Clinical Review

Ob/Gyns are being called on more than ever to initiate treatment for urinary incontinence, and new treatment options are enabling us to play a more active role than ever before in treating one of the most common and distressing of chronic diseases in women. Urinary incontinence affects women after menopause, primarily. Prevalence increases (though not in a linear fashion)—from 20% to 30% in reproductive-aged women, to 30% to 40% in postmenopausal women. Approximately 16 million Americans are affected, and the number of women affected is more than double that of men.

20% cancel surgery after duloxetine therapy

Cardozo L, Drutz HP, Baygani SK, Bump RC for the Duloxetine Severe UI Study Group. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol. 2004;104:511–519.

Efforts to treat stress incontinence with drugs have not succeeded well in the past, but the development of duloxetine may change that.

Duloxetine (Cymbalta; Eli Lilly, Indianapolis, Ind) is a balanced serotonin-norepinephrine reuptake inhibitor that may act by stimulating pudendal nerve output and improving urethral closure. The FDA approved duloxetine for treatment of major depression for adults in August 2004, and for management of diabetic peripheral neuropathic pain in September 2004. However, duloxetine is not yet FDA-approved for the treatment of stress incontinence.

A randomized, placebo-controlled, double-blinded study involving 14 centers in Australia, Canada, the Netherlands, and the United Kingdom enrolled women aged 18 to 75 years, all of whom had severe stress incontinence, and had already scheduled surgery. All patients had at least 14 episodes of stress incontinence per week. The dose of duloxetine started at 40 mg twice daily for 4 weeks, then increased to 60 mg twice daily for another 4 weeks.

The study randomized 109 women and included 98 in the intention-to-treat analyses, 46 of whom took duloxetine, and 52, placebo.

Response was defined as at least a 50% reduction in incontinence episode frequency. Of the women taking duloxetine, 63% were responders, compared with 13.5% of the placebo group.

Using the Patient Global Impression of Improvement (PGI-I), one third of women taking duloxetine described themselves as “very much better” or “much better,” compared with 8% of women taking placebo.

Ten of 49 women (20%) indicated they were not interested in surgery while taking duloxetine, compared with 0 of 45 women taking placebo. Drug discontinuation occurred more frequently in the duloxetine group: 18 of 55 (33%), compared with 3 of 54 (6%) in the placebo group.

Cure rate low, but so is risk

Even if the “cure” rate is relatively low, duloxetine offers a low-risk form of treatment for women who might otherwise be considered surgical candidates.

In addition, pharmacological treatment may be indicated for women whose incontinence is not severe enough to warrant surgery.

While there are no studies that report long-term results of duloxetine use, it seems appropriate that duloxetine be included in the discussion of nonsurgical options, along with pelvic muscle exercises and behavioral treatment, before surgery is considered.

Botulinum A toxin for refractory detrusor overactivity

Kuo H-C. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology. 2004;63:868–872.

Cystoscopic detrusor injection of botulinum toxin A appears to be a promising alternative to more invasive treatments for refractory detrusor overactivity.

Urinary incontinence due to detrusor overactivity can be especially difficult to treat when first-line treatment with anticholinergic drugs is unsuccessful. Although newer slow-release or long-acting formulations are tolerated better than the original formulations, many patients still have bothersome symptoms or intolerable side effects.

Previously, such women might have been treated with electrical stimulation.

This less invasive treatment might be an effective option, although further study is needed to identify patients most likely to benefit.

Effectiveness has been observed in patients with detrusor overactivity due to spinal cord injury and, in the study cited above, in patients with neurogenic, idiopathic, and postobstructive detrusor over-activity. Botulinum toxin A is not FDA-approved for incontinence indications.

In the Kuo study, 30 patients (12 women and 18 men) with detrusor overactivity refractory to anticholinergic agents were treated with cystoscopic detrusor injection of 200 units botulinum toxin A at 40 sites in the posterior and lateral bladder (sparing the anterior bladder). Eight patients (27%) regained urinary continence; 14 (46%) had improvement in frequency, urgency, and incontinence; and treatment failed in 8 (27%).

Excellent results were most likely in patients with previous bladder outlet obstruction, and least likely in patients with neurogenic detrusor overactivity. Men were more often successfully treated (83%) than women (58%). Maximal effect was noted at 10 to 14 days after treatment, and the effect lasted 3 to 9 months (average, 5.3 months).

 

Side effects were not serious: urinary tract infection in 3 patients and transient urinary retention in 4. Six patients with detrusor overactivity and impaired contractility were treated with intermittent self-catheterization for 1 month, after treatment resulted in increased postvoid residual urine volumes.

Patients with impaired bladder emptying before treatment may be at higher risk of posttreatment retention, although even when retention occurs, it seems to be transient and responds well to time-limited management with intermittent self-catheterization.

Stress incontinence surgery: What’s in, what’s out

Is TVT out?

Costa P, Grise P, Droupy S, et al. Surgical treatment of female stress urinary incontinence with a transobturator-tape (TOT) Uratape: Short-term results of a prospective multicentric study. Eur Urol. 2004;46:102–107.

Faster than you can say “tension-free vaginal tape,” an even newer procedure is coming to the fore: TOT, the transobturator tape.

The TVT operation revolutionized stress incontinence surgery, with placement at the midurethra instead of traditional placement at the bladder neck. Although case series and the first randomized trials showed good results with TVT, concern about retropubic complications fueled development of alternate placement through the obturator foramen. This alternative is intended to avoid complications attributable to penetration of the peritoneal cavity or retropubic space with TVT.

In a study conducted by Costa et al, 183 women with stress or mixed incontinence associated with urethral hypermobility underwent the TOT procedure, which involved midurethral placement of a polypropylene tape with a silicone-coated central part, using a transobturator percutaneous approach. With follow-up at more than 6 months on 130 of the 183 study subjects, 83% were reported as “cured” (absence of subjective complaint of urine leakage and absence of leakage on cough stress testing) and 5.4% as “improved” (decrease of stress incontinence, not further specified).

Obviously, we need more information and, ideally, comparative information to determine how this new technique fits in with other surgical options for stress incontinence. So far, 2 trials comparing TVT and TOT were reported in abstract at the 2004 meeting of the International Continence Society.

Of 17 failures, tape removal was necessary in 5, due to vaginal extrusion in 3 and urethral erosion in 2. Because of this high rate of extrusion, the silicone portion of the tape has been removed.

TOT (but not silicone) is in

Comiter CV, Colegrove PM. High rate of vaginal extrusion of silicone-coated polyester sling. Urology. 2004;63:1066–1070.

This case series reported 10 patients treated with the silicone-coated polyester sling for stress or mixed urinary incontinence. Two patients (20%) developed vaginal extrusion requiring tape removal, at 6 and at 10 months after initial placement. Although the sling was otherwise effective in treating stress incontinence, this high rate of extrusion obviously precludes further use. No silicone on slings!

Laparoscopic Burch is out

Ankardal M, Ekerydh A, Crafoord K, et al. A randomized trial comparing open Burch colposuspension using sutures with laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. Br J Obstet Gynaecol. 2004;111:974–981.

What about laparoscopy, the grandfather of minimally invasive surgery? In this large, adequately powered, randomized trial of open Burch and laparoscopic colposuspension, the open technique was performed with permanent suture, 2 stitches on each side; the laparoscopic technique used polypropylene mesh and titanium staples. Of 120 subjects randomly assigned to each group, 98 underwent open and 109 underwent laparoscopic colposuspension.

Unfortunately, twice as many subjects (22) assigned to open Burch were excluded after randomization, compared with the laparoscopic group (11). Nonetheless, the results 1 year after surgery unequivocally favored open versus laparoscopic colposuspension: objective cure by pad test in 92% versus 74%, and subjectively dry in 89% versus 62%, respectively.

One wonders why any more trials of laparoscopic colposuspension should be performed at all, although the authors call for future randomized studies comparing different laparoscopic techniques such as suture versus staples and mesh. If the goal is to provide effective, “minimally invasive” surgery for incontinence, with traditional slings updated to include TVT and now TOT, it seems we already have reasonably good alternatives—with the caveat, “pending further studies,” especially for long-term results of the new techniques.

Clinicians who prefer slings have always wondered why laparoscopy—with 3 or 4 abdominal ports, pneumoperitoneum, and general anesthesia—was seen as minimally invasive. Not that laparoscopic continence procedures should never be performed, but it seems likely that they will occupy a narrow niche in the range of surgeries for stress incontinence in women.

Watch for these 2 reports

In other incontinence news, look for results from 2 important trials in 2006:

 

• Burch versus sling in 650 women with stress incontinence; performed by the Urinary Incontinence Treatment Network (an NIH-funded network of 9 clinical sites).
  
• Burch versus no Burch in 480 women without stress incontinence symptoms with advanced prolapse undergoing abdominal sacral colpopexy; performed by the Pelvic Floor Disorders Network (an NIH-funded network of 7 clinical sites).
  

A reminder: Inform the patient

We all want better results of surgical treatment in our patients and, to accomplish that, we need surgical experimentation, which I wholeheartedly support. But such research must be carried out with the patient’s knowledge that she is receiving new and experimental therapy. To do otherwise is unethical.

Dr. Weber serves as an NIH consultant, and reports no other financial relationships in any other capacity.

Ob/Gyns are being called on more than ever to initiate treatment for urinary incontinence, and new treatment options are enabling us to play a more active role than ever before in treating one of the most common and distressing of chronic diseases in women. Urinary incontinence affects women after menopause, primarily. Prevalence increases (though not in a linear fashion)—from 20% to 30% in reproductive-aged women, to 30% to 40% in postmenopausal women. Approximately 16 million Americans are affected, and the number of women affected is more than double that of men.

20% cancel surgery after duloxetine therapy

Cardozo L, Drutz HP, Baygani SK, Bump RC for the Duloxetine Severe UI Study Group. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol. 2004;104:511–519.

Efforts to treat stress incontinence with drugs have not succeeded well in the past, but the development of duloxetine may change that.

Duloxetine (Cymbalta; Eli Lilly, Indianapolis, Ind) is a balanced serotonin-norepinephrine reuptake inhibitor that may act by stimulating pudendal nerve output and improving urethral closure. The FDA approved duloxetine for treatment of major depression for adults in August 2004, and for management of diabetic peripheral neuropathic pain in September 2004. However, duloxetine is not yet FDA-approved for the treatment of stress incontinence.

A randomized, placebo-controlled, double-blinded study involving 14 centers in Australia, Canada, the Netherlands, and the United Kingdom enrolled women aged 18 to 75 years, all of whom had severe stress incontinence, and had already scheduled surgery. All patients had at least 14 episodes of stress incontinence per week. The dose of duloxetine started at 40 mg twice daily for 4 weeks, then increased to 60 mg twice daily for another 4 weeks.

The study randomized 109 women and included 98 in the intention-to-treat analyses, 46 of whom took duloxetine, and 52, placebo.

Response was defined as at least a 50% reduction in incontinence episode frequency. Of the women taking duloxetine, 63% were responders, compared with 13.5% of the placebo group.

Using the Patient Global Impression of Improvement (PGI-I), one third of women taking duloxetine described themselves as “very much better” or “much better,” compared with 8% of women taking placebo.

Ten of 49 women (20%) indicated they were not interested in surgery while taking duloxetine, compared with 0 of 45 women taking placebo. Drug discontinuation occurred more frequently in the duloxetine group: 18 of 55 (33%), compared with 3 of 54 (6%) in the placebo group.

Cure rate low, but so is risk

Even if the “cure” rate is relatively low, duloxetine offers a low-risk form of treatment for women who might otherwise be considered surgical candidates.

In addition, pharmacological treatment may be indicated for women whose incontinence is not severe enough to warrant surgery.

While there are no studies that report long-term results of duloxetine use, it seems appropriate that duloxetine be included in the discussion of nonsurgical options, along with pelvic muscle exercises and behavioral treatment, before surgery is considered.

Botulinum A toxin for refractory detrusor overactivity

Kuo H-C. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology. 2004;63:868–872.

Cystoscopic detrusor injection of botulinum toxin A appears to be a promising alternative to more invasive treatments for refractory detrusor overactivity.

Urinary incontinence due to detrusor overactivity can be especially difficult to treat when first-line treatment with anticholinergic drugs is unsuccessful. Although newer slow-release or long-acting formulations are tolerated better than the original formulations, many patients still have bothersome symptoms or intolerable side effects.

Previously, such women might have been treated with electrical stimulation.

This less invasive treatment might be an effective option, although further study is needed to identify patients most likely to benefit.

Effectiveness has been observed in patients with detrusor overactivity due to spinal cord injury and, in the study cited above, in patients with neurogenic, idiopathic, and postobstructive detrusor over-activity. Botulinum toxin A is not FDA-approved for incontinence indications.

In the Kuo study, 30 patients (12 women and 18 men) with detrusor overactivity refractory to anticholinergic agents were treated with cystoscopic detrusor injection of 200 units botulinum toxin A at 40 sites in the posterior and lateral bladder (sparing the anterior bladder). Eight patients (27%) regained urinary continence; 14 (46%) had improvement in frequency, urgency, and incontinence; and treatment failed in 8 (27%).

Excellent results were most likely in patients with previous bladder outlet obstruction, and least likely in patients with neurogenic detrusor overactivity. Men were more often successfully treated (83%) than women (58%). Maximal effect was noted at 10 to 14 days after treatment, and the effect lasted 3 to 9 months (average, 5.3 months).

 

Side effects were not serious: urinary tract infection in 3 patients and transient urinary retention in 4. Six patients with detrusor overactivity and impaired contractility were treated with intermittent self-catheterization for 1 month, after treatment resulted in increased postvoid residual urine volumes.

Patients with impaired bladder emptying before treatment may be at higher risk of posttreatment retention, although even when retention occurs, it seems to be transient and responds well to time-limited management with intermittent self-catheterization.

Stress incontinence surgery: What’s in, what’s out

Is TVT out?

Costa P, Grise P, Droupy S, et al. Surgical treatment of female stress urinary incontinence with a transobturator-tape (TOT) Uratape: Short-term results of a prospective multicentric study. Eur Urol. 2004;46:102–107.

Faster than you can say “tension-free vaginal tape,” an even newer procedure is coming to the fore: TOT, the transobturator tape.

The TVT operation revolutionized stress incontinence surgery, with placement at the midurethra instead of traditional placement at the bladder neck. Although case series and the first randomized trials showed good results with TVT, concern about retropubic complications fueled development of alternate placement through the obturator foramen. This alternative is intended to avoid complications attributable to penetration of the peritoneal cavity or retropubic space with TVT.

In a study conducted by Costa et al, 183 women with stress or mixed incontinence associated with urethral hypermobility underwent the TOT procedure, which involved midurethral placement of a polypropylene tape with a silicone-coated central part, using a transobturator percutaneous approach. With follow-up at more than 6 months on 130 of the 183 study subjects, 83% were reported as “cured” (absence of subjective complaint of urine leakage and absence of leakage on cough stress testing) and 5.4% as “improved” (decrease of stress incontinence, not further specified).

Obviously, we need more information and, ideally, comparative information to determine how this new technique fits in with other surgical options for stress incontinence. So far, 2 trials comparing TVT and TOT were reported in abstract at the 2004 meeting of the International Continence Society.

Of 17 failures, tape removal was necessary in 5, due to vaginal extrusion in 3 and urethral erosion in 2. Because of this high rate of extrusion, the silicone portion of the tape has been removed.

TOT (but not silicone) is in

Comiter CV, Colegrove PM. High rate of vaginal extrusion of silicone-coated polyester sling. Urology. 2004;63:1066–1070.

This case series reported 10 patients treated with the silicone-coated polyester sling for stress or mixed urinary incontinence. Two patients (20%) developed vaginal extrusion requiring tape removal, at 6 and at 10 months after initial placement. Although the sling was otherwise effective in treating stress incontinence, this high rate of extrusion obviously precludes further use. No silicone on slings!

Laparoscopic Burch is out

Ankardal M, Ekerydh A, Crafoord K, et al. A randomized trial comparing open Burch colposuspension using sutures with laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. Br J Obstet Gynaecol. 2004;111:974–981.

What about laparoscopy, the grandfather of minimally invasive surgery? In this large, adequately powered, randomized trial of open Burch and laparoscopic colposuspension, the open technique was performed with permanent suture, 2 stitches on each side; the laparoscopic technique used polypropylene mesh and titanium staples. Of 120 subjects randomly assigned to each group, 98 underwent open and 109 underwent laparoscopic colposuspension.

Unfortunately, twice as many subjects (22) assigned to open Burch were excluded after randomization, compared with the laparoscopic group (11). Nonetheless, the results 1 year after surgery unequivocally favored open versus laparoscopic colposuspension: objective cure by pad test in 92% versus 74%, and subjectively dry in 89% versus 62%, respectively.

One wonders why any more trials of laparoscopic colposuspension should be performed at all, although the authors call for future randomized studies comparing different laparoscopic techniques such as suture versus staples and mesh. If the goal is to provide effective, “minimally invasive” surgery for incontinence, with traditional slings updated to include TVT and now TOT, it seems we already have reasonably good alternatives—with the caveat, “pending further studies,” especially for long-term results of the new techniques.

Clinicians who prefer slings have always wondered why laparoscopy—with 3 or 4 abdominal ports, pneumoperitoneum, and general anesthesia—was seen as minimally invasive. Not that laparoscopic continence procedures should never be performed, but it seems likely that they will occupy a narrow niche in the range of surgeries for stress incontinence in women.

Watch for these 2 reports

In other incontinence news, look for results from 2 important trials in 2006:

 

• Burch versus sling in 650 women with stress incontinence; performed by the Urinary Incontinence Treatment Network (an NIH-funded network of 9 clinical sites).
  
• Burch versus no Burch in 480 women without stress incontinence symptoms with advanced prolapse undergoing abdominal sacral colpopexy; performed by the Pelvic Floor Disorders Network (an NIH-funded network of 7 clinical sites).
  

A reminder: Inform the patient

We all want better results of surgical treatment in our patients and, to accomplish that, we need surgical experimentation, which I wholeheartedly support. But such research must be carried out with the patient’s knowledge that she is receiving new and experimental therapy. To do otherwise is unethical.

Dr. Weber serves as an NIH consultant, and reports no other financial relationships in any other capacity.

Ob/Gyns are being called on more than ever to initiate treatment for urinary incontinence, and new treatment options are enabling us to play a more active role than ever before in treating one of the most common and distressing of chronic diseases in women. Urinary incontinence affects women after menopause, primarily. Prevalence increases (though not in a linear fashion)—from 20% to 30% in reproductive-aged women, to 30% to 40% in postmenopausal women. Approximately 16 million Americans are affected, and the number of women affected is more than double that of men.

20% cancel surgery after duloxetine therapy

Cardozo L, Drutz HP, Baygani SK, Bump RC for the Duloxetine Severe UI Study Group. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol. 2004;104:511–519.

Efforts to treat stress incontinence with drugs have not succeeded well in the past, but the development of duloxetine may change that.

Duloxetine (Cymbalta; Eli Lilly, Indianapolis, Ind) is a balanced serotonin-norepinephrine reuptake inhibitor that may act by stimulating pudendal nerve output and improving urethral closure. The FDA approved duloxetine for treatment of major depression for adults in August 2004, and for management of diabetic peripheral neuropathic pain in September 2004. However, duloxetine is not yet FDA-approved for the treatment of stress incontinence.

A randomized, placebo-controlled, double-blinded study involving 14 centers in Australia, Canada, the Netherlands, and the United Kingdom enrolled women aged 18 to 75 years, all of whom had severe stress incontinence, and had already scheduled surgery. All patients had at least 14 episodes of stress incontinence per week. The dose of duloxetine started at 40 mg twice daily for 4 weeks, then increased to 60 mg twice daily for another 4 weeks.

The study randomized 109 women and included 98 in the intention-to-treat analyses, 46 of whom took duloxetine, and 52, placebo.

Response was defined as at least a 50% reduction in incontinence episode frequency. Of the women taking duloxetine, 63% were responders, compared with 13.5% of the placebo group.

Using the Patient Global Impression of Improvement (PGI-I), one third of women taking duloxetine described themselves as “very much better” or “much better,” compared with 8% of women taking placebo.

Ten of 49 women (20%) indicated they were not interested in surgery while taking duloxetine, compared with 0 of 45 women taking placebo. Drug discontinuation occurred more frequently in the duloxetine group: 18 of 55 (33%), compared with 3 of 54 (6%) in the placebo group.

Cure rate low, but so is risk

Even if the “cure” rate is relatively low, duloxetine offers a low-risk form of treatment for women who might otherwise be considered surgical candidates.

In addition, pharmacological treatment may be indicated for women whose incontinence is not severe enough to warrant surgery.

While there are no studies that report long-term results of duloxetine use, it seems appropriate that duloxetine be included in the discussion of nonsurgical options, along with pelvic muscle exercises and behavioral treatment, before surgery is considered.

Botulinum A toxin for refractory detrusor overactivity

Kuo H-C. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology. 2004;63:868–872.

Cystoscopic detrusor injection of botulinum toxin A appears to be a promising alternative to more invasive treatments for refractory detrusor overactivity.

Urinary incontinence due to detrusor overactivity can be especially difficult to treat when first-line treatment with anticholinergic drugs is unsuccessful. Although newer slow-release or long-acting formulations are tolerated better than the original formulations, many patients still have bothersome symptoms or intolerable side effects.

Previously, such women might have been treated with electrical stimulation.

This less invasive treatment might be an effective option, although further study is needed to identify patients most likely to benefit.

Effectiveness has been observed in patients with detrusor overactivity due to spinal cord injury and, in the study cited above, in patients with neurogenic, idiopathic, and postobstructive detrusor over-activity. Botulinum toxin A is not FDA-approved for incontinence indications.

In the Kuo study, 30 patients (12 women and 18 men) with detrusor overactivity refractory to anticholinergic agents were treated with cystoscopic detrusor injection of 200 units botulinum toxin A at 40 sites in the posterior and lateral bladder (sparing the anterior bladder). Eight patients (27%) regained urinary continence; 14 (46%) had improvement in frequency, urgency, and incontinence; and treatment failed in 8 (27%).

Excellent results were most likely in patients with previous bladder outlet obstruction, and least likely in patients with neurogenic detrusor overactivity. Men were more often successfully treated (83%) than women (58%). Maximal effect was noted at 10 to 14 days after treatment, and the effect lasted 3 to 9 months (average, 5.3 months).

 

Side effects were not serious: urinary tract infection in 3 patients and transient urinary retention in 4. Six patients with detrusor overactivity and impaired contractility were treated with intermittent self-catheterization for 1 month, after treatment resulted in increased postvoid residual urine volumes.

Patients with impaired bladder emptying before treatment may be at higher risk of posttreatment retention, although even when retention occurs, it seems to be transient and responds well to time-limited management with intermittent self-catheterization.

Stress incontinence surgery: What’s in, what’s out

Is TVT out?

Costa P, Grise P, Droupy S, et al. Surgical treatment of female stress urinary incontinence with a transobturator-tape (TOT) Uratape: Short-term results of a prospective multicentric study. Eur Urol. 2004;46:102–107.

Faster than you can say “tension-free vaginal tape,” an even newer procedure is coming to the fore: TOT, the transobturator tape.

The TVT operation revolutionized stress incontinence surgery, with placement at the midurethra instead of traditional placement at the bladder neck. Although case series and the first randomized trials showed good results with TVT, concern about retropubic complications fueled development of alternate placement through the obturator foramen. This alternative is intended to avoid complications attributable to penetration of the peritoneal cavity or retropubic space with TVT.

In a study conducted by Costa et al, 183 women with stress or mixed incontinence associated with urethral hypermobility underwent the TOT procedure, which involved midurethral placement of a polypropylene tape with a silicone-coated central part, using a transobturator percutaneous approach. With follow-up at more than 6 months on 130 of the 183 study subjects, 83% were reported as “cured” (absence of subjective complaint of urine leakage and absence of leakage on cough stress testing) and 5.4% as “improved” (decrease of stress incontinence, not further specified).

Obviously, we need more information and, ideally, comparative information to determine how this new technique fits in with other surgical options for stress incontinence. So far, 2 trials comparing TVT and TOT were reported in abstract at the 2004 meeting of the International Continence Society.

Of 17 failures, tape removal was necessary in 5, due to vaginal extrusion in 3 and urethral erosion in 2. Because of this high rate of extrusion, the silicone portion of the tape has been removed.

TOT (but not silicone) is in

Comiter CV, Colegrove PM. High rate of vaginal extrusion of silicone-coated polyester sling. Urology. 2004;63:1066–1070.

This case series reported 10 patients treated with the silicone-coated polyester sling for stress or mixed urinary incontinence. Two patients (20%) developed vaginal extrusion requiring tape removal, at 6 and at 10 months after initial placement. Although the sling was otherwise effective in treating stress incontinence, this high rate of extrusion obviously precludes further use. No silicone on slings!

Laparoscopic Burch is out

Ankardal M, Ekerydh A, Crafoord K, et al. A randomized trial comparing open Burch colposuspension using sutures with laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. Br J Obstet Gynaecol. 2004;111:974–981.

What about laparoscopy, the grandfather of minimally invasive surgery? In this large, adequately powered, randomized trial of open Burch and laparoscopic colposuspension, the open technique was performed with permanent suture, 2 stitches on each side; the laparoscopic technique used polypropylene mesh and titanium staples. Of 120 subjects randomly assigned to each group, 98 underwent open and 109 underwent laparoscopic colposuspension.

Unfortunately, twice as many subjects (22) assigned to open Burch were excluded after randomization, compared with the laparoscopic group (11). Nonetheless, the results 1 year after surgery unequivocally favored open versus laparoscopic colposuspension: objective cure by pad test in 92% versus 74%, and subjectively dry in 89% versus 62%, respectively.

One wonders why any more trials of laparoscopic colposuspension should be performed at all, although the authors call for future randomized studies comparing different laparoscopic techniques such as suture versus staples and mesh. If the goal is to provide effective, “minimally invasive” surgery for incontinence, with traditional slings updated to include TVT and now TOT, it seems we already have reasonably good alternatives—with the caveat, “pending further studies,” especially for long-term results of the new techniques.

Clinicians who prefer slings have always wondered why laparoscopy—with 3 or 4 abdominal ports, pneumoperitoneum, and general anesthesia—was seen as minimally invasive. Not that laparoscopic continence procedures should never be performed, but it seems likely that they will occupy a narrow niche in the range of surgeries for stress incontinence in women.

Watch for these 2 reports

In other incontinence news, look for results from 2 important trials in 2006:

 

• Burch versus sling in 650 women with stress incontinence; performed by the Urinary Incontinence Treatment Network (an NIH-funded network of 9 clinical sites).
  
• Burch versus no Burch in 480 women without stress incontinence symptoms with advanced prolapse undergoing abdominal sacral colpopexy; performed by the Pelvic Floor Disorders Network (an NIH-funded network of 7 clinical sites).
  

A reminder: Inform the patient

We all want better results of surgical treatment in our patients and, to accomplish that, we need surgical experimentation, which I wholeheartedly support. But such research must be carried out with the patient’s knowledge that she is receiving new and experimental therapy. To do otherwise is unethical.

Dr. Weber serves as an NIH consultant, and reports no other financial relationships in any other capacity.

COMMENTARY

Putting new guidelines into practice is easier said than done

Steven Goldstein, MD
New York University Medical Center

Is the Pap test still necessary for every woman, every year? No, according to the latest guidelines, but old habits die hard, even for physicians.

And there is little doubt that yearly screening, though not scientifically based, has contributed much to the reduction of cervical cancer incidence and mortality in American women. Our patients and we as providers have long considered a Pap test the cornerstone of the annual gynecologic exam, as we’ve been urged to do for decades by our leading academic institutions. However, the American College of Obstetricians and Gynecologists (ACOG) and the American Cancer Society (ACS) revised their guidelines last year, and no longer support yearly screening for every woman, every year.^1,2 The US Preventive Services Task Force (USPSTF) revised its guidelines in accord, with the exception that it found the evidence insufficient to support screening low-risk women more often than every 3 years, at any age.³

Original rationale: “Pap smear prompt”

These organizations, as well as the National Cancer Institutes (NCI), had supported annual Pap testing since the mid-1950s—long before any data suggested whether one screening interval might be better than another.

In fact, part of the original rationale for annual screening was that it would serve as a vehicle to bring women in for their annual gynecologic exam.⁴

 

Why change? How will patients react?

Cumulative findings suggest an age- and risk-based approach

Research over the past few decades has revealed much about the pathogenesis of cervical cancer which supports an age- and risk-based approach to screening for cervical cancer—when to start, when to stop, and how often to perform cervical cytology.

The main questions

In this article, I’ll review some of the data on these concerns:

• Why wait 3 years after first intercourse for the first Pap test?
  
• Why is 21 the ‘default’ age for first Pap test?
  
• What are the risks and costs of screening every 2 to 3 years in well-screened women over age 30? Over age 65?
  
• Do most women without a cervix require screening?
  
• What is the role of HPV DNA testing?
  
• How should we deal with abnormal results?
  
• How should we counsel the patient?
  
• What’s the harm in continuing Pap tests in all women?
  
• Will women return for annual exams as we advise, if we change their Pap test routine?
  

ADOLESCENCEWhy wait 3 years after onset of intercourse for first Pap test?

Care is not compromised

Delaying screening until at least 3 years after coitarche does not compromise the diagnosis of high-grade lesions, yet does allow discovery and eradication long before they become malignant. On the other hand, screening young women sooner than 3 years after first sexual intercourse risks diagnosing numerous self-limited HPV infections and transient low-grade dysplastic lesions, which have very low premalignant potential.

Persistent high-risk HPV must precede cancer. Cervical cancer develops only after persistent HPV infection, many years from the initial HPV exposure.

We now know that at least 15 to 18 types of human papillomavirus (HPV) can cause cervical cancer, and that infection with a high-risk type of HPV is the necessary antecedent—but not by itself a sufficient antecedent—for high-grade cervical dysplasia and cervical cancer.^5,6

We also know that HPV is most often acquired through sexual intercourse and that it is very efficiently acquired by young women.^7,8 For example, a study of young college women who were initially HPV negative acquired HPV at a rate of 14% per year.⁷

HPV infections in young women are usually transient, however. Up to 90% of young women who test positive for HPV DNA will revert to negative within 2 years.⁹

The problems of screening too early. Squamous cancer of the cervix is exceedingly rare in women under age 21.¹⁰ Diagnosis of self-limited HPV infections and transient low-grade dysplastic lesions would likely result in repeat Pap tests and colposcopies. In addition to being costly and anxiety-provoking, these interventions may lead to needless destruction of the immature transformation zone in young women of low parity.

Don’t neglect counseling, STD testing, birth control

Delaying the first Pap test in young women until 3 years after initial intercourse, however, does not mean we should neglect gynecologic examinations in this group. They are at high risk for sexually transmitted infections and at extremely high risk for unintended pregnancies. So, while waiting 3 years to do the first Pap test makes sense, an early visit, before or soon after first intercourse is essential for gynecologic health care, including prevention of pregnancy and sexually transmitted disease.

October 2004 opinion on Gyn visits for young teens. ACOG published a committee opinion¹¹ to clear up confusion over when adolescent girls should have their first Pap test versus when they should have their first gynecologic visit. The opinion advises a first visit at age 13 to 15, for health guidance, screening, and preventive services, and says parents and patients need to understand that this visit does not necessarily include a pelvic exam or a Pap test. The advisory stresses that adolescents are unlikely to acknowledge sexual activity without sensitive and direct questions, and suggested a resource: “Asking the Right Questions,” from the STD/HTD Prevention Training Center of New England.

AGES 21 TO 30Why is age 21 the “default” for first Pap?

Because the incidence of high-grade squamous intraepithelial lesions (HSIL) increases with age,¹² cytology screening should start at age 21, irrespective of sexual history. Saslow et al¹ writing for the American Cancer Society, acknowledged the difficulty of obtaining a reliable sexual history. This may be especially true with patients who may have suffered sexual abuse as adolescents. The default age of 21 for initial Pap test allows the provider to sidestep the question of age at first intercourse. On the other hand, a 21-year-old who has never had vaginal intercourse does not need to be screened for cervical cancer.

Aggressive screening until age 30

Women should be screened every year until age 30 if conventional Pap smears are used.^1,2 During a woman’s 20s, precancerous lesions become more common and invasive cancer, while still rare, is seen with increasing frequency. Both ACOG and ACS consider this period of a woman’s life to be a time for aggressive cervical cancer screening.

 

Frequent screening until age 30 allows us to identify and treat young women with histologic cervical intraepithelial neoplasia (CIN) 2 and 3 or worse, and to identify those who, because of persistently negative Pap tests, are at lowest risk.

Since these women schedule more frequent visits for contraception and prenatal care, we have greater opportunities for cervical cancer screening.

Does type of Pap test determine screening interval?

Every 2 years is sufficient if the liquid Pap test is used: ACS.¹ This recommendation is based on balancing the increase in abnormal results found with liquid-based Paps against the likelihood that most of the additional abnormal findings will be only atypical squamous cells, undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). These minimally abnormal results, while needing follow-up, have a relatively low rate of CIN 2 or 3 on biopsy.

Annual tests until age 30, irrespective of Pap technology: ACOG.² That decision recognizes the fact that, while the data suggest increased sensitivity of liquid-based cervical cytology, this observation is not conclusive, and both technologies fall short of 100% sensitivity.

AGES 30 TO 65Why extend the interval between Pap tests?

High risk calls for yearly screens

Both ACOG and the ACS agree that women at high-risk should be screened annually regardless of age.

Risk factors include:

• history of cervical cancer,
  
• immunocompromise including HIV,
  
• in utero exposure to diethylstilbestrol (DES), and
  
• women over age 30 who were not well screened in their 20s; these women should have at least 3 negative annual exams before the screening interval is extended.
  

Longer interval if risk is low

Up to age 30, frequent screening can be expected to significantly reduce a woman’s risk of cervical cancer. Multiple negative Paps offer a high degree of protection—the more consecutive normal tests, the higher the level of protection.¹³

Research indicates, however, that it seems reasonable to reduce the screening interval from every year to every 2 to 3 years in previously well-screened women over age 30:

• These women have the protection offered by frequent Pap tests during the previous decade.
  
• By the time most women reach their 30s, the area of active squamous metaplasia, which serves as the substrate for cervical neoplasia, is reduced.¹⁴
  

Studies of screening effects

National Breast and Cervical Cancer Early Detection Program. Using data from this program, Sawaya et al¹³ studied 31,728 women aged 30 to 64 with 3 or more consecutive negative Pap tests spaced no more than 3 years apart. They found only 9 women (0.028%) with biopsy-proven CIN 2, only 6 (0.019%) with CIN 3, and none with invasive cancer.

International Agency for Research in Cancer¹⁵ data showed essentially no difference in the protective effect of cytology screening at 1-, 2-, or 3-year intervals in women enrolled in screening programs in 7 Western European countries and 3 Canadian centers, among women aged 35 to 64 who had at least 2 previous negative Pap tests. The authors calculated a cumulative reduction in cervical cancer of 93.5% with annual screening, 92.5% with screening every 2 years, and 90.8% with screening every 3 years, compared to women who had no screening.

National Breast and Cervical Cancer Early Detection Program¹⁶ data also support extending the screening interval beyond 1 year. In 128,805 women followed after at least 1 prior negative Pap, no significant difference was noted in the incidence of cytologic HSIL on a subsequent Pap performed 9 to 12 months, 13 to 24 months, or 25 to 36 months later. The rates of HSIL were 25, 29, and 33 per 100,000 women, respectively.

Do postmenopausal women need screening?

Women over 65 do get cervical cancer. While they represent 13% of the total U.S. population, they have 25% of new cases of cervical cancer and suffer 41% cervical cancer mortality.¹⁷ Incident cases of squamous cancer among older women, however, come from the cohort who have not previously been well screened.

An older woman in a long-term monogamous relationship who has a history of frequent negative Pap tests is at such low risk for acquiring cervical cancer that the US Preventive Services Task Force recommends discontinuing screening in this group at age 65.³

The American Cancer Society recommends discontinuing screening at age 70 in low-risk previously well screened women.¹

ACOG does not set a specific upper age for cytology screening.² While acknowledging the recommendations of these other professional organizations, ACOG notes that there is no good evidence to establish one age over another to discontinue screening, and instead encourages individualization.

ACOG recommends that if an older woman’s sexual practice changes after she is no longer being tested with cytology, some consideration should be given to reinitiating screening. If screening is restarted, 3-year intervals seems appropriate, as older women may have immunity to many HPV types, and their active transformation zone is generally retracted and very narrow.

 

Why not just continue frequent screening in this less vulnerable population? The consequences of continuing screening in the older, previously well-screened population were nicely illustrated in a study by Sawaya et al,¹⁸ using data from the Heart and Estrogen/Progestin Replacement Study (HERS) of postmenopausal women, they evaluated the cytology results of 2,561 women followed over a 4-year period. These women had a Pap test 2 to 2 years after a normal entry cytology.

Subsequent follow-up of cases in which the Pap test was abnormal found only 1 woman with histologic dysplasia, which was a case of mild to moderate dysplasia. To make this diagnosis involved inconvenience, cost and morbidity to the group. To find this single case of mild to moderate dysplasia, 110 women were recalled for follow-ups, which required 231 interventions that included repeat Pap smears, colposcopies, endometrial biopsies, cervical and endocervical biopsies, D&Cs, and excision procedures.

Add to the additional tests, the anxiety inherent in a report of an abnormal Pap test and its follow-up, and the value of limiting screening in this very low risk population become more apparent.

Screen for cervical cancer if there is no cervix?

Since 1996, the US Preventive Services Task Force has recommended against cervical cytology screening in women whose uterus and cervix have been removed for benign indications. Despite this, a recent study showed, as many as 45.6% of such women were still having Pap tests.¹⁹

For any screening procedure to be cost effective, there must be a threshold prevalence of the disease in the population to be screened. While women with prior cervical cancer or high-grade dysplasia remain at increased risk for recurrences at the vaginal cuff, women with no history of such disease are at extremely low risk.

In essence, screening in these women becomes a search for primary vaginal cancer, which is one of the rarest of gynecologic malignancies—only 0.3% of cancers in women, a frequency less than that of cancer of the tongue.⁹ Continued screening in the absence of a cervix implies the need to screen an unacceptably large number of women to diagnose a single lesion. Cytology screening in this group is far more likely to diagnose low-grade vaginal intraepithelial neoplasia (VAIN). VAIN 1 reflects self-limited epithelial changes that are extremely unlikely to progress to cancer.

What is the role of HPV testing?

Last year, the US Food and Drug Administration approved the Hybrid Capture 2 test for high-risk HPV DNA (Digene, Gaithersburg, Md) for use in addition to cervical cytology for screening women over age 30. Both ACOG and the ACS acknowledged this combination of tests as an acceptable option as long as women who test negative on both tests are not retested for 3 years.^1,2

Using HPV DNA screening in women under 30 makes little sense. Many studies have confirmed the high prevalence of high-risk HPV in this age group whose risk of invasive cancer is quite low.^7,12,20 Screening with HPV before age 30 would result in an unacceptably high false-positive rate, with no advantage over annual screening with cytology alone.

High negative predictive value after age 30

On the other hand, after age 30, as the prevalence of HPV declines, the specificity of this test improves markedly.¹² Why wait 3 years before retesting if both tests are negative? The answer lies in the extremely high negative predictive value of the combination. Sherman et al²¹ determined that the negative predictive value of the combination of cytology plus HPV DNA testing 33 months after both tests are negative is 99.88%. At 45 months, it was still 99.84%.

Thus we can provide excellent assurance to women who test negative that their risk of CIN 3 or squamous cancer is negligible over at least the intervening 3 years.

It’s worth noting that in this same study, the negative predictive value of cytology alone at 33 and 45 months was also quite high: 99.61% and 99.47%, respectively.

ABNORMAL RESULTSConsensus guidelines for combined testing

Management is clear when both tests are negative, or when the Pap shows SIL and the HPV is positive. But what if only 1 of the tests is abnormal? A February 2003 consensus workshop held by ACS, the American Society for Colposcopy and Cervical Pathology, and the National Institutes of Health developed recommendations for managing the various combinations of results.²²

ASC-US and positive HPV

Data clearly support triaging these patients to colposcopy. The National Cancer Institute’s ASCUS/LSIL Triage study (ALTS) study showed that, in a group of 1,161 women, this combination of results had a 92% sensitivity for diagnosing CIN 3.²³ Solomon Other studies, done under perhaps less rigorous scientific conditions, also showed high sensitivity, though generally not as high as in the ALTS study.

 

When cytology results are more severe than ASC-US

If results are ASC-H, AGC, LSIL, or HSIL, manage with colposcopy regardless of HPV results.

Negative cytology and positive for high-risk HPV

This scenario is more difficult for both the physician and patient. High-risk HPV is a clear risk factor for subsequent dysplasia.²¹ While most HPV infections are transient, the risk of dysplasia increases when they persist.²⁴ A reasonable course is to repeat both Pap and HPV in 6 to 12 months. This allows time for transient HPV infections to clear and for persistent infections to be identified on the repeat test.

The ultimate prognosis and management are determined by the repeat cytology plus HPV. If both repeat tests are negative, further repeat screening should be delayed for 3 years.

If the cytology is ASC-US, but HPV is negative, the patient may safely be screened again in 1 year with Pap plus HPV. Colposcopy is indicated if the cytology is worse than ASC-US and/or if the HPV remains positive.

Counseling HPV-positive patients

Perhaps the most difficult aspect of screening with cytology plus HPV DNA is what to advise patients whose Pap test is normal but whose HPV is positive.

Many women are aware that HPV is sexually transmitted, and a positive HPV test conjures fears of spousal infidelity, concerns about spreading the infection, and fear of other sexually transmitted infections.

Long latency. I have found it useful to defuse the infidelity concern by pointing to the long latent period associated with HPV infections. A recently diagnosed HPV infection may have been acquired years in the past from a prior partner, or from her current partner early in their relationship.

Neither partner should construe a positive test for high-risk HPV as an indicator of promiscuity. It is just as likely that a temporary change in her immune status allowed a previously latent infection to become productive.

Highly prevalent. The patient may be reassured by knowing that HPV is exceedingly common; up to 75% of women will have one or more subtypes of HPV in their lower genital tract at some time in their lives. Pointing out that it can be considered a marker of ever having had vaginal intercourse may help to eliminate the stigma of a sexually transmitted disease.

Let her know her partner probably carries the same HPV type, or has cleared it in the past.

Low risk of cancer for the partner. Male partners of women who test positive for high-risk HPV DNA do not require any testing. Reassure the couple that the male’s risk of cancer is very low since the penis lacks a transformation zone, the substrate for efficient neoplastic transformation.

Reassure her of low risk without neoplastic changes. The presence of HPV on the cervix is of little clinical importance unless the cervical epithelium has begun to undergo neoplastic changes. Reassure the patient that as long as she has no squamous intraepithelial lesions on Pap testing or a persistently positive HPV DNA test over time, she has a low risk developing cancer.

What’s the harm in yearly testing?

Will our patients skip annual gynecologic exams if we tell them they no longer need an annual Pap test? If Paps are performed only every 3 years, will many women wait 4 or 5 years between screenings?

These and other concerns make it difficult to change an ingrained routine, despite data that support new practice guidelines.

Besides, the Pap test is inexpensive, so what’s the harm in doing it annually? While the Pap test itself remains relatively inexpensive, the wide popularity of the liquid-based Pap test has doubled or tripled the cost of the test in many markets. And annual testing in low-risk women has a high rate of false positives, which require costly follow-up testing.¹³

Though future studies must determine the optimal interval for gynecologic examinations in asymptomatic women, periodic examinations are certainly important—even if a Pap test is not done each year. As primary-care providers, gynecologists offer periodic screenings for conditions such as diabetes, cardiac disease, and colon cancer, in addition to gynecologic evaluations. And it makes good sense to encourage frequent periodic exams for patients at risk, such as young women in need of contraceptive counseling or evaluation for sexually transmitted disease, and older women in need of breast surveillance.

But if we provide periodic screening without the “Pap-smear prompt,” we’ll need to redouble our efforts to teach patients the value of the annual exam for other health assessments, not cervical cytology screening alone.

The authors report no relevant financial relationships.

COMMENTARY

Putting new guidelines into practice is easier said than done

Steven Goldstein, MD
New York University Medical Center

Is the Pap test still necessary for every woman, every year? No, according to the latest guidelines, but old habits die hard, even for physicians.

And there is little doubt that yearly screening, though not scientifically based, has contributed much to the reduction of cervical cancer incidence and mortality in American women. Our patients and we as providers have long considered a Pap test the cornerstone of the annual gynecologic exam, as we’ve been urged to do for decades by our leading academic institutions. However, the American College of Obstetricians and Gynecologists (ACOG) and the American Cancer Society (ACS) revised their guidelines last year, and no longer support yearly screening for every woman, every year.^1,2 The US Preventive Services Task Force (USPSTF) revised its guidelines in accord, with the exception that it found the evidence insufficient to support screening low-risk women more often than every 3 years, at any age.³

Original rationale: “Pap smear prompt”

These organizations, as well as the National Cancer Institutes (NCI), had supported annual Pap testing since the mid-1950s—long before any data suggested whether one screening interval might be better than another.

In fact, part of the original rationale for annual screening was that it would serve as a vehicle to bring women in for their annual gynecologic exam.⁴

 

Why change? How will patients react?

Cumulative findings suggest an age- and risk-based approach

Research over the past few decades has revealed much about the pathogenesis of cervical cancer which supports an age- and risk-based approach to screening for cervical cancer—when to start, when to stop, and how often to perform cervical cytology.

The main questions

In this article, I’ll review some of the data on these concerns:

• Why wait 3 years after first intercourse for the first Pap test?
  
• Why is 21 the ‘default’ age for first Pap test?
  
• What are the risks and costs of screening every 2 to 3 years in well-screened women over age 30? Over age 65?
  
• Do most women without a cervix require screening?
  
• What is the role of HPV DNA testing?
  
• How should we deal with abnormal results?
  
• How should we counsel the patient?
  
• What’s the harm in continuing Pap tests in all women?
  
• Will women return for annual exams as we advise, if we change their Pap test routine?
  

ADOLESCENCEWhy wait 3 years after onset of intercourse for first Pap test?

Care is not compromised

Delaying screening until at least 3 years after coitarche does not compromise the diagnosis of high-grade lesions, yet does allow discovery and eradication long before they become malignant. On the other hand, screening young women sooner than 3 years after first sexual intercourse risks diagnosing numerous self-limited HPV infections and transient low-grade dysplastic lesions, which have very low premalignant potential.

Persistent high-risk HPV must precede cancer. Cervical cancer develops only after persistent HPV infection, many years from the initial HPV exposure.

We now know that at least 15 to 18 types of human papillomavirus (HPV) can cause cervical cancer, and that infection with a high-risk type of HPV is the necessary antecedent—but not by itself a sufficient antecedent—for high-grade cervical dysplasia and cervical cancer.^5,6

We also know that HPV is most often acquired through sexual intercourse and that it is very efficiently acquired by young women.^7,8 For example, a study of young college women who were initially HPV negative acquired HPV at a rate of 14% per year.⁷

HPV infections in young women are usually transient, however. Up to 90% of young women who test positive for HPV DNA will revert to negative within 2 years.⁹

The problems of screening too early. Squamous cancer of the cervix is exceedingly rare in women under age 21.¹⁰ Diagnosis of self-limited HPV infections and transient low-grade dysplastic lesions would likely result in repeat Pap tests and colposcopies. In addition to being costly and anxiety-provoking, these interventions may lead to needless destruction of the immature transformation zone in young women of low parity.

Don’t neglect counseling, STD testing, birth control

Delaying the first Pap test in young women until 3 years after initial intercourse, however, does not mean we should neglect gynecologic examinations in this group. They are at high risk for sexually transmitted infections and at extremely high risk for unintended pregnancies. So, while waiting 3 years to do the first Pap test makes sense, an early visit, before or soon after first intercourse is essential for gynecologic health care, including prevention of pregnancy and sexually transmitted disease.

October 2004 opinion on Gyn visits for young teens. ACOG published a committee opinion¹¹ to clear up confusion over when adolescent girls should have their first Pap test versus when they should have their first gynecologic visit. The opinion advises a first visit at age 13 to 15, for health guidance, screening, and preventive services, and says parents and patients need to understand that this visit does not necessarily include a pelvic exam or a Pap test. The advisory stresses that adolescents are unlikely to acknowledge sexual activity without sensitive and direct questions, and suggested a resource: “Asking the Right Questions,” from the STD/HTD Prevention Training Center of New England.

AGES 21 TO 30Why is age 21 the “default” for first Pap?

Because the incidence of high-grade squamous intraepithelial lesions (HSIL) increases with age,¹² cytology screening should start at age 21, irrespective of sexual history. Saslow et al¹ writing for the American Cancer Society, acknowledged the difficulty of obtaining a reliable sexual history. This may be especially true with patients who may have suffered sexual abuse as adolescents. The default age of 21 for initial Pap test allows the provider to sidestep the question of age at first intercourse. On the other hand, a 21-year-old who has never had vaginal intercourse does not need to be screened for cervical cancer.

Aggressive screening until age 30

Women should be screened every year until age 30 if conventional Pap smears are used.^1,2 During a woman’s 20s, precancerous lesions become more common and invasive cancer, while still rare, is seen with increasing frequency. Both ACOG and ACS consider this period of a woman’s life to be a time for aggressive cervical cancer screening.

 

Frequent screening until age 30 allows us to identify and treat young women with histologic cervical intraepithelial neoplasia (CIN) 2 and 3 or worse, and to identify those who, because of persistently negative Pap tests, are at lowest risk.

Since these women schedule more frequent visits for contraception and prenatal care, we have greater opportunities for cervical cancer screening.

Does type of Pap test determine screening interval?

Every 2 years is sufficient if the liquid Pap test is used: ACS.¹ This recommendation is based on balancing the increase in abnormal results found with liquid-based Paps against the likelihood that most of the additional abnormal findings will be only atypical squamous cells, undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). These minimally abnormal results, while needing follow-up, have a relatively low rate of CIN 2 or 3 on biopsy.

Annual tests until age 30, irrespective of Pap technology: ACOG.² That decision recognizes the fact that, while the data suggest increased sensitivity of liquid-based cervical cytology, this observation is not conclusive, and both technologies fall short of 100% sensitivity.

AGES 30 TO 65Why extend the interval between Pap tests?

High risk calls for yearly screens

Both ACOG and the ACS agree that women at high-risk should be screened annually regardless of age.

Risk factors include:

• history of cervical cancer,
  
• immunocompromise including HIV,
  
• in utero exposure to diethylstilbestrol (DES), and
  
• women over age 30 who were not well screened in their 20s; these women should have at least 3 negative annual exams before the screening interval is extended.
  

Longer interval if risk is low

Up to age 30, frequent screening can be expected to significantly reduce a woman’s risk of cervical cancer. Multiple negative Paps offer a high degree of protection—the more consecutive normal tests, the higher the level of protection.¹³

Research indicates, however, that it seems reasonable to reduce the screening interval from every year to every 2 to 3 years in previously well-screened women over age 30:

• These women have the protection offered by frequent Pap tests during the previous decade.
  
• By the time most women reach their 30s, the area of active squamous metaplasia, which serves as the substrate for cervical neoplasia, is reduced.¹⁴
  

Studies of screening effects

National Breast and Cervical Cancer Early Detection Program. Using data from this program, Sawaya et al¹³ studied 31,728 women aged 30 to 64 with 3 or more consecutive negative Pap tests spaced no more than 3 years apart. They found only 9 women (0.028%) with biopsy-proven CIN 2, only 6 (0.019%) with CIN 3, and none with invasive cancer.

International Agency for Research in Cancer¹⁵ data showed essentially no difference in the protective effect of cytology screening at 1-, 2-, or 3-year intervals in women enrolled in screening programs in 7 Western European countries and 3 Canadian centers, among women aged 35 to 64 who had at least 2 previous negative Pap tests. The authors calculated a cumulative reduction in cervical cancer of 93.5% with annual screening, 92.5% with screening every 2 years, and 90.8% with screening every 3 years, compared to women who had no screening.

National Breast and Cervical Cancer Early Detection Program¹⁶ data also support extending the screening interval beyond 1 year. In 128,805 women followed after at least 1 prior negative Pap, no significant difference was noted in the incidence of cytologic HSIL on a subsequent Pap performed 9 to 12 months, 13 to 24 months, or 25 to 36 months later. The rates of HSIL were 25, 29, and 33 per 100,000 women, respectively.

Do postmenopausal women need screening?

Women over 65 do get cervical cancer. While they represent 13% of the total U.S. population, they have 25% of new cases of cervical cancer and suffer 41% cervical cancer mortality.¹⁷ Incident cases of squamous cancer among older women, however, come from the cohort who have not previously been well screened.

An older woman in a long-term monogamous relationship who has a history of frequent negative Pap tests is at such low risk for acquiring cervical cancer that the US Preventive Services Task Force recommends discontinuing screening in this group at age 65.³

The American Cancer Society recommends discontinuing screening at age 70 in low-risk previously well screened women.¹

ACOG does not set a specific upper age for cytology screening.² While acknowledging the recommendations of these other professional organizations, ACOG notes that there is no good evidence to establish one age over another to discontinue screening, and instead encourages individualization.

ACOG recommends that if an older woman’s sexual practice changes after she is no longer being tested with cytology, some consideration should be given to reinitiating screening. If screening is restarted, 3-year intervals seems appropriate, as older women may have immunity to many HPV types, and their active transformation zone is generally retracted and very narrow.

 

Why not just continue frequent screening in this less vulnerable population? The consequences of continuing screening in the older, previously well-screened population were nicely illustrated in a study by Sawaya et al,¹⁸ using data from the Heart and Estrogen/Progestin Replacement Study (HERS) of postmenopausal women, they evaluated the cytology results of 2,561 women followed over a 4-year period. These women had a Pap test 2 to 2 years after a normal entry cytology.

Subsequent follow-up of cases in which the Pap test was abnormal found only 1 woman with histologic dysplasia, which was a case of mild to moderate dysplasia. To make this diagnosis involved inconvenience, cost and morbidity to the group. To find this single case of mild to moderate dysplasia, 110 women were recalled for follow-ups, which required 231 interventions that included repeat Pap smears, colposcopies, endometrial biopsies, cervical and endocervical biopsies, D&Cs, and excision procedures.

Add to the additional tests, the anxiety inherent in a report of an abnormal Pap test and its follow-up, and the value of limiting screening in this very low risk population become more apparent.

Screen for cervical cancer if there is no cervix?

Since 1996, the US Preventive Services Task Force has recommended against cervical cytology screening in women whose uterus and cervix have been removed for benign indications. Despite this, a recent study showed, as many as 45.6% of such women were still having Pap tests.¹⁹

For any screening procedure to be cost effective, there must be a threshold prevalence of the disease in the population to be screened. While women with prior cervical cancer or high-grade dysplasia remain at increased risk for recurrences at the vaginal cuff, women with no history of such disease are at extremely low risk.

In essence, screening in these women becomes a search for primary vaginal cancer, which is one of the rarest of gynecologic malignancies—only 0.3% of cancers in women, a frequency less than that of cancer of the tongue.⁹ Continued screening in the absence of a cervix implies the need to screen an unacceptably large number of women to diagnose a single lesion. Cytology screening in this group is far more likely to diagnose low-grade vaginal intraepithelial neoplasia (VAIN). VAIN 1 reflects self-limited epithelial changes that are extremely unlikely to progress to cancer.

What is the role of HPV testing?

Last year, the US Food and Drug Administration approved the Hybrid Capture 2 test for high-risk HPV DNA (Digene, Gaithersburg, Md) for use in addition to cervical cytology for screening women over age 30. Both ACOG and the ACS acknowledged this combination of tests as an acceptable option as long as women who test negative on both tests are not retested for 3 years.^1,2

Using HPV DNA screening in women under 30 makes little sense. Many studies have confirmed the high prevalence of high-risk HPV in this age group whose risk of invasive cancer is quite low.^7,12,20 Screening with HPV before age 30 would result in an unacceptably high false-positive rate, with no advantage over annual screening with cytology alone.

High negative predictive value after age 30

On the other hand, after age 30, as the prevalence of HPV declines, the specificity of this test improves markedly.¹² Why wait 3 years before retesting if both tests are negative? The answer lies in the extremely high negative predictive value of the combination. Sherman et al²¹ determined that the negative predictive value of the combination of cytology plus HPV DNA testing 33 months after both tests are negative is 99.88%. At 45 months, it was still 99.84%.

Thus we can provide excellent assurance to women who test negative that their risk of CIN 3 or squamous cancer is negligible over at least the intervening 3 years.

It’s worth noting that in this same study, the negative predictive value of cytology alone at 33 and 45 months was also quite high: 99.61% and 99.47%, respectively.

ABNORMAL RESULTSConsensus guidelines for combined testing

Management is clear when both tests are negative, or when the Pap shows SIL and the HPV is positive. But what if only 1 of the tests is abnormal? A February 2003 consensus workshop held by ACS, the American Society for Colposcopy and Cervical Pathology, and the National Institutes of Health developed recommendations for managing the various combinations of results.²²

ASC-US and positive HPV

Data clearly support triaging these patients to colposcopy. The National Cancer Institute’s ASCUS/LSIL Triage study (ALTS) study showed that, in a group of 1,161 women, this combination of results had a 92% sensitivity for diagnosing CIN 3.²³ Solomon Other studies, done under perhaps less rigorous scientific conditions, also showed high sensitivity, though generally not as high as in the ALTS study.

 

When cytology results are more severe than ASC-US

If results are ASC-H, AGC, LSIL, or HSIL, manage with colposcopy regardless of HPV results.

Negative cytology and positive for high-risk HPV

This scenario is more difficult for both the physician and patient. High-risk HPV is a clear risk factor for subsequent dysplasia.²¹ While most HPV infections are transient, the risk of dysplasia increases when they persist.²⁴ A reasonable course is to repeat both Pap and HPV in 6 to 12 months. This allows time for transient HPV infections to clear and for persistent infections to be identified on the repeat test.

The ultimate prognosis and management are determined by the repeat cytology plus HPV. If both repeat tests are negative, further repeat screening should be delayed for 3 years.

If the cytology is ASC-US, but HPV is negative, the patient may safely be screened again in 1 year with Pap plus HPV. Colposcopy is indicated if the cytology is worse than ASC-US and/or if the HPV remains positive.

Counseling HPV-positive patients

Perhaps the most difficult aspect of screening with cytology plus HPV DNA is what to advise patients whose Pap test is normal but whose HPV is positive.

Many women are aware that HPV is sexually transmitted, and a positive HPV test conjures fears of spousal infidelity, concerns about spreading the infection, and fear of other sexually transmitted infections.

Long latency. I have found it useful to defuse the infidelity concern by pointing to the long latent period associated with HPV infections. A recently diagnosed HPV infection may have been acquired years in the past from a prior partner, or from her current partner early in their relationship.

Neither partner should construe a positive test for high-risk HPV as an indicator of promiscuity. It is just as likely that a temporary change in her immune status allowed a previously latent infection to become productive.

Highly prevalent. The patient may be reassured by knowing that HPV is exceedingly common; up to 75% of women will have one or more subtypes of HPV in their lower genital tract at some time in their lives. Pointing out that it can be considered a marker of ever having had vaginal intercourse may help to eliminate the stigma of a sexually transmitted disease.

Let her know her partner probably carries the same HPV type, or has cleared it in the past.

Low risk of cancer for the partner. Male partners of women who test positive for high-risk HPV DNA do not require any testing. Reassure the couple that the male’s risk of cancer is very low since the penis lacks a transformation zone, the substrate for efficient neoplastic transformation.

Reassure her of low risk without neoplastic changes. The presence of HPV on the cervix is of little clinical importance unless the cervical epithelium has begun to undergo neoplastic changes. Reassure the patient that as long as she has no squamous intraepithelial lesions on Pap testing or a persistently positive HPV DNA test over time, she has a low risk developing cancer.

What’s the harm in yearly testing?

Will our patients skip annual gynecologic exams if we tell them they no longer need an annual Pap test? If Paps are performed only every 3 years, will many women wait 4 or 5 years between screenings?

These and other concerns make it difficult to change an ingrained routine, despite data that support new practice guidelines.

Besides, the Pap test is inexpensive, so what’s the harm in doing it annually? While the Pap test itself remains relatively inexpensive, the wide popularity of the liquid-based Pap test has doubled or tripled the cost of the test in many markets. And annual testing in low-risk women has a high rate of false positives, which require costly follow-up testing.¹³

Though future studies must determine the optimal interval for gynecologic examinations in asymptomatic women, periodic examinations are certainly important—even if a Pap test is not done each year. As primary-care providers, gynecologists offer periodic screenings for conditions such as diabetes, cardiac disease, and colon cancer, in addition to gynecologic evaluations. And it makes good sense to encourage frequent periodic exams for patients at risk, such as young women in need of contraceptive counseling or evaluation for sexually transmitted disease, and older women in need of breast surveillance.

But if we provide periodic screening without the “Pap-smear prompt,” we’ll need to redouble our efforts to teach patients the value of the annual exam for other health assessments, not cervical cytology screening alone.

The authors report no relevant financial relationships.

COMMENTARY

Putting new guidelines into practice is easier said than done

Steven Goldstein, MD
New York University Medical Center

Is the Pap test still necessary for every woman, every year? No, according to the latest guidelines, but old habits die hard, even for physicians.

And there is little doubt that yearly screening, though not scientifically based, has contributed much to the reduction of cervical cancer incidence and mortality in American women. Our patients and we as providers have long considered a Pap test the cornerstone of the annual gynecologic exam, as we’ve been urged to do for decades by our leading academic institutions. However, the American College of Obstetricians and Gynecologists (ACOG) and the American Cancer Society (ACS) revised their guidelines last year, and no longer support yearly screening for every woman, every year.^1,2 The US Preventive Services Task Force (USPSTF) revised its guidelines in accord, with the exception that it found the evidence insufficient to support screening low-risk women more often than every 3 years, at any age.³

Original rationale: “Pap smear prompt”

These organizations, as well as the National Cancer Institutes (NCI), had supported annual Pap testing since the mid-1950s—long before any data suggested whether one screening interval might be better than another.

In fact, part of the original rationale for annual screening was that it would serve as a vehicle to bring women in for their annual gynecologic exam.⁴

 

Why change? How will patients react?

Cumulative findings suggest an age- and risk-based approach

Research over the past few decades has revealed much about the pathogenesis of cervical cancer which supports an age- and risk-based approach to screening for cervical cancer—when to start, when to stop, and how often to perform cervical cytology.

The main questions

In this article, I’ll review some of the data on these concerns:

• Why wait 3 years after first intercourse for the first Pap test?
  
• Why is 21 the ‘default’ age for first Pap test?
  
• What are the risks and costs of screening every 2 to 3 years in well-screened women over age 30? Over age 65?
  
• Do most women without a cervix require screening?
  
• What is the role of HPV DNA testing?
  
• How should we deal with abnormal results?
  
• How should we counsel the patient?
  
• What’s the harm in continuing Pap tests in all women?
  
• Will women return for annual exams as we advise, if we change their Pap test routine?
  

ADOLESCENCEWhy wait 3 years after onset of intercourse for first Pap test?

Care is not compromised

Delaying screening until at least 3 years after coitarche does not compromise the diagnosis of high-grade lesions, yet does allow discovery and eradication long before they become malignant. On the other hand, screening young women sooner than 3 years after first sexual intercourse risks diagnosing numerous self-limited HPV infections and transient low-grade dysplastic lesions, which have very low premalignant potential.

Persistent high-risk HPV must precede cancer. Cervical cancer develops only after persistent HPV infection, many years from the initial HPV exposure.

We now know that at least 15 to 18 types of human papillomavirus (HPV) can cause cervical cancer, and that infection with a high-risk type of HPV is the necessary antecedent—but not by itself a sufficient antecedent—for high-grade cervical dysplasia and cervical cancer.^5,6

We also know that HPV is most often acquired through sexual intercourse and that it is very efficiently acquired by young women.^7,8 For example, a study of young college women who were initially HPV negative acquired HPV at a rate of 14% per year.⁷

HPV infections in young women are usually transient, however. Up to 90% of young women who test positive for HPV DNA will revert to negative within 2 years.⁹

The problems of screening too early. Squamous cancer of the cervix is exceedingly rare in women under age 21.¹⁰ Diagnosis of self-limited HPV infections and transient low-grade dysplastic lesions would likely result in repeat Pap tests and colposcopies. In addition to being costly and anxiety-provoking, these interventions may lead to needless destruction of the immature transformation zone in young women of low parity.

Don’t neglect counseling, STD testing, birth control

Delaying the first Pap test in young women until 3 years after initial intercourse, however, does not mean we should neglect gynecologic examinations in this group. They are at high risk for sexually transmitted infections and at extremely high risk for unintended pregnancies. So, while waiting 3 years to do the first Pap test makes sense, an early visit, before or soon after first intercourse is essential for gynecologic health care, including prevention of pregnancy and sexually transmitted disease.

October 2004 opinion on Gyn visits for young teens. ACOG published a committee opinion¹¹ to clear up confusion over when adolescent girls should have their first Pap test versus when they should have their first gynecologic visit. The opinion advises a first visit at age 13 to 15, for health guidance, screening, and preventive services, and says parents and patients need to understand that this visit does not necessarily include a pelvic exam or a Pap test. The advisory stresses that adolescents are unlikely to acknowledge sexual activity without sensitive and direct questions, and suggested a resource: “Asking the Right Questions,” from the STD/HTD Prevention Training Center of New England.

AGES 21 TO 30Why is age 21 the “default” for first Pap?

Because the incidence of high-grade squamous intraepithelial lesions (HSIL) increases with age,¹² cytology screening should start at age 21, irrespective of sexual history. Saslow et al¹ writing for the American Cancer Society, acknowledged the difficulty of obtaining a reliable sexual history. This may be especially true with patients who may have suffered sexual abuse as adolescents. The default age of 21 for initial Pap test allows the provider to sidestep the question of age at first intercourse. On the other hand, a 21-year-old who has never had vaginal intercourse does not need to be screened for cervical cancer.

Aggressive screening until age 30

Women should be screened every year until age 30 if conventional Pap smears are used.^1,2 During a woman’s 20s, precancerous lesions become more common and invasive cancer, while still rare, is seen with increasing frequency. Both ACOG and ACS consider this period of a woman’s life to be a time for aggressive cervical cancer screening.

 

Frequent screening until age 30 allows us to identify and treat young women with histologic cervical intraepithelial neoplasia (CIN) 2 and 3 or worse, and to identify those who, because of persistently negative Pap tests, are at lowest risk.

Since these women schedule more frequent visits for contraception and prenatal care, we have greater opportunities for cervical cancer screening.

Does type of Pap test determine screening interval?

Every 2 years is sufficient if the liquid Pap test is used: ACS.¹ This recommendation is based on balancing the increase in abnormal results found with liquid-based Paps against the likelihood that most of the additional abnormal findings will be only atypical squamous cells, undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). These minimally abnormal results, while needing follow-up, have a relatively low rate of CIN 2 or 3 on biopsy.

Annual tests until age 30, irrespective of Pap technology: ACOG.² That decision recognizes the fact that, while the data suggest increased sensitivity of liquid-based cervical cytology, this observation is not conclusive, and both technologies fall short of 100% sensitivity.

AGES 30 TO 65Why extend the interval between Pap tests?

High risk calls for yearly screens

Both ACOG and the ACS agree that women at high-risk should be screened annually regardless of age.

Risk factors include:

• history of cervical cancer,
  
• immunocompromise including HIV,
  
• in utero exposure to diethylstilbestrol (DES), and
  
• women over age 30 who were not well screened in their 20s; these women should have at least 3 negative annual exams before the screening interval is extended.
  

Longer interval if risk is low

Up to age 30, frequent screening can be expected to significantly reduce a woman’s risk of cervical cancer. Multiple negative Paps offer a high degree of protection—the more consecutive normal tests, the higher the level of protection.¹³

Research indicates, however, that it seems reasonable to reduce the screening interval from every year to every 2 to 3 years in previously well-screened women over age 30:

• These women have the protection offered by frequent Pap tests during the previous decade.
  
• By the time most women reach their 30s, the area of active squamous metaplasia, which serves as the substrate for cervical neoplasia, is reduced.¹⁴
  

Studies of screening effects

National Breast and Cervical Cancer Early Detection Program. Using data from this program, Sawaya et al¹³ studied 31,728 women aged 30 to 64 with 3 or more consecutive negative Pap tests spaced no more than 3 years apart. They found only 9 women (0.028%) with biopsy-proven CIN 2, only 6 (0.019%) with CIN 3, and none with invasive cancer.

International Agency for Research in Cancer¹⁵ data showed essentially no difference in the protective effect of cytology screening at 1-, 2-, or 3-year intervals in women enrolled in screening programs in 7 Western European countries and 3 Canadian centers, among women aged 35 to 64 who had at least 2 previous negative Pap tests. The authors calculated a cumulative reduction in cervical cancer of 93.5% with annual screening, 92.5% with screening every 2 years, and 90.8% with screening every 3 years, compared to women who had no screening.

National Breast and Cervical Cancer Early Detection Program¹⁶ data also support extending the screening interval beyond 1 year. In 128,805 women followed after at least 1 prior negative Pap, no significant difference was noted in the incidence of cytologic HSIL on a subsequent Pap performed 9 to 12 months, 13 to 24 months, or 25 to 36 months later. The rates of HSIL were 25, 29, and 33 per 100,000 women, respectively.

Do postmenopausal women need screening?

Women over 65 do get cervical cancer. While they represent 13% of the total U.S. population, they have 25% of new cases of cervical cancer and suffer 41% cervical cancer mortality.¹⁷ Incident cases of squamous cancer among older women, however, come from the cohort who have not previously been well screened.

An older woman in a long-term monogamous relationship who has a history of frequent negative Pap tests is at such low risk for acquiring cervical cancer that the US Preventive Services Task Force recommends discontinuing screening in this group at age 65.³

The American Cancer Society recommends discontinuing screening at age 70 in low-risk previously well screened women.¹

ACOG does not set a specific upper age for cytology screening.² While acknowledging the recommendations of these other professional organizations, ACOG notes that there is no good evidence to establish one age over another to discontinue screening, and instead encourages individualization.

ACOG recommends that if an older woman’s sexual practice changes after she is no longer being tested with cytology, some consideration should be given to reinitiating screening. If screening is restarted, 3-year intervals seems appropriate, as older women may have immunity to many HPV types, and their active transformation zone is generally retracted and very narrow.

 

Why not just continue frequent screening in this less vulnerable population? The consequences of continuing screening in the older, previously well-screened population were nicely illustrated in a study by Sawaya et al,¹⁸ using data from the Heart and Estrogen/Progestin Replacement Study (HERS) of postmenopausal women, they evaluated the cytology results of 2,561 women followed over a 4-year period. These women had a Pap test 2 to 2 years after a normal entry cytology.

Subsequent follow-up of cases in which the Pap test was abnormal found only 1 woman with histologic dysplasia, which was a case of mild to moderate dysplasia. To make this diagnosis involved inconvenience, cost and morbidity to the group. To find this single case of mild to moderate dysplasia, 110 women were recalled for follow-ups, which required 231 interventions that included repeat Pap smears, colposcopies, endometrial biopsies, cervical and endocervical biopsies, D&Cs, and excision procedures.

Add to the additional tests, the anxiety inherent in a report of an abnormal Pap test and its follow-up, and the value of limiting screening in this very low risk population become more apparent.

Screen for cervical cancer if there is no cervix?

Since 1996, the US Preventive Services Task Force has recommended against cervical cytology screening in women whose uterus and cervix have been removed for benign indications. Despite this, a recent study showed, as many as 45.6% of such women were still having Pap tests.¹⁹

For any screening procedure to be cost effective, there must be a threshold prevalence of the disease in the population to be screened. While women with prior cervical cancer or high-grade dysplasia remain at increased risk for recurrences at the vaginal cuff, women with no history of such disease are at extremely low risk.

In essence, screening in these women becomes a search for primary vaginal cancer, which is one of the rarest of gynecologic malignancies—only 0.3% of cancers in women, a frequency less than that of cancer of the tongue.⁹ Continued screening in the absence of a cervix implies the need to screen an unacceptably large number of women to diagnose a single lesion. Cytology screening in this group is far more likely to diagnose low-grade vaginal intraepithelial neoplasia (VAIN). VAIN 1 reflects self-limited epithelial changes that are extremely unlikely to progress to cancer.

What is the role of HPV testing?

Last year, the US Food and Drug Administration approved the Hybrid Capture 2 test for high-risk HPV DNA (Digene, Gaithersburg, Md) for use in addition to cervical cytology for screening women over age 30. Both ACOG and the ACS acknowledged this combination of tests as an acceptable option as long as women who test negative on both tests are not retested for 3 years.^1,2

Using HPV DNA screening in women under 30 makes little sense. Many studies have confirmed the high prevalence of high-risk HPV in this age group whose risk of invasive cancer is quite low.^7,12,20 Screening with HPV before age 30 would result in an unacceptably high false-positive rate, with no advantage over annual screening with cytology alone.

High negative predictive value after age 30

On the other hand, after age 30, as the prevalence of HPV declines, the specificity of this test improves markedly.¹² Why wait 3 years before retesting if both tests are negative? The answer lies in the extremely high negative predictive value of the combination. Sherman et al²¹ determined that the negative predictive value of the combination of cytology plus HPV DNA testing 33 months after both tests are negative is 99.88%. At 45 months, it was still 99.84%.

Thus we can provide excellent assurance to women who test negative that their risk of CIN 3 or squamous cancer is negligible over at least the intervening 3 years.

It’s worth noting that in this same study, the negative predictive value of cytology alone at 33 and 45 months was also quite high: 99.61% and 99.47%, respectively.

ABNORMAL RESULTSConsensus guidelines for combined testing

Management is clear when both tests are negative, or when the Pap shows SIL and the HPV is positive. But what if only 1 of the tests is abnormal? A February 2003 consensus workshop held by ACS, the American Society for Colposcopy and Cervical Pathology, and the National Institutes of Health developed recommendations for managing the various combinations of results.²²

ASC-US and positive HPV

Data clearly support triaging these patients to colposcopy. The National Cancer Institute’s ASCUS/LSIL Triage study (ALTS) study showed that, in a group of 1,161 women, this combination of results had a 92% sensitivity for diagnosing CIN 3.²³ Solomon Other studies, done under perhaps less rigorous scientific conditions, also showed high sensitivity, though generally not as high as in the ALTS study.

 

When cytology results are more severe than ASC-US

If results are ASC-H, AGC, LSIL, or HSIL, manage with colposcopy regardless of HPV results.

Negative cytology and positive for high-risk HPV

This scenario is more difficult for both the physician and patient. High-risk HPV is a clear risk factor for subsequent dysplasia.²¹ While most HPV infections are transient, the risk of dysplasia increases when they persist.²⁴ A reasonable course is to repeat both Pap and HPV in 6 to 12 months. This allows time for transient HPV infections to clear and for persistent infections to be identified on the repeat test.

The ultimate prognosis and management are determined by the repeat cytology plus HPV. If both repeat tests are negative, further repeat screening should be delayed for 3 years.

If the cytology is ASC-US, but HPV is negative, the patient may safely be screened again in 1 year with Pap plus HPV. Colposcopy is indicated if the cytology is worse than ASC-US and/or if the HPV remains positive.

Counseling HPV-positive patients

Perhaps the most difficult aspect of screening with cytology plus HPV DNA is what to advise patients whose Pap test is normal but whose HPV is positive.

Many women are aware that HPV is sexually transmitted, and a positive HPV test conjures fears of spousal infidelity, concerns about spreading the infection, and fear of other sexually transmitted infections.

Long latency. I have found it useful to defuse the infidelity concern by pointing to the long latent period associated with HPV infections. A recently diagnosed HPV infection may have been acquired years in the past from a prior partner, or from her current partner early in their relationship.

Neither partner should construe a positive test for high-risk HPV as an indicator of promiscuity. It is just as likely that a temporary change in her immune status allowed a previously latent infection to become productive.

Highly prevalent. The patient may be reassured by knowing that HPV is exceedingly common; up to 75% of women will have one or more subtypes of HPV in their lower genital tract at some time in their lives. Pointing out that it can be considered a marker of ever having had vaginal intercourse may help to eliminate the stigma of a sexually transmitted disease.

Let her know her partner probably carries the same HPV type, or has cleared it in the past.

Low risk of cancer for the partner. Male partners of women who test positive for high-risk HPV DNA do not require any testing. Reassure the couple that the male’s risk of cancer is very low since the penis lacks a transformation zone, the substrate for efficient neoplastic transformation.

Reassure her of low risk without neoplastic changes. The presence of HPV on the cervix is of little clinical importance unless the cervical epithelium has begun to undergo neoplastic changes. Reassure the patient that as long as she has no squamous intraepithelial lesions on Pap testing or a persistently positive HPV DNA test over time, she has a low risk developing cancer.

What’s the harm in yearly testing?

Will our patients skip annual gynecologic exams if we tell them they no longer need an annual Pap test? If Paps are performed only every 3 years, will many women wait 4 or 5 years between screenings?

These and other concerns make it difficult to change an ingrained routine, despite data that support new practice guidelines.

Besides, the Pap test is inexpensive, so what’s the harm in doing it annually? While the Pap test itself remains relatively inexpensive, the wide popularity of the liquid-based Pap test has doubled or tripled the cost of the test in many markets. And annual testing in low-risk women has a high rate of false positives, which require costly follow-up testing.¹³

Though future studies must determine the optimal interval for gynecologic examinations in asymptomatic women, periodic examinations are certainly important—even if a Pap test is not done each year. As primary-care providers, gynecologists offer periodic screenings for conditions such as diabetes, cardiac disease, and colon cancer, in addition to gynecologic evaluations. And it makes good sense to encourage frequent periodic exams for patients at risk, such as young women in need of contraceptive counseling or evaluation for sexually transmitted disease, and older women in need of breast surveillance.

But if we provide periodic screening without the “Pap-smear prompt,” we’ll need to redouble our efforts to teach patients the value of the annual exam for other health assessments, not cervical cytology screening alone.

The authors report no relevant financial relationships.

A woman’s first cesarean may be more fateful than ever, because 1 low-transverse cesarean delivery is the new limit for a trial of labor in subsequent pregnancies, advises a 2004 practice bulletin from the American College of Obstetricians and Gynecologists (ACOG).¹ The previous bulletin on vaginal birth after cesarean (VBAC) recommended a limit of 2.

The new bulletin reaffirms the previous recommendation that obstetric and anesthesia personnel be immediately available throughout active labor, in case emergency cesarean is necessary.

VBAC is still within the standard of care, but rates were declining even before the new bulletin was released: from a high of 28.3% in 1996 to 12.6% in 2002.²

Benefits of VBAC may outweigh the risks in most women with 1 previous low-transverse cesarean,³ but even with optimal facilities and personnel, numerous factors warrant special caution, according to recent studies I’ll review in this article.

Recent studies of risks and benefits

No randomized trials. ACOG notes,¹ “Despite thousands of citations in the world’s literature, there are currently no randomized trials comparing maternal or neonatal outcomes for both repeat cesarean delivery and VBAC.”

Success rates are similar for gravidas with previous cesarean for a nonrecurring indication and those with no previous cesarean.^4-6

Uterine rupture is more likely during a trial of labor, but the rate is usually below 1%.^7-9

Other limiting factors may include labor augmentation and induction, maternal obesity, gestational age beyond 40 weeks, birth weight over 4,000 g, and an interdelivery interval of less than 19 months.^10-17

When a trial of labor fails, women face a heightened risk of uterine rupture, hysterectomy, transfusion, and endometritis.^3,4,9

Perinatal death is more likely during VBAC than planned repeat cesarean, although the death rate is usually less than 1%.^3,8,9,18

Indications and contraindications

The TABLE outlines potential candidates, ineligible gravidas, resources needed, and situations that warrant caution.

Don’t assume: Check the previous operative note

It is all too easy to presume that a previous cesarean section at term was performed through a transverse incision in the lower uterine segment.

While this may be true in the majority of cases, the actual operative note may reveal information relevant to the delivery decision: an extensive tear of the uterine incision, previously unrecognized uterine anomalies, or the need to perform a classical or T-shaped incision to facilitate delivery of the infant.

For these reasons, review the actual operative report whenever possible before a trial of labor.

2 prior low-transverse incisions

While this is not an absolute contraindication to VBAC, in today’s cautious climate ACOG recommends VBAC proceed only when there is also a history of successful vaginal delivery.^1,19 Otherwise, women with 2 or more previous cesareans should undergo repeat abdominal birth.

Prior low-vertical incision

Although successful VBACs have been reported in women with a prior low-vertical uterine incision, many experts feel that these incisions often extend superiorly into the upper uterus and thus increase the likelihood of uterine rupture in subsequent labors.^20,21

Greater risk with single-layer closure

Single-layer uterine closure appears to increase the likelihood of rupture during subsequent labors.²² As a result, many physicians have returned to 2-layer closure of the lower transverse uterine incision. It is unclear whether single-layer closure is a contraindication to subsequent labor, but it does warrant caution due to a 4-fold increase in the risk of rupture.²²

Discourage closely spaced gestations

The shorter the interval between deliveries, the more likely is uterine rupture during a trial of labor.^23,24 For those considering a subsequent VBAC, I recommend trying to space their next delivery at least 18 months after cesarean birth.

Labor induction increases risk

Spontaneous labor leads to successful VBAC more often than does labor induction or augmentation. In addition, a recent study found 5 times the risk of uterine rupture when oxytocin was used to induce labor, compared with elective repeat cesarean—although the rate of rupture was less than 1% in both groups.²⁵

 

The use of prostaglandins in labor induction greatly increases the risk of rupture, with rates of 24.5 per 1,000 reported, compared with 5.2 per 1,000 in women with spontaneous labor.²⁶ ACOG strongly discourages the use of prostaglandin cervical ripening agents in labor inductions.²⁶

Seek out other factors

Women who initially appear eligible may harbor other characteristics or conditions that warrant special attention.^15,26-28

External cephalic version. Although 1 study²⁹ concluded it is effective in women undergoing a trial of labor after cesarean, vigilance is recommended.

Twin gestations. Two retrospective studies involving a total of 45 women found VBAC to be safe in twin gestations. Because of the limited number of women studied and the lack of randomized, controlled trials, caution is strongly advised.^30,31

Macrosomia. The rate of uterine rupture rises in women who have not had a previous vaginal delivery.²⁷

Postdates. Although VBAC is less likely to succeed after 40 weeks’ gestation, the risk of uterine rupture increases only with induction of labor.¹¹

Analgesia. Women undergoing a trial of labor can receive epidural anesthesia without increasing the risk of rupture or failed VBAC and without obscuring the signs and symptoms of uterine rupture.^32,33 In fact, as ACOG notes, effective pain relief may encourage more women to try VBAC.¹

Previous vaginal delivery. Women who have delivered vaginally are more likely to succeed at VBAC—by a factor of 9 to 28—than those who have not.^34,35

Other conditions such as maternal obesity and advanced age should be evaluated in light of the patient’s overall risk-benefit profile. Although caution is recommended, definitive data are lacking.

TABLE

Criteria for trial of labor

QUALIFICATIONS
1 prior low-transverse cesarean section
Clinically adequate pelvis
No other uterine scars
DISQUALIFICATIONS
Prior classical or T-shaped uterine incision
Multiple uterine incisions
Previous uterine rupture
Contracted pelvis
Contraindications to vaginal birth
REQUIREMENTS THROUGHOUT ACTIVE LABOR
Obstetrician immediately available
Continuous electronic monitoring of the fetal heart rate
Personnel skilled in interpreting fetal tracings
Anesthesia for emergency cesarean
Physician qualified for emergency cesarean
PRECAUTIONS
Unknown uterine scars
Prior low vertical uterine incision
Uterine malformations
Prior single-layer uterine closure
Short interdelivery interval
Need for labor induction
Need for external cephalic version
Twin gestation
Suspected macrosomia
Maternal obesity
Postdates
Advanced maternal age
No prior vaginal delivery
Source: ACOG1

Prognostic formulas

One decision analysis³⁶ concluded that VBAC is a reasonable option when the chance of success exceeds 50% and the desire for future pregnancy is 10% to 20% or more. Although scoring systems have been proposed to predict the likelihood of success, individualized assessment of each patient is ideal. (See “Case by case: Adding up the decisive factors”.)

 

VBAC is not an option where facilities fall short

Despite meeting VBAC criteria for previous incision or pelvic adequacy, many US women do not have the option of a trial of labor. The reason: the need for obstetric care providers throughout active labor and the ability to perform an emergency cesarean.¹ As a result, many midwives and family practitioners can no longer care for VBAC patients independently.

Continuous monitoring is a must

It is the potential for uterine rupture that places patients at risk for unfavorable obstetric outcomes—and rupture can be hard to predict. A nonreassuring fetal heart rate is the most frequent sign.¹ Others are uterine or abdominal pain, vaginal bleeding, loss of station of the presenting part, and hypovolemia.¹

Continuous electronic monitoring of the fetal heart has the potential to detect nonreassuring events earlier than intermittent auscultation. Thus, continuous fetal heart rate monitoring has become the standard for women attempting VBAC. When it is unavailable, VBAC should not be offered.

Also crucial: Anesthesiology

ACOG recommends that anesthesia and other personnel be on hand in case emergency cesarean is warranted.¹ While teaching hospitals and large referral centers are constantly staffed with obstetricians and anesthesiologists, birthing centers and smaller community-based hospitals often lack such coverage. As a result, some physicians and hospitals have withdrawn VBAC as an option

Reducing medicolegal risk

When a trial of labor results in uterine rupture or other adverse outcomes, the patient is more likely to sue. Informed consent and thorough documentation of the VBAC decision are crucial and should include³⁷:

• Appropriate discussion of maternal and perinatal risks and benefits, and documentation of this exchange.
  
• A clear statement of the woman’s intention to undergo a trial of labor after cesarean delivery.
  
• If possible, documentation of previous uterine scar on the prenatal record.
  
• Appropriate counseling about the increased risk of rupture when labor is induced with oxytocin, and documentation of this discussion.
  
• Counseling about the increased risk of rupture when a trial of labor follows a previous cesarean by less than 19 months.
  
• Discussion about decreased likelihood of success if the woman is obese, is of advanced age, or has not had a prior vaginal birth.
  

Is VBAC availability better for health and happiness?

Many women want the option of a trial of labor after cesarean because it affords them the opportunity to experience vaginal delivery. Women who have undergone both cesarean and vaginal deliveries usually opt for a trial of labor in their next pregnancy.³⁸ When a physician or hospital eliminates VBAC as an option, it can lead to patient dissatisfaction—as well as loss of revenue if a woman seeks care elsewhere.

Risk of placenta accreta

If elective repeat cesarean were the only option, the incidence of placenta accreta would increase over time.

Placenta accreta is strongly linked to placenta previa, a condition recognized to increase as the number of previous cesarean sections rises.^39,40 A woman with 2 prior cesareans has a 2% incidence of placenta previa; nearly half of these cases are associated with placenta accreta.⁴¹ As a result, complications of accreta such as maternal death, need for substantial transfusion, postoperative infection, and intraoperative urinary tract injuries would be expected to increase if VBAC were abandoned.⁴²

For this reason, it is important to ask about the patient’s childbearing goals. If a large family is planned, the potential risk of placenta accreta should be explained.

Assess for accreta. All patients with a prior cesarean section require careful evaluation of placental location and assessment for possible accreta should placenta previa or a low-lying placenta be identified prenatally.

I have found both ultrasound and magnetic resonance imaging useful in recognizing accreta, allowing for adequate preoperative preparation and more favorable outcomes. If accreta is not detected until the time of elective repeat cesarean, it can be life-threatening for the patient.

Should we abandon VBAC?

An unfortunate result of the initiatives promoting VBAC in the 1980s and 90s was a higher rate of uterine rupture, since many women with previous cesarean were strongly encouraged—even required—to undergo a trial of labor. Now that elective repeat cesareans are again on the rise, the risk of rupture should diminish due to better VBAC patient selection, but will probably remain substantially higher than for repeat cesarean.

What exactly is the risk of rupture?

In 1 population-based, retrospective cohort analysis²⁵ involving 20,095 women with 1 previous cesarean section, researchers found a rate of uterine rupture of 5.2 per 1,000 women when labor was spontaneous, compared with 1.6 per 1,000 women who underwent elective repeat cesarean without labor. For women having labor induced with prostaglandins or by other means, the rates were 24.5 and 7.7 per 1,000, respectively.

 

In the same study, the relative risk of uterine rupture was 3.3 for women presenting in spontaneous labor, compared with those who underwent repeat cesarean without labor; it was 15.6 and 4.9 for women whose labor was induced with prostaglandins or by other means, respectively. The rate of infant mortality was 5.5% in cases involving uterine rupture, compared with 0.5% without rupture.²⁵

Note that this study covered the years 1987 through 1996—and thus predated ACOG rules requiring round-the-clock obstetric and anesthesia care, and those barring prostaglandins for labor induction.

Perinatal death more likely with VBAC, but absolute risk is low

A separate population-based, retrospective, cohort study¹⁸ focused on different outcomes: intrapartum stillbirth or neonatal death. This study involved 313,238 singleton births at 37 to 43 weeks’ gestation with the fetus in a cephalic presentation.

Among the women opting for VBAC, the overall rate of delivery-related perinatal death was 12.9 per 10,000 women. This was approximately 11 times greater than the risk associated with planned repeat cesarean, more than twice the risk associated with labor in multiparous women, and similar to the risk among nulliparous women in labor. However, in absolute terms, the risk of perinatal death associated with a trial of labor and uterine rupture was low: 1 in 2,200.¹⁸

What’s the bottom line?

Are findings such as these reason to abandon VBAC? Not necessarily. VBAC success rates range from 60% to 80%, and a 1991 meta-analysis⁴³ of more than 30 US studies found lower maternal febrile morbidity after a trial of labor than after repeat cesarean, and no differences between the 2 approaches in uterine dehiscence, rupture, or perinatal mortality.

A more recent meta-analysis⁹ of international studies involving 47,682 women found a uterine rupture rate of 0.4% for women undergoing a trial of labor versus 0.2% for those having elective repeat cesarean. A later meta-analysis, also international, found an overall uterine rupture rate of 6.2 per 1,000 women attempting VBAC, with a perinatal mortality rate of 0.4 per 1,000. Perinatal mortality was significantly lower among US studies.⁶

Nevertheless, when it comes to VBAC, absolute risks are low, and planned repeat cesarean does not eliminate them entirely. Elective cesarean carries a risk of maternal death up to 2.8 times that of vaginal delivery, though absolute risk is low.⁴⁴

Thus, when patients are carefully selected and fully informed of benefits and risks, VBAC should remain an available option.

The author reports no relevant financial relationships.

A woman’s first cesarean may be more fateful than ever, because 1 low-transverse cesarean delivery is the new limit for a trial of labor in subsequent pregnancies, advises a 2004 practice bulletin from the American College of Obstetricians and Gynecologists (ACOG).¹ The previous bulletin on vaginal birth after cesarean (VBAC) recommended a limit of 2.

The new bulletin reaffirms the previous recommendation that obstetric and anesthesia personnel be immediately available throughout active labor, in case emergency cesarean is necessary.

VBAC is still within the standard of care, but rates were declining even before the new bulletin was released: from a high of 28.3% in 1996 to 12.6% in 2002.²

Benefits of VBAC may outweigh the risks in most women with 1 previous low-transverse cesarean,³ but even with optimal facilities and personnel, numerous factors warrant special caution, according to recent studies I’ll review in this article.

Recent studies of risks and benefits

No randomized trials. ACOG notes,¹ “Despite thousands of citations in the world’s literature, there are currently no randomized trials comparing maternal or neonatal outcomes for both repeat cesarean delivery and VBAC.”

Success rates are similar for gravidas with previous cesarean for a nonrecurring indication and those with no previous cesarean.^4-6

Uterine rupture is more likely during a trial of labor, but the rate is usually below 1%.^7-9

Other limiting factors may include labor augmentation and induction, maternal obesity, gestational age beyond 40 weeks, birth weight over 4,000 g, and an interdelivery interval of less than 19 months.^10-17

When a trial of labor fails, women face a heightened risk of uterine rupture, hysterectomy, transfusion, and endometritis.^3,4,9

Perinatal death is more likely during VBAC than planned repeat cesarean, although the death rate is usually less than 1%.^3,8,9,18

Indications and contraindications

The TABLE outlines potential candidates, ineligible gravidas, resources needed, and situations that warrant caution.

Don’t assume: Check the previous operative note

It is all too easy to presume that a previous cesarean section at term was performed through a transverse incision in the lower uterine segment.

While this may be true in the majority of cases, the actual operative note may reveal information relevant to the delivery decision: an extensive tear of the uterine incision, previously unrecognized uterine anomalies, or the need to perform a classical or T-shaped incision to facilitate delivery of the infant.

For these reasons, review the actual operative report whenever possible before a trial of labor.

2 prior low-transverse incisions

While this is not an absolute contraindication to VBAC, in today’s cautious climate ACOG recommends VBAC proceed only when there is also a history of successful vaginal delivery.^1,19 Otherwise, women with 2 or more previous cesareans should undergo repeat abdominal birth.

Prior low-vertical incision

Although successful VBACs have been reported in women with a prior low-vertical uterine incision, many experts feel that these incisions often extend superiorly into the upper uterus and thus increase the likelihood of uterine rupture in subsequent labors.^20,21

Greater risk with single-layer closure

Single-layer uterine closure appears to increase the likelihood of rupture during subsequent labors.²² As a result, many physicians have returned to 2-layer closure of the lower transverse uterine incision. It is unclear whether single-layer closure is a contraindication to subsequent labor, but it does warrant caution due to a 4-fold increase in the risk of rupture.²²

Discourage closely spaced gestations

The shorter the interval between deliveries, the more likely is uterine rupture during a trial of labor.^23,24 For those considering a subsequent VBAC, I recommend trying to space their next delivery at least 18 months after cesarean birth.

Labor induction increases risk

Spontaneous labor leads to successful VBAC more often than does labor induction or augmentation. In addition, a recent study found 5 times the risk of uterine rupture when oxytocin was used to induce labor, compared with elective repeat cesarean—although the rate of rupture was less than 1% in both groups.²⁵

 

The use of prostaglandins in labor induction greatly increases the risk of rupture, with rates of 24.5 per 1,000 reported, compared with 5.2 per 1,000 in women with spontaneous labor.²⁶ ACOG strongly discourages the use of prostaglandin cervical ripening agents in labor inductions.²⁶

Seek out other factors

Women who initially appear eligible may harbor other characteristics or conditions that warrant special attention.^15,26-28

External cephalic version. Although 1 study²⁹ concluded it is effective in women undergoing a trial of labor after cesarean, vigilance is recommended.

Twin gestations. Two retrospective studies involving a total of 45 women found VBAC to be safe in twin gestations. Because of the limited number of women studied and the lack of randomized, controlled trials, caution is strongly advised.^30,31

Macrosomia. The rate of uterine rupture rises in women who have not had a previous vaginal delivery.²⁷

Postdates. Although VBAC is less likely to succeed after 40 weeks’ gestation, the risk of uterine rupture increases only with induction of labor.¹¹

Analgesia. Women undergoing a trial of labor can receive epidural anesthesia without increasing the risk of rupture or failed VBAC and without obscuring the signs and symptoms of uterine rupture.^32,33 In fact, as ACOG notes, effective pain relief may encourage more women to try VBAC.¹

Previous vaginal delivery. Women who have delivered vaginally are more likely to succeed at VBAC—by a factor of 9 to 28—than those who have not.^34,35

Other conditions such as maternal obesity and advanced age should be evaluated in light of the patient’s overall risk-benefit profile. Although caution is recommended, definitive data are lacking.

TABLE

Criteria for trial of labor

QUALIFICATIONS
1 prior low-transverse cesarean section
Clinically adequate pelvis
No other uterine scars
DISQUALIFICATIONS
Prior classical or T-shaped uterine incision
Multiple uterine incisions
Previous uterine rupture
Contracted pelvis
Contraindications to vaginal birth
REQUIREMENTS THROUGHOUT ACTIVE LABOR
Obstetrician immediately available
Continuous electronic monitoring of the fetal heart rate
Personnel skilled in interpreting fetal tracings
Anesthesia for emergency cesarean
Physician qualified for emergency cesarean
PRECAUTIONS
Unknown uterine scars
Prior low vertical uterine incision
Uterine malformations
Prior single-layer uterine closure
Short interdelivery interval
Need for labor induction
Need for external cephalic version
Twin gestation
Suspected macrosomia
Maternal obesity
Postdates
Advanced maternal age
No prior vaginal delivery
Source: ACOG1

Prognostic formulas

One decision analysis³⁶ concluded that VBAC is a reasonable option when the chance of success exceeds 50% and the desire for future pregnancy is 10% to 20% or more. Although scoring systems have been proposed to predict the likelihood of success, individualized assessment of each patient is ideal. (See “Case by case: Adding up the decisive factors”.)

 

VBAC is not an option where facilities fall short

Despite meeting VBAC criteria for previous incision or pelvic adequacy, many US women do not have the option of a trial of labor. The reason: the need for obstetric care providers throughout active labor and the ability to perform an emergency cesarean.¹ As a result, many midwives and family practitioners can no longer care for VBAC patients independently.

Continuous monitoring is a must

It is the potential for uterine rupture that places patients at risk for unfavorable obstetric outcomes—and rupture can be hard to predict. A nonreassuring fetal heart rate is the most frequent sign.¹ Others are uterine or abdominal pain, vaginal bleeding, loss of station of the presenting part, and hypovolemia.¹

Continuous electronic monitoring of the fetal heart has the potential to detect nonreassuring events earlier than intermittent auscultation. Thus, continuous fetal heart rate monitoring has become the standard for women attempting VBAC. When it is unavailable, VBAC should not be offered.

Also crucial: Anesthesiology

ACOG recommends that anesthesia and other personnel be on hand in case emergency cesarean is warranted.¹ While teaching hospitals and large referral centers are constantly staffed with obstetricians and anesthesiologists, birthing centers and smaller community-based hospitals often lack such coverage. As a result, some physicians and hospitals have withdrawn VBAC as an option

Reducing medicolegal risk

When a trial of labor results in uterine rupture or other adverse outcomes, the patient is more likely to sue. Informed consent and thorough documentation of the VBAC decision are crucial and should include³⁷:

• Appropriate discussion of maternal and perinatal risks and benefits, and documentation of this exchange.
  
• A clear statement of the woman’s intention to undergo a trial of labor after cesarean delivery.
  
• If possible, documentation of previous uterine scar on the prenatal record.
  
• Appropriate counseling about the increased risk of rupture when labor is induced with oxytocin, and documentation of this discussion.
  
• Counseling about the increased risk of rupture when a trial of labor follows a previous cesarean by less than 19 months.
  
• Discussion about decreased likelihood of success if the woman is obese, is of advanced age, or has not had a prior vaginal birth.
  

Is VBAC availability better for health and happiness?

Many women want the option of a trial of labor after cesarean because it affords them the opportunity to experience vaginal delivery. Women who have undergone both cesarean and vaginal deliveries usually opt for a trial of labor in their next pregnancy.³⁸ When a physician or hospital eliminates VBAC as an option, it can lead to patient dissatisfaction—as well as loss of revenue if a woman seeks care elsewhere.

Risk of placenta accreta

If elective repeat cesarean were the only option, the incidence of placenta accreta would increase over time.

Placenta accreta is strongly linked to placenta previa, a condition recognized to increase as the number of previous cesarean sections rises.^39,40 A woman with 2 prior cesareans has a 2% incidence of placenta previa; nearly half of these cases are associated with placenta accreta.⁴¹ As a result, complications of accreta such as maternal death, need for substantial transfusion, postoperative infection, and intraoperative urinary tract injuries would be expected to increase if VBAC were abandoned.⁴²

For this reason, it is important to ask about the patient’s childbearing goals. If a large family is planned, the potential risk of placenta accreta should be explained.

Assess for accreta. All patients with a prior cesarean section require careful evaluation of placental location and assessment for possible accreta should placenta previa or a low-lying placenta be identified prenatally.

I have found both ultrasound and magnetic resonance imaging useful in recognizing accreta, allowing for adequate preoperative preparation and more favorable outcomes. If accreta is not detected until the time of elective repeat cesarean, it can be life-threatening for the patient.

Should we abandon VBAC?

An unfortunate result of the initiatives promoting VBAC in the 1980s and 90s was a higher rate of uterine rupture, since many women with previous cesarean were strongly encouraged—even required—to undergo a trial of labor. Now that elective repeat cesareans are again on the rise, the risk of rupture should diminish due to better VBAC patient selection, but will probably remain substantially higher than for repeat cesarean.

What exactly is the risk of rupture?

In 1 population-based, retrospective cohort analysis²⁵ involving 20,095 women with 1 previous cesarean section, researchers found a rate of uterine rupture of 5.2 per 1,000 women when labor was spontaneous, compared with 1.6 per 1,000 women who underwent elective repeat cesarean without labor. For women having labor induced with prostaglandins or by other means, the rates were 24.5 and 7.7 per 1,000, respectively.

 

In the same study, the relative risk of uterine rupture was 3.3 for women presenting in spontaneous labor, compared with those who underwent repeat cesarean without labor; it was 15.6 and 4.9 for women whose labor was induced with prostaglandins or by other means, respectively. The rate of infant mortality was 5.5% in cases involving uterine rupture, compared with 0.5% without rupture.²⁵

Note that this study covered the years 1987 through 1996—and thus predated ACOG rules requiring round-the-clock obstetric and anesthesia care, and those barring prostaglandins for labor induction.

Perinatal death more likely with VBAC, but absolute risk is low

A separate population-based, retrospective, cohort study¹⁸ focused on different outcomes: intrapartum stillbirth or neonatal death. This study involved 313,238 singleton births at 37 to 43 weeks’ gestation with the fetus in a cephalic presentation.

Among the women opting for VBAC, the overall rate of delivery-related perinatal death was 12.9 per 10,000 women. This was approximately 11 times greater than the risk associated with planned repeat cesarean, more than twice the risk associated with labor in multiparous women, and similar to the risk among nulliparous women in labor. However, in absolute terms, the risk of perinatal death associated with a trial of labor and uterine rupture was low: 1 in 2,200.¹⁸

What’s the bottom line?

Are findings such as these reason to abandon VBAC? Not necessarily. VBAC success rates range from 60% to 80%, and a 1991 meta-analysis⁴³ of more than 30 US studies found lower maternal febrile morbidity after a trial of labor than after repeat cesarean, and no differences between the 2 approaches in uterine dehiscence, rupture, or perinatal mortality.

A more recent meta-analysis⁹ of international studies involving 47,682 women found a uterine rupture rate of 0.4% for women undergoing a trial of labor versus 0.2% for those having elective repeat cesarean. A later meta-analysis, also international, found an overall uterine rupture rate of 6.2 per 1,000 women attempting VBAC, with a perinatal mortality rate of 0.4 per 1,000. Perinatal mortality was significantly lower among US studies.⁶

Nevertheless, when it comes to VBAC, absolute risks are low, and planned repeat cesarean does not eliminate them entirely. Elective cesarean carries a risk of maternal death up to 2.8 times that of vaginal delivery, though absolute risk is low.⁴⁴

Thus, when patients are carefully selected and fully informed of benefits and risks, VBAC should remain an available option.

The author reports no relevant financial relationships.

A woman’s first cesarean may be more fateful than ever, because 1 low-transverse cesarean delivery is the new limit for a trial of labor in subsequent pregnancies, advises a 2004 practice bulletin from the American College of Obstetricians and Gynecologists (ACOG).¹ The previous bulletin on vaginal birth after cesarean (VBAC) recommended a limit of 2.

The new bulletin reaffirms the previous recommendation that obstetric and anesthesia personnel be immediately available throughout active labor, in case emergency cesarean is necessary.

VBAC is still within the standard of care, but rates were declining even before the new bulletin was released: from a high of 28.3% in 1996 to 12.6% in 2002.²

Benefits of VBAC may outweigh the risks in most women with 1 previous low-transverse cesarean,³ but even with optimal facilities and personnel, numerous factors warrant special caution, according to recent studies I’ll review in this article.

Recent studies of risks and benefits

No randomized trials. ACOG notes,¹ “Despite thousands of citations in the world’s literature, there are currently no randomized trials comparing maternal or neonatal outcomes for both repeat cesarean delivery and VBAC.”

Success rates are similar for gravidas with previous cesarean for a nonrecurring indication and those with no previous cesarean.^4-6

Uterine rupture is more likely during a trial of labor, but the rate is usually below 1%.^7-9

Other limiting factors may include labor augmentation and induction, maternal obesity, gestational age beyond 40 weeks, birth weight over 4,000 g, and an interdelivery interval of less than 19 months.^10-17

When a trial of labor fails, women face a heightened risk of uterine rupture, hysterectomy, transfusion, and endometritis.^3,4,9

Perinatal death is more likely during VBAC than planned repeat cesarean, although the death rate is usually less than 1%.^3,8,9,18

Indications and contraindications

The TABLE outlines potential candidates, ineligible gravidas, resources needed, and situations that warrant caution.

Don’t assume: Check the previous operative note

It is all too easy to presume that a previous cesarean section at term was performed through a transverse incision in the lower uterine segment.

While this may be true in the majority of cases, the actual operative note may reveal information relevant to the delivery decision: an extensive tear of the uterine incision, previously unrecognized uterine anomalies, or the need to perform a classical or T-shaped incision to facilitate delivery of the infant.

For these reasons, review the actual operative report whenever possible before a trial of labor.

2 prior low-transverse incisions

While this is not an absolute contraindication to VBAC, in today’s cautious climate ACOG recommends VBAC proceed only when there is also a history of successful vaginal delivery.^1,19 Otherwise, women with 2 or more previous cesareans should undergo repeat abdominal birth.

Prior low-vertical incision

Although successful VBACs have been reported in women with a prior low-vertical uterine incision, many experts feel that these incisions often extend superiorly into the upper uterus and thus increase the likelihood of uterine rupture in subsequent labors.^20,21

Greater risk with single-layer closure

Single-layer uterine closure appears to increase the likelihood of rupture during subsequent labors.²² As a result, many physicians have returned to 2-layer closure of the lower transverse uterine incision. It is unclear whether single-layer closure is a contraindication to subsequent labor, but it does warrant caution due to a 4-fold increase in the risk of rupture.²²

Discourage closely spaced gestations

The shorter the interval between deliveries, the more likely is uterine rupture during a trial of labor.^23,24 For those considering a subsequent VBAC, I recommend trying to space their next delivery at least 18 months after cesarean birth.

Labor induction increases risk

Spontaneous labor leads to successful VBAC more often than does labor induction or augmentation. In addition, a recent study found 5 times the risk of uterine rupture when oxytocin was used to induce labor, compared with elective repeat cesarean—although the rate of rupture was less than 1% in both groups.²⁵

 

The use of prostaglandins in labor induction greatly increases the risk of rupture, with rates of 24.5 per 1,000 reported, compared with 5.2 per 1,000 in women with spontaneous labor.²⁶ ACOG strongly discourages the use of prostaglandin cervical ripening agents in labor inductions.²⁶

Seek out other factors

Women who initially appear eligible may harbor other characteristics or conditions that warrant special attention.^15,26-28

External cephalic version. Although 1 study²⁹ concluded it is effective in women undergoing a trial of labor after cesarean, vigilance is recommended.

Twin gestations. Two retrospective studies involving a total of 45 women found VBAC to be safe in twin gestations. Because of the limited number of women studied and the lack of randomized, controlled trials, caution is strongly advised.^30,31

Macrosomia. The rate of uterine rupture rises in women who have not had a previous vaginal delivery.²⁷

Postdates. Although VBAC is less likely to succeed after 40 weeks’ gestation, the risk of uterine rupture increases only with induction of labor.¹¹

Analgesia. Women undergoing a trial of labor can receive epidural anesthesia without increasing the risk of rupture or failed VBAC and without obscuring the signs and symptoms of uterine rupture.^32,33 In fact, as ACOG notes, effective pain relief may encourage more women to try VBAC.¹

Previous vaginal delivery. Women who have delivered vaginally are more likely to succeed at VBAC—by a factor of 9 to 28—than those who have not.^34,35

Other conditions such as maternal obesity and advanced age should be evaluated in light of the patient’s overall risk-benefit profile. Although caution is recommended, definitive data are lacking.

TABLE

Criteria for trial of labor

QUALIFICATIONS
1 prior low-transverse cesarean section
Clinically adequate pelvis
No other uterine scars
DISQUALIFICATIONS
Prior classical or T-shaped uterine incision
Multiple uterine incisions
Previous uterine rupture
Contracted pelvis
Contraindications to vaginal birth
REQUIREMENTS THROUGHOUT ACTIVE LABOR
Obstetrician immediately available
Continuous electronic monitoring of the fetal heart rate
Personnel skilled in interpreting fetal tracings
Anesthesia for emergency cesarean
Physician qualified for emergency cesarean
PRECAUTIONS
Unknown uterine scars
Prior low vertical uterine incision
Uterine malformations
Prior single-layer uterine closure
Short interdelivery interval
Need for labor induction
Need for external cephalic version
Twin gestation
Suspected macrosomia
Maternal obesity
Postdates
Advanced maternal age
No prior vaginal delivery
Source: ACOG1

Prognostic formulas

One decision analysis³⁶ concluded that VBAC is a reasonable option when the chance of success exceeds 50% and the desire for future pregnancy is 10% to 20% or more. Although scoring systems have been proposed to predict the likelihood of success, individualized assessment of each patient is ideal. (See “Case by case: Adding up the decisive factors”.)

 

VBAC is not an option where facilities fall short

Despite meeting VBAC criteria for previous incision or pelvic adequacy, many US women do not have the option of a trial of labor. The reason: the need for obstetric care providers throughout active labor and the ability to perform an emergency cesarean.¹ As a result, many midwives and family practitioners can no longer care for VBAC patients independently.

Continuous monitoring is a must

It is the potential for uterine rupture that places patients at risk for unfavorable obstetric outcomes—and rupture can be hard to predict. A nonreassuring fetal heart rate is the most frequent sign.¹ Others are uterine or abdominal pain, vaginal bleeding, loss of station of the presenting part, and hypovolemia.¹

Continuous electronic monitoring of the fetal heart has the potential to detect nonreassuring events earlier than intermittent auscultation. Thus, continuous fetal heart rate monitoring has become the standard for women attempting VBAC. When it is unavailable, VBAC should not be offered.

Also crucial: Anesthesiology

ACOG recommends that anesthesia and other personnel be on hand in case emergency cesarean is warranted.¹ While teaching hospitals and large referral centers are constantly staffed with obstetricians and anesthesiologists, birthing centers and smaller community-based hospitals often lack such coverage. As a result, some physicians and hospitals have withdrawn VBAC as an option

Reducing medicolegal risk

When a trial of labor results in uterine rupture or other adverse outcomes, the patient is more likely to sue. Informed consent and thorough documentation of the VBAC decision are crucial and should include³⁷:

• Appropriate discussion of maternal and perinatal risks and benefits, and documentation of this exchange.
  
• A clear statement of the woman’s intention to undergo a trial of labor after cesarean delivery.
  
• If possible, documentation of previous uterine scar on the prenatal record.
  
• Appropriate counseling about the increased risk of rupture when labor is induced with oxytocin, and documentation of this discussion.
  
• Counseling about the increased risk of rupture when a trial of labor follows a previous cesarean by less than 19 months.
  
• Discussion about decreased likelihood of success if the woman is obese, is of advanced age, or has not had a prior vaginal birth.
  

Is VBAC availability better for health and happiness?

Many women want the option of a trial of labor after cesarean because it affords them the opportunity to experience vaginal delivery. Women who have undergone both cesarean and vaginal deliveries usually opt for a trial of labor in their next pregnancy.³⁸ When a physician or hospital eliminates VBAC as an option, it can lead to patient dissatisfaction—as well as loss of revenue if a woman seeks care elsewhere.

Risk of placenta accreta

If elective repeat cesarean were the only option, the incidence of placenta accreta would increase over time.

Placenta accreta is strongly linked to placenta previa, a condition recognized to increase as the number of previous cesarean sections rises.^39,40 A woman with 2 prior cesareans has a 2% incidence of placenta previa; nearly half of these cases are associated with placenta accreta.⁴¹ As a result, complications of accreta such as maternal death, need for substantial transfusion, postoperative infection, and intraoperative urinary tract injuries would be expected to increase if VBAC were abandoned.⁴²

For this reason, it is important to ask about the patient’s childbearing goals. If a large family is planned, the potential risk of placenta accreta should be explained.

Assess for accreta. All patients with a prior cesarean section require careful evaluation of placental location and assessment for possible accreta should placenta previa or a low-lying placenta be identified prenatally.

I have found both ultrasound and magnetic resonance imaging useful in recognizing accreta, allowing for adequate preoperative preparation and more favorable outcomes. If accreta is not detected until the time of elective repeat cesarean, it can be life-threatening for the patient.

Should we abandon VBAC?

An unfortunate result of the initiatives promoting VBAC in the 1980s and 90s was a higher rate of uterine rupture, since many women with previous cesarean were strongly encouraged—even required—to undergo a trial of labor. Now that elective repeat cesareans are again on the rise, the risk of rupture should diminish due to better VBAC patient selection, but will probably remain substantially higher than for repeat cesarean.

What exactly is the risk of rupture?

In 1 population-based, retrospective cohort analysis²⁵ involving 20,095 women with 1 previous cesarean section, researchers found a rate of uterine rupture of 5.2 per 1,000 women when labor was spontaneous, compared with 1.6 per 1,000 women who underwent elective repeat cesarean without labor. For women having labor induced with prostaglandins or by other means, the rates were 24.5 and 7.7 per 1,000, respectively.

 

In the same study, the relative risk of uterine rupture was 3.3 for women presenting in spontaneous labor, compared with those who underwent repeat cesarean without labor; it was 15.6 and 4.9 for women whose labor was induced with prostaglandins or by other means, respectively. The rate of infant mortality was 5.5% in cases involving uterine rupture, compared with 0.5% without rupture.²⁵

Note that this study covered the years 1987 through 1996—and thus predated ACOG rules requiring round-the-clock obstetric and anesthesia care, and those barring prostaglandins for labor induction.

Perinatal death more likely with VBAC, but absolute risk is low

A separate population-based, retrospective, cohort study¹⁸ focused on different outcomes: intrapartum stillbirth or neonatal death. This study involved 313,238 singleton births at 37 to 43 weeks’ gestation with the fetus in a cephalic presentation.

Among the women opting for VBAC, the overall rate of delivery-related perinatal death was 12.9 per 10,000 women. This was approximately 11 times greater than the risk associated with planned repeat cesarean, more than twice the risk associated with labor in multiparous women, and similar to the risk among nulliparous women in labor. However, in absolute terms, the risk of perinatal death associated with a trial of labor and uterine rupture was low: 1 in 2,200.¹⁸

What’s the bottom line?

Are findings such as these reason to abandon VBAC? Not necessarily. VBAC success rates range from 60% to 80%, and a 1991 meta-analysis⁴³ of more than 30 US studies found lower maternal febrile morbidity after a trial of labor than after repeat cesarean, and no differences between the 2 approaches in uterine dehiscence, rupture, or perinatal mortality.

A more recent meta-analysis⁹ of international studies involving 47,682 women found a uterine rupture rate of 0.4% for women undergoing a trial of labor versus 0.2% for those having elective repeat cesarean. A later meta-analysis, also international, found an overall uterine rupture rate of 6.2 per 1,000 women attempting VBAC, with a perinatal mortality rate of 0.4 per 1,000. Perinatal mortality was significantly lower among US studies.⁶

Nevertheless, when it comes to VBAC, absolute risks are low, and planned repeat cesarean does not eliminate them entirely. Elective cesarean carries a risk of maternal death up to 2.8 times that of vaginal delivery, though absolute risk is low.⁴⁴

Thus, when patients are carefully selected and fully informed of benefits and risks, VBAC should remain an available option.

The author reports no relevant financial relationships.

Ob/Gyns are well trained to care for more than 99% of women with osteopenia and osteoporosis. Yet most women at risk are not being diagnosed or treated. Since recent publication of randomized clinical trials, however, we have clearer direction on the decisive diagnosis and management questions.

Who should have a bone mass test?

Ob/Gyns know best

Solomon DH, Connelly MT, Rosen CJ, et al. Factors related to the use of bone densitometry: survey responses of 494 primary care physicians in New England. Osteoporosis Int. 2003;14:123–129.

Ob/Gyns were significantly more likely to order bone densitometry than internists and family physicians. However, any physician, including Ob/Gyns, who believed (mistakenly) that calcium-plus-vitamin D effectively treats osteoporosis or that osteoporosis should not be diagnosed by densitometry used screening less frequently than physicians without those beliefs.

Any woman should have bone density testing if it might influence her medical care. Osteoporosis is notoriously difficult to diagnose without densitometry.¹

Besides identifying women at risk of fracture due to osteopenia or osteoporosis who are good candidates for drug therapy, testing can help motivate women to stop smoking, exercise, and take calcium and vitamin D to prevent bone loss. Just as women should know their weight, serum cholesterol, blood pressure, and mammographic findings, hypoestrogenic women should know their T-score.

The issue of relative costs and benefits of bone density testing is complex and continues to evolve. Although national organizations have guidelines (TABLE 1), it is not clear if their sensitivity and specificity are optimal for identifying appropriate candidates for screening.

A reliable, quick tool identifies who to test

Cadarette SM, Jaglal SB, Murray TM, McIsaac WJ, Lawrence L, Brown JP. Evaluation of decision rules for referring women for bone density by dual-energy X-ray absorptiometry. JAMA. 2001;286:57–63.

A 3-item Osteoporosis Risk Assessment Instrument was more sensitive and specific in identifying screening candidates than the National Osteoporosis Foundation (NOF) criteria, according to an analysis of screening algorithms used in 2,365 menopausal women in the Canadian Multicentre Osteoporosis Study. A simple calculation based on age, weight, and estrogen use (TABLE 2) was clinically applicable.

In my practice, I focus on all women who have been hypoestrogenic for 12 to 24 months regardless of age, women with a previous low-trauma fracture, and women who weigh less than 132 pounds. Evidence is mounting that early treatment of bone loss is the best way to prevent future fracture. Well before osteoporosis is detected, significant structural integrity of the spine and hip has been lost.

It is my belief that guidelines will ultimately recommend bone mineral testing for all hypoestrogenic and menopausal women. This practice will help start pharmacologic therapy early in the disease, maximally protecting bone and reducing fracture risk. A large-scale randomized prospective trial of bone mineral density testing with long-term follow-up will be needed to crystallize this recommendation.

TABLE 1

Criteria, risk factors for densitometry

The National Osteoporosis Foundation, the North American Menopause Society, the American College of Obstetricians and Gynecologists, and the American Association of Clinical Endocrinologists concur on these criteria and risk factors for bone mineral density testing:
CRITERIA FOR SCREENING
Age 65 years or older
Age less than 65 years with risk factors (see below)
Low-trauma fracture
If densitometry results will influence use of drug treatment
Diseases and treatments associated with osteoporosis (eg, rheumatoid diseases, chronic glucocorticoid therapy)
RISK FACTORS
Prior fracture
Diseases associated with osteoporosis
Body weight less than 127 pounds
Low-trauma fracture in a first-degree relative
Use of chronic glucocorticoid therapy
Cigarette smoking

TABLE 2

Rapid risk assessment: Test bone density if score is 9 or more

The Osteoporosis Risk Assessment Instrument advises testing all women age 65 or older, and menopausal women starting at age 55 who weigh less than 154 pounds and are not taking estrogen.
CRITERIA	POINTS
Age
55-64	5
65-74	9
Older than 74	15
Weight
Less than 60 kg (132 pounds)	9
60 to 70 kg (132 to 154 pounds)	3
Estrogen therapy
Not currently using estrogen	2
Source: Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ, Darlington GA, Tu JV. Development and validation of the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry. CMAJ. 2000;162:1289–1294.

When should treatment start?

Fracture begets fracture, treatment reduces risk

Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E, Adachi JD. Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone. 2003;33:522–532.

 

Baseline fractures in 7,705 postmenopausal women were assessed by semiquantitative spinal radiographs.

In women with severe prevalent vertebral fractures (more than 40% loss of vertebral body height), risk of additional vertebral fractures over 3 years was 38% and risk of new nonvertebral fracture (wrist, hip) was 14%.

Treatment of severe prevalent vertebral fractures with raloxifene 60 mg daily reduced the risk of new vertebral fractures by 26% and new nonvertebral fractures by 47% over 3 years.

To prevent 1 new nonvertebral fracture, 10 patients needed to be treated; to prevent 1 additional nonvertebral fracture, 18 patients needed to be treated.

Women who have already suffered a low-trauma fracture and women with osteoporosis have the greatest risk of fracture. The majority of women who suffer a low-trauma fracture have had neither a bone density measurement nor treatment with a bone medicine, many studies indicate. The Delmas study highlights the importance of prevalent vertebral fractures on the risk of subsequent fractures.

When to treat osteopenia. Many women with osteopenia should be on drug treatment, as should all women with osteoporosis, the NOF advises.

Although a woman with osteoporosis is more likely than a woman with osteopenia to suffer a fracture, the greatest absolute number of fractures occurs in osteopenic women, because that population is so large.

The NOF recommends starting treatment when the T–score measured by dual-energy X-ray absorptiometry (DXA) bone density testing is:

• less than –1.5 and the patient has 1 risk factor, or
  
• less than –2.0.²
  

This approach, it is hoped, will reduce progression to frank osteoporosis and reduce the number of fractures suffered by women with osteopenia.

What are the treatments for low bone mass?

Alendronate, risedronate, and raloxifene

The 3 most commonly used drugs for prevention and treatment of osteoporosis are: 2 bisphosphonates (alendronate and risedronate) and the selective estrogen receptor modulator raloxifene (TABLE 3). All prevent fractures and cost about the same. Alendronate and risedronate are taken by mouth once weekly; raloxifene, daily. A raspberry-flavored liquid alendronate was recently added, for the 10% of women who prefer not to take pills.

Patients must be careful to take alendronate and risedronate in the fasting state and with sufficient water to ensure the pill enters the stomach, then continue to fast another 30 minutes for maximal absorption. The patient needs to remain erect to reduce risk of reflux and esophageal irritation.

Teriparatide

Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87: 4528–4535.

Postmenopausal women with osteoporosis (n = 146) were randomized to receive either teriparatide injections (20 μg daily) plus placebo pills or alendronate 10 mg daily plus placebo injections for a median of 14 months. After 3 months of therapy, bone mineral density in the lumbar spine increased 12.2% and 5.6% in the teriparatide and alendronate groups, respectively. Teriparatide treatment resulted in fewer nonvertebral fractures than alendronate therapy.

Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207–1215.

Postmenopausal women with osteoporosis (n = 238) were randomized to receive daily parathyroid hormone (PTH) (full length 1 to 84) injections (100 μg daily), alendronate 10 mg daily, or the combination. After 1 year, lumbar spine bone density as assessed by DXA increased 6.3%, 6.1%, and 4.6% in the PTH alone, PTH plus alendronate and alendronatealone groups, respectively. In this study, PTH plus alendronate conferred no additional benefits over PTH alone.

Recombinant PTH 1-34 (teriparatide, Forteo) was approved in November 2002 for treatment of osteoporosis in postmenopausal women at high risk of fracture. It is very effective and likely superior to alendronate treatment. However, teriparatide, which is an injectable formulation, is expensive and this will likely limit its use to complex cases.

Interestingly, the combination of PTH plus alendronate does not appear to be additive in the treatment of osteoporosis. Given current data, the bisphosphonates should not be combined with PTH.

TABLE 3

Drugs for prevention and treatment of osteoporosis

CLASS, GENERIC NAME, AND INDICATION	BRAND NAME	DOSAGE		APPROXIMATE MONTHLY COST*
		DAILY	WEEKLY
Estrogen for prevention of postmenopausal osteoporosis (loss of bone mass)
Conjugated equine estrogen	Premarin	0.625 mg		$28
Calcitonin-salmon for prevention of progressive loss of bone mass in postmenopausal osteoporosis
Calcitonin	Miacalcin	200 IU by nasal spray		$60
Bisphosphonates for treatment and prevention of osteoporosis in postmenopausal women
Risedronate	Actonel		35 mg	$64
Alendronate	Fosamax		70 mg	$65
Selective estrogen receptor modulator for treatment and prevention of osteoporosis in postmenopausal women
Raloxifene	Evista	60 mg		$71
Parathyroid hormone for treatment of postmenopausal women with osteoporosis who are at high risk for fracture
Teriparatide-PTH 1-35	Forteo	20 μg by injection		$410
* Source: drugstore.com

 

How long should treatment continue?

This question can be answered from both scientific and practical clinical viewpoints.

The practical clinical problem is that when patients ask: “Doctor, how long do I need to take my bone medicine?” they are not emotionally prepared to hear, “Forever.”

It is probably better to say that it’s important to stay on treatment at least 1 to 2 years, and adhere closely to the regimen. When follow-up testing is obtained, the results can influence the next recommendation—which is likely to be that treatment should continue at least 1 or 2 more years. This pattern is more likely to ensure that the patient has high morale and follows the regimen.

Bone mass accrues as treatment continues

Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189–1199.

In postmenopausal women with osteoporosis (n = 86) who were treated for 10 years with alendronate, 10 mg daily, hip and spinal bone density continued to increase throughout follow-up.

Women who stopped therapy gradually lost bone density. After 10 years of alendronate, the increase in bone mineral density was 14% at the lumbar spine and 10% at the hip trochanter.

Studies have demonstrated that bone density continues to increase with up to 10 years of therapy with alendronate.

Alendronate halts bone loss after stopping estrogen

Ascott-Evans BH, Guanabens N, Kivinen S, et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy. Arch Intern Med. 2003;163:789–794.

Postmenopausal women (n = 144) who had recently discontinued estrogen therapy were randomized to receive a placebo or alendronate, 10 mg daily. After 1 year, the alendronate group had a 2.3% increase in spinal bone density; the placebo group, a 3.2% decrease.

Once drug therapy stops, bone density begins to decrease—more rapidly after estrogen than after bisphosphonates. In women who stop estrogen, initiation of alendronate blocks bone loss that will otherwise occur. Therefore, women with osteopenia or osteoporosis who stop estrogen therapy should consider starting an alternative bone medicine.

How should you monitor treatment?

Nurses improve adherence

Clowes JA, Peel NFA, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:1117–1123.

In this study, 75 postmenopausal women with osteopenia on raloxifene treatment were randomized to 3 different monitoring regimens: no monitoring, nurse interactions with the patient to ensure treatment compliance, or monitoring of urinary markers of bone turnover.

The patients who had the best adherence to therapy had the greatest increase in bone mineral density.

Adherence increased by 57% in the nurse interaction group compared to no monitoring. Measuring urinary markers of bone turnover did not improve adherence or persistence with therapy compared to nurse interactions.

Nurse monitoring of treatment adherence appeared worthwhile, in this comparison of monitoring methods. In routine clinical practice, there is seldom a need to measure markers of bone turnover in women taking bisphosphonates.

Densitometry every 2 years

Greenspan SL, Resnick NM, Parker RA. Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women. JAMA. 2003;289: 2525–2533.

A total of 373 women over age 65 were randomized to placebo, conjugated equine estrogen 0.625 mg daily, alendronate 10 mg daily, or both estrogen and alendronate. After 3 years, increases in spinal and hip bone density were greatest in the alendronate plus estrogen group. Alendronate alone was slightly better than estrogen alone in improving bone density at the hip. Alendronate and estrogen were similarly efficacious in improving spine bone density. All active regimens were superior to placebo.

In my practice, I measure bone density every other year to assess response to antiresorptive therapy. Since bone turnover is slow, more frequent measurements are seldom warranted. If bone density stabilizes or increases, I continue therapy.

If bone density decreases significantly on standard monotherapy, I would consider adding estrogen and repeating bone mineral testing in 1 year.

I would also check for secondary causes of bone disease by measuring serum thyroid-stimulating hormone, calcium, albumin, PTH and 25-hydroxyvitamin D.

Alternatively, a woman who has lost bone density on monotherapy can be referred to an endocrinologist.

Dr. Barbieri reports no financial relationships relevant to this article.

Ob/Gyns are well trained to care for more than 99% of women with osteopenia and osteoporosis. Yet most women at risk are not being diagnosed or treated. Since recent publication of randomized clinical trials, however, we have clearer direction on the decisive diagnosis and management questions.

Who should have a bone mass test?

Ob/Gyns know best

Solomon DH, Connelly MT, Rosen CJ, et al. Factors related to the use of bone densitometry: survey responses of 494 primary care physicians in New England. Osteoporosis Int. 2003;14:123–129.

Ob/Gyns were significantly more likely to order bone densitometry than internists and family physicians. However, any physician, including Ob/Gyns, who believed (mistakenly) that calcium-plus-vitamin D effectively treats osteoporosis or that osteoporosis should not be diagnosed by densitometry used screening less frequently than physicians without those beliefs.

Any woman should have bone density testing if it might influence her medical care. Osteoporosis is notoriously difficult to diagnose without densitometry.¹

Besides identifying women at risk of fracture due to osteopenia or osteoporosis who are good candidates for drug therapy, testing can help motivate women to stop smoking, exercise, and take calcium and vitamin D to prevent bone loss. Just as women should know their weight, serum cholesterol, blood pressure, and mammographic findings, hypoestrogenic women should know their T-score.

The issue of relative costs and benefits of bone density testing is complex and continues to evolve. Although national organizations have guidelines (TABLE 1), it is not clear if their sensitivity and specificity are optimal for identifying appropriate candidates for screening.

A reliable, quick tool identifies who to test

Cadarette SM, Jaglal SB, Murray TM, McIsaac WJ, Lawrence L, Brown JP. Evaluation of decision rules for referring women for bone density by dual-energy X-ray absorptiometry. JAMA. 2001;286:57–63.

A 3-item Osteoporosis Risk Assessment Instrument was more sensitive and specific in identifying screening candidates than the National Osteoporosis Foundation (NOF) criteria, according to an analysis of screening algorithms used in 2,365 menopausal women in the Canadian Multicentre Osteoporosis Study. A simple calculation based on age, weight, and estrogen use (TABLE 2) was clinically applicable.

In my practice, I focus on all women who have been hypoestrogenic for 12 to 24 months regardless of age, women with a previous low-trauma fracture, and women who weigh less than 132 pounds. Evidence is mounting that early treatment of bone loss is the best way to prevent future fracture. Well before osteoporosis is detected, significant structural integrity of the spine and hip has been lost.

It is my belief that guidelines will ultimately recommend bone mineral testing for all hypoestrogenic and menopausal women. This practice will help start pharmacologic therapy early in the disease, maximally protecting bone and reducing fracture risk. A large-scale randomized prospective trial of bone mineral density testing with long-term follow-up will be needed to crystallize this recommendation.

TABLE 1

Criteria, risk factors for densitometry

The National Osteoporosis Foundation, the North American Menopause Society, the American College of Obstetricians and Gynecologists, and the American Association of Clinical Endocrinologists concur on these criteria and risk factors for bone mineral density testing:
CRITERIA FOR SCREENING
Age 65 years or older
Age less than 65 years with risk factors (see below)
Low-trauma fracture
If densitometry results will influence use of drug treatment
Diseases and treatments associated with osteoporosis (eg, rheumatoid diseases, chronic glucocorticoid therapy)
RISK FACTORS
Prior fracture
Diseases associated with osteoporosis
Body weight less than 127 pounds
Low-trauma fracture in a first-degree relative
Use of chronic glucocorticoid therapy
Cigarette smoking

TABLE 2

Rapid risk assessment: Test bone density if score is 9 or more

The Osteoporosis Risk Assessment Instrument advises testing all women age 65 or older, and menopausal women starting at age 55 who weigh less than 154 pounds and are not taking estrogen.
CRITERIA	POINTS
Age
55-64	5
65-74	9
Older than 74	15
Weight
Less than 60 kg (132 pounds)	9
60 to 70 kg (132 to 154 pounds)	3
Estrogen therapy
Not currently using estrogen	2
Source: Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ, Darlington GA, Tu JV. Development and validation of the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry. CMAJ. 2000;162:1289–1294.

When should treatment start?

Fracture begets fracture, treatment reduces risk

Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E, Adachi JD. Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone. 2003;33:522–532.

 

Baseline fractures in 7,705 postmenopausal women were assessed by semiquantitative spinal radiographs.

In women with severe prevalent vertebral fractures (more than 40% loss of vertebral body height), risk of additional vertebral fractures over 3 years was 38% and risk of new nonvertebral fracture (wrist, hip) was 14%.

Treatment of severe prevalent vertebral fractures with raloxifene 60 mg daily reduced the risk of new vertebral fractures by 26% and new nonvertebral fractures by 47% over 3 years.

To prevent 1 new nonvertebral fracture, 10 patients needed to be treated; to prevent 1 additional nonvertebral fracture, 18 patients needed to be treated.

Women who have already suffered a low-trauma fracture and women with osteoporosis have the greatest risk of fracture. The majority of women who suffer a low-trauma fracture have had neither a bone density measurement nor treatment with a bone medicine, many studies indicate. The Delmas study highlights the importance of prevalent vertebral fractures on the risk of subsequent fractures.

When to treat osteopenia. Many women with osteopenia should be on drug treatment, as should all women with osteoporosis, the NOF advises.

Although a woman with osteoporosis is more likely than a woman with osteopenia to suffer a fracture, the greatest absolute number of fractures occurs in osteopenic women, because that population is so large.

The NOF recommends starting treatment when the T–score measured by dual-energy X-ray absorptiometry (DXA) bone density testing is:

• less than –1.5 and the patient has 1 risk factor, or
  
• less than –2.0.²
  

This approach, it is hoped, will reduce progression to frank osteoporosis and reduce the number of fractures suffered by women with osteopenia.

What are the treatments for low bone mass?

Alendronate, risedronate, and raloxifene

The 3 most commonly used drugs for prevention and treatment of osteoporosis are: 2 bisphosphonates (alendronate and risedronate) and the selective estrogen receptor modulator raloxifene (TABLE 3). All prevent fractures and cost about the same. Alendronate and risedronate are taken by mouth once weekly; raloxifene, daily. A raspberry-flavored liquid alendronate was recently added, for the 10% of women who prefer not to take pills.

Patients must be careful to take alendronate and risedronate in the fasting state and with sufficient water to ensure the pill enters the stomach, then continue to fast another 30 minutes for maximal absorption. The patient needs to remain erect to reduce risk of reflux and esophageal irritation.

Teriparatide

Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87: 4528–4535.

Postmenopausal women with osteoporosis (n = 146) were randomized to receive either teriparatide injections (20 μg daily) plus placebo pills or alendronate 10 mg daily plus placebo injections for a median of 14 months. After 3 months of therapy, bone mineral density in the lumbar spine increased 12.2% and 5.6% in the teriparatide and alendronate groups, respectively. Teriparatide treatment resulted in fewer nonvertebral fractures than alendronate therapy.

Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207–1215.

Postmenopausal women with osteoporosis (n = 238) were randomized to receive daily parathyroid hormone (PTH) (full length 1 to 84) injections (100 μg daily), alendronate 10 mg daily, or the combination. After 1 year, lumbar spine bone density as assessed by DXA increased 6.3%, 6.1%, and 4.6% in the PTH alone, PTH plus alendronate and alendronatealone groups, respectively. In this study, PTH plus alendronate conferred no additional benefits over PTH alone.

Recombinant PTH 1-34 (teriparatide, Forteo) was approved in November 2002 for treatment of osteoporosis in postmenopausal women at high risk of fracture. It is very effective and likely superior to alendronate treatment. However, teriparatide, which is an injectable formulation, is expensive and this will likely limit its use to complex cases.

Interestingly, the combination of PTH plus alendronate does not appear to be additive in the treatment of osteoporosis. Given current data, the bisphosphonates should not be combined with PTH.

TABLE 3

Drugs for prevention and treatment of osteoporosis

CLASS, GENERIC NAME, AND INDICATION	BRAND NAME	DOSAGE		APPROXIMATE MONTHLY COST*
		DAILY	WEEKLY
Estrogen for prevention of postmenopausal osteoporosis (loss of bone mass)
Conjugated equine estrogen	Premarin	0.625 mg		$28
Calcitonin-salmon for prevention of progressive loss of bone mass in postmenopausal osteoporosis
Calcitonin	Miacalcin	200 IU by nasal spray		$60
Bisphosphonates for treatment and prevention of osteoporosis in postmenopausal women
Risedronate	Actonel		35 mg	$64
Alendronate	Fosamax		70 mg	$65
Selective estrogen receptor modulator for treatment and prevention of osteoporosis in postmenopausal women
Raloxifene	Evista	60 mg		$71
Parathyroid hormone for treatment of postmenopausal women with osteoporosis who are at high risk for fracture
Teriparatide-PTH 1-35	Forteo	20 μg by injection		$410
* Source: drugstore.com

 

How long should treatment continue?

This question can be answered from both scientific and practical clinical viewpoints.

The practical clinical problem is that when patients ask: “Doctor, how long do I need to take my bone medicine?” they are not emotionally prepared to hear, “Forever.”

It is probably better to say that it’s important to stay on treatment at least 1 to 2 years, and adhere closely to the regimen. When follow-up testing is obtained, the results can influence the next recommendation—which is likely to be that treatment should continue at least 1 or 2 more years. This pattern is more likely to ensure that the patient has high morale and follows the regimen.

Bone mass accrues as treatment continues

Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189–1199.

In postmenopausal women with osteoporosis (n = 86) who were treated for 10 years with alendronate, 10 mg daily, hip and spinal bone density continued to increase throughout follow-up.

Women who stopped therapy gradually lost bone density. After 10 years of alendronate, the increase in bone mineral density was 14% at the lumbar spine and 10% at the hip trochanter.

Studies have demonstrated that bone density continues to increase with up to 10 years of therapy with alendronate.

Alendronate halts bone loss after stopping estrogen

Ascott-Evans BH, Guanabens N, Kivinen S, et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy. Arch Intern Med. 2003;163:789–794.

Postmenopausal women (n = 144) who had recently discontinued estrogen therapy were randomized to receive a placebo or alendronate, 10 mg daily. After 1 year, the alendronate group had a 2.3% increase in spinal bone density; the placebo group, a 3.2% decrease.

Once drug therapy stops, bone density begins to decrease—more rapidly after estrogen than after bisphosphonates. In women who stop estrogen, initiation of alendronate blocks bone loss that will otherwise occur. Therefore, women with osteopenia or osteoporosis who stop estrogen therapy should consider starting an alternative bone medicine.

How should you monitor treatment?

Nurses improve adherence

Clowes JA, Peel NFA, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:1117–1123.

In this study, 75 postmenopausal women with osteopenia on raloxifene treatment were randomized to 3 different monitoring regimens: no monitoring, nurse interactions with the patient to ensure treatment compliance, or monitoring of urinary markers of bone turnover.

The patients who had the best adherence to therapy had the greatest increase in bone mineral density.

Adherence increased by 57% in the nurse interaction group compared to no monitoring. Measuring urinary markers of bone turnover did not improve adherence or persistence with therapy compared to nurse interactions.

Nurse monitoring of treatment adherence appeared worthwhile, in this comparison of monitoring methods. In routine clinical practice, there is seldom a need to measure markers of bone turnover in women taking bisphosphonates.

Densitometry every 2 years

Greenspan SL, Resnick NM, Parker RA. Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women. JAMA. 2003;289: 2525–2533.

A total of 373 women over age 65 were randomized to placebo, conjugated equine estrogen 0.625 mg daily, alendronate 10 mg daily, or both estrogen and alendronate. After 3 years, increases in spinal and hip bone density were greatest in the alendronate plus estrogen group. Alendronate alone was slightly better than estrogen alone in improving bone density at the hip. Alendronate and estrogen were similarly efficacious in improving spine bone density. All active regimens were superior to placebo.

In my practice, I measure bone density every other year to assess response to antiresorptive therapy. Since bone turnover is slow, more frequent measurements are seldom warranted. If bone density stabilizes or increases, I continue therapy.

If bone density decreases significantly on standard monotherapy, I would consider adding estrogen and repeating bone mineral testing in 1 year.

I would also check for secondary causes of bone disease by measuring serum thyroid-stimulating hormone, calcium, albumin, PTH and 25-hydroxyvitamin D.

Alternatively, a woman who has lost bone density on monotherapy can be referred to an endocrinologist.

Dr. Barbieri reports no financial relationships relevant to this article.

Ob/Gyns are well trained to care for more than 99% of women with osteopenia and osteoporosis. Yet most women at risk are not being diagnosed or treated. Since recent publication of randomized clinical trials, however, we have clearer direction on the decisive diagnosis and management questions.

Who should have a bone mass test?

Ob/Gyns know best

Solomon DH, Connelly MT, Rosen CJ, et al. Factors related to the use of bone densitometry: survey responses of 494 primary care physicians in New England. Osteoporosis Int. 2003;14:123–129.

Ob/Gyns were significantly more likely to order bone densitometry than internists and family physicians. However, any physician, including Ob/Gyns, who believed (mistakenly) that calcium-plus-vitamin D effectively treats osteoporosis or that osteoporosis should not be diagnosed by densitometry used screening less frequently than physicians without those beliefs.

Any woman should have bone density testing if it might influence her medical care. Osteoporosis is notoriously difficult to diagnose without densitometry.¹

Besides identifying women at risk of fracture due to osteopenia or osteoporosis who are good candidates for drug therapy, testing can help motivate women to stop smoking, exercise, and take calcium and vitamin D to prevent bone loss. Just as women should know their weight, serum cholesterol, blood pressure, and mammographic findings, hypoestrogenic women should know their T-score.

The issue of relative costs and benefits of bone density testing is complex and continues to evolve. Although national organizations have guidelines (TABLE 1), it is not clear if their sensitivity and specificity are optimal for identifying appropriate candidates for screening.

A reliable, quick tool identifies who to test

Cadarette SM, Jaglal SB, Murray TM, McIsaac WJ, Lawrence L, Brown JP. Evaluation of decision rules for referring women for bone density by dual-energy X-ray absorptiometry. JAMA. 2001;286:57–63.

A 3-item Osteoporosis Risk Assessment Instrument was more sensitive and specific in identifying screening candidates than the National Osteoporosis Foundation (NOF) criteria, according to an analysis of screening algorithms used in 2,365 menopausal women in the Canadian Multicentre Osteoporosis Study. A simple calculation based on age, weight, and estrogen use (TABLE 2) was clinically applicable.

In my practice, I focus on all women who have been hypoestrogenic for 12 to 24 months regardless of age, women with a previous low-trauma fracture, and women who weigh less than 132 pounds. Evidence is mounting that early treatment of bone loss is the best way to prevent future fracture. Well before osteoporosis is detected, significant structural integrity of the spine and hip has been lost.

It is my belief that guidelines will ultimately recommend bone mineral testing for all hypoestrogenic and menopausal women. This practice will help start pharmacologic therapy early in the disease, maximally protecting bone and reducing fracture risk. A large-scale randomized prospective trial of bone mineral density testing with long-term follow-up will be needed to crystallize this recommendation.

TABLE 1

Criteria, risk factors for densitometry

The National Osteoporosis Foundation, the North American Menopause Society, the American College of Obstetricians and Gynecologists, and the American Association of Clinical Endocrinologists concur on these criteria and risk factors for bone mineral density testing:
CRITERIA FOR SCREENING
Age 65 years or older
Age less than 65 years with risk factors (see below)
Low-trauma fracture
If densitometry results will influence use of drug treatment
Diseases and treatments associated with osteoporosis (eg, rheumatoid diseases, chronic glucocorticoid therapy)
RISK FACTORS
Prior fracture
Diseases associated with osteoporosis
Body weight less than 127 pounds
Low-trauma fracture in a first-degree relative
Use of chronic glucocorticoid therapy
Cigarette smoking

TABLE 2

Rapid risk assessment: Test bone density if score is 9 or more

The Osteoporosis Risk Assessment Instrument advises testing all women age 65 or older, and menopausal women starting at age 55 who weigh less than 154 pounds and are not taking estrogen.
CRITERIA	POINTS
Age
55-64	5
65-74	9
Older than 74	15
Weight
Less than 60 kg (132 pounds)	9
60 to 70 kg (132 to 154 pounds)	3
Estrogen therapy
Not currently using estrogen	2
Source: Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ, Darlington GA, Tu JV. Development and validation of the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry. CMAJ. 2000;162:1289–1294.

When should treatment start?

Fracture begets fracture, treatment reduces risk

Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E, Adachi JD. Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone. 2003;33:522–532.

 

Baseline fractures in 7,705 postmenopausal women were assessed by semiquantitative spinal radiographs.

In women with severe prevalent vertebral fractures (more than 40% loss of vertebral body height), risk of additional vertebral fractures over 3 years was 38% and risk of new nonvertebral fracture (wrist, hip) was 14%.

Treatment of severe prevalent vertebral fractures with raloxifene 60 mg daily reduced the risk of new vertebral fractures by 26% and new nonvertebral fractures by 47% over 3 years.

To prevent 1 new nonvertebral fracture, 10 patients needed to be treated; to prevent 1 additional nonvertebral fracture, 18 patients needed to be treated.

Women who have already suffered a low-trauma fracture and women with osteoporosis have the greatest risk of fracture. The majority of women who suffer a low-trauma fracture have had neither a bone density measurement nor treatment with a bone medicine, many studies indicate. The Delmas study highlights the importance of prevalent vertebral fractures on the risk of subsequent fractures.

When to treat osteopenia. Many women with osteopenia should be on drug treatment, as should all women with osteoporosis, the NOF advises.

Although a woman with osteoporosis is more likely than a woman with osteopenia to suffer a fracture, the greatest absolute number of fractures occurs in osteopenic women, because that population is so large.

The NOF recommends starting treatment when the T–score measured by dual-energy X-ray absorptiometry (DXA) bone density testing is:

• less than –1.5 and the patient has 1 risk factor, or
  
• less than –2.0.²
  

This approach, it is hoped, will reduce progression to frank osteoporosis and reduce the number of fractures suffered by women with osteopenia.

What are the treatments for low bone mass?

Alendronate, risedronate, and raloxifene

The 3 most commonly used drugs for prevention and treatment of osteoporosis are: 2 bisphosphonates (alendronate and risedronate) and the selective estrogen receptor modulator raloxifene (TABLE 3). All prevent fractures and cost about the same. Alendronate and risedronate are taken by mouth once weekly; raloxifene, daily. A raspberry-flavored liquid alendronate was recently added, for the 10% of women who prefer not to take pills.

Patients must be careful to take alendronate and risedronate in the fasting state and with sufficient water to ensure the pill enters the stomach, then continue to fast another 30 minutes for maximal absorption. The patient needs to remain erect to reduce risk of reflux and esophageal irritation.

Teriparatide

Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87: 4528–4535.

Postmenopausal women with osteoporosis (n = 146) were randomized to receive either teriparatide injections (20 μg daily) plus placebo pills or alendronate 10 mg daily plus placebo injections for a median of 14 months. After 3 months of therapy, bone mineral density in the lumbar spine increased 12.2% and 5.6% in the teriparatide and alendronate groups, respectively. Teriparatide treatment resulted in fewer nonvertebral fractures than alendronate therapy.

Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207–1215.

Postmenopausal women with osteoporosis (n = 238) were randomized to receive daily parathyroid hormone (PTH) (full length 1 to 84) injections (100 μg daily), alendronate 10 mg daily, or the combination. After 1 year, lumbar spine bone density as assessed by DXA increased 6.3%, 6.1%, and 4.6% in the PTH alone, PTH plus alendronate and alendronatealone groups, respectively. In this study, PTH plus alendronate conferred no additional benefits over PTH alone.

Recombinant PTH 1-34 (teriparatide, Forteo) was approved in November 2002 for treatment of osteoporosis in postmenopausal women at high risk of fracture. It is very effective and likely superior to alendronate treatment. However, teriparatide, which is an injectable formulation, is expensive and this will likely limit its use to complex cases.

Interestingly, the combination of PTH plus alendronate does not appear to be additive in the treatment of osteoporosis. Given current data, the bisphosphonates should not be combined with PTH.

TABLE 3

Drugs for prevention and treatment of osteoporosis

CLASS, GENERIC NAME, AND INDICATION	BRAND NAME	DOSAGE		APPROXIMATE MONTHLY COST*
		DAILY	WEEKLY
Estrogen for prevention of postmenopausal osteoporosis (loss of bone mass)
Conjugated equine estrogen	Premarin	0.625 mg		$28
Calcitonin-salmon for prevention of progressive loss of bone mass in postmenopausal osteoporosis
Calcitonin	Miacalcin	200 IU by nasal spray		$60
Bisphosphonates for treatment and prevention of osteoporosis in postmenopausal women
Risedronate	Actonel		35 mg	$64
Alendronate	Fosamax		70 mg	$65
Selective estrogen receptor modulator for treatment and prevention of osteoporosis in postmenopausal women
Raloxifene	Evista	60 mg		$71
Parathyroid hormone for treatment of postmenopausal women with osteoporosis who are at high risk for fracture
Teriparatide-PTH 1-35	Forteo	20 μg by injection		$410
* Source: drugstore.com

 

How long should treatment continue?

This question can be answered from both scientific and practical clinical viewpoints.

The practical clinical problem is that when patients ask: “Doctor, how long do I need to take my bone medicine?” they are not emotionally prepared to hear, “Forever.”

It is probably better to say that it’s important to stay on treatment at least 1 to 2 years, and adhere closely to the regimen. When follow-up testing is obtained, the results can influence the next recommendation—which is likely to be that treatment should continue at least 1 or 2 more years. This pattern is more likely to ensure that the patient has high morale and follows the regimen.

Bone mass accrues as treatment continues

Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189–1199.

In postmenopausal women with osteoporosis (n = 86) who were treated for 10 years with alendronate, 10 mg daily, hip and spinal bone density continued to increase throughout follow-up.

Women who stopped therapy gradually lost bone density. After 10 years of alendronate, the increase in bone mineral density was 14% at the lumbar spine and 10% at the hip trochanter.

Studies have demonstrated that bone density continues to increase with up to 10 years of therapy with alendronate.

Alendronate halts bone loss after stopping estrogen

Ascott-Evans BH, Guanabens N, Kivinen S, et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy. Arch Intern Med. 2003;163:789–794.

Postmenopausal women (n = 144) who had recently discontinued estrogen therapy were randomized to receive a placebo or alendronate, 10 mg daily. After 1 year, the alendronate group had a 2.3% increase in spinal bone density; the placebo group, a 3.2% decrease.

Once drug therapy stops, bone density begins to decrease—more rapidly after estrogen than after bisphosphonates. In women who stop estrogen, initiation of alendronate blocks bone loss that will otherwise occur. Therefore, women with osteopenia or osteoporosis who stop estrogen therapy should consider starting an alternative bone medicine.

How should you monitor treatment?

Nurses improve adherence

Clowes JA, Peel NFA, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:1117–1123.

In this study, 75 postmenopausal women with osteopenia on raloxifene treatment were randomized to 3 different monitoring regimens: no monitoring, nurse interactions with the patient to ensure treatment compliance, or monitoring of urinary markers of bone turnover.

The patients who had the best adherence to therapy had the greatest increase in bone mineral density.

Adherence increased by 57% in the nurse interaction group compared to no monitoring. Measuring urinary markers of bone turnover did not improve adherence or persistence with therapy compared to nurse interactions.

Nurse monitoring of treatment adherence appeared worthwhile, in this comparison of monitoring methods. In routine clinical practice, there is seldom a need to measure markers of bone turnover in women taking bisphosphonates.

Densitometry every 2 years

Greenspan SL, Resnick NM, Parker RA. Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women. JAMA. 2003;289: 2525–2533.

A total of 373 women over age 65 were randomized to placebo, conjugated equine estrogen 0.625 mg daily, alendronate 10 mg daily, or both estrogen and alendronate. After 3 years, increases in spinal and hip bone density were greatest in the alendronate plus estrogen group. Alendronate alone was slightly better than estrogen alone in improving bone density at the hip. Alendronate and estrogen were similarly efficacious in improving spine bone density. All active regimens were superior to placebo.

In my practice, I measure bone density every other year to assess response to antiresorptive therapy. Since bone turnover is slow, more frequent measurements are seldom warranted. If bone density stabilizes or increases, I continue therapy.

If bone density decreases significantly on standard monotherapy, I would consider adding estrogen and repeating bone mineral testing in 1 year.

I would also check for secondary causes of bone disease by measuring serum thyroid-stimulating hormone, calcium, albumin, PTH and 25-hydroxyvitamin D.

Alternatively, a woman who has lost bone density on monotherapy can be referred to an endocrinologist.

Dr. Barbieri reports no financial relationships relevant to this article.

THE CASE: SIGNS AND SYMPTOMS

A 29–year–old nullipara at 18 weeks’ gestation complains of fevers and back pain. She had a diagnosis of urinary tract infection with sulfonamide-resistant Escherichia coli at 9 weeks of gestation, which was treated with nitrofurantoin, 100 mg by mouth twice a day for 7 days. A test of cure by urine culture was negative.

Now her temperature is 101°F and she has right costovertebral angle tenderness.

How should you proceed?

Anatomy is destiny, in the case of susceptibility to urinary tract infection (UTI). The female urethra is only 3 cm to 4 cm long, and its proximity to the vagina, anus, and rectum facilitates colonization of normal gastrointestinal flora in the bladder.¹

Sexual activity also facilitates migration of normal gastrointestinal flora to the female urethra.²

Anatomical features of pregnancy exacerbate the female predisposition to urinary tract infection. In pregnancy, hormonal and mechanical changes that occur in the urinary tract lead to urinary stasis and ureterovesical reflux—setting the stage for urinary tract infection (FIGURE 1).

Who should be screened?

All pregnant women should be screened for UTI early in pregnancy, according to the American College of Obstetricians and Gynecologists.³

I recommend a urine culture screening for all pregnant women at their first prenatal visit.

Screen often if she has risk factors

I recommend frequent screening (at least every trimester) by urine culture, in pregnant women with any of these risk factors:

• diabetes mellitus, including gestational diabetes⁴;
  
• urologic abnormalities—specifically, neurogenic bladder;
  
• prepregnancy (for example, 2 to 3 infections per year) and antepartum history of UTI prior to initiation of prenatal care⁵;
  
• sickle cell hemoglobinopathy.⁵
  

Which test is best?

The gold standard for detecting bacteria in urine is by culture.

Which threshold to use?

The standard definition of a positive urine culture from a clean-catch, midstream, voided specimen is ≥100,000 colony forming units (CFU) per mL of a single organism. However, in symptomatic patients, the test’s sensitivity is increased by lowering the cut-off to 100 CFU/mL of a single organism.⁶ In women with urinary symptoms, only 50% of patients had 100,000 CFU/mL by urine culture collected from clean-catch, midstream, voided specimens, though all of them had positive cultures from suprapubic taps.

The clean-catch, midstream, voided specimen is the specimen of choice for practical purposes, since it is noninvasive and easily obtained in the office setting.

For the record: The presence of any organism represents UTI in specimens obtained via suprapubic aspiration of the bladder; 100 CFU/mL of a single organism is positive for specimens obtained by urethral catheterization.

I recommend that, when obtaining urine cultures via clean-catch, midstream, voided specimens:

• for asymptomatic patients, use ≥100,000 CFU/mL of a single organism.
  
• in symptomatic patients, use ≥100 CFU/mL of a single organism.
  

What about rapid tests?

Urinary sediment analysis and urine dipstick testing offer speed and low cost, but with lower accuracy than urine cultures, which require 24 to 48 hours for results and cost more.

Urinary sediment analysis can diagnose pyuria, defined as a clean-catch, midstream, voided specimen, which is spun and which has >10 leukocytes per high-power field.

Pyuria can occur without infection due to:

• previous treatment with antibiotics,
  
• contamination of urine sample by sterilizing solution,
  
• contamination of urine sample with vaginal leukocytes,
  
• chronic interstitial nephritis (such as analgesic abuse),
  
• uroepithelial tumor, and
  
• nephrolithiasis.
  

Pyuria on urinalysis has low sensitivity (25%) but high specificity (99%).

Bacteria visualized on microscopic examination is more sensitive (75%) but less specific (60%).⁷

Urinary dipstick testing—fast, convenient, and low in cost—is considered positive if it identifies either leukocyte esterase or nitrite. Positive leukocyte esterase signifies pyuria. Positive nitrite indicates the presence of enteric organisms that convert urinary nitrate to nitrite.

With either finding, dipstick sensitivity is only 50%, although specificity is 97%.⁷

I recommend:

• If a symptomatic patient’s rapid test is positive, obtain a urine culture, empirically treat for UTI, and then use urine culture results to decide whether to continue treatment.
  
• If an asymptomatic patient’s rapid test is positive, obtain a urine culture and treat only if the culture is positive.
  

What urinary tract disorders occur in pregnancy?

First, determine if the patient has urinary tract symptoms and, if so, whether the symptoms are typical of upper or lower urinary tract infections.

 

Lower urinary tract symptoms:

• dysuria
  
• frequency
  
• urgency
  
• suprapubic pain
  
• hematuria in the absence of fever and systemic symptoms
  

Frequency, of course, is difficult to ascertain in pregnancy, since most women experience this complication secondary to increased urinary output due to higher fluid intake, increased plasma volume expansion, and increases in renal blood flow and glomerular filtration rate.

Upper urinary tract symptoms:

• fever
  
• chills
  
• flank pain
  
• nausea and vomiting
  
• The patient may or may not have the symptoms of lower urinary tract infection, as well.
  

Positive culture and no symptoms

This profile is typical of asymptomatic bacteriuria, a lower urinary tract infection that occurs in 2% to 7% of pregnancies.¹

Positive culture with symptoms

This profile probably reflects either:

• Acute cystitis, a lower urinary tract infection affecting 1% to 2% of pregnancies,⁸ or
  
• Acute pyelonephritis, an upper urinary tract infection affecting 2% of pregnancies.⁹
  

What are the consequences of UTI in pregnancy?

Maternal complications

Asymptomatic bacteriuria does not plague the patient with bothersome effects, but if left untreated, asymptomatic bacteriuria will progress to symptomatic UTI: 25% will develop acute pyelonephritis, compared to 3% to 4% of treated patients¹⁰; 20% of women with severe pyelonephritis develop serious complications,¹¹ including:

• sepsis and septic shock,
  
• hemolysis and thrombocytopenia,¹²
  
• acute respiratory distress syndrome,¹³
  
• renal insufficiency.¹⁴
  

Adverse fetal outcomes

Untreated asymptomatic bacteriuria is associated with preterm delivery and low birthweight.^15-17

Acute pyelonephritis is linked to preterm birth.^18,19 Kaul et al,²⁰ in an experimental model of pyelonephritis in mice, confirmed that E. coli plays an important role in the pathogenesis of preterm delivery and low birthweight.

What is the best treatment regimen?

Data are insufficient to recommend any specific regimen.^21,22 The following strategies are based on evaluation of review articles.^3,23

Asymptomatic bacteriuria and acute cystitis

Nitrofurantoin monohydrate macrocrystals is my first-line treatment. Nitrofurantoin has high concentrations in the urinary tract but induces minimal resistance in gram-negative organisms.

If nitrofurantoin is not effective, I change antibiotics based on urine culture antibiotic sensitivity profiles (FIGURE 2).

Keep in mind the current resistance of E. coli to antibiotics: ampicillin, 28% to 39%; trimethoprim-sulfamethoxazole, 31%; and first-generation cephalosporins, 9% to 19%.²⁴

Single-dose treatment for pregnant women with asymptomatic bacteriuria has been evaluated, given its lower cost and better compliance. However, evidence is insufficient to determine whether single-dose or longer-duration regimens are more effective.²⁵

I recommend longer-duration dosages for now, until a large randomized controlled trial can derive conclusive data.

Remember that treatment success is not contingent upon duration of therapy—just be sure that the test-of-cure urine culture is negative 1 to 2 weeks after treatment is completed.

Acute pyelonephritis

Management should include the following:

• hospitalization
  
• urine and blood cultures
  
• laboratory studies of complete blood cell count, electrolytes, creatinine, and liver function
  
• monitoring of vital signs and urine output
  
• intravenous (IV) crystalloid fluid to maintain urine output
  
• IV antibiotics (FIGURE 3).
  

If symptoms persist after 48 hours despite adequate IV antibiotic therapy, consider other causes such as resistant organisms, nephrolithiasis, perinephric abscesses, renal obstruction, or other infections.

Consider imaging by renal ultrasound to assess the presence of nephrolithiasis, perinephric abscess, or obstruction.

I recommend inpatient treatment for pregnant women with acute pyelonephritis at this time, until further studies are available.

To evaluate outpatient treatment, Millar and colleagues randomized 120 women under 24 weeks’ gestation either to inpatient IV cefazolin until 48 hours afebrile or to outpatient ceftriaxone intramuscularly. (Both treatment arms completed a course of oral cephalexin.) There were no differences in therapeutic response or birth outcomes, but 6 patients in the outpatient arm required hospitalization for IV therapy and 1 woman developed sepsis.²⁶

The same researchers studied 92 patients of more than 24 weeks’ gestation who received 2 doses of ceftriaxone intramuscularly, then were randomized to either continued inpatient therapy until 48 hours afebrile or discharge with reevaluation as an outpatient in 48 to 72 hours. Again, there were no differences in therapeutic response or birth outcomes; however, almost two-thirds of patients were excluded from the study as they did not meet criteria for outpatient management, due to sepsis, preterm labor, or concurrent medical conditions.²⁷

Adequate antibiotic coverage is crucial

To ensure adequate antibiotic coverage when treating UTI, it is important to understand which organisms cause these infections in pregnancy.

E. coli causes 75% to 90% of UTIs in nonpregnant women.²⁸Staphylococcus saprophyticus causes 10% to 15% of UTIs in nonpregnant women, but less in pregnant women.

Group B Streptococcus (GBS)—another gram-positive organism—has important implications for pregnant women: Intrapartum prophylaxis is important, to prevent neonatal GBS disease.²⁹

Klebsiella, Enterobacter, Proteus, and Enterococcus species²⁸ infrequently cause UTI in pregnancy.

What about prophylaxis and follow-up cultures?

 

Expect recurrence

One third of pregnant women diagnosed with UTI will have recurrence.¹ Recurrence is either relapse (same strain, within 2 weeks of completing initial treatment for the original infection) or reinfection (different strain or same strain after more than 2 weeks).

2 UTIs or pyelonephritis warrant suppressive therapy

I recommend suppressive therapy if a pregnant woman is diagnosed with 2 lower urinary tract infections or acute pyelonephritis (TABLE).

Nitrofurantoin is the preferred agent, as it has high concentrations in the urinary tract but induces minimal resistance in gram-negative organisms.

Start only after eradication of the acute infection, as evidenced by a negative test-of-cure urine culture at least 1 to 2 weeks after treatment is discontinued.²³

Monthly urine cultures until delivery

I recommend monthly follow-up urine cultures until delivery.

Periodic follow-up screening is often recommended, but opinions differ on which test to use or how often to screen.

THE CASE: DIAGNOSIS, TREATMENT, FOLLOW-UP, AND OUTCOME

The patient with upper urinary tract symptoms had a white blood cell count of 15, a urine dipstick positive for leukocyte esterase and nitrites, and a urine sediment analysis indicating pyuria.

She was diagnosed with acute pyelonephritis and started on ampicillin and gentamicin intravenously. Her urine culture drawn upon admission grew >100,000 CFU/mL of sulfonamide-resistant E. coli.

Within 48 hours, she showed clinical improvement and was discharged home with a 10-day course of nitrofurantoin. One week after completing treatment, her test-of-cure urine culture was negative and she was started on nitrofurantoin 50 mg every night at bedtime.

For the rest of pregnancy, she underwent monthly screening urine cultures, which remained negative. She had an uncomplicated delivery at 38 weeks of gestation.

TABLE

Suppressive therapy to prevent UTI recurrence

Suppressive therapy is recommended for any pregnant woman with:
2 lower urinary tract infections or acute pyelonephritis.
Do not initiate suppressive therapy until a negative test-of-cure urine culture confirms eradication of the acute infection.
ANTIBIOTIC	DOSE (ORAL)
Nitrofurantoin monohydrate macrocrystals	50 mg at bedtime
or
Cephalexin	250 mg at bedtime

Dr. Chen reports support from a Women’s Reproductive Health Research Career Development Center grant from the National Institutes of Child Health and Human Development.

THE CASE: SIGNS AND SYMPTOMS

A 29–year–old nullipara at 18 weeks’ gestation complains of fevers and back pain. She had a diagnosis of urinary tract infection with sulfonamide-resistant Escherichia coli at 9 weeks of gestation, which was treated with nitrofurantoin, 100 mg by mouth twice a day for 7 days. A test of cure by urine culture was negative.

Now her temperature is 101°F and she has right costovertebral angle tenderness.

How should you proceed?

Anatomy is destiny, in the case of susceptibility to urinary tract infection (UTI). The female urethra is only 3 cm to 4 cm long, and its proximity to the vagina, anus, and rectum facilitates colonization of normal gastrointestinal flora in the bladder.¹

Sexual activity also facilitates migration of normal gastrointestinal flora to the female urethra.²

Anatomical features of pregnancy exacerbate the female predisposition to urinary tract infection. In pregnancy, hormonal and mechanical changes that occur in the urinary tract lead to urinary stasis and ureterovesical reflux—setting the stage for urinary tract infection (FIGURE 1).

Who should be screened?

All pregnant women should be screened for UTI early in pregnancy, according to the American College of Obstetricians and Gynecologists.³

I recommend a urine culture screening for all pregnant women at their first prenatal visit.

Screen often if she has risk factors

I recommend frequent screening (at least every trimester) by urine culture, in pregnant women with any of these risk factors:

• diabetes mellitus, including gestational diabetes⁴;
  
• urologic abnormalities—specifically, neurogenic bladder;
  
• prepregnancy (for example, 2 to 3 infections per year) and antepartum history of UTI prior to initiation of prenatal care⁵;
  
• sickle cell hemoglobinopathy.⁵
  

Which test is best?

The gold standard for detecting bacteria in urine is by culture.

Which threshold to use?

The standard definition of a positive urine culture from a clean-catch, midstream, voided specimen is ≥100,000 colony forming units (CFU) per mL of a single organism. However, in symptomatic patients, the test’s sensitivity is increased by lowering the cut-off to 100 CFU/mL of a single organism.⁶ In women with urinary symptoms, only 50% of patients had 100,000 CFU/mL by urine culture collected from clean-catch, midstream, voided specimens, though all of them had positive cultures from suprapubic taps.

The clean-catch, midstream, voided specimen is the specimen of choice for practical purposes, since it is noninvasive and easily obtained in the office setting.

For the record: The presence of any organism represents UTI in specimens obtained via suprapubic aspiration of the bladder; 100 CFU/mL of a single organism is positive for specimens obtained by urethral catheterization.

I recommend that, when obtaining urine cultures via clean-catch, midstream, voided specimens:

• for asymptomatic patients, use ≥100,000 CFU/mL of a single organism.
  
• in symptomatic patients, use ≥100 CFU/mL of a single organism.
  

What about rapid tests?

Urinary sediment analysis and urine dipstick testing offer speed and low cost, but with lower accuracy than urine cultures, which require 24 to 48 hours for results and cost more.

Urinary sediment analysis can diagnose pyuria, defined as a clean-catch, midstream, voided specimen, which is spun and which has >10 leukocytes per high-power field.

Pyuria can occur without infection due to:

• previous treatment with antibiotics,
  
• contamination of urine sample by sterilizing solution,
  
• contamination of urine sample with vaginal leukocytes,
  
• chronic interstitial nephritis (such as analgesic abuse),
  
• uroepithelial tumor, and
  
• nephrolithiasis.
  

Pyuria on urinalysis has low sensitivity (25%) but high specificity (99%).

Bacteria visualized on microscopic examination is more sensitive (75%) but less specific (60%).⁷

Urinary dipstick testing—fast, convenient, and low in cost—is considered positive if it identifies either leukocyte esterase or nitrite. Positive leukocyte esterase signifies pyuria. Positive nitrite indicates the presence of enteric organisms that convert urinary nitrate to nitrite.

With either finding, dipstick sensitivity is only 50%, although specificity is 97%.⁷

I recommend:

• If a symptomatic patient’s rapid test is positive, obtain a urine culture, empirically treat for UTI, and then use urine culture results to decide whether to continue treatment.
  
• If an asymptomatic patient’s rapid test is positive, obtain a urine culture and treat only if the culture is positive.
  

What urinary tract disorders occur in pregnancy?

First, determine if the patient has urinary tract symptoms and, if so, whether the symptoms are typical of upper or lower urinary tract infections.

 

Lower urinary tract symptoms:

• dysuria
  
• frequency
  
• urgency
  
• suprapubic pain
  
• hematuria in the absence of fever and systemic symptoms
  

Frequency, of course, is difficult to ascertain in pregnancy, since most women experience this complication secondary to increased urinary output due to higher fluid intake, increased plasma volume expansion, and increases in renal blood flow and glomerular filtration rate.

Upper urinary tract symptoms:

• fever
  
• chills
  
• flank pain
  
• nausea and vomiting
  
• The patient may or may not have the symptoms of lower urinary tract infection, as well.
  

Positive culture and no symptoms

This profile is typical of asymptomatic bacteriuria, a lower urinary tract infection that occurs in 2% to 7% of pregnancies.¹

Positive culture with symptoms

This profile probably reflects either:

• Acute cystitis, a lower urinary tract infection affecting 1% to 2% of pregnancies,⁸ or
  
• Acute pyelonephritis, an upper urinary tract infection affecting 2% of pregnancies.⁹
  

What are the consequences of UTI in pregnancy?

Maternal complications

Asymptomatic bacteriuria does not plague the patient with bothersome effects, but if left untreated, asymptomatic bacteriuria will progress to symptomatic UTI: 25% will develop acute pyelonephritis, compared to 3% to 4% of treated patients¹⁰; 20% of women with severe pyelonephritis develop serious complications,¹¹ including:

• sepsis and septic shock,
  
• hemolysis and thrombocytopenia,¹²
  
• acute respiratory distress syndrome,¹³
  
• renal insufficiency.¹⁴
  

Adverse fetal outcomes

Untreated asymptomatic bacteriuria is associated with preterm delivery and low birthweight.^15-17

Acute pyelonephritis is linked to preterm birth.^18,19 Kaul et al,²⁰ in an experimental model of pyelonephritis in mice, confirmed that E. coli plays an important role in the pathogenesis of preterm delivery and low birthweight.

What is the best treatment regimen?

Data are insufficient to recommend any specific regimen.^21,22 The following strategies are based on evaluation of review articles.^3,23

Asymptomatic bacteriuria and acute cystitis

Nitrofurantoin monohydrate macrocrystals is my first-line treatment. Nitrofurantoin has high concentrations in the urinary tract but induces minimal resistance in gram-negative organisms.

If nitrofurantoin is not effective, I change antibiotics based on urine culture antibiotic sensitivity profiles (FIGURE 2).

Keep in mind the current resistance of E. coli to antibiotics: ampicillin, 28% to 39%; trimethoprim-sulfamethoxazole, 31%; and first-generation cephalosporins, 9% to 19%.²⁴

Single-dose treatment for pregnant women with asymptomatic bacteriuria has been evaluated, given its lower cost and better compliance. However, evidence is insufficient to determine whether single-dose or longer-duration regimens are more effective.²⁵

I recommend longer-duration dosages for now, until a large randomized controlled trial can derive conclusive data.

Remember that treatment success is not contingent upon duration of therapy—just be sure that the test-of-cure urine culture is negative 1 to 2 weeks after treatment is completed.

Acute pyelonephritis

Management should include the following:

• hospitalization
  
• urine and blood cultures
  
• laboratory studies of complete blood cell count, electrolytes, creatinine, and liver function
  
• monitoring of vital signs and urine output
  
• intravenous (IV) crystalloid fluid to maintain urine output
  
• IV antibiotics (FIGURE 3).
  

If symptoms persist after 48 hours despite adequate IV antibiotic therapy, consider other causes such as resistant organisms, nephrolithiasis, perinephric abscesses, renal obstruction, or other infections.

Consider imaging by renal ultrasound to assess the presence of nephrolithiasis, perinephric abscess, or obstruction.

I recommend inpatient treatment for pregnant women with acute pyelonephritis at this time, until further studies are available.

To evaluate outpatient treatment, Millar and colleagues randomized 120 women under 24 weeks’ gestation either to inpatient IV cefazolin until 48 hours afebrile or to outpatient ceftriaxone intramuscularly. (Both treatment arms completed a course of oral cephalexin.) There were no differences in therapeutic response or birth outcomes, but 6 patients in the outpatient arm required hospitalization for IV therapy and 1 woman developed sepsis.²⁶

The same researchers studied 92 patients of more than 24 weeks’ gestation who received 2 doses of ceftriaxone intramuscularly, then were randomized to either continued inpatient therapy until 48 hours afebrile or discharge with reevaluation as an outpatient in 48 to 72 hours. Again, there were no differences in therapeutic response or birth outcomes; however, almost two-thirds of patients were excluded from the study as they did not meet criteria for outpatient management, due to sepsis, preterm labor, or concurrent medical conditions.²⁷

Adequate antibiotic coverage is crucial

To ensure adequate antibiotic coverage when treating UTI, it is important to understand which organisms cause these infections in pregnancy.

E. coli causes 75% to 90% of UTIs in nonpregnant women.²⁸Staphylococcus saprophyticus causes 10% to 15% of UTIs in nonpregnant women, but less in pregnant women.

Group B Streptococcus (GBS)—another gram-positive organism—has important implications for pregnant women: Intrapartum prophylaxis is important, to prevent neonatal GBS disease.²⁹

Klebsiella, Enterobacter, Proteus, and Enterococcus species²⁸ infrequently cause UTI in pregnancy.

What about prophylaxis and follow-up cultures?

 

Expect recurrence

One third of pregnant women diagnosed with UTI will have recurrence.¹ Recurrence is either relapse (same strain, within 2 weeks of completing initial treatment for the original infection) or reinfection (different strain or same strain after more than 2 weeks).

2 UTIs or pyelonephritis warrant suppressive therapy

I recommend suppressive therapy if a pregnant woman is diagnosed with 2 lower urinary tract infections or acute pyelonephritis (TABLE).

Nitrofurantoin is the preferred agent, as it has high concentrations in the urinary tract but induces minimal resistance in gram-negative organisms.

Start only after eradication of the acute infection, as evidenced by a negative test-of-cure urine culture at least 1 to 2 weeks after treatment is discontinued.²³

Monthly urine cultures until delivery

I recommend monthly follow-up urine cultures until delivery.

Periodic follow-up screening is often recommended, but opinions differ on which test to use or how often to screen.

THE CASE: DIAGNOSIS, TREATMENT, FOLLOW-UP, AND OUTCOME

The patient with upper urinary tract symptoms had a white blood cell count of 15, a urine dipstick positive for leukocyte esterase and nitrites, and a urine sediment analysis indicating pyuria.

She was diagnosed with acute pyelonephritis and started on ampicillin and gentamicin intravenously. Her urine culture drawn upon admission grew >100,000 CFU/mL of sulfonamide-resistant E. coli.

Within 48 hours, she showed clinical improvement and was discharged home with a 10-day course of nitrofurantoin. One week after completing treatment, her test-of-cure urine culture was negative and she was started on nitrofurantoin 50 mg every night at bedtime.

For the rest of pregnancy, she underwent monthly screening urine cultures, which remained negative. She had an uncomplicated delivery at 38 weeks of gestation.

TABLE

Suppressive therapy to prevent UTI recurrence

Suppressive therapy is recommended for any pregnant woman with:
2 lower urinary tract infections or acute pyelonephritis.
Do not initiate suppressive therapy until a negative test-of-cure urine culture confirms eradication of the acute infection.
ANTIBIOTIC	DOSE (ORAL)
Nitrofurantoin monohydrate macrocrystals	50 mg at bedtime
or
Cephalexin	250 mg at bedtime

Dr. Chen reports support from a Women’s Reproductive Health Research Career Development Center grant from the National Institutes of Child Health and Human Development.