A 2008 Cochrane Review, which analyzed 10 studies of cranberry for the prevention of UTIs, concluded that cranberry products — such as juices or capsules — significantly reduced the occurrence of UTIs at 12 months, particularly in women with recurrent infections.⁶ An update of the review, published in October 2012, however, found that “there was a small [but insignificant] trend towards fewer UTIs in people taking cranberry products compared to placebo or no treatment.” Although the authors noted a number of potential weaknesses in the reviewed studies, they concluded that “until there are more studies of products containing enough of the active ingredient [emphasis added], measured in a standardised way, cranberry products cannot be recommended for preventing UTIs.”⁴

Unusually high dropout rates and methodological issues with many of the studies included in the 2012 review — such as failure to quantify the main active ingredient for UTI prevention in cranberry and small sample sizes — have led some to question the validity of the Cochrane group’s findings. 

“It is essential that cranberry continue to be regarded and researched as an important area of study to help address the public health challenge that urinary tract infections and their treatment presents to antibiotic resistance,” said Amy Howell, PhD, an associate research scientist at Rutgers University’s Marucci Center for Blueberry and Cranberry Research (email, November 27, 2012). “UTIs are a significant public health challenge with more than 15 million cases in the US each year, and their treatment accounting for 15 percent of all community-prescribed antibiotics. I think that cranberry has great potential to help slow the pace of resistance development in an era when consumers are concerned with having to rely on pharmaceuticals to prevent and treat disease. ”


Cranberries as a Preventative Measure

Fresh cranberries are composed of roughly 90 percent water and are known for their elevated concentration in total polyphenols, such as anthocyanins, tannins, flavonoids (flavonols and flavan-3-ols), and most notably proanthocyanidins (PACs). The amount of polyphenols in cranberry, however, comprises just a small percentage of the fruit’s total organic constituents. Previously, scientists believed that organic acid in cranberry acidified the urine, which acted as an antimicrobial agent. However, current hypotheses revolve around a specific type of PACs — those with type-A linkages — that are thought to be responsible for the fruit’s ability to inhibit bacteria from sticking to the urinary tract lining, thus preventing infection. According to authors of an unrelated 2012 review of cranberries for lower UTI prevention, PACs “function as a natural plant defense system against microbes.”⁷ However, this well-studied in vitro effect did not translate to a measurable effect in the populations analyzed by the Cochrane group.

Dr. Howell, who has been researching cranberries for two decades, did not agree with the Cochrane group’s essential dismissal of cranberries — particularly cranberry juice — for the prevention of UTIs. “I was disappointed by the authors' conclusions given that, as a cranberry researcher, my lab has consistently found that cranberries effectively help prevent bacterial adhesion to bladder cells, the first step in the initiation of a UTI,” she said. “If the bacteria are prevented from adhering, they will not be able to grow and cause an infection. They are washed out of the body in the urine stream.”


Methodological Issues

Ruth Jepson, PhD, of the Department of Nursing and Midwifery at the University of Sterling, in Scotland, and lead author of the 2012, 2008, and other previous Cochrane Reviews of cranberry, mentioned in an email a number of possible weaknesses in the chosen studies. In total, the latest analysis included 24 studies — 14 more than the 2008 review — totaling 4,473 participants. The 14 new studies were published after the group’s original literature search in January 2007. To meet inclusion criteria, all studies had to be randomized controlled trials (RCTs) or quasi-RCTs of cranberry products for UTI prevention. Even with this criteria, studies varied greatly in terms of cranberry product used, type of placebo or control, and study design.

Funding for the 2012 Cochrane Review came from the UK National Health Service’s National Institute for Health Research, a government initiative. Importantly, Dr. Jepson noted that the authors of the review did not receive any funding from cranberry product manufacturers or drug companies.

As noted in the review, of the 24 studies included, 11 used a cranberry juice product, nine evaluated cranberry tablets or capsules, two used a liquid cranberry concentrate or syrup, one compared juice and tablets, and one compared capsules and tablets. Of the studies that examined the effectiveness of cranberry tablets or capsules, only one reported the amount of PACs in the product. Without prior analysis, the precise amount of PACs in cranberry juice products — which are often not marketed as dietary supplements — is impossible to determine.

Dr. Jepson said that the lack of active ingredient quantities for products in many of the studies might have had an impact on the review’s outcome. “I think there are two reasons for why we did not see [the in vitro effects] translate to a living population, both related to which cranberry product is being consumed,” she said (email, November 9 and December 6, 2012). “Firstly, the effects of the PACs only last for about 10 hours. So to get maximum benefit, someone would have to drink two glasses of juice a day every day.… Indeed many people dropped out of the studies, possibly because it was difficult to drink these amounts.” However, Dr. Howell pointed out that the 10-hour effect is from in vitro data and that previous clinical work has shown that cranberry juice can be effective if a single serving is consumed only once per day.

Dropout or withdrawal rates ranged from 3 to 55 percent in studies where the data were available. The Cochrane group noted that adherence was varied, with several studies reporting “participants withdrawing because of the unpalatable or intolerable nature of the cranberry product.”⁴ The resulting large number of dropouts is one reason why there has been an increased interest in cranberry tablets and capsules, which may be more suitable to consume on a daily basis as a preventative measure.

Dr. Jepson noted that future studies should focus on cranberry tablets or capsules, where amounts of PACs can be more accurately determined. “We know now that a specific process is needed to make sure that the PACs remain active in the dried preparations,” she said. “However, many of the studies did not specify whether this process was undertaken, or indeed how much of the active ingredient was in the preparations (if any).”


Room for Improvement

Similarly, Dr. Howell sees room for improvement in many of the studies’ designs. “Cranberry researchers use different dosages and product types which in many cases were not standardized to the active anti-adhesion compounds (proanthocyanidins) and may not have had sufficient amounts to achieve efficacy. I agree that this has been a problem in past studies and has most likely led to the results showing little effect, but I strongly believe that this is a very good reason to continue with clinical research and do it the right way, using well-characterized products and protocols,” she said.

Gunter Haesaerts, founder and CEO of Pharmatoka — which manufactures Ellura^®, a cranberry capsule with a significantly high standardized amount of PACs⁸ — also takes umbrage with the Cochrane Review’s apparent dismissal of cranberry juice products.

“Cochrane’s jumping to the conclusion that it would be a waste of time to conduct more juice studies is a little bit unfair [to] the juice industry (led by Ocean Spray). But that same juice industry should realize once and for all that either they conduct and finance serious trials or they abstain from further inadequate clinical trials that can only irritate scientists and regulators,” said Haesaerts (email, November 30, 2012). “On the other hand, the ‘capsules and tablets’ industry, to which Pharmatoka belongs, is explicitly encouraged by Cochrane to conduct more clinical studies on [the] condition that they use efficacious products.”

Specifically, Haesaerts mentioned three prerequisites for the inclusion of cranberry capsules or tablets to achieve measurable results, two of which were mentioned in the Cochrane Review. “To ensure potency in cranberry powders, levels of PACs must be quantified properly; and the 4-dimethylaminocinnamaldehyde [DMAC] method is currently the most validated standard method,” Jepson wrote. One peer reviewer of this article, however, noted that the DMAC method might not adequately account for larger molecules in cranberry, including some PACs. Further, the Cochrane Review noted that a recent study “found that to achieve a bacterial anti-adhesion effect in urine, 36 mg of cranberry PAC equivalents per day is effective, but 72 mg may offer better protection in some cases.”

In order to maximize bioactivity, Haesaerts also suggested that bioactive PACs should be extracted from the juice, not from the cranberry presscake — the remaining material after juice extraction that includes seeds and skin — that also contains PACs but shows little bioactivity.⁹

“The mechanism of anti-adhesion of cranberry PAC is quite well known, even though certain aspects of the mechanism are still under study,” he added. “Therefore, you cannot say that cranberry does not work. It does work. But to prove it’s working clinically is another issue, and an immense challenge for the juice producers.”


Looking Beyond the Cochrane Analysis

Dr. Howell urges consumers to be skeptical when dealing with meta-analyses that attempt to find answers to complicated questions. Whenever large amounts of data are involved, there is usually room for varying interpretations.

“The recent review on cranberry needs to be put into perspective and weighed against the other positive clinical trials over the past couple of decades in which cranberry was effective in maintaining urinary tract health.… There is a wealth of evidence from independent research institutions globally that has demonstrated that regular consumption of cranberry products helps to promote urinary tract health,” she said. “Much of the recent prevention research is actually quite positive. Those studies that came out negatively all had issues with the products used, or design flaws in the methodologies that resulted in poor outcomes. Consumers need to be aware of these issues, especially when it comes to clinical trial results on functional foods. Just because a study does not yield significant results, it does not necessarily mean that the food is ineffective.”

In particular, Dr. Howell noted the outcome of a recent analysis by Wang et al. published in The Archives of Internal Medicine, which included 13 clinical trials with a total of 1,616 participants. According to Risa Schulman, PhD, author of a research review of Wang’s paper that appeared in HerbalGram 96, “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,” she wrote. “On the other hand, juice has the potential drawbacks that it is high in sugar and may cause gastrointestinal or other adverse side effects.”¹⁰ Importantly, Wang noted that the results of his analysis should be treated with caution due to heterogeneity among the studies.¹¹

Additionally, a 2012 paper in the Open Access Journal of Clinical Trials by Uberos et al. compared the efficacy of cranberry syrup against trimethoprim, a common antibiotic, for the prevention of UTIs in children aged one month to 13 years. “Our study confirms that cranberry syrup is a safe treatment for the pediatric population,” Uberos wrote. The author also noted that, due to limits imposed on studies of children by the Declaration of Helsinki, no placebos were given, resulting in a simple “test of equivalence or non-inferiority.” Therefore, the author concluded that “cranberry prophylaxis is not equivalent to trimethoprim, but it is shown to be non-inferior versus trimethoprim in recurrent UTI.”¹²


Future Trials

Despite the negative results of the 2012 Cochrane Review of cranberry for UTI prevention, many experts agree that more and better research is needed. Dr. Jepson noted that certain aspects of the included studies — such as the lack of quantified, standardized PACs — were cause for some concern. “[That] was why we recommended further studies using [a] standardised amount. It was difficult to say whether we were looking at a true estimate of effectiveness or not. If the underlying hypothesis is correct I would expect that new studies would show it,” she said. “It is very possible, that if studies were undertaken using a standardised product which we were sure of the active ingredient, an effect would be seen.”

Dr. Howell believes similarly and urges consumers not to change their habits based solely on the recent meta-analysis. “I have been doing research at Rutgers University for the past 20 years and have found that cranberry consumption prevents bacterial adhesion to cells from the urinary tract — the initial step in the urinary tract infection process,” she said. “If women are currently consuming cranberry products, the results of this one review do not provide a reason for them to change their current practices.”

Haesaerts of Pharmatoka believes cranberry’s fate now lies in the hands of researchers conducting clinical trials. With better study designs, he hopes future results will more accurately reflect cranberry’s potential to provide urinary tract health benefits. “We are walking a very dangerous path. No new families of [conventional pharmaceutical] antibiotics are in sight. Cranberry as a prophylactic treatment of recurrent UTI is going to be dearly needed in the future because of the fast-growing resistance of uropathogens against existing antibiotics,” he said. “Let highly respected experts like Cochrane continue their critical work, but give them study results that match their criteria and expectations. Cranberries deserve no less.”


—Tyler Smith


References

1. Urinary tract infection in adults. National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC) website. Available here. Accessed November 27, 2012.

2. Urinary tract. The Cranberry Institute website. Available here. Accessed November 27, 2012.

3. About us. The Cochrane Collaboration website. Available here. Accessed November 30, 2012.

4. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections (review). The Cochrane Library; 2012:10. Available here. Accessed November 12, 2012.

5. Blumenthal M, Lindstrom A, Ooyen C, Lynch ME. Herb supplement sales increase 4.5% in 2011. HerbalGram. August 2012;95:60-64. Available here. Accessed November 27, 2012.

6. Jepson RG, Craig JC. Cranberries for preventing urinary tract infections (review). The Cochrane Library; 2008:1. Available here. Accessed November 12, 2012.

7. Hisano M, Bruschini H, Nicodemo AC, Srougi M. Cranberries and lower urinary tract infection prevention. Clinics; 2012:67(6):661-668. Available here. Accessed November 30, 2012.

8. Products: urinary comfort. Pharmatoka website. Available here. Accessed November 30, 2012.

9. White BL, Howard LR, Prior RL. Release of bound procyanidins from cranberry pomace by alkaline hydrolysis. J Agric Food Chem; 2010:58(13):7572-7579. Available here. Accessed December 7, 2012.

10. 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. In HerbalGram; 2012:96:28-29.

11. 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. Available here. Accessed November 30, 2012.

12. Uberos J, Nogueras-Ocana M, Fernandez-Puentes V, Rodriguez-Belmonte R, et al. Cranberry syrup vs trimethoprim in the prophylaxis of recurrent urinary tract infections among children: a controlled trial. Open Access J of Clinical Trials; 2012:4:31-38. Available here. Accessed November 30, 2012.