CLINICAL GYNECOLOGIC SERIES: AN EXPERT’S VIEW
We have invited select authorities to present background information on challenging clinical problems and practical information on diagnosis and treatment for use by practitioners.
Stress Urinary Incontinence
Ingrid E. Nygaard,
MD,
MS, and Michael Heit,
MD,
MSPH Stress urinary incontinence, the complaint of involuntaryleakage during effort or exertion, occurs at least weekly in one third of adult women. The basic evaluation of women with stress urinary incontinence includes a history, physical examination, cough stress test, voiding diary, postvoid re-sidual urine volume, and urinalysis. Formal urodynamics testing may help guide clinical care, but whether urody-namics improves or predicts the outcome of incontinence treatment is not yet clear. The distinction between urody-namic stress incontinence associated with hypermobility and urodynamic stress incontinence associated with intrin-sic sphincter deficiency should be viewed as a continuum, rather than a dichotomy, of urethral function. Initial treat-ment should include behavioral changes and pelvic floor muscle training. Estrogen is not indicated to treat stress urinary incontinence. Bladder training, vaginal devices, and urethral inserts also may reduce stress incontinence. Bulking agents reduce leakage, but effectiveness generally decreases after 1–2 years. Surgical procedures are more likely to cure stress urinary incontinence than nonsurgical procedures but are associated with more adverse events. Based on available evidence at this time, colposuspension (such as Burch) and pubovaginal sling (including the newer midurethral synthetic slings) are the most effective surgical treatments. (Obstet Gynecol 2004;104:607–20. © 2004 by The American College of Obstetricians and Gynecologists.)
DEFINITION
Stress urinary incontinence as most recently defined by the International Continence Society1is the complaint of
involuntary leakage during effort or exertion or during sneezing or coughing. The termstress urinary incontinence
also describes the sign, that is, the observation of leakage from the urethra, synchronous with coughing or exer-tion. When stress incontinence is confirmed during uro-dynamic testing by identifying leakage from the urethra coincident with increased abdominal pressure (for exam-ple, during a cough or sneeze), but in the absence of a bladder contraction, the diagnosis of urodynamic stress incontinence (previously referred to as “genuine stress incontinence”) is made.
PREVALENCE
The prevalence of stress urinary incontinence represents a spectrum, depending on how incontinence is defined. In questionnaire surveys, a majority of adult women report that they leak drops of urine with physical exer-tion from time to time. Indeed, half of young nulliparous women report occasional leakage with coughing, sneez-ing, or exercise.2 Although few young women report daily leakage, 10% of middle-aged women report daily or severe incontinence and one third report leakage at least weekly. In epidemiologic studies, incontinence peaks in old age. In women with incontinence, the rate of stress incontinence peaks between 45 and 49 years at about 65% and then slowly drifts downward.3It is not clear whether this is related to lower activity levels in older women or whether the increased rate of urge incontinence in older women makes stress incontinence symptoms harder to isolate. Approximately 1 in 4 women with urinary incontinence consult a health care professional for this condition; not surprisingly, as incon-tinence becomes more severe, women are more likely to seek advice.
There is racial and ethnic variation in the prevalence of stress urinary incontinence. For example, in one large population of middle-aged women, both non-Hispanic
From the University of Iowa Carver College of Medicine, Iowa City, Iowa; and Urogynecology Specialists of Kentucky, PLLC, Elizabethtown, Kentucky. Supported in part by grant K24 HD42469-01, from the National Institute of Child Health and Human Development.
The authors thank the following individuals who, in addition to members of our Editorial Board, will serve as referees for this series: Dwight P. Cruikshank,MD,
Ronald S. Gibbs,MD, Gary D. V. Hankins,MD, Philip B. Mead,MD, Kenneth
blacks and Hispanics were 60% less likely to have severe incontinence than non-Hispanic whites, after adjusting for various comorbidities.4Although this may be simply due to differences in reporting, there is some evidence that anatomic differences exist to explain such findings. In one urodynamic study, Caucasian women had lower urethral closure pressures than black women.5 How-ever, leiomyomata, more common in black women, may predispose some to stress urinary incontinence. In a recent analysis of the SWAN (Study of Women’s Health Across the Nation) study6of 3,302 women between ages 42 and 52 years, non-Hispanic black women with uterine leiomyomata had a 1.81-fold higher risk of urinary in-continence than white women, whereas black women without such leiomyomata had a decreased risk of uri-nary incontinence compared with white women (odds ratio关OR兴0.31). Hispanic and Japanese women also had a lower risk than white women (ORs 0.44 and 0.58, respectively).
PATHOPHYSIOLOGY AND RISK FACTORS
The prevailing theory explaining stress urinary inconti-nence is that leakage from the urethra occurs when the intra-abdominal pressure exceeds the urethral pressure. Factors that affect the urethral pressure include bladder neck position, urethral sphincter muscle and nerve integ-rity, urethral smooth muscle and vascular plexuses, and surrounding tissue support. When the bladder fills, it accommodates, and bladder pressure remains very low. As filling increases, activation of a spinal sympathetic reflex inhibits detrusor muscle contraction and activa-tion of␣-adrenergic receptors in the smooth muscle of the urethra increases the outlet resistance. In addition, efferent pudendal nerve activity increases tone in the muscles of the pelvic diaphragm and striated urethral sphincter.
The vagina provides a stable base on which the ure-thra and bladder neck rest. This stable subureure-thral layer of vaginal wall and endopelvic fascia prevents urethral and bladder neck descent, such that the urethra com-presses shut with straining. Figures 1 and 2 depict this “hammock” hypothesis of stress incontinence.7Thus, a sling placed to treat stress incontinence would, following from the hammock hypothesis, be placed under the urethra with no tension, because the goal of the surgery is not to create continence by obstruction, but simply to provide a firm backdrop for the urethra to rest on when intra-abdominal pressure increases. The levator ani and periurethral striated muscles are interesting in that they provide both resting urethral tone and support via slow-twitch fibers, and they contract rapidly via fast-slow-twitch fibers when abdominal pressure increases. Thus, a quick
response time is also needed to maintain continence. The urethra must have enough pliability to coapt and create a tight urethral seal. A rigid urethra (for example, from surgeries or radiation therapy) will not coapt well.
Pregnancy and/or delivery predispose women to stress urinary incontinence, at least during their younger years. Among women who have not borne children, those who are pregnant leak more often than their non-pregnant counterparts; about half of women report symptoms of stress urinary incontinence during preg-nancy, but in most, the symptom resolves after delivery. In a prospective study,832% of 305 primiparas devel-oped stress urinary incontinence during pregnancy and 7% after delivery. By 1 year after delivery, only 3% reported stress urinary incontinence. However, 5 years later, 19% of women with no symptoms after the first delivery had stress urinary incontinence. Of women reporting stress urinary incontinence 3 months postpar-tum (most of whom had resolved by 1 year), 92% had such leakage 5 years later.
Various changes happen after delivery that may pre-dispose women to stress urinary incontinence. Levator ani muscle strength decreases.9About 20% of women develop a visible defect in the levator ani muscles after vaginal delivery.10 The bladder neck descends.11 The Fig. 1.Lateral view of pelvic floor with urethra, vagina, and fascial tissues transected at level of vesical neck, drawn from 3-dimensional reconstruction, indicating compres-sion of urethra by downward force(arrow)against support-ive tissues to illustrate influence of abdominal pressure on urethra (arrow). Adapted from DeLancey JO. Structural support of the urethra as it relates to stress urinary incon-tinence: the hammock hypothesis. Am J Obstet Gynecol 1994;170:1713–20. Copyright © 1994, with permission from Elsevier.
pelvic muscles undergo partial denervation with puden-dal neuropathy.12 In most studies, parity is strongly associated with urinary incontinence in younger wom-en.13However, in studies of women 60 years and older, parity is generally no longer an independent risk factor for incontinence.14 Although the reason for this is not well elucidated, this may be because the changes in muscle, nerve, connective tissue, and hormonal function that occur with aging make other women “catch up” to those that developed incontinence at a younger age because of delivery trauma. Alternately, it may be that medical problems more common in older women ac-count for a larger proportion of incontinence risk as women age.
Stress urinary incontinence is largely impacted by the surrounding intra-abdominal pressure. Thus, as an ex-ample, 2 identical twins could have identical anatomic continence mechanisms and high urethral closure pres-sures, but the twin involved in strenuous physical exer-cise may leak whereas her sedentary sister may not. Similarly, women with chronic coughing and obstructive pulmonary disease are more likely to report leakage. Obesity deserves special mention for its role in causing or exacerbating stress incontinence. Many researchers have reported an association (that holds after adjusting for age and parity) between increased weight and body mass index (BMI) and urinary incontinence. For exam-ple, Hannestad et al15 described a dose-response type relationship between BMI and severe urinary inconti-nence. Compared with women with a BMI less than 25 kg/m2, ORs for the following BMI groups were as fol-lows: BMI 25–29, OR 2.0 (95% confidence interval关CI兴
1.7–2.3); BMI 30–34, OR 3.1 (95% CI 2.6–3.7); BMI 35–39, OR 4.2 (95% CI 3.3–5.3); and BMI 40⫹, OR 5.0 (95% CI 3.4–7.3).
PREVENTION OF STRESS URINARY INCONTINENCE Preventive studies in this area are few. Sparse random-ized trials have addressed the impact of various delivery practices and pelvic muscle strengthening. The Term Breech Trial is the only randomized trial to date to assess urinary incontinence symptoms after planned elective cesarean delivery or planned vaginal birth.16Although the conclusions from the study are limited by the large number of women in the planned vaginal birth group who delivered instead via cesarean, 3 months postpar-tum the women in the planned cesarean delivery group reported less urinary incontinence than those in the planned vaginal birth group (4.5% versus 7.3%; relative risk 0.62, 95% CI 0.41–0.93). In a prospective random-ized trial,17 episiotomy did not protect women from developing stress urinary incontinence after delivery. There is conflicting evidence about the role of other obstetric variables (besides vaginal delivery) in the devel-opment of stress urinary incontinence. Although some studies reported more leakage in women with prolonged second stage, increased head circumference, increased birth weight, and epidural and oxytocin use, others did not.18It is also not clear whether forceps deliveries cause more stress incontinence symptoms afterward. In a case-control study, women who underwent operative vaginal delivery were more likely to have stress incontinence than those who did not.19 However, in a different fol-low-up study 5 years after a randomized trial comparing Fig. 2. Hypotheses concerning effect of abdominal pressure on urethra and pelvic floor depending on stability of the supportive layer.A. Abdominal pressure(arrows) forces urethra against stable supportive layer(black)and compresses urethra closed.B.Unstable supportive layer(shaded)is ineffective in providing resistant backstop against which urethra can be compressed.C.Despite low, extra-abdominal position of urethra and presence of cystourethrocele, supportive layer is firm and provides adequate backstop against which urethra may be compressed closed. Adapted from DeLancey JO. Structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. Am J Obstet Gynecol 1994;170:1713–20. Copyright © 1994, with permission from Elsevier.
forceps and vacuum-assisted deliveries, symptoms of urinary incontinence were common and did not differ between the groups.20
Pelvic floor muscle training (“Kegel exercises”) has long been recommended to prevent the onset of stress urinary incontinence after delivery and is often taught in childbirth preparation classes. A recent Cochrane re-view21 identified 13 randomized trials of pelvic floor muscle training by women done specifically to prevent incontinence. However, most of these trials included women with some incontinence symptoms and so can-not be viewed as purely primary prevention trials. Three of 7 trials in childbearing women reported less urinary incontinence after pelvic muscle training compared with control treatment 3 months postpartum, whereas 4 trials found no difference between the groups. In 1 trial, ben-efit seen at 3 months was no longer present at 12 months (in other words, the women in the nonintervention group decreased their stress urinary incontinence symp-toms to the level of the intervention group). Thus, at this time, there is insufficient evidence to determine whether pelvic floor muscle training can prevent stress inconti-nence.
DIAGNOSTIC APPROACH
The primary goals of an evaluation of women presenting with symptoms of stress urinary incontinence are to 1) provide a clinical diagnosis of stress incontinence versus overactive bladder symptoms, 2) determine factors that may contribute to symptoms or that may require further evaluation, 3) assess whether coexisting pelvic floor dis-orders, such as pelvic organ prolapse or anal inconti-nence, are present, 4) establish baseline stress urinary incontinence severity to aid in assessing treatment ef-fects, and 5) determine the impact of the patient’s symp-toms on her quality of life. It is also important to deter-mine which treatment options are acceptable to each patient and what her own therapeutic goals are and to provide her with appropriate education regarding these goals. Some women desire merely to change from heavy to light pads, whereas for others only absolute conti-nence is acceptable.
Basic Evaluation
The mainstays of evaluation are a careful history and physical examination, augmented by a voiding diary and simple office testing (postvoid residual urine volume and cough stress test). There have been no randomized trials comparing treatment effectiveness or cost in women with stress urinary incontinence symptoms who under-went an initial basic evaluation or a more comprehensive evaluation that included urodynamics testing. There-fore, in our practices, we recommend advanced testing
(urodynamics, radiologic studies, cystoscopy, or neuro-logic studies) only for those women in whom testing results are likely to impact their care (discussed further below). At our tertiary care referral centers, we estimate that fewer than 1 in 3 women presenting with stress urinary incontinence symptoms have urodynamics test-ing done as part of their initial evaluation. We rely heavily on the basic evaluation.
When possible, it is very helpful to send the patient a voiding diary (we use a 3-day diary) in advance of her visit. On the voiding diary, the patient notes the time of each void and incontinent episode. In some diaries, patients also record volume voided, fluid intake, and type of leakage episode. Reviewing the diary with her at the time of her consultation not only helps to determine her primary diagnosis but also involves her in the eval-uation and allows the physician and patient together to draw conclusions about contributing factors, such as infrequent voiding or excessive fluid intake.
During the history, women are queried about the frequency and amount of leakage, precipitating factors, and impact of the leakage on daily life and pad use. Although some women cannot recall when symptoms began, others link such symptoms to temporal events like childbirth, trauma, new medication, surgery or radi-ation therapy, or a medical condition like bronchitis or asthma. Women are also queried about other pelvic floor symptoms, such as a sensation of bulge or pressure in the vagina, urinary urgency or frequency, nocturia, hematu-ria, recurrent urinary tract infections, voiding problems, anal incontinence, and defecating dysfunction. It is par-ticularly important to ask women with stress urinary incontinence symptoms about their actual and desired activity level. Success cannot be attributed to a treat-ment if a woman has stopped doing physical activities that she enjoys (walking, dancing, jogging, etc) to decrease leakage.
The physical examination in women with stress uri-nary incontinence symptoms includes a pelvic examina-tion to rule out pelvic or abdominal masses, pelvic organ prolapse, and vaginal atrophy. It is not clear whether pelvic masses cause stress incontinence symptoms. As previously noted, women with leiomyomata were more likely to report leakage then those without,6 but in a study of 14 women with large uterine leiomyomata and urinary symptoms, frequency, urgency, and nocturia decreased in most after the uterine size was decreased with pharmacologic treatment, but stress incontinence symptoms did not.22
A positive cough stress test, in which leakage is visu-alized at the moment of the cough, is helpful to confirm the diagnosis. On vaginal or rectal examination, the pelvic floor muscles should be palpated with the
exam-ining finger to check muscle quality (for example, sym-metry and bulk) and whether or not, and to what degree, a woman can volitionally contract her muscles. Some clinicians routinely do a test of urethral mobility (the so-called “cotton swab test”). This test has poor predic-tive value for determining either stress urinary inconti-nence diagnosis or predicting treatment success,23but is used by some clinicians to determine how much the anterior vaginal wall moves with Valsalva. A woman with a fixed nonmobile urethra is a poor candidate for a surgery (such as a Burch colposuspension), the aim of which is to elevate the urethra.
To rule out urinary retention and overflow inconti-nence, we assess the postvoid residual volume by either direct catheterization or by ultrasonography. Ultra-sonography is sufficiently accurate for clinical purposes, although the standard error of the residual volume when measured by ultrasonography is 15–20%, using the cath-eterized volume as the gold standard.24It is important to do this test within 10 minutes of a void to prevent the occurrence of an artificially high result because of diure-sis. Most experts agree that a postvoid residual volume less than 50 mL is normal and more than 200 mL is abnormal, but there is much debate about values in between. Many women are unable to void well during an anxiety-ridden first visit, and we recommend recheck-ing the postvoid residual volume at a future visit before embarking on further diagnostic tests. It should be noted that the importance of assessing bladder emptying in neurologically normal women without pelvic organ pro-lapse or symptoms of voiding dysfunction has not been demonstrated. Finally, a urinalysis is done to rule out urinary tract infection as a transient cause of stress urinary incontinence.
Further Evaluation
We recommend further evaluation after basic testing if we are still left with an uncertain diagnosis (for example, as a result of major discrepancies between the history, the voiding diary, and symptom scales), if we are consid-ering surgery, of if the patient has hematuria in the absence of an infection, an elevated postvoid residual volume, a neurologic condition that may complicate treatment (such as multiple sclerosis), marked pelvic organ prolapse, or numerous prior surgical attempts at correction.
We use pad tests widely in patient-oriented research, as an objective way of assessing treatment effectiveness, but rarely in clinical practice. Pad tests, usually per-formed in women with a full bladder, quantify the vol-ume of urine lost by weighing a perineal pad before and after specified activities.
Urodynamics testing refers to a combination of tests that involve simultaneous measurement of various phys-iologic parameters of urethral and bladder function dur-ing bladder filldur-ing and emptydur-ing. Although urodynamics testing is often used in clinical trials as an outcome measure and in clinical practice as an assessment aid, there are minimal data available about the validity and reproducibility of these tests. Recently, a panel of inter-national experts, who convened to evaluate the ability of urodynamics to improve or predict the outcome of in-continence treatment, concluded that, for each type of test, the evidence was based either on case series (level 4 evidence) or expert opinion (level 5 evidence).25Having noted that, we should also note that most aspects of the diagnostic evaluation (including the history and physical examination) for women with stress urinary inconti-nence have also not been rigorously tested, and in the absence of such evidence, we find urodynamics testing a valuable adjunct to the rest of the evaluation.
To assess voiding function, urodynamic testing usu-ally begins with uroflowmetry, in which the volume of urine passed is plotted over time. Flow time, peak flow rate, and time to peak flow increase with the volume voided.
Next, a cystometrogram (also termed cystometry) is done to assess bladder and urethral function during bladder filling. Cystometry is termed simple when only bladder pressure is recorded and complex (or multichan-nel) when both bladder and abdominal pressure (mea-sured via a rectal or vaginal catheter) are recorded. It is easier to differentiate detrusor activity from abdominal activity with complex cystometry. An example of detru-sor overactivity seen during complex cystometry is shown in Figure 3. Surface or needle electromyography is often done during filling and voiding to assess muscle activity of the urethral sphincter or pelvic floor. Electro-myography as generally performed has not been proven useful in neurologically intact women with symptoms of only stress urinary incontinence and is not required in this patient population. Multiple technical factors influ-ence cystometry results, including the choice of distend-ing medium, filldistend-ing rate, patient position, and the type of catheter used to measure changes in bladder pressure.
Several tests of urethral function, including urethral pressure profilometry, Valsalva leak-point pressures, and the fluoroscopic and cystoscopic appearance of the bladder neck, have been used to guide therapy in women with stress urinary incontinence. Women with poor urethral function, evidenced by low Valsalva leak-point pressures, low maximal urethral closure pressures, or a visualized open bladder neck, are thought to be at higher risk of failing standard retropubic urethropexies. Cutoff values for these tests are poorly defined and remain
controversial. Although women with stress urinary in-continence have, on average, significantly lower maxi-mal urethral closure pressures than those without, there is wide overlap in the values between women with and without incontinence, and no lower limit of urethral closure pressure has been established that predisposes women to stress urinary incontinence.
Pressure transmission ratios are obtained as a pressure catheter is slowly withdrawn from the urethra while the patient is coughing repeatedly. The change in urethral pressure is divided by the change in bladder pressure. In assembling an extensive literature review (126 refer-ences), Weber26 concluded that such urethral pressure profilometry is not a useful diagnostic test for stress incontinence in women and that its use in clinical man-agement is unsupported by current evidence.
Leak-point pressure is a urodynamic measure of the minimum intra-abdominal or intravesical pressure re-quired to cause incontinence during abdominal strain or cough. There is no consensus about whether it should be measured from the resting supine baseline (generally near zero) or from the standing resting baseline (which increases depending on body mass). Other factors that may affect the results include the catheter’s type, caliber, and placement (vaginal, rectal, or intravesical), the blad-der volume at which the measurement is obtained, the mechanism by which intra-abdominal pressure is in-creased (coughing versus straining), and patient posi-tion.27Currently, many clinicians use a cutoff point of 60
cm of water pressure to separate women who have intrinsic sphincter deficiency from those who do not. This is problematic for 2 reasons: 1) the marked variabil-ity of results that depend on all the factors described above, and 2) the lack of prospective studies that dem-onstrate the predictive value of leak-point pressure val-ues on surgical outcomes. Results from this and other urodynamics tests must be evaluated as one piece of the patient’s puzzle, along with the history, physical exami-nation, voiding diary, and other tests. Current Medicare guidelines require that when bulking agents, such as collagen, are considered in the treatment of stress incon-tinence, the intra-abdominal leak-point pressure, when the bladder has been filled with at least 150 mL of fluid, must be less than 100 cm H2O. Figure 4 demonstrates urodynamic stress incontinence in a woman whose ab-dominal leak-point pressures with Valsalva at a 200 mL bladder volume are 88 and 110 cm H2O.
Urodynamic testing usually concludes with an instru-mented voiding study (also known as a pressure flow study), in which the vesical, abdominal, and urethral pressures are measured simultaneously during bladder emptying. Various studies have identified Valsalva void-ing, low preoperative flow rate, and high preoperative detrusor pressures during voiding as risk factors for postoperative voiding dysfunction; however, published studies often have contradictory findings.
As noted, there are no large-scale trials that assess the predictive value of urethral function tests. However, a Fig. 3.Multichannel cystometro-gram showing detrusor overactiv-ity. Note that at the peak of the detrusor contractions, the pa-tient leaked urine, and the detru-sor pressure then gradually de-creased. No increase in abdominal pressure over base-line is seen, in contrast to the stable cystometrogram in Figure 4 depicting urodynamic stress incontinence.
Nygaard. Stress Urinary Incontinence. Obstet Gynecol 2004.
National Institutes of Health–sponsored multicenter ran-domized trial comparing the effectiveness of Burch ure-thropexy and rectus fascia sling cystoureure-thropexy as primary surgical treatments for women with stress in-continence is underway and will provide important data about the value of preoperative urodynamics.
NONSURGICAL TREATMENT OF STRESS URINARY INCONTINENCE
Lifestyle Interventions
Lifestyle interventions can decrease stress urinary incon-tinence in many women.28There is evidence that weight loss in both morbidly and moderately obese women
decreases leakage; ongoing studies are evaluating how to optimize this intervention. Postural changes (such as crossing legs) often prevent stress urinary incontinence. There is some evidence that decreasing caffeine im-proves continence; however, fluid intake in general seems to play a minor role in the pathogenesis of tinence. Although smokers are at greater risk for incon-tinence, no data have been reported on whether smoking cessation resolves incontinence.
Pelvic Floor Muscle Training
Medical evidence from well-designed randomized clini-cal trials show that supervised pelvic floor muscle train-ing (“Kegel exercises”) is an effective treatment for stress urinary incontinence. In a systematic literature review, the Cochrane Incontinence Group concluded that pelvic floor muscle training was consistently better than no treatment or placebo treatment for stress incontinence and should be offered as first-line conservative manage-ment to women. Intensive training sessions that include personal contact with a health care professional to teach and supervise pelvic floor muscle training may be more beneficial than standard care. There is no added benefit of biofeedback over pelvic floor muscle training alone in women with stress urinary incontinence.29
Several factors are important in maximizing the chance that pelvic muscle training will alleviate stress urinary incontinence. The woman must do the exercises correctly, regularly, and for an adequate duration. Based on exercise training of skeletal muscles elsewhere in the body, many physical therapists recommend training ses-sions 3–4 times per week, with 3 repetitions of 8–10 sustained contractions each time.
Medications
Traditionally, both␣-agonist medications and estrogens have been used to treat stress incontinence. In early uncontrolled case series, women using various estrogen preparations had less incontinence afterward. However, more recently, in several large randomized trials, women assigned to receive estrogen and progesterone not only did not have less leakage, but in fact were more likely to experience the onset of incontinence or a worsening of baseline symptoms.30Given that randomized controlled trials do not support using estrogen to treat stress incon-tinence and the recent limitations on estrogen use in general, we do not recommend initiating estrogen ther-apy specifically to treat stress urinary incontinence.
A second pharmacologic therapeutic void was left by the Food and Drug Administration’s (FDA’s) decision to withdraw phenylpropanolamine from the market be-cause of hemorrhagic strokes suffered by women taking Fig. 4. Multichannel cystometrogram showing urodynamic
stress incontinence. Each spike represents a Valsalva effort. The abdominal pressure generated by the Valsalva is trans-mitted to the bladder as seen by the increased vesical pressure. However, the detrusor pressure remains low, and leakage(black arrows) occurs in the absence of a detrusor contraction. VH2O, volume of water consumed; Pabd, abdom-inal pressure; Pves, vesical pressure; Pdet, detrusor pressure.
this medication. Other ␣-agonist medications (such as norephedrine) have shown only modest effect in small trials.31
Serotonin and norepinephrine reuptake inhibitors are being investigated for their role in treating stress urinary incontinence, but at this time are not available on the market for this indication. Norton et al32 conducted a multicenter, double-blind, placebo-controlled random-ized trial to study the safety and effectiveness of dulox-etine chloride for the treatment of stress urinary inconti-nence. Participants were randomized to 1 of 3 doses of duloxetine chloride or to placebo and completed weekly bladder diaries and validated questionnaires over a 12-week period. Although statistically significant, the differ-ence in reduction of incontinent episodes among the groups was only modest, largely because of the many women in the placebo group who improved. There was an 18–23% net difference in the percentage reduction in incontinence episode frequency comparing duloxetine chloride 40 mg/d (59% reduction) and 80 mg/d (64% reduction) with placebo (40% reduction). Nausea was the most common adverse event reported.
Other investigators have also found a high response rate in women assigned to placebo. This is partly due to the intensity of research protocols (which requires pay-ing more attention to one’s bladder than usual) but also speaks to the potential therapeutic role of simply com-pleting the voiding diary.
Devices
Vaginal devices (pessaries) and urethral inserts (Fem-Soft; Rochester Medical, Inc, Stewartville, MN) are mar-keted for treating stress urinary incontinence. There are no long-term randomized trials comparing devices and other treatments, but devices appear to be an acceptable treatment for some women. In our tertiary care popula-tion, we found that approximately two thirds of women with stress urinary incontinence offered a trial of vaginal devices chose to undergo pessary fitting (Donnelly MJ, Morgan SP, Olsen AL, Nygaard IE. Vaginal pessaries for the management of stress and mixed urinary incon-tinence. Internat Urogynecol J, in press). Most (89%) achieved a successful fit. Of those that took a pessary home to manage their stress urinary incontinence, ap-proximately half used it for more than 6 months. Women who stopped using the pessary generally did so within the first month. Some women are pleased to be able to avoid surgery or to use a “crutch” while waiting for the effect of pelvic muscle training; others prefer a treatment option (like surgery) that doesn’t require daily intervention.
SURGICAL TREATMENT OF STRESS URINARY INCONTINENCE
In a 1996 systematic review, Black and Downs33 high-light the deficiencies in the literature in this area. Al-though 943 studies were reviewed, only 76 (11 random-ized trials, 20 prospective cohort studies, and 45 retrospective cohort studies) met minimum criteria that the investigators set for reporting results of surgical trials or series. The median follow-up interval was short: 1 year for prospective and 2 years for retrospective studies. None of the studies at that time described quality of life, and few studies obtained the patient’s perception on outcome in a standardized fashion. Of the 31 prospective studies, 28 were single center and 29 were limited to teaching hospitals, making the generalizability of the studies questionable. Although current studies generally do include instruments for measuring the impact of the surgery on the patient’s quality of life, most published studies continue to represent the short-term experience of surgeons from one site.
Choice of Surgical Procedure
For the last couple of decades, gynecologic surgeons have based surgical recommendations on the distinction between whether the patient had stress urinary inconti-nence resulting from “intrinsic sphincter deficiency” or from “hypermobility,” recommending a pubovaginal sling for the former and a colposuspension (also known as retropubic urethropexy) for the latter. This was based initially on a small study in which women under age 50 years with urethral closure pressure less than 20 cm H2O had a higher failure rate after a Burch colposuspension than did women with a closure pressure more than 20 cm H2O.34 (No difference in outcome was seen in women over 50 years.) More recently, this dichotomy has been called into question, in that all women with stress incontinence have some degree of sphincter weak-ness, whether or not they have hypermobility. At this time, it is not known whether women with more severe sphincter weakness have improved success with a spe-cific surgery or whether they are more likely to fail any surgery. The Urinary Incontinence Treatment Net-work, a National Institutes of Health–sponsored net-work consisting of 9 centers and a coordinating center, is currently enrolling 650 women with stress and stress-predominant mixed urinary incontinence in a random-ized trial comparing Burch colposuspension and autolo-gous rectus fascia sling. Women are included in the trial regardless of urodynamic findings (such as low leak-point pressures or low urethral closure pressures). In addition to comparing treatment success at 24 months and beyond, aims include comparing voiding function,
quality of life, and sexual function and satisfaction, as well as determining the urodynamic parameters predic-tive of treatment success or failure.
While awaiting such level 1 evidence, surgeons can make use of clinical guidelines available. In 1997, the American Urological Association convened a clinical guidelines panel to analyze published outcomes data on surgical procedures to treat female stress urinary incon-tinence and to produce practice recommendations to guide surgical decision making.35The clinical guidelines panel concluded that colposuspensions (eg, Burch, Mar-shall-Marchetti-Krantz) and slings were more effective than transvaginal needle suspensions or anterior repairs for long-term success (48-month cure/dry rates). The median probability estimates for cure/dry rates at 48 months and longer were 84% (95% CI 79–88%) for colposuspensions and 83% (95% CI 75–88%) for sling procedures, compared with 67% (95% CI 53–79%) for transvaginal needle suspensions and 61% (95% CI 47– 72%) for anterior repairs. Based on the randomized trials that led to this conclusion, U.S. surgeons have re-sponded by decreasing use of needle suspension proce-dures and anterior repairs in women with stress urinary incontinence. However, the increased effectiveness of the sling and colposuspensions comes at a cost: urinary retention lasting longer than 4 weeks was 5% (95% CI 3–7%) for colposuspensions and 8% (95% CI 6–11%) for sling procedures. Slings were associated with higher complication rates when synthetic allografts were used. The traditional suburethral sling requires an abdominal incision to harvest a rectus abdominus fascial autograft or leg incisions to harvest a tensor fascia lata autograft. Many gynecologic surgeons received no training to per-form this operation or manage its common adverse event, urinary retention, which limits its acceptance as the minimally invasive procedure of choice for treating stress urinary incontinence.
In 1991, Vancaille introduced the laparoscopic colpo-suspension to meet the growing demand for a minimally invasive surgical approach to treatment of stress urinary incontinence. In a summary of randomized comparisons between laparoscopic and open colposuspensions, the Cochrane Incontinence Group concluded that laparo-scopic colposuspension may have short-term benefits, such as quicker recovery, but may have more complica-tions and is more costly because it takes longer to per-form than other surgical procedures for stress urinary incontinence. The long-term success of laparoscopic col-posuspension is unclear, but medical evidence from a single trial suggests it is poorer than open colposuspen-sion, although this may reflect a learning effect and is unreliable in isolation.36
The external validity (generalizability) of surgical tri-als is limited because clinical outcomes are dependent on the skills of the operating physician conducting the re-search. Given the large number of women with stress urinary incontinence, the optimal surgical procedure (and set-up for the procedure) should be simple enough to be done by surgeons with various levels of training. The tension-free vaginal tape (TVT), a polypropylene midurethral sling, quickly gained worldwide use because of its simplicity, lower learning curve than for laparo-scopic procedures, and effective marketing.
Evolution of New Surgeries for Stress Urinary Incontinence
The evolution of the TVT follows the path of many surgical interventions. Initially small case series were published reporting the experiences of surgeons who invented the procedure, followed by small case series from surgeons trained by the initial inventors. Over the next several years, many case series were published by surgeons from individual sites, generally tertiary care centers. Finally, randomized clinical trials were per-formed and reported. However, recruitment into ran-domized trials became increasingly difficult as the “new” treatment (TVT in this case) became the standard of choice in the community before the actual trial was completed, and thus the largest trial comparing TVT and Burch colposuspension was stopped before enroll-ment was completed.
The larger, multicenter trials provide the most realistic look at outcomes of a surgical procedure performed by many surgeons with varying experience on a wide array of patients. Ward and Hilton recently reported on the 2-year follow-up of 344 women with urodynamic stress incontinence enrolled from 14 centers in a multicenter randomized clinical trial comparing TVT and open Burch colposuspension. The objective cure rates (de-fined as a negative 1-hour pad test) ranged from 63% to 85% for the TVT procedure and 51% to 87% for open colposuspension, depending on how missing data were handled, leading the authors to conclude that “TVT may be better, worse, or the same as open colposuspen-sion in the cure of stress incontinence.”37 Subjectively, only 43% of women in the TVT group and 37% of women in the open colposuspension group reported cure of their stress leakage. Women undergoing the TVT were more likely to have a cystocele after surgery, whereas those undergoing the Burch colposuspension were more likely to have apical prolapse. Two years after the index procedure, 7 women (4.8%) in the Burch colposuspension group underwent surgery for pelvic organ prolapse, compared with no women in the TVT group. There was no difference in the number of women
who underwent repeat surgery for stress incontinence (1.8% in the TVT group and 3.4% in the Burch group). Women who underwent TVT were less likely to have voiding disorders requiring intermittent self-catheteriza-tion than those who underwent colposuspension (0 ver-sus 2.7%).37
Surgeons may be surprised by the success rate re-ported in the above trial because it is lower for both groups than most published for incontinence surgery. However, most studies report success rates based on a poorly defined population with nonvalidated outcome measures and often include improvement along with cure. The results from this randomized trial are similar to those reported by Black and colleagues,38in the largest cohort study to date. In that study, 3 months after surgery, 28% of the 442 women reported complete con-tinence and an additional 18% reported inconcon-tinence once a month or less. Although 77% wore pads before the surgery, 29% used them afterward. One year post-operatively, 65–70% rated the outcome as, or better than, expected, whereas 68% would recommend the surgery to a friend.
Thus, most women are satisfied, even if they are not completely dry. It is important to counsel the woman pre-operatively about realistic expectations following surgery.
Adverse Events
In choosing surgical management, surgeons must weigh the chance of cure against the chance of severe compli-cations. In the randomized trial comparing TVT and Burch described above, women undergoing TVT were more likely to experience a bladder perforation than those undergoing the Burch procedure (9% versus 2%, respectively) but less likely to have a fever (1% versus 5%) or prolonged catheterization more than 29 days (3% versus 13%).39 Less common complications require a large sample size to detect differences. In the randomized trial, 2% of women in the TVT group had a retropubic hematoma and 1% a vascular injury, compared with no women in the Burch group. Given the small numbers, it is not clear whether the rate of vascular injuries differs. In the reporting system available on the FDA web site in which worldwide safety data from over 500,000 proce-dures were summarized, as of June 29, 2004, there were 7 deaths reported after TVT, 6 associated with bowel perforation, and 1 from vascular injury (http://www. accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/ search.cfm; accessed July 20, 2004). No such data are available for Burch urethropexy.
In a nationwide analysis of 367 complications associ-ated 1,455 TVT procedures performed in Finland by 1999, there was a 1.9% rate (95% CI 1.2–2.7) of blood
loss over 200 mL, a 1.9% rate (95% CI 1.2–2.7) of retropubic hematoma, a 0.5% rate (95% CI 0.2–1.0) of hematoma outside the retropubic area, a 0.1% rate (95% CI 0.0–0.4) of injury to the epigastric vessel, a 0.1% rate (95% CI 0.0–0.4) of injury to the obturator nerve, and a 3.8% rate (95% CI 2.9–5.0) of bladder perforation.40
Graft erosion is unique to surgeries in which a graft is placed and the rate depends largely on the type of graft used. Rates from one type of material cannot be extrap-olated to another. Tension-free vaginal tape is associated with a low rate of graft erosion, compared with a much higher rate for certain synthetics used for pubovaginal slings in the past. In the randomized trial comparing Burch and TVT described above,37of the 170 women who underwent a TVT procedure, 1 woman had a graft erosion in the first 6 months, and 2 others had graft erosion or extrusion between 6 and 24 months postop-eratively.
Based on the literature, the most common adverse events (generally 5–10% rate for each) after all surgeries for stress urinary incontinence include urinary tract in-fection, failure to cure, new onset detrusor overactivity, voiding dysfunction, genital prolapse, and bladder per-foration. Less common events (generally 2–5% for each) include excessive blood loss, wound infection, pain, nerve injury, or incisional hernia. Events such as sinus tract and fistulae are rare. Erosion rates depend on the material implanted, and as noted above, are rare for the newer midurethral slings. In addition, medical events, such as thromboembolic, cardiac, or pulmonary events are rare.
Marketing of New Surgical Therapies: A Cautionary Tale
Competing with the success of the TVT, many compa-nies are marketing surgical devices to treat stress urinary incontinence, and the reader is likely to encounter many such products. Therefore, we will briefly summarize the process by which such surgical devices are marketed in the United States. It is important for readers to under-stand that the FDA does not generally require clinical trials before surgical devices for incontinence are mar-keted.
Within the FDA, the Center for Devices and Radio-logical Health has 2 main processes that regulate medical devices: the Premarket Approval application and the Premarket Notification application. In the FDA’s most stringent regulatory control, device manufacturers sub-mit an investigational device exemption application so that the device can be used in human clinical trials to collect safety and effectiveness data to support the Pre-market Approval application. This then provides public assurances that a device is safe and effective for its
intended use, based on both nonclinical laboratory stud-ies and human clinical trials.
However, the vast majority of legally marketed med-ical devices in the United States circumvent the stringent regulatory control provided by the Premarket Approval by gaining approval instead through the Premarket No-tification 510(k). A Premarket NoNo-tification 510(k) is a submission to the FDA demonstrating that a new device is substantially equivalent to a legally marketed or “pred-icate” device introduced in the United States either be-fore 1976 or to one approved by the FDA through the 510(k) process itself. Substantial equivalence means the new device has the same intended use as the “predicate” deviceandhas the same technological characteristicsor
different technological characteristics, but is as safe and effective as the “predicate” device.
If the new medical device is approved through the Premarket Notification Process 510(k) it may be legally marketed and distributed in the United States without conducting human clinical trials. Medical device devel-opment is a $78 billion dollar a year industry, and problems arise when the number of medical devices introduced (9,000 devices in 1995 to 13,000 devices in 2000) outpaces the FDA’s ability to inspect the medical device industry (3,602 inspections in 1995 to 1,841 in-spections 2000) (Roane K. Replacement parts: how the FDA allows faulty, and sometimes dangerous, medical devices onto the market. U.S. News and World Report, July 29, 2002).
The beginning of the 21st century may be remem-bered as the period when medical device manufacturers redefined the surgical treatment of stress urinary incon-tinence in response to an economic demand for a quick, cost-effective, reproducible, and safe and effective mini-mally invasive approach. The medical device industry gained a foothold in the stress urinary incontinence surgical market with orthopedic bone anchors implanted into the pubic bone to suspend the urethra with sutures or slings. Despite a lack of medical evidence to support either the bone anchor or the allograft use, bone anchor systems became the quick and minimally invasive method to suspend allograft slings.41However, although bone anchors have not been shown to be superior to standard fixation techniques, their use has led to in-creased complications in several series.
In the absence of clinical trials or registries, even common complications related to new surgical devices are not recognized for a period of time. The ProteGen sling is one example of a surgical device marketed as an exciting new treatment for stress urinary incontinence that later was withdrawn from the market because of an unacceptably high complication rate. The ProteGen sling was a knitted polyester fabric that was impregnated
with bovine collagen patterned after a cardiovascular patch indicated for cardiac and vascular patch grafting. The company received FDA approval of their Premar-ket Notification in 1996 because the sling was found to be substantially equivalent to several synthetic meshes mar-keted. In January 1998, the ProteGen slings were re-called because of complications, despite admonitions that the company may “lose out to the competition from other ‘hot’ sling products that were setting关the兴world on fire” (Roane K. U.S. News and World Report, July 29, 2002). One hundred and twenty-five adverse events were attributed to ProteGen sling implantation before the first human clinical trial ever began. By April 1999, human clinical trials showed a 30% erosion rate of the sling after 5 months (Roane K. U.S. News and World Report, July 29, 2002).
Within the last couple of years, numerous other sur-gical devices for stress incontinence have been intro-duced to the U.S. market. One such example is a trans-vaginal tape modification designed to reduce the incidence of complications associated with suprapubic needle passage. First described in 1998, the transobtura-tor tape (also known as a transobturatransobtura-tor suburethral tape or subfascial hammock) procedure theoretically avoids the risk of bladder, bowel, or vascular injury, because the procedure involves passing the polypropylene midure-thral sling through the obturator membrane along its ischiorectal fossa path, bypassing the pelvic cavity alto-gether. Like the TVT, its predicate device, the clinical effectiveness of the transobturator procedure was estab-lished from case series conducted in Europe before it received Premarket Notification 510(k) approval from the FDA to be legally marketed and distributed in the United States. Such slings are now being marketed by several companies.
Currently, data are limited. Dargent and colleagues42 reported no bladder perforations in their first 71 transob-turator tape procedures and, in 68 patients examined 6–12 weeks postoperatively, reported that 64 were cured and 2 improved. Delorme et al43reported a 90.6% cure rate in 32 patients who were followed for a minimum of 1 year. Five patients had voiding disorders suggestive of bladder outflow obstruction, but only 1 required self-catheterization for 1 month. No problems with urethral erosion, residual pain, or functional impairment were reported. Costa and colleagues (Costa P, Ballanger P, Grise P, et al, Trans-obturator tape for female stress urinary incontinence: preliminary results of a prospec-tive multi-center study. Presented at International Con-tinence Society, Florence, Italy, 2003.) summarized re-sults of 165 such procedures performed at 7 sites. Surgeons reported 1 bladder perforation, 2 urethral per-forations, 1 vaginal perforation, 6 vaginal erosions, and 1
urethral erosion. Six months postoperatively, 60 of 73 women were cured, 5 were improved, and 8 were un-changed. Based on the evolution of surgical literature described above, it is reasonable to anticipate lower success rates and higher complication rates when this procedure is performed in a wider array of patients by a wider array of surgeons.
The reader interested in identifying adverse events reported for new products can access the Manufacturer and User Facility Device Experience Database (MAUDE) at www.fda.gov/cdrh/maude.html. The total number of pro-cedures using various devices is not known, and therefore the information provided simply gives an idea of the types of adverse events reported.
Problems with allograft slings are not confined to xenograft material. Published reports of cadaveric fascia lata sling failures led investigators to question the pro-cessing methodology used. It is possible that slings using freeze-dried cadaveric fascia lata may be less successful than those using chemical dehydrated material because the freeze-drying process alters collagen structure, reduc-ing the longevity of the material.44 However, various fascial preparations have not been compared in head-to-head trials. The longevity of the newer human and animal dermal products now being used for allograft slings remains to be seen. As with the surgical devices mentioned, these products receive FDA approval for marketing and distribution in the United States through the Premarket Notification 510(k) process, often before human clinical trials demonstrate their effectiveness for their intended uses.
Therefore, the surgeon must carefully weigh the ad-vantage of implanting a new, untested device or graft in a woman over that of using procedures that have dem-onstrated effectiveness in level 1 randomized trials and that have a known complication rate that can be dis-cussed with the patient preoperatively.
Bulking Agents
Injectable (so-called “bulking”) agents are less invasive than surgery and, although less likely to cure than sur-gery, relieve symptoms in many women. In the United States, glutaraldehyde cross-linked bovine collagen and carbon beads are approved for treatment of stress uri-nary incontinence and can be injected either peri- or transurethrally. In a 15-article review, the short-term cure or improvement rate was 75%.45However, success declines with time, and patients often need additional procedures every 1–2 years. It is not clear whether this decline reflects degradation of the injected materials or continued deterioration of sphincter function. Repeated procedures become more technically challenging. We find bulking agents to be an acceptable treatment for
women, particularly older ones, with stress urinary incon-tinence who want to avoid the morbidity of surgery be-cause these procedures can be done under local anesthesia in the physician’s office. However, this advantage is offset by the short-term nature of the therapeutic response. CONCLUSION
Stress urinary incontinence is common in women and may impact their activity levels and quality of life. After a basic evaluation, most women can begin treatment. Conservative management should precede surgery. Many gaps remain in our knowledge of this disorder. In the future, therapy may be targeted at an actual diagnosis (such as myopathy, nerve damage, or support defects) rather than the current broad therapeutic approach de-scribed. Further research is also needed to study preven-tion of leakage, factors that impact treatment success, and longevity of various therapies. New therapies should be studied in randomized clinical trials before general clinical use.
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43. Delorme E, Droupy S, Tayrac, Delmas V. Transobturator tape (Uratape): a new minimally-invasive procedure to treat female urinary incontinence. Eur Urol 2004;45:203–7.
44. Soergel T, Shott S, Heit M. Poor surgical outcomes after fascia lata allograft slings. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:247–53.
45. Smith ARB, Daneshgari F, Dmochowski R, Ghoniem G, Jarvis G, Nitti V, et al. Surgical treatment of incontinence in women. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. Plymouth, (UK): Plymbridge Dis-tributors Ltd; 2002. p. 823–63.
Address reprint requests to: Ingrid E. Nygaard, MD, Univer-sity of Iowa, Department of Obstetrics and Gynecology, 200 Hawkins Drive, 2 BT, Iowa City, IA 52242; e-mail: [email protected].
Received April 12, 2004. Received in revised form May 12, 2004. Accepted June 19, 2004.
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