Prediction and prevention of stress urinary incontinence after prolapse surgery van der Ploeg, J.M.

Transcription

1 UvA-DARE (Digital Academic Repository) Prediction and prevention of stress urinary incontinence after prolapse surgery van der Ploeg, J.M. Link to publication Citation for published version (APA): van der Ploeg, J. M. (2019). Prediction and prevention of stress urinary incontinence after prolapse surgery. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 03 Apr 2019

2 Chapter 9 GENERAL DISCUSSION

3 Insufficient support of the pelvic floor can cause pelvic organ prolapse (POP) and stress urinary incontinence (SUI). Approximately 50% of women with POP also report having SUI, and women without SUI symptoms can report de novo SUI after prolapse repair.(50) We studied the prediction and prevention of postoperative SUI in women undergoing vaginal prolapse repair. In this thesis we aimed to answer the following questions: 1. Is there a lower risk of postoperative SUI after prolapse surgery combined with a midurethral sling than after prolapse surgery only in women with POP and (a) coexisting SUI or (b) occult SUI? 2. Is the risk of complications higher after combination surgery than after a two-step strategy? 3. Do women with POP and occult SUI have a higher risk of postoperative SUI than women without occult SUI? 4. Are urodynamic studies necessary to predict postoperative SUI or is basic office evaluation sufficient? 5. Can we predict postoperative SUI and what is the value of the stress test in predicting postoperative SUI? To answer these questions, we conducted two randomised controlled trials (RCTs) to compare vaginal prolapse surgery with and without a midurethral sling (MUS) in women with POP and coexisting SUI (CUPIDO-1) and in women with POP and occult SUI (CUPIDO-2). The protocol for these trials is described in Chapter 2 (28) and the results are presented in Chapter 3 (CUPIDO-1 trial) and Chapter 4 (CUPIDO-2 trial).(29, 30) The data of the CUPIDO trials were combined to study the value of demonstrating SUI in women without SUI symptoms and to compare basic office evaluation and urodynamics in these women (Chapter 5).(31) In 2014 we published a systematic review and meta-analysis of RCTs on the subject (15) and updated it in 2017 (Chapter 6).(32) In 2018, we wrote a clinical opinion about when to combine prolapse repair with incontinence surgery (Chapter 7). Finally, we developed a model based on the data from the CUPIDO trials to predict postoperative SUI in women undergoing vaginal prolapse repair (Chapter 8). Simultaneously, we compared a model with and without stress test to study the additional value of the stress test in predicting postoperative SUI (Chapter 8). In this discussion, we will comment on the findings of the conducted studies. 106

4 Is the risk of postoperative SUI lower after prolapse surgery combined with an incontinence procedure than after prolapse surgery only? Our studies showed that women undergoing prolapse surgery combined with an incontinence procedure have a lower risk of postoperative SUI compared with women undergoing prolapse surgery only. However, the beneficial effect of combination surgery depends on the preoperative status of urinary incontinence. As most RCTs on the subject did, we divided the participants women with POP in four groups to answer the question more precisely (see Table 1). To enhance the readability of the results, we have summarised the SUI risks found in our RCTs and in the update of the review in Table In women with coexisting SUI In the CUPIDO-1 trial (Chapter 3) we compared vaginal prolapse repair with and without MUS in women with coexisting SUI (defined as SUI symptoms >1/week and/or objective SUI without reduction of the POP).(29) We showed that the risk of persisting SUI was significantly lower in women who underwent combination surgery compared with vaginal prolapse surgery only. Subjective SUI, bothersome SUI, objective SUI and any treatment for postoperative SUI were more than halved when POP surgery was combined with a MUS. Almost 40% of the women who received prolapse surgery only underwent subsequent treatment for persisting SUI and 17% received a MUS in the first postoperative year. Ten percent of the women undergoing combination surgery with MUS also needed subsequent therapy for persisting SUI (all physiotherapy). As presented in our updated review (Chapter 6), two other trials compared prolapse surgery with and without an incontinence procedure in women with coexisting SUI symptoms. Costantini et al. compared sacrocolpopexy with and without Burch colposuspension in women with POP and urinary incontinence (defined as SUI, mixed UI or occult SUI).(55) The authors observed no differences in postoperative SUI. Borstad et al. compared vaginal prolapse surgery with and without MUS in women with coexisting SUI symptoms and demonstrable SUI (with or without POP reduction).(16) In the two-step arm, 57% of the women received a MUS for persisting SUI after prolapse surgery only. Combining the two MUS trials showed statistically significant less subsequent surgery for persisting SUI after vaginal prolapse surgery with MUS (0% vs. 40%; RR 0.0; 95% CI ).(32) In women with prolapse and coexisting SUI, vaginal prolapse repair needs to be combined with MUS in an average of 2.5 women to prevent one woman needing subsequent MUS after prolapse surgery only (number needed to treat [NNT]: 2.5). Table 1. Women with POP divided by preoperative SUI status 1. Women with coexisting SUI 2. Women without SUI Not tested for occult 2a. With or without occult symptoms SUI SUI Tested for occult SUI 2b. With occult SUI 2c. Without occult SUI 107

5 Table 2. Postoperative SUI (POSUI) risk by preoperative SUI status Preoperative SUI Outcome Source POP Combination RR status surgery surgery (95% CI) only POP and coexisting SUI SUI endpoint CUPIDO-1 57% 21% 0.4 (Chapter 3) ( ) Surgery for POSUI Updated review 40% 0% 0 a POP without SUI symptoms (Chapter 6) (0 0.1) With occult SUI SUI endpoint CUPIDO-2 38% 0% 0 b (Chapter 4) (0 0.5) Surgery for POSUI Updated review 15% 1% 0.1 (Chapter 6) (0 0.6) With or without occult SUI Surgery for POSUI Updated review 6% 2% 0.4 (Chapter 6) ( ) Without occult SUI SUI endpoint CUPIDO-2 8% - - (Chapter 4) Surgery for POSUI CUPIDO-2 1.5% - - (Chapter 4) SUI endpoint: bothersome SUI or objective SUI 12 months after index surgery, or subsequent therapy for SUI in the first postoperative year Notes a. The RR is estimated by changing 0 into 0.5 using openepi.com (66/165 vs. 0.5/145.5; RR 0.01; 95% CI ) b. The RR is estimated by changing 0 into 0.5 using openepi.com (18/47 vs. 0.5/41.5; RR 0.03; 95% CI ) 2. In women without SUI symptoms Women presenting with POP without SUI symptoms can develop de novo SUI after prolapse surgery. Because occult SUI is considered a risk factor for de novo SUI, one could test for occult SUI before surgery. Occult SUI is defined as objective SUI with reduction of the POP. Women without SUI symptoms can therefore be categorised in three groups: a. Women without SUI symptoms, but not tested for occult SUI Two well-designed trials studied prolapse surgery with or without an incontinence procedure in women without symptoms of UI.(19, 64) Our meta-analysis (Chapter 6) revealed fewer women with subjective SUI after combination surgery compared to prolapse surgery only (50% vs. 67%; RR 0.8; 95% CI ). However, we found only a tendency towards less surgery for de novo SUI (2% vs. 6%; RR 0.4; 95% CI ) with consequently an absolute risk reduction of only 4%.(32) b. Women without SUI symptoms, but with occult SUI In the CUPIDO-2 trial (Chapter 4) women with occult SUI were randomised to undergo vaginal prolapse repair with or without a MUS.(30) Occult SUI was defined as SUI only observed with 108

6 reduction of the POP in women without UI symptoms (defined as UI symptoms 1/week). This trial showed that the risk of de novo SUI was significantly higher in women undergoing vaginal prolapse surgery only. These women had a 21% risk of undergoing therapy for de novo SUI (13% MUS) vs. 0% in women who received a prophylactic MUS.(30) Two other trials specifically studied vaginal prolapse surgery with and without a MUS in women with occult SUI.(9, 71) Both studies defined occult SUI as urodynamic SUI with or without POP reduction in women without UI symptoms. Pooling the three trials in the updated review (Chapter 6) demonstrated that a prophylactic MUS significantly reduces the risk of undergoing subsequent surgery for de novo SUI (1% vs. 15%; RR 0.1; 95% CI ).(32) The NNT is seven to prevent one woman with occult SUI undergoing subsequent surgery for de novo SUI. Two high quality trials could not be included in the pooling, because they only reported on an incontinence endpoint in a sub analysis and not specifically on objective SUI or subsequent surgery. Although outcomes differed slightly, in both trials the risk of postoperative incontinence was almost halved by a prophylactic incontinence procedure.(64, 65) c. Women without SUI symptoms and without occult SUI In the CUPIDO-2 trial (Chapter 4) women without occult SUI were not randomised, but received vaginal prolapse surgery only and were followed in a separate cohort.(30) At one-year followup, 8% reported bothersome SUI, showed objective SUI 12 months after index surgery, or underwent subsequent therapy for de novo SUI in the first postoperative year (Table 2). Of these women, 2% reported bothersome SUI and 5% underwent treatment for de novo SUI (1.5% MUS). Compared with the two other RCTs, these are relatively low percentages. Brubaker et al. compared sacrocolpopexy with and without Burch colposuspension and reported on de novo SUI in women without occult SUI.(8) De novo SUI was defined as objective SUI, bothersome SUI or treatment for SUI. The trial showed significantly fewer women with de novo SUI after sacrocolpopexy with Burch versus no Burch (21% vs. 38%; RR 0.6; 95% CI ). The OPUS trial reported in a sub analysis on an UI endpoint (bothersome UI or objective SUI) and also found less UI 12 months after prolapse repair with MUS compared to prolapse repair only, but the differences were not statistically significant (28% vs. 41%; RR 0.7; 95% CI ).(64) Conclusion The risk of postoperative SUI is lower in women undergoing prolapse surgery with an incontinence procedure than in women undergoing prolapse surgery only. The positive effect of a concomitant incontinence procedure is not surprising as the cure rate of this procedure for treating SUI is already shown to be higher (approximately 80%) than that of an anterior colporrhaphy (approximately 40%).(17, 87, 109) Especially women with coexisting SUI and women with occult SUI benefited from vaginal prolapse surgery with a MUS compared to prolapse surgery only. This finding is also biologically plausible. Women with coexisting SUI confirmed by demonstrable (objective) SUI are likely to have a higher risk of having an impaired urethral closure mechanism, also with a more severe 109

7 deficiency, than women without any sign or symptom of SUI. Hence, the positive effect of prolapse surgery combined with an incontinence procedure is likely to be highest in women with coexisting SUI and lowest in women without any sign or symptom of SUI. We observed more evidence for the benefits of undergoing a MUS than for a Burch colposuspension. As MUS and Burch colposuspension procedures have been shown to be equally effective in treating SUI, the most likely explanation for this counterintuitive finding is simply a lack of evidence in trials studying Burch colposuspension.(87) In women with coexisting SUI, the smallest of the three RCTs compared sacrocolpopexy with and without Burch colposuspension and found no differences in postoperative incontinence.(55) This small RCT included a heterogeneous group of women with incontinence, while the other trials included women with SUI only. If the trial had been repeated with a larger sample and a more homogenous group of women with coexisting SUI, it is likely that results would be comparable with the MUS trials. In women with or without occult SUI, the CARE trial (comparing sacrocolpopexy with and without Burch colposuspension) could not be included in the meta-analysis because only an SUI endpoint was available.(8) Although the CARE trial showed fewer women with de novo SUI after combination surgery, the meta-analysis of women with occult SUI included vaginal procedures with MUS only and pooling was not possible for women without occult SUI. 110

8 Is the risk of complications higher after prolapse surgery combined with an incontinence procedure than after prolapse surgery only? The updated review (Chapter 6) revealed that women undergoing vaginal prolapse surgery combined with MUS have almost a twofold higher risk of complications compared with women undergoing prolapse surgery only. There was no difference in long-term voiding dysfunction and overactive bladder symptoms. Complications Considering combination surgery should not only include the benefits, but also the possible risks. In the CUPIDO-1 trial (Chapter 3) we found overall more complications after prolapse repair with MUS than after prolapse repair only and a tendency towards more severe adverse events (SAEs).(29) SAEs were defined according to the EAU guideline as adverse events (AEs) requiring invasive intervention or reoperation, and included tape extrusion needing surgery, (partial) tape removal or loosening and bladder perforation.(60) These findings were confirmed in the CUPIDO-2 trial (Chapter 4) for all AEs, but not for SAEs.(30) Pooling for SAEs in the updated review (Chapter 6) showed more SAEs after vaginal prolapse repair with MUS than after prolapse repair only (14% vs. 8%; RR 1.7; 95% CI ).(32) AEs were similar between sacrocolpopexy with and without Burch colposuspension. In the CARE trial as well, SAEs did not differ.(65) Adding an incontinence procedure is likely to increase the surgical risks. Firstly, when prolapse surgery is combined with an incontinence procedure (a one-step strategy) more women overall will receive incontinence surgery compared to first prolapse surgery only (a two-step strategy). Thus, more women will be exposed to the risks of incontinence surgery in a one-step strategy. The one-step protocol is beneficial only when there is a high risk of subsequent surgery after prolapse surgery, thus when the advantage of not needing to repeat surgery and anaesthesia outweighs the risk of AEs. This subject will be discussed in more detail below. Secondly, the presence of POP might increase the surgical risks (e.g., trocar injury, tape exposure) due to anatomical changes. Obstructive symptoms, voiding dysfunction Besides surgical complications, women undergoing combination surgery might be at increased risk of experiencing postoperative voiding dysfunction. In the CUPIDO trials, at one-year followup, obstructive symptoms measured with the Urinary Distress Inventory (UDI) were similar in women undergoing prolapse repair with or without a MUS (Chapters 3 and 4).(29, 30) Wei et al. showed the same in the OPUS trial.(64) In addition, bladder emptying at one week and tape loosening for voiding dysfunction were similar between randomised groups in the CUPIDO trials.(29, 30) The meta-analysis showed a tendency towards more prolonged bladder catheterisation (8% vs. 4%; RR 2.3; 95% CI ) and slightly (but not significantly) more surgery for voiding dysfunction (1.3% vs 0.2%; RR 2.4; 95% CI ) after vaginal prolapse repair with a MUS compared to prolapse repair only (Chapter 6).(32) Prolonged catheterisation was similar in women undergoing sacrocolpopexy with or without Burch colposuspension.(32) As with AEs, one would expect a higher risk of voiding dysfunction in women undergoing combination surgery compared with prolapse surgery only. The overall low risk and lack of power to show a difference might explain why we observed a mere statistical tendency towards 111

9 more women needing prolonged catheterisation or tape loosening after vaginal prolapse repair with a MUS. Although we would not exclude a slightly higher risk of short-term voiding dysfunction in women undergoing combination surgery, the overall risks are reassuringly low and did not result in long-term voiding dysfunction. Overactive bladder symptoms In the past, concerns have been raised about an increased risk of overactive bladder symptoms (OAB). In the CUPIDO trials (Chapters 3 and 4) we found no increased risk of OAB in women who underwent vaginal prolapse surgery with a MUS compared to vaginal prolapse repair only. (29, 30) In addition, our meta-analysis in the updated review (Chapter 6) showed no difference in urgency incontinence.(32) Three trials showed similar OAB subscales as measured with the UDI comparing vaginal prolapse repair with or without a MUS.(29, 30, 64) In the CARE trial, most urge outcomes were similar at two-year follow-up, but the MESA urge score was even better in women who had sacrocolpopexy with Burch colposuspension compared to sacrocolpopexy only (MESA: Medical, Epidemiological and Social Aspects of Aging questionnaire).(65) The most important hypothesis for an increased risk of OAB after combination surgery was that obstructive micturition could result in detrusor hypertrophy and detrusor over activity. As we observed no differences in obstructive micturition, this might explain why we also found no differences in overactive bladder symptoms either. 112

10 Do women with POP and occult SUI have a higher risk of postoperative SUI than women without occult SUI? Chapter 5 indicated that women without symptomatic UI, but with demonstrable SUI (with or without reduction of the prolapse), have a six times higher risk of developing bothersome SUI at 12-months follow-up or of undergoing therapy for de novo SUI in the first year after vaginal prolapse repair. Occult SUI Generally, occult SUI is defined as urinary leakage observed only after reduction of the prolapse in continent women.(1) Although rare in women without symptoms of urinary incontinence, SUI can also be demonstrated without reduction of the prolapse. Therefore, we introduced the term demonstrable SUI, defined as SUI demonstrated with (occult SUI) or without (overt SUI) reduction of the prolapse. In Chapter 5 we studied the predictive value of demonstrable SUI in women without symptomatic UI (UI once a week and no bothersome UI).(31) Nineteen percent of the women had demonstrable SUI at basic office evaluation (3% without and 19% with reduction of the prolapse). Other researchers have detected occult SUI in about 20% of the women with prolapse.(8, 9) There is no standard test to detect occult SUI, but Visco et al. have studied several techniques.(8) They showed that reducing the prolapse with a swab produced the best test performance for predicting postoperative SUI, with a positive predictive value (PPV) of 79% and a negative predictive value (NPV) of 65%. This technique was used in the CUPIDO-2 trial. Risk of postoperative SUI The CUPIDO-2 trial (Chapter 4) demonstrated that women with occult SUI had a higher risk of developing de novo SUI after vaginal prolapse repair than women without occult SUI (38% vs 8%; RR 4.7; 95% CI ).(30) De novo SUI was defined as bothersome SUI or objective SUI at 12-month follow-up or any treatment for SUI in the first postoperative year. Combining the data from the CUPIDO trials, we studied women without preoperative UI symptoms (UI 1/week and no bothersome UI) (Chapter 5). De novo SUI was defined as bothersome SUI at 12-month follow-up or treatment for SUI in the first postoperative year. At basic office evaluation, women with SUI (with or without reduction of the prolapse) had an almost six times higher risk of developing de novo SUI: 28% vs. 5%; RR 5.6; 95% CI (31) 113

11 Are urodynamic studies necessary to predict postoperative SUI or is basic office evaluation sufficient? The best method to predict postoperative SUI is still unknown. As mentioned in the previous section, Visco et al. studied several tests during urodynamics and concluded that a reduction test in which the prolapse was reduced with a swab had the best test performances.(8) We compared the predictive value of this stress test during basic office evaluation and urodynamics in Chapter 5 and found that urodynamics generally did not add value and diagnostic accuracy was better with basic office evaluation. Demonstrating SUI with basic office evaluation or urodynamics Occult SUI can be detected in basic office evaluation (BOE) or urodynamic studies (UDS). As occult SUI is defined as involuntary leakage of urine during the Valsalva manoeuvre or coughing with the prolapse reduced, the test is easy to conduct during BOE.(1) UDS have some supposed advantages: (1) standardised circumstances are easier to achieve; (2) the stress test can be done with various bladder fillings; (3) detrusor contraction can be excluded during the stress test; and (4) additional tests can be conducted (e.g. urethral pressure profile). In Chapter 5 we discussed whether the first two possible advantages led to better diagnostic characteristics in predicting postoperative SUI in women without preoperative symptoms of incontinence. Detection of preoperative SUI More women demonstrated SUI during UDS than during BOE.(31) In 19% of the women without UI symptoms, urinary leakage was observed with a stress test during BOE. During UDS 29% had a positive stress test: 5% overt SUI and 29% occult SUI. All women with overt SUI also showed occult SUI. The higher SUI detection rate with UDS is most likely because during UDS, stress tests were done at 300 ml bladder filling and at maximum bladder capacity, while during BOE this was done only with a subjective full bladder. The overall higher bladder volumes during UDS resulted in a lower test threshold and thus more positive tests. Prediction of postoperative SUI Studying the value of demonstrable SUI in predicting de novo SUI (bothersome SUI or treatment for SUI) revealed that the predictive value of demonstrable SUI was better in BOE than in UDS. (31) Both the diagnostic odds ratio and test accuracy were better in BOE. Of the women with a negative stress test during BOE, 23% showed SUI during UDS. However, the de novo SUI risk in these women was comparable with the risk of women with a negative stress test during BOE and UDS (7% vs. 6%). With UDS, the higher detection rate probably led to identifying more women with a low de novo SUI risk and thus worse test performances. Although continent women with demonstrable SUI have a higher risk of developing de novo SUI, we found that the value of a negative test in predicting no postoperative SUI was far better (NPV 95%), than the value of a positive test in predicting de novo SUI (PPV 28%).(31) Visco et al. reported a much higher PPV (79%), but this study included more women with SUI symptoms, resulting in a higher postoperative SUI risk.(8) 114

12 Can we predict postoperative stress urinary incontinence after vaginal prolapse repair and do we need the stress test for this? We developed a prediction model for postoperative SUI in all women planned for vaginal prolapse repair (Chapter 8) and this showed a fair prediction of postoperative SUI (AUC 0.74). By comparing this model with an extended model including the stress test showed that the stress test only added predictive value in women with an intermediate (10-30%) risk of postoperative SUI. This concerned 37% of the women in our set. Jelovsek et al. developed and externally validated a prediction model for postoperative SUI in continent women undergoing vaginal prolapse repair.(10) Based on the data from the CUPIDO trials we developed and validated in Chapter 8 a prediction model for postoperative SUI in all women undergoing vaginal prolapse repair. We first developed a reference model without stress test and then an extended model with the stress test. The reference model included five predictors (age, vaginal parity, stage 2 or more anterior prolapse, subjective UI and MUS), from which subjective UI (OR 8.9; 95% CI ) and MUS (OR 0.2; 95% CI ) were the strongest predictors. The stress test had an odds ratio of 2.4 (95% CI ) which improved the optimism-corrected AUC from 0.74 in the reference model to 0.76 in the extended model (P-value: 0.005). Accuracy of both models was fair and the minor increase in AUC was also found by Jelovsek et al. (AUC 0.73 with stress test and 0.72 without).(10) We showed that the stress test had no additional predictive value in more than 50% of the women. The stress test was especially valuable in women who had an intermediate postoperative SUI risk (10-30%) with the reference model. A negative stress test changed the postoperative SUI risk to a maybe acceptable level, while a positive stress test increased the postoperative SUI risk in case of a risk score of 6, from intermediate (26%) to high (32%). As in the normal preoperative work-up of women with SUI, the stress test might also be helpful in understanding the incontinence mechanism and choosing the right incontinence treatment. Therefore, we would only perform a preoperative stress test when concomitant incontinence surgery during prolapse repair is considered. Roughly, this would include all women with an intermediate to high postoperative SUI risk as estimated with the reference model. 115

13 Should we combine vaginal prolapse surgery with incontinence surgery? When one considers to combine prolapse repair with an incontinence procedure, risks and benefits have to be balanced. However, people weigh risks and benefits differently, one SUI is not like another and individual factors, beyond the scope of our study, might play a role. Therefore, we offered in Chapter 7 two concepts which might be used to approach this dilemma. According these concepts benefits of combination surgery are likely to outweigh risks when the subsequent MUS risk for postoperative SUI is roughly 14% (8-18% depending on the SAE risks related to prolapse and incontinence surgery). The prediction rule in Chapter 7 can be used to calculate a woman s individual risk, although this does not predict the risk of undergoing additional surgery for persisting SUI, but of bothersome SUI or subsequent treatment for postoperative SUI. Only 20 of the 61 women (33%) with this composite outcome underwent a MUS for postoperative SUI (Chapter 8). Therefore, the presented risk percentages in Chapter 8 should roughly be multiplied by one-third to estimate ones subsequent MUS risk: Table 3. Approximation of estimated MUS risk* related to risk score Risk Estimated MUS risk score Reference Model Extended Model WITHOUT stress test WITH stress test 0-4 3% 3% 5 6% 4% 6 9% 7% 7 13% 11% 8 NA 15% * POSUI risk (Chapter 7) x 1/3 (rounded figures) Table 3 shows that using this concept in general only women with a high postoperative SUI risk (score 7 and MUS risk 11%) will probably benefit from combination surgery. This is about 12% of the women undergoing prolapse surgery. Therefore, we would discuss the possibility of combination surgery in women with an intermediate postoperative SUI risk (approximately 37% of the women) and we would advise women with a high risk (approximately 12% of the women) to undergo combination surgery. 116

14 Strengths and limitations Strengths Most of the strengths and limitations have been discussed fully in several other chapters and so we will not discuss them again here. We believe this thesis offers a good oversight of the evidence concerning the prediction and prevention of SUI after prolapse surgery. We not only conducted two new RCTs, but our meta-analysis also added to the evidence and we developed a prediction rule for postoperative SUI. These studies enable us to learn far more about how often women have postoperative SUI after prolapse surgery and how often AEs occur after combination surgery. To improve the implementation, we aimed to conduct studies that are closely related to daily practice and tried to use clinically relevant outcome parameters. Limitations An important limitation is that in the process, we changed the outcomes and this resulted in different definitions for postoperative SUI used in the RCTs (objective or bothersome SUI, or treatment for SUI), diagnostic study and prediction model (bothersome SUI or treatment for SUI) and clinical opinion (subsequent surgery for SUI). This hampers comparisons and is a result of the many ways one can look at the matter. As we used different outcomes, women will also use different effects in comparing a one- and two-step strategy. We must pay attention to this in shared decision making. Generally, follow-up was relatively short (one year), which may have led to an underestimation of postoperative SUI. Another limitation is that we paid more attention to the benefits than to the risks. The beneficial effect of combination surgery was predictable; the CARE and OPUS trials confirmed this already in 2006 and 2012, respectively. The following explains our choice to focus on the benefits: Back in 2007 there were far more uncertainties about the beneficial effect than now. Although the benefits were predictable, the effect size was not. It was easier to power a RCT based on a frequently occurring outcome (postoperative SUI), than on an infrequent outcome (adverse event). Concerning the meta-analysis, a limitation is that SAEs were pooled independently of the preoperative incontinence status. From the point of view that incontinence will not influence the SAE risk, this was defendable for the intervention group (combination surgery). However, as shown in the study by Borstad et al, preoperative incontinence, indirectly, influences the SAE risk in the control group. After all, the SAE risk will increase with an increasing risk of undergoing subsequent surgery for postoperative SUI.(16) Because the postoperative SUI risk was very high in the Borstad trial, this resulted in a not significant difference in SAEs between groups after one year. In other words, the higher the risk of subsequent surgery for postoperative SUI is, the lower the difference in SAEs between a one-step and two-step strategy will be. This subject is thoroughly described in the clinical opinion in Chapter 8, but should also have been discussed in the review, and weighing the pros and cons of combination surgery, this should be included in patient counselling. Finally, the generalisability of the results might be a limitation. Our findings may be only partially useful in other countries as differences in population and postoperative SUI risk might exist (e.g. more diabetes and CARA). But maybe more importantly differences in culture, health system 117

15 (e.g. accessibility and health insurance) and legislation can lead to other notions of balancing risks and benefits. Based purely on our subjective gut feeling, some hypothetical differences could be: Dutch women tend to go for a two-step strategy more than a one-step strategy, possibly because they weigh potential SAEs heavier than the potential benefits and think that there is no such thing as a free lunch (i.e., you can t get something for nothing; there will always be risks involved). Women in other countries might be less pessimistic or anxious and might think more along the lines of an ounce of prevention is worth a pound of cure. Dutch physicians in general might be more conservative than in other countries. Inspired by the Hippocratic oath first do no harm, the evidence to change common practice (the two-step strategy) must be very strong. Dutch women might accept postoperative UI more easily (as a fact of life) than women in other countries and this might result in overall less postoperative SUI (bothersome SUI or treatment for SUI). In the case of postoperative SUI, this might also influence a possible question of guilt. Dutch women would possibly not blame the physician, especially if they have been fully informed of the risks preoperatively ( you told me ), while women in other countries might tend to accuse the physician ( I will sue you ). The Dutch health system is completely different from most other countries. Access is relatively easy, the time to travel to a hospital is short, and health and disability insurance is mandatory. Therefore, in choosing between treatment options, financial arguments hardly play a role for the patient. International differences might explain why some countries (like the Netherlands) often do not perform combination surgery, while in other countries not combining prolapse and incontinence surgery might be regarded as malpractice. 118

16 Future research We have contributed important new evidence about the prediction and prevention of SUI after prolapse surgery. However, due to the study design, some questions remain incompletely answered. Like other researchers before us, we were unable to include many women in our RCTs. This hampers analysis concerning infrequent outcomes like SAEs. An observational study that offers the opportunity to include far more women is likely to add important information. If constructed properly, this observational study can be used to externally validate the prediction model. The development and validation of a prediction model which combines the risks and benefits, would be an excellent tool for women and physicians to weigh the pros and cons before considering prolapse surgery combined with an incontinence procedure. 119