Chinese herbal medicine for treating recurrent urinary tract infections in women

  • Protocol
  • Intervention

Authors

  • Andrew Flower,

    Corresponding author
    1. University of Southampton, Complementary and Integrated Medicine Research Unit, Department of Primary Care, Southampton, Sussex, UK
    • Andrew Flower, Complementary and Integrated Medicine Research Unit, Department of Primary Care, University of Southampton, Southampton, Sussex, BN8 5SG, UK. flower.power@which.net.

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  • George Lewith,

    1. University of Southampton, Complementary and Integrated Medicine Research Unit, Department of Primary Care, Southampton, Sussex, UK
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  • Jian Ping Liu,

    1. Beijing University of Chinese Medicine, Centre for Evidence-Based Chinese Medicine, Beijing, China
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  • Qing Li

    1. Beijing University of Chinese Medicine, Centre for Evidence-Based Chinese Medicine, Beijing, China
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

This review aims to look at the benefits and harms of CHM for the treatment of RUTIs in adult women, both as a stand-alone therapy and in conjunction with other pharmaceutical interventions.

Background

Description of the condition

Acute lower urinary tract infection (UTI), also known as cystitis, is a superficial bacterial infection of the bladder mucosa characterised by symptoms of burning on urination, urinary frequency including nocturia, and urgency. UTIs are considered uncomplicated if the patient is not pregnant or elderly, and if there are no known functional or anatomical abnormalities of the genitourinary tract (Hooton 1996).

UTIs are the most common bacterial infection presented by women in the primary care setting (Butler 2006; Foxman 2002; Little 2010). Around 40% to 50% of women experience one UTI episode during their lives (Kunin 1994). The impact of treating UTIs is substantial. UTIs were reported to account for between 1% and 3% of all consultations in general practice in the UK (Stapleton 1999), and nearly seven million office visits and one million emergency department visits, resulting in 100,000 hospitalisations in the US (Foxman 2002). The most common pathogens causing uncomplicated UTI are Escherichia coli (80% to 90%), Staphylococcus saprophyticus (5% to 10%), Proteus spp. and other gram-negative rods (Milo 2005).

Recurrent UTIs (RUTIs) are commonly defined in the literature as three UTI episodes in the last 12 months or two episodes in the last six months (Albert 2004). Between 20% and 30% of women who have had one UTI episode will have a recurrent UTI (Sanford 1975), and around 25% of these will develop subsequent recurrent episodes (Hooton 1996). RUTIs can have a significant negative effect on quality of life, and a high impact on healthcare costs as a result of outpatient visits, diagnostic tests and prescriptions. Precise estimates on the economic impact of UTIs are difficult to derive. In the US, approximately 15% of all community-prescribed antibiotics are dispensed for UTIs at an estimated annual cost of over USD 1 billion (Mazzulli 2002). The direct and indirect costs associated with community-acquired UTIs in the US are estimated at around USD 2 billion each year (Foxman 2002).

Antibiotics are currently the mainstay treatment for both acute and recurrent UTIs. Although antibiotics may be effective in reducing the duration of severe symptoms in acute episodes (Falagas 2008; Little 2010a), antibiotic resistance is currently estimated at 20% for trimethoprim and cephalosporins, and 50% for amoxicillin (Christiaens 2002). Antibiotic resistance and previous episodes of cystitis have been positively associated with an increased duration of severe symptoms of UTIs (Little 2010). It is predicted that antibiotic resistance will continue to increase (Kumarasamy 2010).

Antibiotic prophylaxis is used to prevent RUTIs. Treatment usually lasts for between six and 12 months but can be extended for up to five years (Franco 2005). A Cochrane systematic review of antibiotics used to prevent RUTIs in non-pregnant women found that antibiotics given continuously for six to 12 months were significantly more effective than placebo in preventing recurrent infection (RR 0.15, 95% CI 0.08 to 0.28; number needed to treat = 1.85, 95% CI 1.60 to 2.20) (Albert 2004). Severe side effects such as urticaria, nausea and vomiting, and less serious but unpleasant side effects including oral and vaginal candidiasis, and gastrointestinal disturbances may require treatment to be withdrawn. These side effects can cause considerable discomfort and may contribute to some women’s expressed preference to avoid using antibiotics (Leydon 2010).

Once prophylaxis is discontinued, even after extended periods of therapy, approximately 50% to 60% of women will become re-infected within three months (Car 2003; Harding 1982). Therefore, antibiotic prophylaxis does not exert a long-term effect on the baseline infection rate.

A number of complementary therapies are used to treat RUTIs. A recently revised Cochrane review of the use of cranberries for preventing UTIs (Jepson 2012) found that they had little effect in reducing the rate of recurrent infection. There is some preliminary evidence that Chinese herbal medicine (CHM) may be of use in the treatment of RUTI.

Description of the intervention

CHM is one part of a system of Traditional Chinese Medicine (TCM). CHM involves the use of complex herbal formulae usually comprising between 10 and 15 herbs that are delivered as decoctions, encapsulated herbal granules, or pills. CHM formulae may be standardised or individualised according to specific patient needs. Although biomedical diagnoses are commonly used in CHM practice to optimise treatment effectiveness, these may be differentiated into TCM syndromes according to analysis of presenting signs and symptoms.

CHM has a recorded history of use in treating the symptoms of UTIs for over 2000 years (Maciocia 1994). More recent clinical research in China suggests that CHM may alleviate UTI symptoms (Liu 1987; Xu 1989; Zhan 2007; Zhang 2005) and reduce one year post-treatment recurrence rates from 30% when antibiotics were used alone, to 4.4% when antibiotics and CHM were combined (Zhang 2005).

How the intervention might work

The herbal products used in CHM contain highly active compounds that have been extensively researched, and in some instances, developed as pharmaceutical drugs. Active compounds that have been refined to develop conventional medicines include ephedrine (Ma Huang, Radix Ephedra sinensis); artemisinin (Qing Hao, Herba Artemisiae annuae); and genistein (Glycine max).

The biological plausibility of CHM for RUTIs is supported by in vitro research suggesting that some CHM may have significant diuretic, antiblastic, immune enhancing, antipyretic, anti-inflammatory and pain relieving activities (Peng 2010; Zhu 1998). There is growing evidence that some herbal medicines can disable bacterial efflux pumps, which are an important mechanism underlying the development of bacterial resistance to antibiotic drugs (Stavri 2007) and may thereby serve as an important adjuvant treatment to conventional antibiotics.

Why it is important to do this review

There is a need to conduct a systematic review to evaluate the extent and quality of clinical evidence relating to CHM for RUTIs. If the benefits of these interventions, either as stand-alone or adjuvant treatment are confirmed by rigorous data, then CHM may make an important contribution to managing this common and problematic condition.

Objectives

This review aims to look at the benefits and harms of CHM for the treatment of RUTIs in adult women, both as a stand-alone therapy and in conjunction with other pharmaceutical interventions.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) comparing treatment using CHM with either an inactive placebo group or conventional biomedical treatment, will be reviewed. RCTs comparing different CHM strategies and treatments will also be considered. Quasi-randomised studies will be excluded from this review because they would introduce an unacceptable level of bias into the analysis.

Types of participants

Inclusion criteria

We will include ambulatory, otherwise healthy women, aged 16 years or over, who have histories of three or more RUTIs in the preceding 12 months. At least one episode must have laboratory confirmation of bacterial infection (bacterial growth of at least 10² cfu/mL in urine (Franco 2005)) in association with symptoms and signs of UTI including dysuria, frequency, urgency including nocturia, pyuria and haematuria.

Exclusion criteria

We will exclude women under the age of 16 years, pregnant women and older women (over the age of 65 years), those with complicated UTIs (such as pyelonephritis, diabetes, neurological conditions, urinary tract obstruction, or who are catheterised), or who do not have a laboratory confirmation of at least one UTI in the previous 12 months.

Types of interventions

  1. CHM versus placebo

  2. CHM versus biomedicine

  3. CHM + biomedicine versus biomedicine (with or without placebo)

  4. CHM versus CHM.

For our purposes, 'biomedicine' will refer to the practice of clinical medicine based on current biological understanding of pathophysiological processes. All forms of oral herbal interventions (pills, herbal granules, herbal decoctions) will be considered. Herbs administered as injection and CHM combined with acupuncture or another TCM therapy will be excluded.

Types of outcome measures

Primary outcomes
  1. Reduction in both symptomatic episodes, including urinary frequency, urgency, dysuria, haematuria; and bacteriologically-confirmed episodes of UTI during the study

  2. Rates of relapse within 12 months of completing the study.

Secondary outcomes
  1. Reduction in severity (e.g. intensity of lower abdominal pain, urgency, frequency and burning) and duration of acute UTIs

  2. Reduction in the use of acute and prophylactic antibiotics

  3. Improvements in quality of life (as estimated by validated outcomes measures such as SF-36)

  4. Any recorded adverse events (including liver and renal toxicity)

  5. Health economic data relating to CHM treatment.

This review will not consider changes in surrogate biochemical markers reported in studies. 

Search methods for identification of studies

Electronic searches

We will search the Cochrane Renal Group's specialised register through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group’s specialised register contains studies identified from:

  1. Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

  6. Searches of the WHO International Clinical Trials Register Search Portal (ICTRP) and ClinicalTrials.gov.

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.

See Appendix 1 for search terms used in strategies for this review.

The following English language electronic databases will also be searched from their inception to the present:

  • AMED (Allied and Complementary Medicine via OvidSP)

  • CINAHL (Cumulative Index to Nursing and Allied Health via Ebsco)

The following Chinese language electronic databases will be searched from inception to the most recent date using the following terms: urinary tract infection, cystitis, recurrent urinary tract infection, Chinese medicine, herbal medicine, plant extract, complementary medicine.

  • Chinese BioMedical Literature Database (CBM)

  • CNKI (China Network on Knowledge Infrastructure)

  • VIP database

  • Wan Fang Database

Searching other resources

  1. Reference lists of nephrology textbooks, review articles and relevant studies.

  2. Handsearching of relevant journals and articles which may not be included in the electronic databases will also be undertaken.

Data collection and analysis

Selection of studies

The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.

Data extraction and management

Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, these will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (such as a reported UTI versus no reported UTI) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (for example, number of days reported with symptoms of a UTI), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.

The decision to use either a fixed-effect or a random-effects model will be determined according to an assessment of study heterogeneity.

Because RUTIs are episodic and provide outcomes that are not stable and difficult to measure precisely, a meta-analysis of change scores, based on a comparison of changes from baseline, is both unlikely and not recommended. In the event that studies included in this review include both changes-from-baseline and final value scores, the method of analysis recommended in the Cochrane Handbook for Systematic Reviews of Interventions (section 9.4.5.2) will be adopted (Higgins 2011).

Unit of analysis issues

The unit of analysis will be the RCT considering individual patients. A single measurement for each outcome from each participant will be collected and analysed. If alternative designs such as cross-over studies, cluster RCTs or repeated measures on the same participants are used, then appropriate methods of statistical analysis will be employed under the advice of a statistician.

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (by emailing and/or writing to corresponding author/s) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. Attrition rates, such as drop-outs, losses to follow-up and withdrawals, will be investigated. Issues of missing data and imputation methods (for example, last-observation-carried-forward) will be critically appraised (Higgins 2011).

Assessment of heterogeneity

Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2011). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011)

Data synthesis

Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. the effects of different formulations of CHM such as standardised formula versus tailored formula), the type of control group and the effects of treatment on diagnostic syndromes determined according to the theory of TCM.

Adverse effects will be tabulated and assessed with descriptive techniques because they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared with no treatment or another agent.

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:

  • repeating the analysis excluding unpublished studies

  • repeating the analysis taking account of risk of bias

  • repeating the analysis excluding any very long or large studies to establish how much they dominate the results

  • repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.

Acknowledgements

We wish to thank the referees for their comments and feedback during the preparation of this protocol.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. (urin* near/3 infection*):ti,ab,kw

  2. ("uti" or "utis"):ti,ab,kw

  3. bacteriuri*:ti,ab,kw

  4. pyuri*:ti,ab,kw

  5. cystitis:ti,ab,kw

  6. (#1 OR #2 OR #3 OR #4 OR #5)

  7. ((traditional or integrative) near/3 (chinese or medicine)):ti,ab,kw

  8. "chinese medicine":ti,ab,kw

  9. herb*:ti,ab,kw

  10. ((plant or plants) near/5 (chinese or traditional or extract* or preparation* or medicinal))

  11. phytotherapy:ti,ab,kw

  12. "alternative medicine":ti,ab,kw

  13. complimentary next therap*:ti,ab,kw

  14. (decoction or granule* or pill or pills or tablet*):ti,ab,kw

  15. ("shi wei" or shiwei):ti,ab,kw

  16. huangbai:ti,ab,kw

  17. "ba zheng"

  18. "tong lin":ti,ab,kw

  19. ("li zhi cao" or "lizhi cao"):ti,ab,kw

  20. "tu fu ling":ti,ab,kw

  21. (#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)

  22. (#6 AND #21)

MEDLINE
  1. Drugs, Chinese Herbal/

  2. Medicine, Traditional/

  3. Medicine, Chinese Traditional/

  4. Phytotherapy/

  5. Plants, Medicinal/

  6. Plant Extracts/

  7. Herbal Medicine/

  8. Plant Preparations/

  9. Drugs, Non-Prescription/

  10. Complementary Therapies/

  11. ((traditional or integrative) adj3 (chinese or medicine)).tw.

  12. chinese medicine.tw.

  13. ((plant or plants) adj5 (chinese or traditional or extract* or preparation* or medicinal)).tw.

  14. herb*.tw.

  15. (decoction or granule* or pill or pills or tablet*).tw.

  16. or/1-15

  17. Urinary Tract Infections/

  18. Bacteriuria/

  19. Pyuria/

  20. Cystitis/

  21. (urin* adj3 infection*).tw.

  22. bacteriur*.tw.

  23. pyuri*.tw.

  24. (uti or utis).tw.

  25. cystitis.tw.

  26. or/17-25

EMBASE
  1. Alternative Medicine/

  2. Traditional medicine/

  3. Chinese Medicine/

  4. Herbal Medicine/

  5. Chinese Drug/

  6. Chinese Herb/

  7. Medicinal Plant/

  8. Plant Medicinal Product/

  9. Phytotherapy/

  10. Plant Extract/

  11. Herb/

  12. Non prescription Drug/

  13. ((traditional or integrative) adj3 (chinese or medicine)).tw.

  14. chinese medicine.tw.

  15. ((plant or plants) adj5 (chinese or traditional or extract* or preparation* or medicinal)).tw.

  16. herb*.tw.

  17. (decoction or granule* or pill or pills or tablet*).tw.

  18. or/1-17

  19. Urinary Tract Infection/

  20. Bacteriuria/

  21. Pyuria/

  22. Cystitis/

  23. (urin* adj3 infection*).tw.

  24. bacteriur*.tw.

  25. pyuri*.tw.

  26. (uti or utis).tw.

  27. cystitis.tw.

  28. or/19-27

AMED
  1. drugs chinese herbal/

  2. traditional medicine chinese/

  3. plants medicinal/

  4. plant extracts/

  5. herbal drugs/

  6. ((traditional or integrative) adj3 (chinese or medicine)).tw.

  7. chinese medicine.tw.

  8. ((plant or plants) adj5 (chinese or traditional or extract* or preparation*)).tw.

  9. herb*.tw.

  10. (decoction or granule* or pill or pills or tablet*).tw.

  11. or/1-10

  12. urinary tract infections/

  13. cystitis/

  14. bacteriur*.tw.

  15. pyuri*.tw.

  16. cystitis.tw.

  17. (urin* adj3 infection*).tw.

  18. (uti or utis).tw.

  19. or/12-18

  20. and/11,19

CINAHL

S24 S14 and S23 

S23 S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 

S22 (TI cystitis) OR (AB cystitis) 

S21 (TI bacteriur* OR pyuri*) OR (AB bacteriur* OR pyuri*) 

S20 (TI uti OR utis) OR (AB uti OR utis) 

S19 (AB urin*) n3 (AB infection*) 

S18 (TI urin*) n3 (TI infection*) 

S17 (MH "Cystitis") 

S16 (MH "Bacteriuria") 

S15 (MH "Urinary Tract Infections") 

S14 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 

S13 (TI decoction OR granule* OR pill OR pills OR tablet*) 

S12 (TI herb*) OR (AB herb*) 

S11 (AB plant OR plants) n5 (AB chinese OR traditional OR extract* OR preparation* OR medicinal) 

S10 (TI plant OR plants) n5 (TI chinese OR traditional OR extract* OR preparation* OR medicinal) 

S9 (TI "chinese medicine") OR (AB "chinese medicine") 

S8 (AB traditional OR integrative) n3 (AB chinese OR medicine) 

S7 (TI traditional OR integrative) n3 (TI chinese OR medicine) 

S6 (MH "Plant Extracts") 

S5 (MH "Plants, Medicinal") 

S4 (MH "Medicine, Herbal") AND (MH "China") 

S3 (MH "Medicine, Traditional") AND (MH "China") 

S2 (MH "Drugs, Chinese Herbal") 

S1 (MH "Medicine, Chinese Traditional") 

Appendix 2. Risk of bias assessment tool

Potential source of biasAssessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

  1. Draft the protocol: AF, JPL, GL, PL

  2. Study selection: QL, AF

  3. Extract data from studies: QL, AF

  4. Enter data into RevMan: QL, AF

  5. Carry out the analysis: AF, QL, JPL

  6. Interpret the analysis: AF, QL, JPL, GL, PL

  7. Draft the final review: AF

  8. Disagreement resolution: JPL, GL

  9. Update the review: AF

Declarations of interest

Andrew Flower is currently funded for a post doctoral Fellowship by the UK National Institute of Health Research to investigate the possible role of Chinese herbal medicine in the treatment of recurrent urinary tract infections .

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute of Health Research, UK.

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