Postoperative interventions for preventing bladder dysfunction after radical hysterectomy in women with early‐stage cervical cancer

Apiwat Aue-aungkul; Chumnan Kietpeerakool; Siwanon Rattanakanokchai; Khadra Galaal; Teerayut Temtanakitpaisan; Chetta Ngamjarus; Pisake Lumbiganon

doi:10.1002/14651858.CD012863.pub2

. 2021 Jan 25;2021(1):CD012863. doi: 10.1002/14651858.CD012863.pub2

Postoperative interventions for preventing bladder dysfunction after radical hysterectomy in women with early‐stage cervical cancer

Apiwat Aue-aungkul ¹, Chumnan Kietpeerakool ^1,^✉, Siwanon Rattanakanokchai ², Khadra Galaal ³, Teerayut Temtanakitpaisan ⁴, Chetta Ngamjarus ², Pisake Lumbiganon ¹

Editor: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

PMCID: PMC8092645 PMID: 33491176

Abstract

Background

Bladder dysfunction is a common complication following radical hysterectomy, caused by the damage to pelvic autonomic nerves that innervate the muscles of the bladder, urethral sphincter, and pelvic floor fasciae. Bladder dysfunction increases the rates of urinary tract infection, hospital visits or admission, and patient dissatisfaction. In addition, bladder dysfunction can also negatively impact patient quality of life (QoL). Several postoperative interventions have been proposed to prevent bladder dysfunction following radical hysterectomy. To our knowledge, there has been no systematic review evaluating the effectiveness and safety of these interventions for preventing bladder dysfunction following radical hysterectomy in women with cervical cancer.

Objectives

To evaluate the effectiveness and safety of postoperative interventions for preventing bladder dysfunction following radical hysterectomy in women with early‐stage cervical cancer (stage IA2 to IIA2).

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) in the Cochrane Library, MEDLINE via Ovid (1946 to April week 2, 2020), and Embase via Ovid (1980 to 2020, week 16). We also checked registers of clinical trials, grey literature, conference reports, and citation lists of included studies.

Selection criteria

We included randomised controlled trials (RCTs) evaluating the effectiveness and safety of any type of postoperative interventions for preventing bladder dysfunction following a radical hysterectomy in women with stage IA2 to IIA2 cervical cancer.

Data collection and analysis

Two review authors independently selected potentially relevant RCTs, extracted data, assessed risk of bias, compared results, and made judgments on the quality and certainty of the evidence. We resolved any disagreements through discussion or consultation with a third review author. Outcomes of interest consisted of spontaneous voiding recovery one week after the operation, quality of life (QoL), adverse events, post‐void residual urine volume one month after the operation, urinary tract infection over the one month following the operation, and subjective urinary symptoms.

Main results

We identified 1464 records as a result of the search (excluding duplicates). Of the 20 records that potentially met the review criteria, we included five reports of four studies. Most of the studies had unclear risks of selection and reporting biases. Of the four studies, one compared bethanechol versus placebo and three studies compared suprapubic catheterisation with intermittent self‐catheterisation. We identified two ongoing studies.

Bethanechol versus placebo The study reported no information on the rate of spontaneous voiding recovery at one week following the operation, QoL, adverse events, urinary tract infection in the first month after surgery, and subjective urinary symptoms for this comparison. The volume of post‐void residual urine, assessed at one month after surgery, among women receiving bethanechol was lower than those in the placebo group (mean difference (MD) ‐37.4 mL, 95% confidence interval (CI) ‐60.35 to ‐14.45; one study, 39 participants; very‐low certainty evidence).

Suprapubic catheterisation versus intermittent self‐catheterisation The studies reported no information on the rate of spontaneous voiding recovery at one week and post‐void residual urine volume at one month following the operation for this comparison. There was no difference in risks of acute complication (risk ratio (RR) 0.77, 95% CI 0.24 to 2.49; one study, 71 participants; very low certainty evidence) and urinary tract infections during the first month after surgery (RR 0.77, 95% CI 0.53 to 1.13; two studies, 95 participants; very‐ low certainty evidence) between participants who underwent suprapubic catheterisation and those who underwent intermittent self‐catheterisation. Available data were insufficient to calculate the relative measures of the effect of interventions on QoL and subjective urinary symptoms.

Authors' conclusions

Limited evidence suggested that bethanechol may minimise the risk of bladder dysfunction after radical hysterectomy by lowering post‐void residual urine volume. The certainty of this evidence, however, was very low. The effectiveness of different types of postoperative urinary catheterisation (suprapubic and intermittent self‐catheterisation) remain unproven.

Plain language summary

Postoperative interventions for preventing bladder dysfunction after radical hysterectomy in women with early‐stage cervical cancer

The issue Radical hysterectomy with pelvic lymphadenectomy (removal of the uterus (womb) with its surrounding tissues and lymph glands in the pelvis) is the treatment for early‐stage cervical cancer (when cancer is still within the cervix and upper vagina, without spread into nearby tissues). Bladder dysfunction (problems with the way the bladder holds and releases urine) is a common problem following radical hysterectomy, caused by the damage to the nerves controlling urination.

The aim of the review To assess the usefulness and safety of treatment to prevent bladder dysfunction following radical hysterectomy in women with early‐stage cervical cancer. We searched the scientific databases for randomised controlled trials (studies in which people or groups of people are allocated by chance to two or more groups, treating them differently) published to April 2020.

Main findings We found four studies that met the inclusion criteria. One study compared a medication called bethanechol to placebo (a substance that has no therapeutic effect, used as a control in testing drugs). Three studies compared suprapubic catheterisation (insertion of a flexible tube (catheter) into the bladder through a cut in the lower abdomen to drain urine) with intermittent self‐catheterisation (insertion of a catheter via the urethra, into the bladder at intervals throughout the day).

Bethanechol versus placebo

Bethanecol may reduce the chance of bladder dysfunction by lowering the volume of post‐void residual urine, assessed at one month after surgery. However, the certainty of this evidence is very low and further studies have the potential to better inform this outcome.

Suprapubic catheterisation versus intermittent self‐catheterisation There was insufficient evidence to indicate the effectiveness of suprapubic catheterisation and intermittent self‐catheterisation for preventing bladder dysfunction. Very‐low certainty evidence noted no difference between these two treatments in the risk of an unfavourable result and urinary tract infections during the first month after surgery.

Conclusions

None of the included studies reported rate of spontaneous voiding recovery one week after surgery, time to a post‐void residual volume of urine of 50 mL or less, or post‐void residual urine volume at 6 and 12 months after surgery, all of which are important outcomes for assessing postoperative bladder dysfunction. Limited evidence suggested that bethanechol may prevent bladder dysfunction after radical hysterectomy by lowering post‐void residual urine volume. The certainty of this evidence, however, was very low. The effectiveness of different types of postoperative urinary catheterisation (suprapubic and intermittent self‐catheterisation) remains unproven.

Summary of findings

Background

Please see Appendix 1 for a glossary of terms.

Description of the condition

Cervical cancer is the fourth most common cancer affecting women worldwide, with an estimated 569,847 new cases and 311,365 cervical cancer‐related deaths globally in 2018 (Bray 2018). Cervical cancer is a major health problem among women in developing countries, with almost 70% of the global burden and 90% of cervical cancer‐related deaths occurring in these regions (Ferlay 2015; Bray 2018). The high burden of cervical cancer among less economically developed settings is secondary to the failure to provide effective, large‐scale screening programmes (Torre 2015; Bray 2018).

Treatment of cervical cancer depends on the extent of the disease. Appendix 2 displays a 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer (Bhatla 2019), which was revised from the 2009 FIGO staging system (Appendix 3). Women with early‐stage cervical cancer (FIGO stage IA2 to IIA2) can be treated with either radical hysterectomy with pelvic lymphadenectomy (removal of the uterus with its surrounding tissues and lymph glands in the pelvis) or pelvic chemoradiation (radiation therapy to lower abdomen being given at the same time as chemotherapy) (Landoni 1997). In premenopausal women, radical hysterectomy with pelvic lymphadenectomy may be preferable to pelvic radiation in order to preserve ovarian function and vaginal elasticity, as well as prevent the long‐term risks of pelvic radiation (Cull 1993; Viswanathan 2014).

The aim of radical hysterectomy is to remove the primary tumour with an adequate margin of normal tissue to ensure complete resection (Piver 1974; Querleu 2008; Verleye 2009). Appendix 4 lists details of the three systems for the classification of radical hysterectomy (Piver‐Rutledge‐Smith, Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer, and Querleu and Morrow). The stage of cervical cancer is the fundamental factor to be taken into consideration when considering radical hysterectomy. Women with early‐stage cervical cancer are traditionally treated with Piver type III radical hysterectomy. However, a previous randomised controlled trial (RCT) demonstrated that women with early‐stage cervical cancer who underwent Piver type II hysterectomy (also called modified radical hysterectomy) had comparable oncological outcomes to those who underwent type III hysterectomy (Landoni 2001). Pelvic lymphadenectomy is performed to look for metastatic lesions in the pelvic lymph nodes. The survival of women with early‐stage cervical cancer who undergo radical hysterectomy with pelvic lymphadenectomy is excellent. Estimated five‐year survival rates range between 70% and 90% (Kim 2000; Suprasert 2010; Srisomboon 2011; Mahawerawat 2013).

One of the most distressing morbidities that can occur following radical hysterectomy is bladder dysfunction (problems with the way the bladder holds and releases urine) (Lin 1998; Plotti 2011; Laterza 2015). The incidence of bladder dysfunction after radical hysterectomy varies from 12% to 85% depending on the method used in evaluating bladder dysfunction and the duration of follow‐up (Zullo 2003; Wit 2014). In addition, the risk of bladder dysfunction depends on the extent of surgery. Women undergoing type II radical hysterectomy are at lower risk of postoperative bladder dysfunction than those who undergo type III radical hysterectomy (Landoni 2001; Raspagliesi 2006). By magnifying anatomical structures in the pelvis, laparoscopic approaches may help reduce the denervation of pelvic nerves during radical hysterectomy. However, it has yet to be shown that these approaches have a significant effect on the prevention of bladder dysfunction (Laterza 2015; Kietpeerakool 2019). Minimally invasive radical hysterectomy, however, is associated with inferior survival to laparotomy radical hysterectomy in women with early‐stage cervical cancer. Consequently, a minimally invasive radical hysterectomy is not recommended. Although there may be a selective group of women for whom minimally invasive radical hysterectomy remains safe, further studies are needed (Ramirez 2018; Cusimano 2019; Chen 2020).

Causes of bladder dysfunction following radical hysterectomy are secondary to the damage of pelvic autonomic nerves that innervate the muscles of the bladder (detrusor muscle), urethral sphincter and pelvic floor fasciae (Zullo 2003; Sellers 2012). Bladder dysfunction following radical hysterectomy includes various functional disorders of the lower urinary tract, such as urinary retention, voiding difficulty, urinary hesitancy, urinary tract infection, and urinary stress incontinence (Chen 2002). Bladder dysfunction increases the rates of urinary tract infection, hospital visits or admission, patient dissatisfaction, and the need for intermittent self‐catheterisation (Manchana 2010). Bladder dysfunction can also negatively impact patient quality of life (QoL), which can lead to embarrassment or even social isolation (Zhou 2016).

Description of the intervention

Postoperative interventions for preventing bladder dysfunction after radical hysterectomy can be classified broadly into two groups: pharmacological interventions and non‐pharmacological interventions. Pharmacological interventions use parasympathomimetic agents to stimulate contraction of the smooth muscles of the detrusor muscle and can improve the symptoms associated with bladder hypotonia (Sellers 2012). The drugs frequently used in treating bladder dysfunction following radical hysterectomy are bethanechol chloride and cisapride (Kemp 1997; Madeiro 2006). A wide range of non‐pharmacological interventions have been used to reduce bladder dysfunction following radical hysterectomy, including postoperative suprapubic catheterisation, intermittent self‐catheterisation, bladder training and acupuncture (Fernandez 2005; Naik 2005; Geller 2014; Kidd 2015).

How the intervention might work

Previous studies have demonstrated that a malfunctioning bladder detrusor muscle is a major cause of bladder dysfunction following radical hysterectomy (Plotti 2011; Laterza 2015). Contraction of the detrusor muscle of the urinary bladder is stimulated by parasympathetic nerve impulses mediated by the neurotransmitter acetylcholine (Sellers 2012). Pharmacological therapy for voiding disorders consists of drugs that improve detrusor muscle contraction and those that reduce urethral resistance, which may have a role in the prevention of postoperative bladder dysfunction.

Bethanechol, a cholinergic agent, is a synthetic ester, and is structurally and pharmacologically related to acetylcholine. Bethanechol increases the tone of the detrusor muscle by stimulating the parasympathetic nervous system (Kemp 1997; Madeiro 2006).

Cisapride is a prokinetic agent. It is principally prescribed for treating gastro‐oesophageal reflux in children. The mechanism of action of cisapride is to stimulate the release of acetylcholine, thus promoting detrusor muscle contractility. Hence, as a result of its parasympathomimetic effect, cisapride may be effective for treating bladder hypotonia after surgery (Madeiro 2006). Cisapride, however, has been restricted to a limited access programme in the USA and Europe because it is associated with serious side effects, including cardiac arrhythmias (irregular heart rhythms) and death (Henney 2000).

Suprapubic catheterisation (SPC), an insertion of a catheter via postoperative suprapubic cystostomy, has been proposed to hasten the recovery of bladder function compared with an indwelling urethral catheter, by minimising the risks of a urinary tract infection and asymptomatic bacteriuria, which can impede bladder function activity returning to normal (Kidd 2015).

Bladder training is an important form of behaviour therapy that can be effective in treating bladder dysfunction following radical hysterectomy (Goldfarb 1967). Bladder training targets the detrusor muscle and aims to promote bladder filling and emptying according to a normal pattern (Oberst 1981). As bladder training has been acknowledged as an effective intervention for managing individuals with neurogenic bladder (Wallace 2004), this intervention may be effective for managing bladder dysfunction following radical hysterectomy.

Acupuncture is a treatment derived from traditional Chinese medicine. Fine needles are inserted at certain sites in the body for either therapeutic or preventative purposes. A small electrical current passing between pairs of acupuncture needles may be used at the same time, a technique called electroacupuncture (Yi 2011). Previous studies have reported the efficacy of acupuncture for the treatment of postoperative urinary retention after gynaecological surgery (Wang 2007; Geller 2014). However, the actual mechanism of action remains unknown.

Why it is important to do this review

Although survival outcomes of women with early‐stage cervical cancer after radical hysterectomy with pelvic lymphadenectomy are excellent, surgery is frequently associated with postoperative complications (an unfavourable result of the operation), particularly bladder dysfunction (Suprasert 2010). As bladder dysfunction diminishes QoL and is one of the most distressing complications following radical hysterectomy (Zhou 2016), effective interventions are needed in order to prevent or reduce the severity of the symptoms of this condition. Several postoperative interventions have been proposed to prevent bladder dysfunction following radical hysterectomy. To our knowledge, there has been no systematic review evaluating the effectiveness and safety of postoperative interventions for preventing bladder dysfunction following a radical hysterectomy in women with cervical cancer.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs).

Types of participants

Women aged 18 years or over with early‐stage cervical cancer who have undergone radical hysterectomy (Piver type II, Piver type III, Querleu‐Morrow class B2, or class C1). Early‐stage cervical cancer was defined as cervical cancer stage IA2 to IIA2 by either the 2009 or 2018 FIGO staging system. If studies included women with other types of gynaecological cancer (i.e. endometrial cancer), we planned to contact the trial authors to retrieve data related to participants with cervical cancer only. If this was not possible, we planned to include the study only if at least 80% of participants were diagnosed with cervical cancer.

Types of interventions

We planned to include any trial that attempted to compare the following.

A pharmacological agent and placebo or standard care.
A non‐pharmacological intervention and a standard care. Specific non‐pharmacological interventions include postoperative suprapubic catheterisation, bladder training and acupuncture.
A pharmacological agent and a non‐pharmacological intervention.
A pharmacological agent and another agent.
A non‐pharmacological intervention and another intervention.
Combinations of intervention and placebo or standard care.
Combinations of intervention and single intervention.
Combinations of intervention and other combinations.

Types of outcome measures

Primary outcomes

Rate of spontaneous voiding recovery at one week after surgery. We defined spontaneous voiding recovery as a voluntary void that has 50 mL or less of urine remaining in the bladder, measured by clean intermittent catheterisation after the woman feels as though her bladder is empty.
Quality of life (QoL), determined using a scale that has been validated in accordance with the norms reported in a peer‐reviewed publication (i.e. the European Organisation for Research and Treatment of Cancer (EORTC) QLQ‐CX24 cervical cancer‐specific QoL questionnaire (Greimel 2006)).

Secondary outcomes

Time after surgery to a post‐void residual urine volume of 50 mL or less (days). Post‐void residual urine was defined as the amount of urine retained in the bladder after a voluntary void, measured by clean intermittent catheterisation after the participant feels as though bladder is empty.
Time after surgery to a post‐void residual urine volume of 75 mL or less (days). See Differences between protocol and review
Time after surgery to a post‐void residual urine volume of 100 mL or less (days). See Differences between protocol and review
Adverse events (excluding bladder dysfunction). We categorised the severity of the following adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE 2010). (A) Acute complications including postoperative mortality; digestive complications (e.g. bowel injuries, bowel obstruction); urological injuries; haematological complications (e.g. anaemia from acute blood loss); and cardiovascular and thromboembolic complications (e.g. myocardial infarction, arterial thrombosis, venous thrombosis, pulmonary embolism). (B) Late complications including symptomatic lymphocysts; incisional hernia; digestive complications (e.g. intestinal obstruction and fistula formation); and urological complications (e.g. ureteral stenosis and fistulae).
Post‐void residual urine volume (amount of urine measured by clean intermittent catheterisation after the participant feels that her bladder is empty) at 1, 6 and 12 months after surgery (mL)
Rate of urinary tract infections in the first month after surgery, diagnosed by urine culture
Subjective urinary symptoms, determined using a standard questionnaire (i.e. International Prostate Symptom Score (Barry 1992))
Flow rate (mL per second), obtained by urodynamic measurement
Maximum flow rate (mL per second) and number of women with low maximum flow rate (< 15 mL per second, as defined by Abrams 2003), obtained by urodynamic measures
Detrusor pressure at maximum flow and number of women with low detrusor pressure at maximum flow (< 25 cmH₂O)
Bladder compliance (mL/cmH₂O). See Differences between protocol and review
Poor bladder compliance, defined as bladder compliance less than 10 mL/cmH₂O following the guidelines of the International Continence Society (Cho 2009)

We planned to present a 'Summary of findings' table reporting the following outcomes listed in order of priority.

Rate of spontaneous voiding recovery at one week after surgery.
QoL.
Time after surgery to a post‐void residual urine volume of 50 mL or less (days).
Adverse events.
Post‐void residual urine volume one month after surgery.
Urinary tract infections in the first month after surgery.
Subjective urinary symptoms.

Search methods for identification of studies

We included only randomised controlled trials (RCTs), irrespective of the language of publication, publication status or sample size.

Electronic searches

We searched the following electronic databases on 20 April 2020.

The Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) in the Cochrane Library;
MEDLINE via Ovid (1946 to April week 2 2020);
Embase via Ovid (1980 to 2020 week 16).

Appendix 5, Appendix 6, and Appendix 7 display the search strategies for CENTRAL, MEDLINE, and Embase, respectively.

Searching other resources

We searched the World Health Organization International Clinical Trials Registry Platform (who.int/ictrp/en/) and ClinicalTrials.gov to identify any ongoing trials. If we identified ongoing trials that had not been published, we planned to approach the principal investigators and major co‐operative groups active in this area to ask for relevant data. We searched the following databases for grey literature: Open‐Grey (opengrey.eu/) and Index to theses (proquest.com/products-services/pqdt_uk_ireland.html).

Hand searching

We handsearched reports of conferences from the following sources.

Annual Meeting of the Society of Gynecologic Oncology.
Annual Meeting of the International Gynecologic Cancer Society.
Annual Meeting of the European Society of Medical Oncology.
Annual Meeting of the British Gynaecological Cancer Society.
Biennial Meeting of the Asian Society of Gynecologic Oncology.
Biennial Meeting of Asia and Oceania Federation of Obstetrics and Gynaecology.
Biennial Meeting of the European Society of Gynaecologic Oncology.

We checked the citation lists of the included studies and key textbooks for potentially relevant references. We searched for papers in all languages and translated them, if necessary. We planned to include unpublished trials only if trial data and methodological descriptions were provided in written form or through direct contact with the trial authors.

Data collection and analysis

Selection of studies

We downloaded all titles and abstracts retrieved via an electronic search of the Endnote reference management database. After duplicates were removed, we transferred these data to Covidence (covidence.org). Two review authors (AA and CK) examined the remaining references independently. We excluded those studies which clearly did not meet the inclusion criteria, and we obtained full‐text copies of potentially relevant references. Two review authors (AA and CK) independently assessed the eligibility of the retrieved reports or publications. We resolved any disagreement through discussion or, if required, we planned to consult a third review author (KG or PL). We identified and excluded duplicates and collated multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We used the details obtained from the selection process in Covidence to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Liberati 2009).

Data extraction and management

Two review authors (AA and CK) independently extracted study characteristics and outcome data from included studies using Covidence. We noted in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We resolved disagreements by consensus or by involving a third review author (KG or TT). One review author (CK) checked study characteristics for accuracy against the trial report.

For included studies, we extracted the following data.

Author, year of publication, and journal citation (including language).
Country.
Setting.
Inclusion and exclusion criteria.
Study methodology.
Study population and disease characteristics:
- total number enrolled;
- participant characteristics;
- age;
- co‐morbidities;
- other baseline characteristics;
- percentage of participants with non‐cervical cancer (only RCTs involving mixed gynaecologic malignancies);
- FIGO stage of cervical cancer;
- the histopathological subtype of cervical cancer;
- tumour size (largest tumour diameter);
- the radicality of surgery (Piver or Querleu‐Morrow).
Intervention details:
- schedule of bladder training;
- suprapubic cystostomy technique;
- acupuncture;
- cholinergic agents (dose, duration).
Comparison:
- placebo;
- no intervention.
Risk of bias in the study (see below).
Duration of follow‐up.
Outcomes: for each outcome, we extracted the outcome definition and unit of measurement (if relevant); for adjusted estimates, we recorded variables adjusted for in analyses.
Results: we extracted the number of participants allocated to each intervention group, the total number analysed for each outcome, and the missing participants.
Notes: funding for trial and notable conflicts of interest of trial authors.

Assessment of risk of bias in included studies

We assessed and reported on the methodological quality and risk of bias in included studies in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019), which recommends the explicit reporting of the following individual elements for RCTs.

Selection bias: random sequence generation and allocation concealment.
Performance bias: blinding of participants and personnel (treatment providers).
Detection bias: blinding of outcome assessment.
Attrition bias: incomplete outcome data.
Reporting bias: selective reporting of outcomes.
Other possible bias.

We considered outcome data as complete if at least 80% of participants underwent follow‐ups and were assessed for primary outcomes. Two review authors (AA and CK) independently applied the 'Risk of bias' tool and resolved differences by discussion or by appeal to a third review author (KG or PL). We judged each item as being at high, low or unclear risk of bias as set out in the criteria displayed in Appendix 8. We provided a quote from the study report or a statement, or both, as justification for our judgement for each item in the 'Risk of bias' table. We summarised results in both a 'Risk of bias' graph and a 'Risk of bias' summary. When interpreting treatment effects and meta‐analyses, we took into account the risk of bias in the studies that contribute to that outcome. Where information on risk of bias relates to unpublished data or correspondence with trial authors, we planned to note this in the table.

Measures of treatment effect

We used the following measures of the effect of treatment.

For dichotomous outcomes (e.g. rate of spontaneous voiding recovery one week after surgery, rate of urethral catheter removal, rate of urinary tract infections, number of participants with normal detrusor pressure at maximum flow, adverse events), we analysed data based on the number of events and the number of women assessed in the intervention and comparison groups. We used these to calculate the risk ratio and 95% confidence interval.
For continuous outcomes (e.g. duration of postoperative retained urethral catheterisation, post‐void residual urine volume and QoL measures), we analysed data based on the means, standard deviations and number of women assessed for both the intervention and comparison groups to calculate the mean differences between treatment arms with their 95% confidence intervals. If the mean difference was reported without individual group data, we used this to report the study results. If more than one study measured the same outcome using different tools, we calculated the standardised mean difference and 95% confidence interval using the inverse variance method.
For time‐to‐event data (e.g. time after surgery to a post‐void residual urine volume of 50 mL or less), we planned to extract the log of the hazard ratio (log_HR) and its standard error from trial reports. If these were not reported, we planned to estimate the log_HR and its standard error using the methods of Parmar 1998.

Unit of analysis issues

We included studies in which individual women were randomised. In a study with multiple intervention groups, we planned to combine all relevant experimental intervention groups into a single group to create a single pair‐wise comparison, where possible (Higgins 2019).

Dealing with missing data

We planned to contact the original investigators to request missing data. If we could not contact the investigators or could not obtain the requested missing data, we planned to analyse only the available data and not to impute missing outcome data for any of the outcomes.

Assessment of heterogeneity

We clinically assessed heterogeneity by visual inspection of forest plots. We assessed statistical heterogeneity in each meta‐analysis using the I² statistic and Chi² test (Higgins 2003). We regarded heterogeneity as substantial if the I² statistic value was greater than 50% or there was a low P value (< 0.10) in the Chi² test for heterogeneity (Deeks 2001; Higgins 2019). If there was substantial statistical heterogeneity, we planned to carry out subgroup analyses to assess differences among the included studies. However, if there was both clinical and methodological heterogeneity across included studies, we planned to not report pooled results from meta‐analysis, but instead use a narrative approach to data synthesis.

Assessment of reporting biases

See Differences between protocol and review.

We were unable to assess reporting bias, as only four studies met our inclusion criteria.

Data synthesis

We applied the random‐effects model with inverse variance weighting for all meta‐analyses (DeSimonian 1986). We performed statistical analysis using Review Manager 5.4 (Review Manager 2014).

For time‐to‐event data, we planned to pool hazard ratios using the generic inverse variance.
For any dichotomous outcomes, we calculated the risk ratios for each study and then pooled them.
For continuous outcomes, we pooled the mean differences among the treatment arms, if all trials measure the outcome on the same scale; otherwise we planned to pool standardised mean differences

Subgroup analysis and investigation of heterogeneity

See Differences between protocol and review.

We intended to carry out subgroup analyses in order to assess the effect of the following factors.

Tumour size (2 cm or less versus more than 2 cm).
Surgical approach (laparotomy versus minimally invasive surgery).
Nerve‐sparing approach during a radical hysterectomy (yes versus no).
Radicality of surgery (Piver type II versus Piver type III, or Querleu‐Morrow class B2 versus class C1).
Extent of pelvic lymph node dissection determined by the number of lymph nodes removed.

We planned to assess subgroup differences using the interaction tests available within Review Manager 2014. We planned to report the results of subgroup analyses by quoting the Chi² statistic and P value, the interaction test, and the I² statistic. However, we did not perform subgroup analysis, as most analyses were based on only one or two included studies. Nevertheless, we acknowledged these factors in the interpretation of review findings.

Sensitivity analysis

See Differences between protocol and review.

We were unable to conduct any of the planned sensitivity analyses due to insufficient data. If more studies are included in a future update, we plan to perform sensitivity analyses in order to assess the effect of the following factors.

Repeating the analysis excluding unpublished studies (if any).
Repeating the analysis excluding studies judged to be at 'high' or 'unclear' risk of bias for allocation concealment.

Summary of findings and assessment of the certainty of the evidence

We created Summary of findings tables to summarise the results of the meta‐analyses conducted for each of the outcomes, as outlined in the section Types of outcome measures. We graded the overall certainty of the evidence for each outcome according to the GRADE approach, which takes into account issues related not only to internal validity (risk of bias, inconsistency, imprecision, publication bias) but also to external validity, such as directness of results (Langendam 2013). We created a 'Summary of findings' table based on the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011), and used GRADEpro GDT (Table 1; Table 2).

Summary of findings 1. Bethanechol compared to placebo for preventing bladder dysfunction after radical hysterectomy in women with early‐stage cervical cancer.

Comparison 1: Bethanechol versus placebo
Patients: women with early‐stage cervical cancer undergoing radical hysterectomy Setting: tertiary hospital Intervention: bethanechol Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Assumed risk: placebo	Corresponding risk: bethanechol	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Rate of spontaneous voiding recovery 1 week after surgery	‐	‐	‐	‐	‐	Not reported
Quality of life (QoL)	‐	‐	‐	‐	‐	Not reported
Time after surgery to post‐void residual volume of urine ≤ 50 mL (days)	‐	‐	‐	‐	‐	Not reported
Adverse events	‐	‐	‐	‐	‐	Not reported
Post‐void residual urine volume (mL) at 1 month after surgery	Mean 98.4	MD 37.4 lower (60.35 lower to 14.45 lower)	‐	39 participants (1 RCT)	⊕⊝⊝⊝ Very low ^a,b
Urinary tract infections in the first month after surgery	‐	‐	‐	‐	‐	Not reported
Subjective urinary symptoms	‐	‐	‐	‐	‐	Not reported
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

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^aThe evidence was downgraded by two levels due to imprecision (combination of sparse data and a low number of events). ^bThe evidence was downgraded by one level due to unclear risk of selection bias.

Summary of findings 2. Suprapubic catheterisation compared to intermittent self‐catheterisation for preventing bladder dysfunction after radical hysterectomy in women with early‐stage cervical cancer.

Comparison 2: Suprapubic catheterisation versus intermittent self‐catheterisation
Patients: women with early‐stage cervical cancer Setting: tertiary hospital Intervention: suprapubic catheterisation (SPC) Comparison: intermittent self‐catheterisation (ISC)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Assumed risk: suprapubic catheterisation	Corresponding risk: intermittent catheterisation	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Rate of spontaneous voiding recovery 1 week after surgery	‐	‐	‐	‐	‐	Not reported
Quality of life (QoL)	‐	‐	No differences of QoL between the comparison groups. See comment	‐	‐	Data were insufficient for calculating the relative measures
Time after surgery to post‐void residual volume of urine ≤ 50 mL (days)	‐	‐	‐	‐	‐	Not reported
Adverse events (acute complication after surgery)	12 per 100	9 per 100 fewer (3 fewer to 30 more)	RR 0.77 (0.24 to 2.49)	71 participants (1 RCT)	⊕⊝⊝⊝ Very low ^a,b	4 of 33 in SPC group versus 6 of 38 in ISC group
Post‐void residual urine volume (mL) at 1 month after surgery	‐	‐	‐	‐	‐	Not reported
Urinary tract infections in the first month after surgery	35 per 100	27 per 100 (18 fewer to 39 more)	RR 0.77 (0.53 to 1.13)	95 participants (2 RCTs)	⊕⊝⊝⊝ Very low ^a,c	Nwabineli 1993: 7 of 10 in SPC group versus 13 of 14 in ISC group Suprasert 2002: 8 of 33 in SPC group versus 11 of 38 in ISC group
Subjective urinary symptoms	‐	‐	No differences between the comparison group See comment	‐	‐	Available data were insufficient to calculate the relative measures of the effect of interventions.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

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^aThe evidence was downgraded by two levels due to serious imprecision (small sample size and wide CI crossing the line of no effect). ^bThe evidence was downgraded by one level due to indirectness (reporting adverse events of unclear severity and unclear their association with the intervention). ^cThe evidence was downgraded by one level due to unclear risk of selection bias.

High certainty: the true effect lies close to that of the estimate of the effect.
Moderate certainty: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: the true effect may be substantially different from the estimate of the effect.
Very low certainty: the true effect is likely to be substantially different from the estimate of effect.

We downgraded the evidence from 'high' certainty by one level for each serious (or by two for each very serious) limitation.

Results

Description of studies

Results of the search

An extensive search of the literature databases in April 2020 yielded the following results: CENTRAL (71 references), MEDLINE (758 references), and Embase (1055 references). After eliminating duplicates, we screened titles and abstracts of 1464 references and excluded 1444 that obviously did not meet the review inclusion criteria. Of the 20 references that potentially met the review inclusion criteria, we excluded ‐ with reasons ‐ 15 reports after reviewing the full texts (see Characteristics of excluded studies). The search found two ongoing studies (Boonthongtho 2016; Sun 2017; see Characteristics of ongoing studies), and one study awaiting classification (Cheng 2017; see Characteristics of studies awaiting classification). Figure 1 shows the PRISMA flow chart for study selection.

Included studies

Four studies (five reports) met the inclusion criteria (Nwabineli 1993; Suprasert 2002; Naik 2005; Madeiro 2006). One report (Roberts 2006) described updated results of Naik 2005. See Characteristics of included studies table for details of each study.

Participants

Nwabineli 1993 was a two‐armed parallel RCT conducted between September 1989 and February 1990. Participants were 24 women with cervical cancer stage IB or IIA who underwent type II or type III radical hysterectomy. Inclusion criteria were age less than 50 years, no history of voiding problems, and no previous radiotherapy. Exclusion criteria were a history of tricyclic antidepressants or anticholinergics used.

Suprasert 2002 was a two‐armed parallel RCT conducted between September 1998 and June 1999. Participants were 71 women with cervical cancer stage IB1 or IIA with normal bladder function and urinary analysis who underwent type III radical hysterectomy following bilateral pelvic lymphadenectomy. Women were considered ineligible if they had a history of urinary tract infection more than two times per year, or a history of renal stone or bladder calculi, or previous urinary incontinence, or intraoperative bowel or urinary tract complication, or inability to perform intermittent self‐catheterisation.

Naik 2005 was a two‐armed parallel RCT undertaken between July 1999 and June 2002. Participants were 40 women with cervical cancer stage IB1 who underwent type III radical hysterectomy. Updated data of this report were subsequently published in 2006 (Roberts 2006).

Madeiro 2006 was a four‐armed parallel RCT conducted between March 2002 and February 2003. Participants were 79 women with cervical cancer stage IB who underwent a standard class III hysterectomy with bilateral pelvic lymphadenectomy via laparotomy approach. An indwelling urethral catheter remained postoperatively in all patients for 10 days. Exclusion criteria were previous pelvic radiation therapy, or recurrent urinary tract infections, or urinary calculi, or uncontrolled diabetes mellitus, or bronchial asthma, or potential risk factors for cisapride use such as heart disease and family history of sudden death. We excluded two arms that administered cisapride and cisapride plus bethanechol due to the fact that cisapride now has been restricted in the USA and Europe because of its serious side effects.

Surgical procedure

Radical hysterectomies performed in Nwabineli 1993, Suprasert 2002, and Naik 2005 were carried out via laparotomy approach. The type of surgical approach for radical hysterectomy in Madeiro 2006 was unknown.

Interventions

Madeiro 2006 compared bethanechol versus placebo. Dosage of oral bethanechol was 10 mg repeated every 8 hours.

Nwabineli 1993, Suprasert 2002, and Naik 2005 compared suprapubic catheterisation (SPC) versus intermittent self‐catheterisation (ISC). Suprapubic catheterisation consisted of insertion of a Bonanno suprapubic catheter at the time of surgery, followed by free drainage, followed by catheter removal at five to seven days after the surgery.

Outcomes reported

None of the included studies reported rate of spontaneous voiding recovery at one week after surgery, time to a post‐void residual urine volume of 50 mL or less, post‐void residual urine volume at 6 and 12 months after surgery, and poor bladder compliance.

Nwabineli 1993 reported time after surgery to a post‐void residual urine volume of less than 100 mL, adverse events, and rate of urinary tract infections in the first month after surgery.

Suprasert 2002 reported time after surgery to a post‐void residual urine volume of less than 75 mL, adverse events, and rate of urinary tract infections in the first month after surgery.

Naik 2005 reported QoL, time after surgery to a post‐void residual urine volume of less than 100 mL, adverse events, rate of urinary tract infections in the first month after surgery, and subjective urinary symptoms.

Madeiro 2006 reported post‐void residual urine volume one month after surgery, flow rate, maximum flow rate, number of women with low maximum flow rate, number of women with low detrusor pressure at maximum flow, and bladder compliance.

Excluded studies

See Characteristics of excluded studies, Characteristics of ongoing studies, and Characteristics of studies awaiting classification.

We excluded seven reports because their participants were not the population that this review aimed to assess (Kuo 2005; Dy Echo 2011; Manchana 2011; Dy Echo 2012; Fanfani 2015; Wang 2015; Gong 2016). We excluded Pengsaa 1992 and Wells 2008 because their studies were not RCTs. We excluded Chen 2012 and Chen 2014 because of wrong intervention. We excluded Li 2019 because of wrong outcomes. In addition, we excluded two ongoing studies (Boonthongtho 2016; Sun 2017), and one conference proceeding awaiting classification (Cheng 2017).

Risk of bias in included studies

See Characteristics of included studies table, Figure 2, and Figure 3 for full details.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Suprasert 2002 stated that the participants were randomised by drawing a sealed envelope that contained computer‐generated random numbers thus indicating a low risk of selection bias.

Madeiro 2006 stated that the participants were allocated using a computerised randomisation schedule. However, they did not state the concealment process. This trial therefore was at unclear risk of selection bias.

Naik 2005 stated that the participants were randomised by drawing a sealed envelope that developed from an independent administrator, but did not state the methods of random sequence generation. Consequently, this trial was judged as having an unclear risk of selection bias.

Nwabineli 1993 stated that the participants were randomised using random sampling numbers. However, they did not state the allocation concealment process. This trial therefore was at unclear risk of selection bias.

Blinding

Madeiro 2006 stated that all medications were provided in packages of identical appearance. Identification was only made by a standardised code. Randomisation was only revealed at the end of the trial and was controlled by an independent investigator. This trial, therefore, was at low risk of performance and detection biases.

Blinding of participants and personnel was not feasible in Nwabineli 1993, Suprasert 2002, and Naik 2005, which compared suprapubic catheterisation versus intermittent self‐catheterisation. However, the outcomes of interest (i.e. time after surgery to a post‐void residual urine volume less than 75 mL, adverse events, and rate of urinary tract infections in the first month after surgery) were unlikely to be affected by lack of blinding of participants and personnel. Hence, we considered these studies as having a low risk of bias for this domain.

Incomplete outcome data

All included studies were at low risk of attrition bias as they had low percentages of withdrawals and dropouts (Nwabineli 1993; Suprasert 2002; Naik 2005; Madeiro 2006). See Characteristics of included studies for the proportion of participants analysed.

Selective reporting

None of the included studies reported the rate of spontaneous voiding recovery one week after surgery, or post‐void residual urine volume at 6 and 12 months after surgery. Quality of life (QoL), adverse events and subjective urinary symptoms, which are important outcomes, were rarely reported. An adverse event was assessed only in Suprasert 2002. Naik 2005 reported QoL and subjective urinary symptoms but available data, however, were insufficient to calculate the relative measures of the effect of interventions. Due to a lack of reported outcomes that are the elements necessary for decision‐making, all included studies thus were at high risk of reporting bias (Higgins 2017).

Other potential sources of bias

There was no Information indicating other important risks of bias. Accordingly, all included studies were judged as having a low risk of bias for this domain.

Effects of interventions

See: Table 1; Table 2

None of the studies reported the rate of spontaneous voiding recovery one week after surgery, time after surgery to a post‐void residual urine volume of 50 mL or less, post‐void residual urine volume at 6 and 12 months after surgery, and poor bladder compliance. Consequently, we added time after surgery to a post‐void residual urine volume of 75 mL or less, and 100 mL or less, respectively, and bladder compliance, as additional secondary outcomes (see Differences between protocol and review).

Madeiro 2006 compared bethanechol with placebo. Nwabineli 1993, Suprasert 2002, and Naik 2005 compared suprapubic catheterisation (SPC) with intermittent self‐catheterisation (ISC).

Comparison 1: Bethanechol versus placebo

Madeiro 2006 reported four‐arm comparisons including placebo; bethanechol alone given 10 mg orally every eight hours; cisapride alone given 10 mg orally every eight hours; and a combination of 10 mg of bethanechol and cisapride given orally every eight hours. As cisapride has been restricted in the USA and Europe due to its serious side effects, including cardiac arrhythmias (irregular heart rhythms) and death, we, therefore, included only the data obtained from participants allocated to placebo and bethanechol alone in the analyses.