Expert Commentary

Yes. A progressive increase in the rate of uterine rupture with increasing oxytocin dosage was observed in this retrospective study in women attempting vaginal birth after cesarean delivery (VBAC), beginning at maximum dosages of 6–10 mU/min (adjusted odds ratio, 1.97) and greatest at the highest range studied, 21–30 mU/min (adjusted odds ratio, 2.98). However, the overall rate of rupture in this study—even at the highest oxytocin dosages studied—was, at 2%, relatively low.

EXPERT COMMENTARY

Numerous studies support the safety of a trial of labor after one low-transverse cesarean as an alternative to elective repeat cesarean delivery, with favorable maternal and perinatal outcomes expected for the vast majority of carefully selected patients. Although ACOG acknowledges that oxytocin appears to be relatively safe in patients attempting VBAC, some studies have shown an increased rate of uterine rupture with labor induction and augmentation than with spontaneous labor, suggesting that use of oxytocin may be a risk factor for rupture.¹

A focus on maximum dosages

This retrospective study is one of several derived from a large cohort of women with at least one previous low-transverse cesarean delivery performed at one of 17 centers in the United States. Earlier studies from this cohort found that oxytocin alone was not associated with uterine rupture and that no single factor was sufficient to predict rupture.^2,3 The majorobjective of this subanalysis was to determine whether higher maximum dosages of oxytocin increase the rate of rupture.

Findings are probably not useful

Despite the strengths of this large study, with observations adjusted for significant confounders, it is limited by its retrospective design, potential bias introduced by nonrandomization, and use of maximum dosage of oxytocin as the primary variable. Many factors are weighed by practitioners when they consider a patient for VBAC and for oxytocin administration, and not all of them could be accounted for in this study: Timing of oxytocin administration, dosing intervals, duration of oxytocin exposure, and total cumulative dosage of oxytocin were not assessed.

Maximum oxytocin dosage was only a fair predictor of uterine rupture, and the authors acknowledge that the maximum dosage of oxytocin is not sufficiently predictive to be clinically useful. Maximum oxytocin dosage is likely only one of the variables affecting the rate of rupture.

Counsel women about greater risk

Although this study contributes to our understanding of uterine rupture in VBAC, its findings do not warrant a change in current clinical practice. The absolute increase of uterine rupture with higher maximum oxytocin dosages was about 1%. Patients should be informed about the possible increased risk of rupture with higher dosages of oxytocin. However, ACOG’s existing recommendations on VBAC should still guide practitioners, and oxytocin should remain an option for properly selected patients in adequately staffed and monitored hospitals.¹

Yes. A progressive increase in the rate of uterine rupture with increasing oxytocin dosage was observed in this retrospective study in women attempting vaginal birth after cesarean delivery (VBAC), beginning at maximum dosages of 6–10 mU/min (adjusted odds ratio, 1.97) and greatest at the highest range studied, 21–30 mU/min (adjusted odds ratio, 2.98). However, the overall rate of rupture in this study—even at the highest oxytocin dosages studied—was, at 2%, relatively low.

EXPERT COMMENTARY

Numerous studies support the safety of a trial of labor after one low-transverse cesarean as an alternative to elective repeat cesarean delivery, with favorable maternal and perinatal outcomes expected for the vast majority of carefully selected patients. Although ACOG acknowledges that oxytocin appears to be relatively safe in patients attempting VBAC, some studies have shown an increased rate of uterine rupture with labor induction and augmentation than with spontaneous labor, suggesting that use of oxytocin may be a risk factor for rupture.¹

A focus on maximum dosages

This retrospective study is one of several derived from a large cohort of women with at least one previous low-transverse cesarean delivery performed at one of 17 centers in the United States. Earlier studies from this cohort found that oxytocin alone was not associated with uterine rupture and that no single factor was sufficient to predict rupture.^2,3 The majorobjective of this subanalysis was to determine whether higher maximum dosages of oxytocin increase the rate of rupture.

Findings are probably not useful

Despite the strengths of this large study, with observations adjusted for significant confounders, it is limited by its retrospective design, potential bias introduced by nonrandomization, and use of maximum dosage of oxytocin as the primary variable. Many factors are weighed by practitioners when they consider a patient for VBAC and for oxytocin administration, and not all of them could be accounted for in this study: Timing of oxytocin administration, dosing intervals, duration of oxytocin exposure, and total cumulative dosage of oxytocin were not assessed.

Maximum oxytocin dosage was only a fair predictor of uterine rupture, and the authors acknowledge that the maximum dosage of oxytocin is not sufficiently predictive to be clinically useful. Maximum oxytocin dosage is likely only one of the variables affecting the rate of rupture.

Counsel women about greater risk

Although this study contributes to our understanding of uterine rupture in VBAC, its findings do not warrant a change in current clinical practice. The absolute increase of uterine rupture with higher maximum oxytocin dosages was about 1%. Patients should be informed about the possible increased risk of rupture with higher dosages of oxytocin. However, ACOG’s existing recommendations on VBAC should still guide practitioners, and oxytocin should remain an option for properly selected patients in adequately staffed and monitored hospitals.¹

Yes. A progressive increase in the rate of uterine rupture with increasing oxytocin dosage was observed in this retrospective study in women attempting vaginal birth after cesarean delivery (VBAC), beginning at maximum dosages of 6–10 mU/min (adjusted odds ratio, 1.97) and greatest at the highest range studied, 21–30 mU/min (adjusted odds ratio, 2.98). However, the overall rate of rupture in this study—even at the highest oxytocin dosages studied—was, at 2%, relatively low.

EXPERT COMMENTARY

Numerous studies support the safety of a trial of labor after one low-transverse cesarean as an alternative to elective repeat cesarean delivery, with favorable maternal and perinatal outcomes expected for the vast majority of carefully selected patients. Although ACOG acknowledges that oxytocin appears to be relatively safe in patients attempting VBAC, some studies have shown an increased rate of uterine rupture with labor induction and augmentation than with spontaneous labor, suggesting that use of oxytocin may be a risk factor for rupture.¹

A focus on maximum dosages

This retrospective study is one of several derived from a large cohort of women with at least one previous low-transverse cesarean delivery performed at one of 17 centers in the United States. Earlier studies from this cohort found that oxytocin alone was not associated with uterine rupture and that no single factor was sufficient to predict rupture.^2,3 The majorobjective of this subanalysis was to determine whether higher maximum dosages of oxytocin increase the rate of rupture.

Findings are probably not useful

Despite the strengths of this large study, with observations adjusted for significant confounders, it is limited by its retrospective design, potential bias introduced by nonrandomization, and use of maximum dosage of oxytocin as the primary variable. Many factors are weighed by practitioners when they consider a patient for VBAC and for oxytocin administration, and not all of them could be accounted for in this study: Timing of oxytocin administration, dosing intervals, duration of oxytocin exposure, and total cumulative dosage of oxytocin were not assessed.

Maximum oxytocin dosage was only a fair predictor of uterine rupture, and the authors acknowledge that the maximum dosage of oxytocin is not sufficiently predictive to be clinically useful. Maximum oxytocin dosage is likely only one of the variables affecting the rate of rupture.

Counsel women about greater risk

Although this study contributes to our understanding of uterine rupture in VBAC, its findings do not warrant a change in current clinical practice. The absolute increase of uterine rupture with higher maximum oxytocin dosages was about 1%. Patients should be informed about the possible increased risk of rupture with higher dosages of oxytocin. However, ACOG’s existing recommendations on VBAC should still guide practitioners, and oxytocin should remain an option for properly selected patients in adequately staffed and monitored hospitals.¹

Yes. This population-based cohort study from Sweden found that hysterectomy for benign indications by itself doubles the risk of future surgery for urinary stress incontinence, regardless of hysterectomy technique. The risk of stress-incontinence surgery varied with the length of follow-up, with the highest overall risk observed within 5 years of hysterectomy and the lowest risk after 10 years or more (2.7 versus 2.1).

EXPERT COMMENTARY

Urologists, among others, have long suspected that hysterectomy is somehow implicated in the development of stress incontinence, a point of view that has met with considerable resistance from gynecologists. Now comes this carefully designed study by Altman and colleagues, which lends considerable support to this belief.

Strengths of the study include use of Swedish health registry

The study design used by the authors is impressive. Because Sweden (unlike the United States) has a national health-care system with an integrated national database, the authors were able to select more than 165,000 women from the Swedish health registry who had undergone hysterectomy (the “exposed” cohort) and compare them with almost 480,000 women who had not had a hysterectomy (three controls for every exposed case), matching them by year of birth and county of residence. Because of the integrated nature of the Swedish health registry, they were able to follow these women for 30 years and link their medical records to subsequent surgical procedures for urinary stress incontinence.

The authors eliminated from consideration any patient whose surgery had been done for malignancy. Because patients undergoing hysterectomy for pelvic organ prolapse might well be predisposed to develop stress incontinence in later life, the authors considered as a separate subset those women whose hysterectomy was done for prolapse or who had an associated procedure performed for prolapse at the same time.

As might be expected, women who underwent hysterectomy for prolapse had the highest risk of undergoing stress-incontinence surgery within 5 years of the removal of their uterus.

Vaginal delivery magnified the impact of hysterectomy

Altman and colleagues also considered the impact of vaginal delivery on subsequent surgery for stress incontinence, finding an additive effect. There was a “dose-response” increase in risk related to the number of vaginal births. Women who had four vaginal deliveries had a sixfold increase in the risk of stress incontinence surgery, and women who had four vaginal deliveries plus a hysterectomy had a 16-fold increase in the risk of stress-incontinence surgery.

Were some women predisposed to elective surgery?

Because surgery for urinary stress incontinence is an elective procedure to improve quality of life, the argument could be made that the women who chose this form of therapy had a lower threshold for elective surgery. The authors attempted to control for this by analyzing the likelihood of undergoing osteotomy of the great toe (hallux valgus surgery) and varicose vein stripping. They found no meaningful association between these elective operations and hysterectomy or stress-incontinence surgery.

“Escalator effect” may be involved

An important question that this study is unable to answer concerns the “escalator effect.” Because urinary stress incontinence is highly prevalent, it affects many women who also have other, more pressing gynecologic complaints. We do not know how many women had stress incontinence that was much less troubling than, say, leiomyomata or dysfunctional uterine bleeding and who, after these problems were solved by hysterectomy, then had their attention increasingly focused on this new complaint, which then moved higher up their list of concerns as other problems were treated.

The authors also acknowledge that other behavioral and lifestyle factors that are probably associated with stress incontinence, such as smoking, strenuous work, and elevated body mass index, were not accounted for in their study.

Should this study alter clinical practice?

Women undergoing hysterectomy should probably be informed that the operation may increase the likelihood of their undergoing surgery for stress incontinence later in life. In some cases, this information may lead women to reconsider the need for elective hysterectomy, but a possible future risk of undergoing a generally safe and effective operation for stress incontinence is unlikely to be determinative for most women who are contemplating surgery for other debilitating gynecologic conditions that can be treated permanently and effectively by hysterectomy.

Yes. This population-based cohort study from Sweden found that hysterectomy for benign indications by itself doubles the risk of future surgery for urinary stress incontinence, regardless of hysterectomy technique. The risk of stress-incontinence surgery varied with the length of follow-up, with the highest overall risk observed within 5 years of hysterectomy and the lowest risk after 10 years or more (2.7 versus 2.1).

EXPERT COMMENTARY

Urologists, among others, have long suspected that hysterectomy is somehow implicated in the development of stress incontinence, a point of view that has met with considerable resistance from gynecologists. Now comes this carefully designed study by Altman and colleagues, which lends considerable support to this belief.

Strengths of the study include use of Swedish health registry

The study design used by the authors is impressive. Because Sweden (unlike the United States) has a national health-care system with an integrated national database, the authors were able to select more than 165,000 women from the Swedish health registry who had undergone hysterectomy (the “exposed” cohort) and compare them with almost 480,000 women who had not had a hysterectomy (three controls for every exposed case), matching them by year of birth and county of residence. Because of the integrated nature of the Swedish health registry, they were able to follow these women for 30 years and link their medical records to subsequent surgical procedures for urinary stress incontinence.

The authors eliminated from consideration any patient whose surgery had been done for malignancy. Because patients undergoing hysterectomy for pelvic organ prolapse might well be predisposed to develop stress incontinence in later life, the authors considered as a separate subset those women whose hysterectomy was done for prolapse or who had an associated procedure performed for prolapse at the same time.

As might be expected, women who underwent hysterectomy for prolapse had the highest risk of undergoing stress-incontinence surgery within 5 years of the removal of their uterus.

Vaginal delivery magnified the impact of hysterectomy

Altman and colleagues also considered the impact of vaginal delivery on subsequent surgery for stress incontinence, finding an additive effect. There was a “dose-response” increase in risk related to the number of vaginal births. Women who had four vaginal deliveries had a sixfold increase in the risk of stress incontinence surgery, and women who had four vaginal deliveries plus a hysterectomy had a 16-fold increase in the risk of stress-incontinence surgery.

Were some women predisposed to elective surgery?

Because surgery for urinary stress incontinence is an elective procedure to improve quality of life, the argument could be made that the women who chose this form of therapy had a lower threshold for elective surgery. The authors attempted to control for this by analyzing the likelihood of undergoing osteotomy of the great toe (hallux valgus surgery) and varicose vein stripping. They found no meaningful association between these elective operations and hysterectomy or stress-incontinence surgery.

“Escalator effect” may be involved

An important question that this study is unable to answer concerns the “escalator effect.” Because urinary stress incontinence is highly prevalent, it affects many women who also have other, more pressing gynecologic complaints. We do not know how many women had stress incontinence that was much less troubling than, say, leiomyomata or dysfunctional uterine bleeding and who, after these problems were solved by hysterectomy, then had their attention increasingly focused on this new complaint, which then moved higher up their list of concerns as other problems were treated.

The authors also acknowledge that other behavioral and lifestyle factors that are probably associated with stress incontinence, such as smoking, strenuous work, and elevated body mass index, were not accounted for in their study.

Should this study alter clinical practice?

Women undergoing hysterectomy should probably be informed that the operation may increase the likelihood of their undergoing surgery for stress incontinence later in life. In some cases, this information may lead women to reconsider the need for elective hysterectomy, but a possible future risk of undergoing a generally safe and effective operation for stress incontinence is unlikely to be determinative for most women who are contemplating surgery for other debilitating gynecologic conditions that can be treated permanently and effectively by hysterectomy.

Yes. This population-based cohort study from Sweden found that hysterectomy for benign indications by itself doubles the risk of future surgery for urinary stress incontinence, regardless of hysterectomy technique. The risk of stress-incontinence surgery varied with the length of follow-up, with the highest overall risk observed within 5 years of hysterectomy and the lowest risk after 10 years or more (2.7 versus 2.1).

EXPERT COMMENTARY

Urologists, among others, have long suspected that hysterectomy is somehow implicated in the development of stress incontinence, a point of view that has met with considerable resistance from gynecologists. Now comes this carefully designed study by Altman and colleagues, which lends considerable support to this belief.

Strengths of the study include use of Swedish health registry

The study design used by the authors is impressive. Because Sweden (unlike the United States) has a national health-care system with an integrated national database, the authors were able to select more than 165,000 women from the Swedish health registry who had undergone hysterectomy (the “exposed” cohort) and compare them with almost 480,000 women who had not had a hysterectomy (three controls for every exposed case), matching them by year of birth and county of residence. Because of the integrated nature of the Swedish health registry, they were able to follow these women for 30 years and link their medical records to subsequent surgical procedures for urinary stress incontinence.

The authors eliminated from consideration any patient whose surgery had been done for malignancy. Because patients undergoing hysterectomy for pelvic organ prolapse might well be predisposed to develop stress incontinence in later life, the authors considered as a separate subset those women whose hysterectomy was done for prolapse or who had an associated procedure performed for prolapse at the same time.

As might be expected, women who underwent hysterectomy for prolapse had the highest risk of undergoing stress-incontinence surgery within 5 years of the removal of their uterus.

Vaginal delivery magnified the impact of hysterectomy

Altman and colleagues also considered the impact of vaginal delivery on subsequent surgery for stress incontinence, finding an additive effect. There was a “dose-response” increase in risk related to the number of vaginal births. Women who had four vaginal deliveries had a sixfold increase in the risk of stress incontinence surgery, and women who had four vaginal deliveries plus a hysterectomy had a 16-fold increase in the risk of stress-incontinence surgery.

Were some women predisposed to elective surgery?

Because surgery for urinary stress incontinence is an elective procedure to improve quality of life, the argument could be made that the women who chose this form of therapy had a lower threshold for elective surgery. The authors attempted to control for this by analyzing the likelihood of undergoing osteotomy of the great toe (hallux valgus surgery) and varicose vein stripping. They found no meaningful association between these elective operations and hysterectomy or stress-incontinence surgery.

“Escalator effect” may be involved

An important question that this study is unable to answer concerns the “escalator effect.” Because urinary stress incontinence is highly prevalent, it affects many women who also have other, more pressing gynecologic complaints. We do not know how many women had stress incontinence that was much less troubling than, say, leiomyomata or dysfunctional uterine bleeding and who, after these problems were solved by hysterectomy, then had their attention increasingly focused on this new complaint, which then moved higher up their list of concerns as other problems were treated.

The authors also acknowledge that other behavioral and lifestyle factors that are probably associated with stress incontinence, such as smoking, strenuous work, and elevated body mass index, were not accounted for in their study.

Should this study alter clinical practice?

Women undergoing hysterectomy should probably be informed that the operation may increase the likelihood of their undergoing surgery for stress incontinence later in life. In some cases, this information may lead women to reconsider the need for elective hysterectomy, but a possible future risk of undergoing a generally safe and effective operation for stress incontinence is unlikely to be determinative for most women who are contemplating surgery for other debilitating gynecologic conditions that can be treated permanently and effectively by hysterectomy.

Yes. This retrospective study found considerable variation among 123 radiologists who interpreted 35,895 diagnostic mammograms between 1996 and 2003. The mammograms were performed to assess a clinical sign or symptom of breast cancer—not to evaluate abnormal or equivocal imaging. Sensitivity ranged from 27% to 100% (median: 79%), and the false-positive rate ranged from 0 to 16% (median: 4.3%). Sensitivity varied substantially even among radiologists who had similar false-positive rates.

Neither the total number of mammography exams interpreted over the preceding year nor the percentage of mammograms that were diagnostic affected the radiologists’ performance.

EXPERT COMMENTARY

Previous studies have suggested high variability among radiologists who interpret diagnostic mammograms. In this study, funded by the National Cancer Institute, mammograms were considered positive when they were interpreted as suspicious or highly suggestive of cancer (BI-RADS 4 or 5), or when biopsy or surgical consultation was recommended. All others were considered negative. Breast cancer was confirmed if the woman was diagnosed with invasive or in situ breast cancer within 1 year of the diagnostic mammogram. Sensitivity was defined as the percentage of positive examinations among women diagnosed with breast cancer, and the false-positive rate as the percentage of positive examinations among women without a breast cancer diagnosis.

Diagnostic mammograms are more likely to be positive

The prevalence of breast cancer is 10 times higher in women undergoing diagnostic mammography than it is in women undergoing screening mammography. That makes the high variability in diagnostic interpretation reported in this study especially troubling.

High sensitivity expedites the diagnosis of breast cancer, but also tends to increase the rate of false positives, which lead to invasive procedures and considerable anxiety among women who do not have breast cancer. Therefore, it is preferable to achieve high sensitivity without excessive numbers of false positives.

In this study, radiologists practicing at an academic center were more accurate at breast cancer diagnosis than their nonacademic peers, but this improvement was of borderline statistical significance—and few of the radiologists studied practiced in an academic setting. Moreover, women who get diagnostic mammograms at academic centers may differ from other women. In the US, most mammograms are read by general radiologists.

Alas, no concrete suggestions

This study highlights considerable variability among radiologists interpreting diagnostic mammograms, but does not specify how these mammograms can be interpreted more consistently. ObGyns should keep up-to-date on training and quality-control measures that may influence how radiologists interpret mammograms and other breast imaging.

Yes. This retrospective study found considerable variation among 123 radiologists who interpreted 35,895 diagnostic mammograms between 1996 and 2003. The mammograms were performed to assess a clinical sign or symptom of breast cancer—not to evaluate abnormal or equivocal imaging. Sensitivity ranged from 27% to 100% (median: 79%), and the false-positive rate ranged from 0 to 16% (median: 4.3%). Sensitivity varied substantially even among radiologists who had similar false-positive rates.

Neither the total number of mammography exams interpreted over the preceding year nor the percentage of mammograms that were diagnostic affected the radiologists’ performance.

EXPERT COMMENTARY

Previous studies have suggested high variability among radiologists who interpret diagnostic mammograms. In this study, funded by the National Cancer Institute, mammograms were considered positive when they were interpreted as suspicious or highly suggestive of cancer (BI-RADS 4 or 5), or when biopsy or surgical consultation was recommended. All others were considered negative. Breast cancer was confirmed if the woman was diagnosed with invasive or in situ breast cancer within 1 year of the diagnostic mammogram. Sensitivity was defined as the percentage of positive examinations among women diagnosed with breast cancer, and the false-positive rate as the percentage of positive examinations among women without a breast cancer diagnosis.

Diagnostic mammograms are more likely to be positive

The prevalence of breast cancer is 10 times higher in women undergoing diagnostic mammography than it is in women undergoing screening mammography. That makes the high variability in diagnostic interpretation reported in this study especially troubling.

High sensitivity expedites the diagnosis of breast cancer, but also tends to increase the rate of false positives, which lead to invasive procedures and considerable anxiety among women who do not have breast cancer. Therefore, it is preferable to achieve high sensitivity without excessive numbers of false positives.

In this study, radiologists practicing at an academic center were more accurate at breast cancer diagnosis than their nonacademic peers, but this improvement was of borderline statistical significance—and few of the radiologists studied practiced in an academic setting. Moreover, women who get diagnostic mammograms at academic centers may differ from other women. In the US, most mammograms are read by general radiologists.

Alas, no concrete suggestions

This study highlights considerable variability among radiologists interpreting diagnostic mammograms, but does not specify how these mammograms can be interpreted more consistently. ObGyns should keep up-to-date on training and quality-control measures that may influence how radiologists interpret mammograms and other breast imaging.

Yes. This retrospective study found considerable variation among 123 radiologists who interpreted 35,895 diagnostic mammograms between 1996 and 2003. The mammograms were performed to assess a clinical sign or symptom of breast cancer—not to evaluate abnormal or equivocal imaging. Sensitivity ranged from 27% to 100% (median: 79%), and the false-positive rate ranged from 0 to 16% (median: 4.3%). Sensitivity varied substantially even among radiologists who had similar false-positive rates.

Neither the total number of mammography exams interpreted over the preceding year nor the percentage of mammograms that were diagnostic affected the radiologists’ performance.

EXPERT COMMENTARY

Previous studies have suggested high variability among radiologists who interpret diagnostic mammograms. In this study, funded by the National Cancer Institute, mammograms were considered positive when they were interpreted as suspicious or highly suggestive of cancer (BI-RADS 4 or 5), or when biopsy or surgical consultation was recommended. All others were considered negative. Breast cancer was confirmed if the woman was diagnosed with invasive or in situ breast cancer within 1 year of the diagnostic mammogram. Sensitivity was defined as the percentage of positive examinations among women diagnosed with breast cancer, and the false-positive rate as the percentage of positive examinations among women without a breast cancer diagnosis.

Diagnostic mammograms are more likely to be positive

The prevalence of breast cancer is 10 times higher in women undergoing diagnostic mammography than it is in women undergoing screening mammography. That makes the high variability in diagnostic interpretation reported in this study especially troubling.

High sensitivity expedites the diagnosis of breast cancer, but also tends to increase the rate of false positives, which lead to invasive procedures and considerable anxiety among women who do not have breast cancer. Therefore, it is preferable to achieve high sensitivity without excessive numbers of false positives.

In this study, radiologists practicing at an academic center were more accurate at breast cancer diagnosis than their nonacademic peers, but this improvement was of borderline statistical significance—and few of the radiologists studied practiced in an academic setting. Moreover, women who get diagnostic mammograms at academic centers may differ from other women. In the US, most mammograms are read by general radiologists.

Alas, no concrete suggestions

This study highlights considerable variability among radiologists interpreting diagnostic mammograms, but does not specify how these mammograms can be interpreted more consistently. ObGyns should keep up-to-date on training and quality-control measures that may influence how radiologists interpret mammograms and other breast imaging.

The answer isn’t clear. This case-control study found that women 40 to 49 years old who had at least one screening mammogram within 2 years before diagnosis of breast cancer had an adjusted odds ratio (OR) for death from breast cancer within 5 years after diagnosis of 0.89 (95% confidence interval [CI], 0.65–1.23), and women aged 50 to 64 years had an OR of 0.47 (95% CI, 0.35–0.63). Among premenopausal women, the adjusted OR for breast cancer death was 0.74 (95% CI, 0.53–1.04), and it was 0.45 (95% CI, 0.33–0.62) among postmenopausal women. However, these findings are unreliable.

EXPERT COMMENTARY

This article reports a case-control study based on a cohort of 3,886 women aged 40 to 64 years who had a new diagnosis of breast cancer between 1994 and 1998. Of these, 553 died in the subsequent 5 years; these were the cases. The 4,016 women in the control group had no breast cancer and were drawn from the same population as the original cohort.

A much higher percentage of women in the control group had a screening history. Although the ORs reported above are impossibly far from any credible claim about the benefits of screening, the authors concluded that their study supports current screening guidelines.

Why these results are unreliable

Case-control studies have many biases, including selection bias and recall bias. This study is subject to more serious biases that are associated with nonrandomized screening studies: lead-time bias and length bias.

The former is easier to understand. Consider an extreme example: Assume that screening reveals breast cancer 5 years before it would become symptomatic. Then the only women who would die of breast cancer within 5 years (the cases in this study) would be those whose cancer was detected on the basis of symptoms. These women are unlikely to have been screened in the previous 2 years because, if they had been, their cancers probably would have shown up on mammogram. In this scenario, the incidence of screening is lower—much lower—among cases than controls. And this is pure bias, having nothing to do with screening effectiveness.

Of course, not all lead times are 5 years. Some are shorter—possibly even negative—and some are longer than 5 years. But the principle holds for any distribution of lead times among the cases. Length bias is also critical.

The authors try to address lead-time bias by considering follow-up periods of up to 7 years, but this is inadequate to eliminate the bias. Lead-time bias may sometimes be slightly less important with longer follow-up, but both types of bias are real and important for any length of follow-up. That means the conception of this study is fundamentally flawed.

Not only are the estimates biased, the confidence intervals convey an unreasonable sense of accuracy. Anyone who thinks that screening reduces the odds of breast cancer death between 37% and 65% for women aged 50 to 64 years is delusional. The most recent data from randomized trials in Sweden show that reduction in the odds of death is 14% (follow-up analysis).¹ And the Canadian National Breast Screening Study 2, which involved women aged 50 to 59 years, showed an increase of 2%.²

Difference between age groups is more revealing

One might draw an intriguing conclusion from this study based on the different results for women aged 40 to 49 (OR for screening: 0.89, with a 95% CI of 0.65 to 1.3), compared with older women. It is reasonable to hypothesize that the biases would be similar in the two age brackets. Applying an adjustment in the OR that would be reasonable for women aged 50 to 64 years to the younger women would change the OR of 0.89 to almost 1.00, suggesting little or no benefit for screening women in their 40s.

Issue must be settled by randomized trials

Because the results of this study can be easily explained by biases, it provides no evidence at all about the benefits of screening. Given our present knowledge of cancer biology, observational screening studies are hopelessly flawed. Randomized trials are difficult to run and come with their own inferential baggage—but they offer the only credible evidence about the effectiveness of screening.

This study by Norman and colleagues certainly does not warrant any change in breast cancer screening for women at any age.

The answer isn’t clear. This case-control study found that women 40 to 49 years old who had at least one screening mammogram within 2 years before diagnosis of breast cancer had an adjusted odds ratio (OR) for death from breast cancer within 5 years after diagnosis of 0.89 (95% confidence interval [CI], 0.65–1.23), and women aged 50 to 64 years had an OR of 0.47 (95% CI, 0.35–0.63). Among premenopausal women, the adjusted OR for breast cancer death was 0.74 (95% CI, 0.53–1.04), and it was 0.45 (95% CI, 0.33–0.62) among postmenopausal women. However, these findings are unreliable.

EXPERT COMMENTARY

This article reports a case-control study based on a cohort of 3,886 women aged 40 to 64 years who had a new diagnosis of breast cancer between 1994 and 1998. Of these, 553 died in the subsequent 5 years; these were the cases. The 4,016 women in the control group had no breast cancer and were drawn from the same population as the original cohort.

A much higher percentage of women in the control group had a screening history. Although the ORs reported above are impossibly far from any credible claim about the benefits of screening, the authors concluded that their study supports current screening guidelines.

Why these results are unreliable

Case-control studies have many biases, including selection bias and recall bias. This study is subject to more serious biases that are associated with nonrandomized screening studies: lead-time bias and length bias.

The former is easier to understand. Consider an extreme example: Assume that screening reveals breast cancer 5 years before it would become symptomatic. Then the only women who would die of breast cancer within 5 years (the cases in this study) would be those whose cancer was detected on the basis of symptoms. These women are unlikely to have been screened in the previous 2 years because, if they had been, their cancers probably would have shown up on mammogram. In this scenario, the incidence of screening is lower—much lower—among cases than controls. And this is pure bias, having nothing to do with screening effectiveness.

Of course, not all lead times are 5 years. Some are shorter—possibly even negative—and some are longer than 5 years. But the principle holds for any distribution of lead times among the cases. Length bias is also critical.

The authors try to address lead-time bias by considering follow-up periods of up to 7 years, but this is inadequate to eliminate the bias. Lead-time bias may sometimes be slightly less important with longer follow-up, but both types of bias are real and important for any length of follow-up. That means the conception of this study is fundamentally flawed.

Not only are the estimates biased, the confidence intervals convey an unreasonable sense of accuracy. Anyone who thinks that screening reduces the odds of breast cancer death between 37% and 65% for women aged 50 to 64 years is delusional. The most recent data from randomized trials in Sweden show that reduction in the odds of death is 14% (follow-up analysis).¹ And the Canadian National Breast Screening Study 2, which involved women aged 50 to 59 years, showed an increase of 2%.²

Difference between age groups is more revealing

One might draw an intriguing conclusion from this study based on the different results for women aged 40 to 49 (OR for screening: 0.89, with a 95% CI of 0.65 to 1.3), compared with older women. It is reasonable to hypothesize that the biases would be similar in the two age brackets. Applying an adjustment in the OR that would be reasonable for women aged 50 to 64 years to the younger women would change the OR of 0.89 to almost 1.00, suggesting little or no benefit for screening women in their 40s.

Issue must be settled by randomized trials

Because the results of this study can be easily explained by biases, it provides no evidence at all about the benefits of screening. Given our present knowledge of cancer biology, observational screening studies are hopelessly flawed. Randomized trials are difficult to run and come with their own inferential baggage—but they offer the only credible evidence about the effectiveness of screening.

This study by Norman and colleagues certainly does not warrant any change in breast cancer screening for women at any age.

The answer isn’t clear. This case-control study found that women 40 to 49 years old who had at least one screening mammogram within 2 years before diagnosis of breast cancer had an adjusted odds ratio (OR) for death from breast cancer within 5 years after diagnosis of 0.89 (95% confidence interval [CI], 0.65–1.23), and women aged 50 to 64 years had an OR of 0.47 (95% CI, 0.35–0.63). Among premenopausal women, the adjusted OR for breast cancer death was 0.74 (95% CI, 0.53–1.04), and it was 0.45 (95% CI, 0.33–0.62) among postmenopausal women. However, these findings are unreliable.

EXPERT COMMENTARY

This article reports a case-control study based on a cohort of 3,886 women aged 40 to 64 years who had a new diagnosis of breast cancer between 1994 and 1998. Of these, 553 died in the subsequent 5 years; these were the cases. The 4,016 women in the control group had no breast cancer and were drawn from the same population as the original cohort.

A much higher percentage of women in the control group had a screening history. Although the ORs reported above are impossibly far from any credible claim about the benefits of screening, the authors concluded that their study supports current screening guidelines.

Why these results are unreliable

Case-control studies have many biases, including selection bias and recall bias. This study is subject to more serious biases that are associated with nonrandomized screening studies: lead-time bias and length bias.

The former is easier to understand. Consider an extreme example: Assume that screening reveals breast cancer 5 years before it would become symptomatic. Then the only women who would die of breast cancer within 5 years (the cases in this study) would be those whose cancer was detected on the basis of symptoms. These women are unlikely to have been screened in the previous 2 years because, if they had been, their cancers probably would have shown up on mammogram. In this scenario, the incidence of screening is lower—much lower—among cases than controls. And this is pure bias, having nothing to do with screening effectiveness.

Of course, not all lead times are 5 years. Some are shorter—possibly even negative—and some are longer than 5 years. But the principle holds for any distribution of lead times among the cases. Length bias is also critical.

The authors try to address lead-time bias by considering follow-up periods of up to 7 years, but this is inadequate to eliminate the bias. Lead-time bias may sometimes be slightly less important with longer follow-up, but both types of bias are real and important for any length of follow-up. That means the conception of this study is fundamentally flawed.

Not only are the estimates biased, the confidence intervals convey an unreasonable sense of accuracy. Anyone who thinks that screening reduces the odds of breast cancer death between 37% and 65% for women aged 50 to 64 years is delusional. The most recent data from randomized trials in Sweden show that reduction in the odds of death is 14% (follow-up analysis).¹ And the Canadian National Breast Screening Study 2, which involved women aged 50 to 59 years, showed an increase of 2%.²

Difference between age groups is more revealing

One might draw an intriguing conclusion from this study based on the different results for women aged 40 to 49 (OR for screening: 0.89, with a 95% CI of 0.65 to 1.3), compared with older women. It is reasonable to hypothesize that the biases would be similar in the two age brackets. Applying an adjustment in the OR that would be reasonable for women aged 50 to 64 years to the younger women would change the OR of 0.89 to almost 1.00, suggesting little or no benefit for screening women in their 40s.

Issue must be settled by randomized trials

Because the results of this study can be easily explained by biases, it provides no evidence at all about the benefits of screening. Given our present knowledge of cancer biology, observational screening studies are hopelessly flawed. Randomized trials are difficult to run and come with their own inferential baggage—but they offer the only credible evidence about the effectiveness of screening.

This study by Norman and colleagues certainly does not warrant any change in breast cancer screening for women at any age.

Yes. In this comparison of the two methods among women aged 30 to 69 years, testing for oncogenic strains of human papillomavirus (HPV) using the Hybrid Capture 2 test (Digene) was more sensitive than conventional Papanicolaou (Pap) testing in identifying cervical intraepithelial neoplasia (CIN) grade 2 or 3 (94.6% versus 55.4%) and only marginally less specific (94.1% versus 96.8%). Negative predictive values for each test exceeded 99%.

Combining Pap and HPV testing raised sensitivity to 100% and incrementally increased the percentage of women referred for colposcopy (7.9%), compared with Pap (2.9%) or HPV testing (6.1%) alone.

EXPERT COMMENTARY

This study from Canada involving more than 10,000 nonpregnant women is likely the first randomized, controlled trial of HPV testing “as a stand-alone screening test for cervical cancer precursors in a North American population with access to quality care,” the authors observe. All participants were screened using both Pap and HPV testing, with roughly half of them undergoing the Pap test first and the other half undergoing HPV testing first. Those whose cytologic results were classified as atypical squamous cells or higher underwent colposcopy, as did all women testing positive for oncogenic HPV strains. Colposcopy was also performed in a random sample of women who had negative screening tests.

Although this trial was partially funded by an unrestricted grant from Merck Frosst Canada, the company “had no role in the design of the study, data accrual, data interpretation, or manuscript preparation,” the authors note.

Many clinicians already use both tests

Many clinicians in the United States have integrated HPV testing into cervical cancer screening on a “reflex” basis. That is, any woman whose Pap test result is classified as atypical squamous cells has her cytologic sample tested for oncogenic HPV strains. If it is HPV-positive, the woman is triaged to colposcopy.

Switch to routine HPV testing is likely a matter of time

The high sensitivity of HPV testing makes its use as primary screening particularly appealing for women who are infrequently screened.

Although sensitivity reached 100% when HPV testing was added to conventional Pap testing, it remains unclear whether both tests should be used routinely in cervical cancer screening. As Mayrand and colleagues point out in this trial, routine use of both tests “only marginally improved sensitivity as compared with HPV testing alone, while doubling the number of tests and increasing referrals.”

These important findings may propel clinicians who manage cervical cancer screening programs to make the shift from cytology-based evaluation toward routine HPV testing as the primary screen.

Yes. In this comparison of the two methods among women aged 30 to 69 years, testing for oncogenic strains of human papillomavirus (HPV) using the Hybrid Capture 2 test (Digene) was more sensitive than conventional Papanicolaou (Pap) testing in identifying cervical intraepithelial neoplasia (CIN) grade 2 or 3 (94.6% versus 55.4%) and only marginally less specific (94.1% versus 96.8%). Negative predictive values for each test exceeded 99%.

Combining Pap and HPV testing raised sensitivity to 100% and incrementally increased the percentage of women referred for colposcopy (7.9%), compared with Pap (2.9%) or HPV testing (6.1%) alone.

EXPERT COMMENTARY

This study from Canada involving more than 10,000 nonpregnant women is likely the first randomized, controlled trial of HPV testing “as a stand-alone screening test for cervical cancer precursors in a North American population with access to quality care,” the authors observe. All participants were screened using both Pap and HPV testing, with roughly half of them undergoing the Pap test first and the other half undergoing HPV testing first. Those whose cytologic results were classified as atypical squamous cells or higher underwent colposcopy, as did all women testing positive for oncogenic HPV strains. Colposcopy was also performed in a random sample of women who had negative screening tests.

Although this trial was partially funded by an unrestricted grant from Merck Frosst Canada, the company “had no role in the design of the study, data accrual, data interpretation, or manuscript preparation,” the authors note.

Many clinicians already use both tests

Many clinicians in the United States have integrated HPV testing into cervical cancer screening on a “reflex” basis. That is, any woman whose Pap test result is classified as atypical squamous cells has her cytologic sample tested for oncogenic HPV strains. If it is HPV-positive, the woman is triaged to colposcopy.

Switch to routine HPV testing is likely a matter of time

The high sensitivity of HPV testing makes its use as primary screening particularly appealing for women who are infrequently screened.

Although sensitivity reached 100% when HPV testing was added to conventional Pap testing, it remains unclear whether both tests should be used routinely in cervical cancer screening. As Mayrand and colleagues point out in this trial, routine use of both tests “only marginally improved sensitivity as compared with HPV testing alone, while doubling the number of tests and increasing referrals.”

These important findings may propel clinicians who manage cervical cancer screening programs to make the shift from cytology-based evaluation toward routine HPV testing as the primary screen.

Yes. In this comparison of the two methods among women aged 30 to 69 years, testing for oncogenic strains of human papillomavirus (HPV) using the Hybrid Capture 2 test (Digene) was more sensitive than conventional Papanicolaou (Pap) testing in identifying cervical intraepithelial neoplasia (CIN) grade 2 or 3 (94.6% versus 55.4%) and only marginally less specific (94.1% versus 96.8%). Negative predictive values for each test exceeded 99%.

Combining Pap and HPV testing raised sensitivity to 100% and incrementally increased the percentage of women referred for colposcopy (7.9%), compared with Pap (2.9%) or HPV testing (6.1%) alone.

EXPERT COMMENTARY

This study from Canada involving more than 10,000 nonpregnant women is likely the first randomized, controlled trial of HPV testing “as a stand-alone screening test for cervical cancer precursors in a North American population with access to quality care,” the authors observe. All participants were screened using both Pap and HPV testing, with roughly half of them undergoing the Pap test first and the other half undergoing HPV testing first. Those whose cytologic results were classified as atypical squamous cells or higher underwent colposcopy, as did all women testing positive for oncogenic HPV strains. Colposcopy was also performed in a random sample of women who had negative screening tests.

Although this trial was partially funded by an unrestricted grant from Merck Frosst Canada, the company “had no role in the design of the study, data accrual, data interpretation, or manuscript preparation,” the authors note.

Many clinicians already use both tests

Many clinicians in the United States have integrated HPV testing into cervical cancer screening on a “reflex” basis. That is, any woman whose Pap test result is classified as atypical squamous cells has her cytologic sample tested for oncogenic HPV strains. If it is HPV-positive, the woman is triaged to colposcopy.

Switch to routine HPV testing is likely a matter of time

The high sensitivity of HPV testing makes its use as primary screening particularly appealing for women who are infrequently screened.

Although sensitivity reached 100% when HPV testing was added to conventional Pap testing, it remains unclear whether both tests should be used routinely in cervical cancer screening. As Mayrand and colleagues point out in this trial, routine use of both tests “only marginally improved sensitivity as compared with HPV testing alone, while doubling the number of tests and increasing referrals.”

These important findings may propel clinicians who manage cervical cancer screening programs to make the shift from cytology-based evaluation toward routine HPV testing as the primary screen.

Not necessarily. In this chart review, 29% of adolescents with biopsy-proven cervical intraepithelial neoplasia (CIN) grades 2 or 3 opted for conservative treatment rather than excision. Over 18 months, the condition regressed in 65% of these patients, remained stable in 20%, and progressed without cancer in 5%. No invasive cancers developed.

Overall, CIN 2,3 was present in 35% of adolescent patients referred to colposcopy for cervical dysplasia.

EXPERT COMMENTARY

Adolescents differ from adults in many ways—no surprise. Some of the less obvious differences are their tendency to have multiple sexual partners, which exposes them to a number of human papillomavirus (HPV) types; the fact that most have not yet developed a protective immune response to the virus; and their larger, more active and vulnerable cervical transformation zone.

As a result, cytologic abnormalities are very common in adolescents shortly after they become sexually active. But although lesions develop very quickly, they regress just as rapidly. Low-grade squamous intraepithelial lesions (LSIL) regress in 70% to 94% of adolescents (usually in the first 24 months), and progress in only 3% to 7%.^1,2 The rate of invasive cancer in adolescents is only 0.3 for every 100,000 individuals.³

In adults, HPV disease is more likely to progress and less likely to regress. Adolescents have primarily incident infection, whereas adults have a mixture of incident and prevalent infection— and prevalent infections are more likely to be persistent infections and less likely to regress over the short term than incident infections are.

CIN 2 can be an unreliable diagnosis

Some patients with CIN 2 really have CIN 1,2 (often adolescents), whereas others have CIN 2,3 (often adults). That may be one reason CIN 2 is more likely to regress in adolescents than adults. Surprisingly, a recent study by Wright and colleagues⁴ found otherwise: Both the incidence and natural history of CIN 2 were similar in adults and adolescents. Moore and associates set out to validate these findings by reviewing medical records at the University of Oklahoma Health Science Center in Oklahoma City.

Details of the study

Patients were managed according to the 2001 guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP). Patients younger than 21 who had CIN 2,3 were offered conservative management or excision. Those who underwent immediate conization were compared with those who were followed at 4- to 6-month intervals:

• Of 501 patients identified in the colposcopy clinic, 146 (29%) underwent immediate conization, and 77 (53%) were found to have CIN 2.
  
• Of the 355 (71%) who were followed conservatively, data were available for 125 patients over a median of 18 months. Regression was reported in 56%, persistence in 35%, and progression in 14%.
  
• Of the 55 patients with CIN 2 who opted for conservative follow-up, data were available for 23 for a median of 18 months. Lesions persisted in 17% of this cohort and progressed in 13%. Excision of progressive or stable disease was eventually performed in 17%.
  

Regression more likely in adolescents

Adolescents and adults had similar rates of CIN 2 in this study, but lesions regressed at a much higher rate in adolescents. This supports the ASCCP’s conservative but cautious recommendation regarding adolescents: Observation with colposcopy and cytology at 4- to 6-month intervals for 1 year is acceptable for biopsy-confirmed CIN 2, provided colposcopy is satisfactory, endocervical sampling is negative, and the patient accepts the risk of occult disease.

Perhaps the most revealing finding was that 100% of the 77 patients with CIN 2 who opted for immediate loop electrical excision procedure (LEEP) underwent conization. In the group managed conservatively, the corresponding figure was 17% of 23 patients. The implication: 83% of patients undergoing immediate LEEP might have been spared conization had they been followed more conservatively.

Not necessarily. In this chart review, 29% of adolescents with biopsy-proven cervical intraepithelial neoplasia (CIN) grades 2 or 3 opted for conservative treatment rather than excision. Over 18 months, the condition regressed in 65% of these patients, remained stable in 20%, and progressed without cancer in 5%. No invasive cancers developed.

Overall, CIN 2,3 was present in 35% of adolescent patients referred to colposcopy for cervical dysplasia.

EXPERT COMMENTARY

Adolescents differ from adults in many ways—no surprise. Some of the less obvious differences are their tendency to have multiple sexual partners, which exposes them to a number of human papillomavirus (HPV) types; the fact that most have not yet developed a protective immune response to the virus; and their larger, more active and vulnerable cervical transformation zone.

As a result, cytologic abnormalities are very common in adolescents shortly after they become sexually active. But although lesions develop very quickly, they regress just as rapidly. Low-grade squamous intraepithelial lesions (LSIL) regress in 70% to 94% of adolescents (usually in the first 24 months), and progress in only 3% to 7%.^1,2 The rate of invasive cancer in adolescents is only 0.3 for every 100,000 individuals.³

In adults, HPV disease is more likely to progress and less likely to regress. Adolescents have primarily incident infection, whereas adults have a mixture of incident and prevalent infection— and prevalent infections are more likely to be persistent infections and less likely to regress over the short term than incident infections are.

CIN 2 can be an unreliable diagnosis

Some patients with CIN 2 really have CIN 1,2 (often adolescents), whereas others have CIN 2,3 (often adults). That may be one reason CIN 2 is more likely to regress in adolescents than adults. Surprisingly, a recent study by Wright and colleagues⁴ found otherwise: Both the incidence and natural history of CIN 2 were similar in adults and adolescents. Moore and associates set out to validate these findings by reviewing medical records at the University of Oklahoma Health Science Center in Oklahoma City.

Details of the study

Patients were managed according to the 2001 guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP). Patients younger than 21 who had CIN 2,3 were offered conservative management or excision. Those who underwent immediate conization were compared with those who were followed at 4- to 6-month intervals:

• Of 501 patients identified in the colposcopy clinic, 146 (29%) underwent immediate conization, and 77 (53%) were found to have CIN 2.
  
• Of the 355 (71%) who were followed conservatively, data were available for 125 patients over a median of 18 months. Regression was reported in 56%, persistence in 35%, and progression in 14%.
  
• Of the 55 patients with CIN 2 who opted for conservative follow-up, data were available for 23 for a median of 18 months. Lesions persisted in 17% of this cohort and progressed in 13%. Excision of progressive or stable disease was eventually performed in 17%.
  

Regression more likely in adolescents

Adolescents and adults had similar rates of CIN 2 in this study, but lesions regressed at a much higher rate in adolescents. This supports the ASCCP’s conservative but cautious recommendation regarding adolescents: Observation with colposcopy and cytology at 4- to 6-month intervals for 1 year is acceptable for biopsy-confirmed CIN 2, provided colposcopy is satisfactory, endocervical sampling is negative, and the patient accepts the risk of occult disease.

Perhaps the most revealing finding was that 100% of the 77 patients with CIN 2 who opted for immediate loop electrical excision procedure (LEEP) underwent conization. In the group managed conservatively, the corresponding figure was 17% of 23 patients. The implication: 83% of patients undergoing immediate LEEP might have been spared conization had they been followed more conservatively.

Not necessarily. In this chart review, 29% of adolescents with biopsy-proven cervical intraepithelial neoplasia (CIN) grades 2 or 3 opted for conservative treatment rather than excision. Over 18 months, the condition regressed in 65% of these patients, remained stable in 20%, and progressed without cancer in 5%. No invasive cancers developed.

Overall, CIN 2,3 was present in 35% of adolescent patients referred to colposcopy for cervical dysplasia.

EXPERT COMMENTARY

Adolescents differ from adults in many ways—no surprise. Some of the less obvious differences are their tendency to have multiple sexual partners, which exposes them to a number of human papillomavirus (HPV) types; the fact that most have not yet developed a protective immune response to the virus; and their larger, more active and vulnerable cervical transformation zone.

As a result, cytologic abnormalities are very common in adolescents shortly after they become sexually active. But although lesions develop very quickly, they regress just as rapidly. Low-grade squamous intraepithelial lesions (LSIL) regress in 70% to 94% of adolescents (usually in the first 24 months), and progress in only 3% to 7%.^1,2 The rate of invasive cancer in adolescents is only 0.3 for every 100,000 individuals.³

In adults, HPV disease is more likely to progress and less likely to regress. Adolescents have primarily incident infection, whereas adults have a mixture of incident and prevalent infection— and prevalent infections are more likely to be persistent infections and less likely to regress over the short term than incident infections are.

CIN 2 can be an unreliable diagnosis

Some patients with CIN 2 really have CIN 1,2 (often adolescents), whereas others have CIN 2,3 (often adults). That may be one reason CIN 2 is more likely to regress in adolescents than adults. Surprisingly, a recent study by Wright and colleagues⁴ found otherwise: Both the incidence and natural history of CIN 2 were similar in adults and adolescents. Moore and associates set out to validate these findings by reviewing medical records at the University of Oklahoma Health Science Center in Oklahoma City.

Details of the study

Patients were managed according to the 2001 guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP). Patients younger than 21 who had CIN 2,3 were offered conservative management or excision. Those who underwent immediate conization were compared with those who were followed at 4- to 6-month intervals:

• Of 501 patients identified in the colposcopy clinic, 146 (29%) underwent immediate conization, and 77 (53%) were found to have CIN 2.
  
• Of the 355 (71%) who were followed conservatively, data were available for 125 patients over a median of 18 months. Regression was reported in 56%, persistence in 35%, and progression in 14%.
  
• Of the 55 patients with CIN 2 who opted for conservative follow-up, data were available for 23 for a median of 18 months. Lesions persisted in 17% of this cohort and progressed in 13%. Excision of progressive or stable disease was eventually performed in 17%.
  

Regression more likely in adolescents

Adolescents and adults had similar rates of CIN 2 in this study, but lesions regressed at a much higher rate in adolescents. This supports the ASCCP’s conservative but cautious recommendation regarding adolescents: Observation with colposcopy and cytology at 4- to 6-month intervals for 1 year is acceptable for biopsy-confirmed CIN 2, provided colposcopy is satisfactory, endocervical sampling is negative, and the patient accepts the risk of occult disease.

Perhaps the most revealing finding was that 100% of the 77 patients with CIN 2 who opted for immediate loop electrical excision procedure (LEEP) underwent conization. In the group managed conservatively, the corresponding figure was 17% of 23 patients. The implication: 83% of patients undergoing immediate LEEP might have been spared conization had they been followed more conservatively.

Yes—in women over 40. This analysis of data from the multicenter ASCUS-LSIL Triage Study (ALTS) found endocervical curettage (ECC) to be of questionable value as an ancillary diagnostic technique to colposcopically directed biopsy in women under age 40. In women age 40 or older, however, the sensitivity of colposcopic biopsy decreased and the sensitivity of ECC increased, so ECC may be of value in assessing mildly abnormal cytology in this population.

EXPERT COMMENTARY

Routine ECC as part of the colposcopy exam is controversial. Many colposcopists perform ECC with every colposcopy in nonpregnant patients. The rationale is that it will increase the sensitivity of the overall exam. A recent study by Pretorius and colleagues lends support to this view. The authors diagnosed high-grade dysplasia—CIN 2,3—based on ECC specimens alone in 20 of 364 women (5.5%) who had satisfactory colposcopy exams.¹

The opposing view holds that squamous dysplasia arises at the squamocolumnar junction and does not “skip” over apparently normal endocervical tissue to restart de novo within the canal. The proponents of this argument maintain that ECC adds little other than cost and discomfort when colposcopy is “satisfactory” or “adequate.”

Solomon and associates have contributed to this debate with their analysis of data from the ALTS trial, in which ECC was performed on 1,119 women, 41 (3.7%) of whom were diagnosed with CIN 2 or worse. In 10 of those women (0.89%), the diagnosis was based solely on the ECC.

More sensitive in older women

As in other analyses of colposcopy from the ALTS trial,² the sensitivity of colposcopy with biopsy was disappointingly low: 72.5%. Solomon and colleagues estimate that ECC adds an additional 3% overall to sensitivity. When stratified by age, however, this marginal increase was higher in women age 40 or older than it was in younger women—13% and 2.2%, respectively. In the Pretorius study already mentioned,¹ in which 5.5% of women were diagnosed with CIN 2 or worse solely on the basis of ECC, the mean age of the population was 42.

Weaknesses of the study

The study by Solomon and associates had several limitations, most of which were adequately discussed by the authors. ECC was performed at the discretion of the colposcopist; indications were not standardized. Moreover, the number of women age 40 and older was relatively small, and the study was not powered to address the issue of ECC and age.

Improvement in sensitivity is small but welcome in an older population

Older women are at higher risk of CIN 3 and unsatisfactory colposcopy and tend to have less accurate colposcopic impressions. Anything that can add to the sensitivity of colposcopy in this population is welcome. The authors point to the low utility of ECC in women under 40 and wisely stop short of recommending it in older women—although they come closer to such a recommendation in the abstract than in the body of the paper. This analysis of ALTS data certainly adds to the discussion of ECC, but more studies are clearly needed.

In the meantime, endocervical sampling with curettage or brush has an established role in colposcopy. It should be performed in women whose endocervical canal cannot be assessed, i.e., those with unsatisfactory colposcopy in whom an excision procedure is not otherwise planned. Endocervical sampling is also recommended as part of conservative management of women with high-grade squamous intraepithelial lesions on cytology but no cervical intraepithelial neoplasia or worse on biopsy. Other indications include women with low-grade squamous intraepithelial lesions or atypical squamous cells of undetermined significance in whom no lesion is identified, and those with atypical glandular cells on cytology.³

Yes—in women over 40. This analysis of data from the multicenter ASCUS-LSIL Triage Study (ALTS) found endocervical curettage (ECC) to be of questionable value as an ancillary diagnostic technique to colposcopically directed biopsy in women under age 40. In women age 40 or older, however, the sensitivity of colposcopic biopsy decreased and the sensitivity of ECC increased, so ECC may be of value in assessing mildly abnormal cytology in this population.

EXPERT COMMENTARY

Routine ECC as part of the colposcopy exam is controversial. Many colposcopists perform ECC with every colposcopy in nonpregnant patients. The rationale is that it will increase the sensitivity of the overall exam. A recent study by Pretorius and colleagues lends support to this view. The authors diagnosed high-grade dysplasia—CIN 2,3—based on ECC specimens alone in 20 of 364 women (5.5%) who had satisfactory colposcopy exams.¹

The opposing view holds that squamous dysplasia arises at the squamocolumnar junction and does not “skip” over apparently normal endocervical tissue to restart de novo within the canal. The proponents of this argument maintain that ECC adds little other than cost and discomfort when colposcopy is “satisfactory” or “adequate.”

Solomon and associates have contributed to this debate with their analysis of data from the ALTS trial, in which ECC was performed on 1,119 women, 41 (3.7%) of whom were diagnosed with CIN 2 or worse. In 10 of those women (0.89%), the diagnosis was based solely on the ECC.

More sensitive in older women

As in other analyses of colposcopy from the ALTS trial,² the sensitivity of colposcopy with biopsy was disappointingly low: 72.5%. Solomon and colleagues estimate that ECC adds an additional 3% overall to sensitivity. When stratified by age, however, this marginal increase was higher in women age 40 or older than it was in younger women—13% and 2.2%, respectively. In the Pretorius study already mentioned,¹ in which 5.5% of women were diagnosed with CIN 2 or worse solely on the basis of ECC, the mean age of the population was 42.

Weaknesses of the study

The study by Solomon and associates had several limitations, most of which were adequately discussed by the authors. ECC was performed at the discretion of the colposcopist; indications were not standardized. Moreover, the number of women age 40 and older was relatively small, and the study was not powered to address the issue of ECC and age.

Improvement in sensitivity is small but welcome in an older population

Older women are at higher risk of CIN 3 and unsatisfactory colposcopy and tend to have less accurate colposcopic impressions. Anything that can add to the sensitivity of colposcopy in this population is welcome. The authors point to the low utility of ECC in women under 40 and wisely stop short of recommending it in older women—although they come closer to such a recommendation in the abstract than in the body of the paper. This analysis of ALTS data certainly adds to the discussion of ECC, but more studies are clearly needed.

In the meantime, endocervical sampling with curettage or brush has an established role in colposcopy. It should be performed in women whose endocervical canal cannot be assessed, i.e., those with unsatisfactory colposcopy in whom an excision procedure is not otherwise planned. Endocervical sampling is also recommended as part of conservative management of women with high-grade squamous intraepithelial lesions on cytology but no cervical intraepithelial neoplasia or worse on biopsy. Other indications include women with low-grade squamous intraepithelial lesions or atypical squamous cells of undetermined significance in whom no lesion is identified, and those with atypical glandular cells on cytology.³

Yes—in women over 40. This analysis of data from the multicenter ASCUS-LSIL Triage Study (ALTS) found endocervical curettage (ECC) to be of questionable value as an ancillary diagnostic technique to colposcopically directed biopsy in women under age 40. In women age 40 or older, however, the sensitivity of colposcopic biopsy decreased and the sensitivity of ECC increased, so ECC may be of value in assessing mildly abnormal cytology in this population.

EXPERT COMMENTARY

Routine ECC as part of the colposcopy exam is controversial. Many colposcopists perform ECC with every colposcopy in nonpregnant patients. The rationale is that it will increase the sensitivity of the overall exam. A recent study by Pretorius and colleagues lends support to this view. The authors diagnosed high-grade dysplasia—CIN 2,3—based on ECC specimens alone in 20 of 364 women (5.5%) who had satisfactory colposcopy exams.¹

The opposing view holds that squamous dysplasia arises at the squamocolumnar junction and does not “skip” over apparently normal endocervical tissue to restart de novo within the canal. The proponents of this argument maintain that ECC adds little other than cost and discomfort when colposcopy is “satisfactory” or “adequate.”

Solomon and associates have contributed to this debate with their analysis of data from the ALTS trial, in which ECC was performed on 1,119 women, 41 (3.7%) of whom were diagnosed with CIN 2 or worse. In 10 of those women (0.89%), the diagnosis was based solely on the ECC.

More sensitive in older women

As in other analyses of colposcopy from the ALTS trial,² the sensitivity of colposcopy with biopsy was disappointingly low: 72.5%. Solomon and colleagues estimate that ECC adds an additional 3% overall to sensitivity. When stratified by age, however, this marginal increase was higher in women age 40 or older than it was in younger women—13% and 2.2%, respectively. In the Pretorius study already mentioned,¹ in which 5.5% of women were diagnosed with CIN 2 or worse solely on the basis of ECC, the mean age of the population was 42.

Weaknesses of the study

The study by Solomon and associates had several limitations, most of which were adequately discussed by the authors. ECC was performed at the discretion of the colposcopist; indications were not standardized. Moreover, the number of women age 40 and older was relatively small, and the study was not powered to address the issue of ECC and age.

Improvement in sensitivity is small but welcome in an older population

Older women are at higher risk of CIN 3 and unsatisfactory colposcopy and tend to have less accurate colposcopic impressions. Anything that can add to the sensitivity of colposcopy in this population is welcome. The authors point to the low utility of ECC in women under 40 and wisely stop short of recommending it in older women—although they come closer to such a recommendation in the abstract than in the body of the paper. This analysis of ALTS data certainly adds to the discussion of ECC, but more studies are clearly needed.

In the meantime, endocervical sampling with curettage or brush has an established role in colposcopy. It should be performed in women whose endocervical canal cannot be assessed, i.e., those with unsatisfactory colposcopy in whom an excision procedure is not otherwise planned. Endocervical sampling is also recommended as part of conservative management of women with high-grade squamous intraepithelial lesions on cytology but no cervical intraepithelial neoplasia or worse on biopsy. Other indications include women with low-grade squamous intraepithelial lesions or atypical squamous cells of undetermined significance in whom no lesion is identified, and those with atypical glandular cells on cytology.³

A. It may affect premenstrual mood. In this comparison of two oral contraceptives (OCs) containing the same progestin but different dosages of ethinyl estradiol, women using the 25-μg formulation were significantly more likely to report improvement in premenstrual mood than were those using the 35-μg pill, although this effect was not reflected in measures of free testosterone (FT) or dehydroepiandrosterone sulfate (DHEA-S). Sexual interest was not affected significantly with either formulation.

The progestin used in this study was a triphasic regimen of norgestimate in dosages of 0.18, 0.215, and 0.25 mg.

Expert Commentary

OCs are the most widely used method of reversible contraception in the world.¹ Since the 1970s, at least 50% of users have reported emotional lability, depression, magnification of premenstrual symptoms, and decreased libido^2-4—and almost 30% have cited these effects as a reason for discontinuing the pill.⁵ As Greco and colleagues point out, complaints of depression and decreased libido have diminished somewhat since lower-dose (

There are many potential reasons for the emotional lability, increased premenstrual symptoms, and decreased libido associated with OCs, including:

• abrupt withdrawal of hormones in regimens containing 21 active pills followed by a 7-day pill-free interval
  
• suppression of endogenous hormones, including biologically available testosterone, dehydroepiandrosterone, and other neuroactive steroid metabolites of progesterone
  
• direct adverse effects of the estrogen or progestin
  
• genetic and environmentally determined “vulnerability factors.”
  

Strengths of the study

By comparing two triphasic OCs with identical progestin dosages but different quantities of ethinyl estradiol, the authors isolated the variable of estrogen dose. They also assessed concentrations of FT and DHEA-S, and measured depression and sexual interest using reliable tools.

Another strength is that women were prospectively randomized to the two regimens and studied during the first 3 months of OC use—before discontinuation due to side effects, although there were some study dropouts.

Effects on hormones, mood

As expected, the lower-dose OC reduced FT to a lesser degree than did the 35-μg pill. Overall, scores on the Beck Depression Inventory during the premenstrual week showed a slight improvement in mood in both groups after 3 months on the OC. However, a greater percentage of women using the 25-μg formulation showed improvement in mood, although the authors were careful to point out that a causal relationship between this improvement and the dosage of estradiol cannot be confirmed.

The authors also noted that improvement in premenstrual mood with OC use has previously been reported, but wrongly claimed that placebo-controlled studies have not shown a significant difference between OC and placebo for this variable. On the contrary, I would point to two recent randomized trials that demonstrated efficacy of an OC containing 20 μg of ethinyl estradiol and 3 mg of the progestin drospirenone in a 24/4-day regimen for the severe form of premenstrual syndrome called premenstrual dysphoric disorder (PMDD).^6,7 This formulation received Food and Drug Administration approval for treatment of PMDD in women who desire hormonal contraception.

The mildly anti-androgenic drospirenone, a spironolactone analogue equivalent to approximately 25 mg of spironolactone, has not been studied in isolation (ie, apart from a combination OC) with respect to premenstrual mood and sexual functioning. However, its anti-androgenic effect was not deleterious in the PMDD studies^6,7 and may have played a role in treatment outcome—although a similar study of the same dose of drospirenone combined with 30 μg of ethinyl estradiol in a 21/7-day regimen was not more effective than placebo for severe premenstrual symptoms.⁸ One reason may be that the 24/4-day regimen provides more complete suppression of the hypothalamic–pituitary–ovarian axis.

DHEA-S and other neuroactive steroid metabolites of progesterone are suppressed in women taking OCs. One study found no deterioration in mood despite suppression of these steroids in women given a 20-μg OC.⁹ Paoletti and associates¹⁰ have even suggested that the suppression of DHEA-S may be responsible for mood improvement with the OC containing 30 μg of ethinyl estradiol and 3 mg of drospirenone, compared with untreated women.

Symptoms were assessed only during premenstrual week. Because the women in the study by Greco and colleagues did not complete daily mood ratings, it is impossible to know whether the OC with the lower dose of ethinyl estradiol was better for moodiness unrelated to the premenstrum. Other symptoms of premenstrual syndrome, such as anxiety, irritability, and mood swings, were not assessed prospectively.

Bottom line: Lower dose of estradiol is probably better

 

The study by Greco and colleagues adds to evidence that an OC containing a lower dose of ethinyl estradiol is better for premenstrual mood, although this effect is unlikely to be related to its effect on androgens. It remains unclear how a lower estrogen dose affects mood in women who have a history of premenstrual syndrome and whether mood improvement with a lower estrogen dose is related to a lower degree of androgen suppression.

When there is concern about a patient’s mood or depression, prescribe a low-dose OC, such as one containing 20 μg of ethinyl estradiol and 3 mg of drospirenone in a 24/4-day regimen (Yaz). Most women experience no adverse effects of OCs on mood. Those with a history of depression should be aware that there may be a deterioration of mood on the OC.

A. It may affect premenstrual mood. In this comparison of two oral contraceptives (OCs) containing the same progestin but different dosages of ethinyl estradiol, women using the 25-μg formulation were significantly more likely to report improvement in premenstrual mood than were those using the 35-μg pill, although this effect was not reflected in measures of free testosterone (FT) or dehydroepiandrosterone sulfate (DHEA-S). Sexual interest was not affected significantly with either formulation.

The progestin used in this study was a triphasic regimen of norgestimate in dosages of 0.18, 0.215, and 0.25 mg.

Expert Commentary

OCs are the most widely used method of reversible contraception in the world.¹ Since the 1970s, at least 50% of users have reported emotional lability, depression, magnification of premenstrual symptoms, and decreased libido^2-4—and almost 30% have cited these effects as a reason for discontinuing the pill.⁵ As Greco and colleagues point out, complaints of depression and decreased libido have diminished somewhat since lower-dose (

There are many potential reasons for the emotional lability, increased premenstrual symptoms, and decreased libido associated with OCs, including:

• abrupt withdrawal of hormones in regimens containing 21 active pills followed by a 7-day pill-free interval
  
• suppression of endogenous hormones, including biologically available testosterone, dehydroepiandrosterone, and other neuroactive steroid metabolites of progesterone
  
• direct adverse effects of the estrogen or progestin
  
• genetic and environmentally determined “vulnerability factors.”
  

Strengths of the study

By comparing two triphasic OCs with identical progestin dosages but different quantities of ethinyl estradiol, the authors isolated the variable of estrogen dose. They also assessed concentrations of FT and DHEA-S, and measured depression and sexual interest using reliable tools.

Another strength is that women were prospectively randomized to the two regimens and studied during the first 3 months of OC use—before discontinuation due to side effects, although there were some study dropouts.

Effects on hormones, mood

As expected, the lower-dose OC reduced FT to a lesser degree than did the 35-μg pill. Overall, scores on the Beck Depression Inventory during the premenstrual week showed a slight improvement in mood in both groups after 3 months on the OC. However, a greater percentage of women using the 25-μg formulation showed improvement in mood, although the authors were careful to point out that a causal relationship between this improvement and the dosage of estradiol cannot be confirmed.

The authors also noted that improvement in premenstrual mood with OC use has previously been reported, but wrongly claimed that placebo-controlled studies have not shown a significant difference between OC and placebo for this variable. On the contrary, I would point to two recent randomized trials that demonstrated efficacy of an OC containing 20 μg of ethinyl estradiol and 3 mg of the progestin drospirenone in a 24/4-day regimen for the severe form of premenstrual syndrome called premenstrual dysphoric disorder (PMDD).^6,7 This formulation received Food and Drug Administration approval for treatment of PMDD in women who desire hormonal contraception.

The mildly anti-androgenic drospirenone, a spironolactone analogue equivalent to approximately 25 mg of spironolactone, has not been studied in isolation (ie, apart from a combination OC) with respect to premenstrual mood and sexual functioning. However, its anti-androgenic effect was not deleterious in the PMDD studies^6,7 and may have played a role in treatment outcome—although a similar study of the same dose of drospirenone combined with 30 μg of ethinyl estradiol in a 21/7-day regimen was not more effective than placebo for severe premenstrual symptoms.⁸ One reason may be that the 24/4-day regimen provides more complete suppression of the hypothalamic–pituitary–ovarian axis.

DHEA-S and other neuroactive steroid metabolites of progesterone are suppressed in women taking OCs. One study found no deterioration in mood despite suppression of these steroids in women given a 20-μg OC.⁹ Paoletti and associates¹⁰ have even suggested that the suppression of DHEA-S may be responsible for mood improvement with the OC containing 30 μg of ethinyl estradiol and 3 mg of drospirenone, compared with untreated women.

Symptoms were assessed only during premenstrual week. Because the women in the study by Greco and colleagues did not complete daily mood ratings, it is impossible to know whether the OC with the lower dose of ethinyl estradiol was better for moodiness unrelated to the premenstrum. Other symptoms of premenstrual syndrome, such as anxiety, irritability, and mood swings, were not assessed prospectively.

Bottom line: Lower dose of estradiol is probably better

 

The study by Greco and colleagues adds to evidence that an OC containing a lower dose of ethinyl estradiol is better for premenstrual mood, although this effect is unlikely to be related to its effect on androgens. It remains unclear how a lower estrogen dose affects mood in women who have a history of premenstrual syndrome and whether mood improvement with a lower estrogen dose is related to a lower degree of androgen suppression.

When there is concern about a patient’s mood or depression, prescribe a low-dose OC, such as one containing 20 μg of ethinyl estradiol and 3 mg of drospirenone in a 24/4-day regimen (Yaz). Most women experience no adverse effects of OCs on mood. Those with a history of depression should be aware that there may be a deterioration of mood on the OC.

A. It may affect premenstrual mood. In this comparison of two oral contraceptives (OCs) containing the same progestin but different dosages of ethinyl estradiol, women using the 25-μg formulation were significantly more likely to report improvement in premenstrual mood than were those using the 35-μg pill, although this effect was not reflected in measures of free testosterone (FT) or dehydroepiandrosterone sulfate (DHEA-S). Sexual interest was not affected significantly with either formulation.

The progestin used in this study was a triphasic regimen of norgestimate in dosages of 0.18, 0.215, and 0.25 mg.

Expert Commentary

OCs are the most widely used method of reversible contraception in the world.¹ Since the 1970s, at least 50% of users have reported emotional lability, depression, magnification of premenstrual symptoms, and decreased libido^2-4—and almost 30% have cited these effects as a reason for discontinuing the pill.⁵ As Greco and colleagues point out, complaints of depression and decreased libido have diminished somewhat since lower-dose (

There are many potential reasons for the emotional lability, increased premenstrual symptoms, and decreased libido associated with OCs, including:

• abrupt withdrawal of hormones in regimens containing 21 active pills followed by a 7-day pill-free interval
  
• suppression of endogenous hormones, including biologically available testosterone, dehydroepiandrosterone, and other neuroactive steroid metabolites of progesterone
  
• direct adverse effects of the estrogen or progestin
  
• genetic and environmentally determined “vulnerability factors.”
  

Strengths of the study

By comparing two triphasic OCs with identical progestin dosages but different quantities of ethinyl estradiol, the authors isolated the variable of estrogen dose. They also assessed concentrations of FT and DHEA-S, and measured depression and sexual interest using reliable tools.

Another strength is that women were prospectively randomized to the two regimens and studied during the first 3 months of OC use—before discontinuation due to side effects, although there were some study dropouts.

Effects on hormones, mood

As expected, the lower-dose OC reduced FT to a lesser degree than did the 35-μg pill. Overall, scores on the Beck Depression Inventory during the premenstrual week showed a slight improvement in mood in both groups after 3 months on the OC. However, a greater percentage of women using the 25-μg formulation showed improvement in mood, although the authors were careful to point out that a causal relationship between this improvement and the dosage of estradiol cannot be confirmed.

The authors also noted that improvement in premenstrual mood with OC use has previously been reported, but wrongly claimed that placebo-controlled studies have not shown a significant difference between OC and placebo for this variable. On the contrary, I would point to two recent randomized trials that demonstrated efficacy of an OC containing 20 μg of ethinyl estradiol and 3 mg of the progestin drospirenone in a 24/4-day regimen for the severe form of premenstrual syndrome called premenstrual dysphoric disorder (PMDD).^6,7 This formulation received Food and Drug Administration approval for treatment of PMDD in women who desire hormonal contraception.

The mildly anti-androgenic drospirenone, a spironolactone analogue equivalent to approximately 25 mg of spironolactone, has not been studied in isolation (ie, apart from a combination OC) with respect to premenstrual mood and sexual functioning. However, its anti-androgenic effect was not deleterious in the PMDD studies^6,7 and may have played a role in treatment outcome—although a similar study of the same dose of drospirenone combined with 30 μg of ethinyl estradiol in a 21/7-day regimen was not more effective than placebo for severe premenstrual symptoms.⁸ One reason may be that the 24/4-day regimen provides more complete suppression of the hypothalamic–pituitary–ovarian axis.

DHEA-S and other neuroactive steroid metabolites of progesterone are suppressed in women taking OCs. One study found no deterioration in mood despite suppression of these steroids in women given a 20-μg OC.⁹ Paoletti and associates¹⁰ have even suggested that the suppression of DHEA-S may be responsible for mood improvement with the OC containing 30 μg of ethinyl estradiol and 3 mg of drospirenone, compared with untreated women.

Symptoms were assessed only during premenstrual week. Because the women in the study by Greco and colleagues did not complete daily mood ratings, it is impossible to know whether the OC with the lower dose of ethinyl estradiol was better for moodiness unrelated to the premenstrum. Other symptoms of premenstrual syndrome, such as anxiety, irritability, and mood swings, were not assessed prospectively.

Bottom line: Lower dose of estradiol is probably better

 

The study by Greco and colleagues adds to evidence that an OC containing a lower dose of ethinyl estradiol is better for premenstrual mood, although this effect is unlikely to be related to its effect on androgens. It remains unclear how a lower estrogen dose affects mood in women who have a history of premenstrual syndrome and whether mood improvement with a lower estrogen dose is related to a lower degree of androgen suppression.

When there is concern about a patient’s mood or depression, prescribe a low-dose OC, such as one containing 20 μg of ethinyl estradiol and 3 mg of drospirenone in a 24/4-day regimen (Yaz). Most women experience no adverse effects of OCs on mood. Those with a history of depression should be aware that there may be a deterioration of mood on the OC.

A. Yes. In this randomized, placebo-controlled study of 250 gravidas with a cervical length of 15 mm or less, those who were randomized to a daily dose of 200 mg of intravaginal micronized progesterone starting at 24 weeks’ gestation had a lower rate of spontaneous delivery before 34 weeks (19.2%) than did women in the control group (34.4%) (relative risk, 0.56; 95% confidence interval, 0.36 to 0.65). However, progesterone did not reduce the rate of perinatal mortality or neonatal morbidity.

The trial included both singleton and twin gestations.

Expert Commentary

The study by Fonseca and colleagues is an important contribution to the ever-expanding body of literature on ways to reduce preterm birth. It immediately follows a paper in the same issue of the New England Journal of Medicine declaring the failure of intramuscular 17α-hydroxyprogesterone caproate (17P) to prevent preterm birth in twin gestations.¹ In contrast, an earlier study from 2003 found 17P to be more effective than no treatment in preventing spontaneous preterm delivery in singleton pregnancies of women with a history of premature delivery.²

The trial by Fonseca and colleagues capitalizes on two unique aspects of the prematurity debate. The first is that history is probably not any more useful in screening for risk of prematurity than it is for screening for gestational diabetes. This is not to say that history is unimportant, but rather to emphasize that history alone may be insufficient to identify populations that may be at risk for preterm delivery and therefore might possibly benefit from intervention.

The second is the suggestion, based on earlier work by Iams and associates,³ that decreased cervical length may distinguish a group of women at high risk for preterm delivery.

What to make of equivocal findings?

Is an intervention worthwhile if it has no effect on key outcomes such as morbidity and mortality? And what are we to make of the fact that intramuscular 17P is effective in singleton but not twin gestations?

The current trial was insufficiently powered to affirm the null hypothesis with respect to perinatal mortality and neonatal morbidity—ie, there were not enough patients in the study to determine whether the lack of difference in these variables was real or due to insufficient sample size. However, intravaginal progesterone seems more attractive than intramuscular injection—at least intuitively. It may be that a local anti-inflammatory response is what reduced spontaneous preterm delivery—and that may be why intramuscular injection of synthetic progestin at a remote site was less effective, depending on whether the pregnancy was a singleton or twin gestation.

We must also be concerned about the yet-unexplained observation of higher—though statistically insignificant—rates of miscarriage and intrauterine fetal death among women receiving intramuscular 17P, compared with placebo.²

Too early to elevate either regimen to “standard of care”

In my opinion, it is still too early to elevate either intravaginal or intramuscular progesterone to the level of “standard of care.” What may be reasonable in this age of increasing use of first- and mid-trimester ultrasonographic screening is to make certain that information on cervical length is provided. Also important is a candid discussion with the patient about the range of options for management of a short cervix in pregnancy. In the meantime, more than a dozen trials on the prevention of prematurity are in progress. The hope is that more definitive answers to the prematurity riddle are “just around the corner”—which, I suspect, was also the hope in 1975.⁴

A. Yes. In this randomized, placebo-controlled study of 250 gravidas with a cervical length of 15 mm or less, those who were randomized to a daily dose of 200 mg of intravaginal micronized progesterone starting at 24 weeks’ gestation had a lower rate of spontaneous delivery before 34 weeks (19.2%) than did women in the control group (34.4%) (relative risk, 0.56; 95% confidence interval, 0.36 to 0.65). However, progesterone did not reduce the rate of perinatal mortality or neonatal morbidity.

The trial included both singleton and twin gestations.

Expert Commentary

The study by Fonseca and colleagues is an important contribution to the ever-expanding body of literature on ways to reduce preterm birth. It immediately follows a paper in the same issue of the New England Journal of Medicine declaring the failure of intramuscular 17α-hydroxyprogesterone caproate (17P) to prevent preterm birth in twin gestations.¹ In contrast, an earlier study from 2003 found 17P to be more effective than no treatment in preventing spontaneous preterm delivery in singleton pregnancies of women with a history of premature delivery.²

The trial by Fonseca and colleagues capitalizes on two unique aspects of the prematurity debate. The first is that history is probably not any more useful in screening for risk of prematurity than it is for screening for gestational diabetes. This is not to say that history is unimportant, but rather to emphasize that history alone may be insufficient to identify populations that may be at risk for preterm delivery and therefore might possibly benefit from intervention.

The second is the suggestion, based on earlier work by Iams and associates,³ that decreased cervical length may distinguish a group of women at high risk for preterm delivery.

What to make of equivocal findings?

Is an intervention worthwhile if it has no effect on key outcomes such as morbidity and mortality? And what are we to make of the fact that intramuscular 17P is effective in singleton but not twin gestations?

The current trial was insufficiently powered to affirm the null hypothesis with respect to perinatal mortality and neonatal morbidity—ie, there were not enough patients in the study to determine whether the lack of difference in these variables was real or due to insufficient sample size. However, intravaginal progesterone seems more attractive than intramuscular injection—at least intuitively. It may be that a local anti-inflammatory response is what reduced spontaneous preterm delivery—and that may be why intramuscular injection of synthetic progestin at a remote site was less effective, depending on whether the pregnancy was a singleton or twin gestation.

We must also be concerned about the yet-unexplained observation of higher—though statistically insignificant—rates of miscarriage and intrauterine fetal death among women receiving intramuscular 17P, compared with placebo.²

Too early to elevate either regimen to “standard of care”

In my opinion, it is still too early to elevate either intravaginal or intramuscular progesterone to the level of “standard of care.” What may be reasonable in this age of increasing use of first- and mid-trimester ultrasonographic screening is to make certain that information on cervical length is provided. Also important is a candid discussion with the patient about the range of options for management of a short cervix in pregnancy. In the meantime, more than a dozen trials on the prevention of prematurity are in progress. The hope is that more definitive answers to the prematurity riddle are “just around the corner”—which, I suspect, was also the hope in 1975.⁴

A. Yes. In this randomized, placebo-controlled study of 250 gravidas with a cervical length of 15 mm or less, those who were randomized to a daily dose of 200 mg of intravaginal micronized progesterone starting at 24 weeks’ gestation had a lower rate of spontaneous delivery before 34 weeks (19.2%) than did women in the control group (34.4%) (relative risk, 0.56; 95% confidence interval, 0.36 to 0.65). However, progesterone did not reduce the rate of perinatal mortality or neonatal morbidity.

The trial included both singleton and twin gestations.

Expert Commentary

The study by Fonseca and colleagues is an important contribution to the ever-expanding body of literature on ways to reduce preterm birth. It immediately follows a paper in the same issue of the New England Journal of Medicine declaring the failure of intramuscular 17α-hydroxyprogesterone caproate (17P) to prevent preterm birth in twin gestations.¹ In contrast, an earlier study from 2003 found 17P to be more effective than no treatment in preventing spontaneous preterm delivery in singleton pregnancies of women with a history of premature delivery.²

The trial by Fonseca and colleagues capitalizes on two unique aspects of the prematurity debate. The first is that history is probably not any more useful in screening for risk of prematurity than it is for screening for gestational diabetes. This is not to say that history is unimportant, but rather to emphasize that history alone may be insufficient to identify populations that may be at risk for preterm delivery and therefore might possibly benefit from intervention.

The second is the suggestion, based on earlier work by Iams and associates,³ that decreased cervical length may distinguish a group of women at high risk for preterm delivery.

What to make of equivocal findings?

Is an intervention worthwhile if it has no effect on key outcomes such as morbidity and mortality? And what are we to make of the fact that intramuscular 17P is effective in singleton but not twin gestations?

The current trial was insufficiently powered to affirm the null hypothesis with respect to perinatal mortality and neonatal morbidity—ie, there were not enough patients in the study to determine whether the lack of difference in these variables was real or due to insufficient sample size. However, intravaginal progesterone seems more attractive than intramuscular injection—at least intuitively. It may be that a local anti-inflammatory response is what reduced spontaneous preterm delivery—and that may be why intramuscular injection of synthetic progestin at a remote site was less effective, depending on whether the pregnancy was a singleton or twin gestation.

We must also be concerned about the yet-unexplained observation of higher—though statistically insignificant—rates of miscarriage and intrauterine fetal death among women receiving intramuscular 17P, compared with placebo.²

Too early to elevate either regimen to “standard of care”

In my opinion, it is still too early to elevate either intravaginal or intramuscular progesterone to the level of “standard of care.” What may be reasonable in this age of increasing use of first- and mid-trimester ultrasonographic screening is to make certain that information on cervical length is provided. Also important is a candid discussion with the patient about the range of options for management of a short cervix in pregnancy. In the meantime, more than a dozen trials on the prevention of prematurity are in progress. The hope is that more definitive answers to the prematurity riddle are “just around the corner”—which, I suspect, was also the hope in 1975.⁴

A. No. In the FUTURE I trial, among women who were naïve to all strains of the human papillomavirus (HPV) vaccine at the time of inoculation, the vaccine was 100% effective in preventing anogenital lesions, cervical intraepithelial neoplasia (CIN) 2,3, adenocarcinoma in situ, and cervical cancer. In FUTURE II, among the same population, it was 98% effective in preventing all cervical lesions.

However, in FUTURE I, when the groups comprising HPV-naïve and HPV-positive subjects and those with and without preexisting neoplasia were combined, the vaccine was 20% effective in preventing CIN 2,3, adenocarcinoma in situ, and cervical cancer, and 34% effective in preventing genital warts and vulvar and vaginal intraepithelial neoplasia and cancer due to vaccine and nonvaccine HPV types. In FUTURE II, when the same groups were included, the vaccine was 17% effective in preventing all cervical lesions (regardless of the causal HPV type).

The women involved in these trials fell within the target age range for prophylactic vaccination, with ages from 15 to 26 years.

Expert Commentary

Even females in the target population for HPV vaccination (ages 9 to 26) present with different histories and risk status. An individual may be a candidate for:

• true primary prevention (no evidence of any HPV subtype or neoplasia)
• primary prevention for the vaccine subtypes (ie, negative for HPV type 6, 11, 16, or 18)
• prevention despite the presence of HPV type 6, 11, 16, or 18
• prevention despite the presence of a subtype not covered in the vaccine
• vaccination despite existing vulvar, vaginal, or cervical neoplasia.

The effect of the vaccine on this last group would be considered both prophylactic and therapeutic, defined as secondary prevention of cervical cancer. Secondary prevention (reversal of HPV effect in CIN lesions, leading to regression) has not been demonstrated with the quadrivalent HPV vaccine (Gardasil).

Trials followed women over 3 years

In these randomized trials, both vaccine efficacy (lesions prevented) and safety (side effects) were evaluated.

FUTURE I enrolled nearly 5,500 young women within the advised age range for prophylaxis who were randomized to the quadrivalent HPV vaccine or placebo. Cervical screening and colposcopic biopsy (if indicated) were conducted at baseline, and HPV status was determined. Investigators studied the effect of prophylactic vaccination in women naïve to the four viral subtypes targeted by the vaccine (6, 11, 16, and 18), as well as women in each of the other groups listed above.

The principal aim of FUTURE I was to provide an “ideal” frequent visit schedule with broader referral to colposcopy and determine whether the vaccine would reduce the combined incidence of anogenital warts, vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), CIN 1,2,3, and cancer related to HPV subtypes 6, 11, 16, and 18.

FUTURE II involved 12,167 women and a wider visit interval more consistent with clinical practice than FUTURE I. The aim was to determine whether the quadrivalent vaccine would reduce the incidence of CIN 2,3, adenocarcinoma in situ, or invasive carcinoma of the cervix related to HPV subtypes 16 and 18.

In both trials, polymerase chain reaction was used to identify the HPV subtype associated with any CIN, adenocarcinoma in situ, or anogenital lesion that was biopsy-proven, and this information was correlated with the patient’s HPV status before and after vaccination. The baseline and postvaccination serological status against HPV subtypes was also measured.

Safety is not a concern thus far

There were no adverse events that caused death or withdrawal from the studies. The most common side effect was pain at the injection site, which occurred more frequently among vaccinated women.

Bottom line: Keep screening

The quadrivalent vaccine is not equally effective among all female candidates. I recommend the following:

• Encourage vaccination in very young girls and virgins. The vaccine is most effective in females who have not been exposed to any of the four subtypes targeted.
• A lack of type-specific, clinically available serology or lower genital tract screening in a woman who is already sexually active leaves the clinician in the dark about how to counsel her. Because most women I counsel do not harbor all four subtypes covered by the vaccine and lack anogenital disease, I offer the vaccine to all women in the age range that is indicated.
• Counsel women who are already sexually active and who harbor HPV before vaccination, as well as those who acquire the virus during the vaccination period, that even with inoculation they are susceptible to infection and neoplastic transformation, unlike those naïve to the vaccine-specific subtypes. Efficacy is still substantial, however—near 90% overall.
• If type-specific HPV testing becomes commercially available, counsel women who test positive for one of the four HPV subtypes targeted by the vaccine, as well as those with other HPV subtypes, that they are susceptible to neoplastic transformation even with the vaccine.
• Advise women who already have CIN, adenocarcinoma in situ, VIN, VAIN, or benign anogenital disease that the vaccine is not therapeutic and will not prevent the natural progression of these lesions toward cancer.
• Remember that few women harbor all four subtypes targeted by the vaccine. The vaccine may provide some marginal benefit to women already being treated for intraepithelial neoplasia, but each patient should be counseled about the potential lack of benefit.
• Be aware that there is clear benefit in the prevention of anogenital disease independent of the oncogenic risks associated with the virus.
• Don’t forget the other 13 known oncogenic HPV subtypes and the many more nononcogenic types identified so far. The effect of the vaccine is modestly reduced in women who harbor one or more of those subtypes when compared with its efficacy in uninfected recipients and virgins. Therefore, screening for cervical cancer and lower genital tract lesions should continue despite vaccination.
• In an editorial accompanying the FUTURE I and II trials, Sawaya and Smith-McCune observed that oncogenic HPV strains not targeted by the vaccine were responsible for a large number of CIN 2,3 and adenocarcinoma lesions in the FUTURE II trial.¹ Although there are no concrete data, the editorialists suggest that, as we vaccinate for known strains, existing strains that are not included or new strains that evolve may “fill the niche” and continue to cause incident cases of neoplasia despite vaccination. This is another reason to screen women cytologically or by direct visual or other in-vivo methods to detect neoplasia.

A. No. In the FUTURE I trial, among women who were naïve to all strains of the human papillomavirus (HPV) vaccine at the time of inoculation, the vaccine was 100% effective in preventing anogenital lesions, cervical intraepithelial neoplasia (CIN) 2,3, adenocarcinoma in situ, and cervical cancer. In FUTURE II, among the same population, it was 98% effective in preventing all cervical lesions.

However, in FUTURE I, when the groups comprising HPV-naïve and HPV-positive subjects and those with and without preexisting neoplasia were combined, the vaccine was 20% effective in preventing CIN 2,3, adenocarcinoma in situ, and cervical cancer, and 34% effective in preventing genital warts and vulvar and vaginal intraepithelial neoplasia and cancer due to vaccine and nonvaccine HPV types. In FUTURE II, when the same groups were included, the vaccine was 17% effective in preventing all cervical lesions (regardless of the causal HPV type).

The women involved in these trials fell within the target age range for prophylactic vaccination, with ages from 15 to 26 years.

Expert Commentary

Even females in the target population for HPV vaccination (ages 9 to 26) present with different histories and risk status. An individual may be a candidate for:

• true primary prevention (no evidence of any HPV subtype or neoplasia)
• primary prevention for the vaccine subtypes (ie, negative for HPV type 6, 11, 16, or 18)
• prevention despite the presence of HPV type 6, 11, 16, or 18
• prevention despite the presence of a subtype not covered in the vaccine
• vaccination despite existing vulvar, vaginal, or cervical neoplasia.

The effect of the vaccine on this last group would be considered both prophylactic and therapeutic, defined as secondary prevention of cervical cancer. Secondary prevention (reversal of HPV effect in CIN lesions, leading to regression) has not been demonstrated with the quadrivalent HPV vaccine (Gardasil).

Trials followed women over 3 years

In these randomized trials, both vaccine efficacy (lesions prevented) and safety (side effects) were evaluated.

FUTURE I enrolled nearly 5,500 young women within the advised age range for prophylaxis who were randomized to the quadrivalent HPV vaccine or placebo. Cervical screening and colposcopic biopsy (if indicated) were conducted at baseline, and HPV status was determined. Investigators studied the effect of prophylactic vaccination in women naïve to the four viral subtypes targeted by the vaccine (6, 11, 16, and 18), as well as women in each of the other groups listed above.

The principal aim of FUTURE I was to provide an “ideal” frequent visit schedule with broader referral to colposcopy and determine whether the vaccine would reduce the combined incidence of anogenital warts, vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), CIN 1,2,3, and cancer related to HPV subtypes 6, 11, 16, and 18.

FUTURE II involved 12,167 women and a wider visit interval more consistent with clinical practice than FUTURE I. The aim was to determine whether the quadrivalent vaccine would reduce the incidence of CIN 2,3, adenocarcinoma in situ, or invasive carcinoma of the cervix related to HPV subtypes 16 and 18.

In both trials, polymerase chain reaction was used to identify the HPV subtype associated with any CIN, adenocarcinoma in situ, or anogenital lesion that was biopsy-proven, and this information was correlated with the patient’s HPV status before and after vaccination. The baseline and postvaccination serological status against HPV subtypes was also measured.

Safety is not a concern thus far

There were no adverse events that caused death or withdrawal from the studies. The most common side effect was pain at the injection site, which occurred more frequently among vaccinated women.

Bottom line: Keep screening

The quadrivalent vaccine is not equally effective among all female candidates. I recommend the following:

• Encourage vaccination in very young girls and virgins. The vaccine is most effective in females who have not been exposed to any of the four subtypes targeted.
• A lack of type-specific, clinically available serology or lower genital tract screening in a woman who is already sexually active leaves the clinician in the dark about how to counsel her. Because most women I counsel do not harbor all four subtypes covered by the vaccine and lack anogenital disease, I offer the vaccine to all women in the age range that is indicated.
• Counsel women who are already sexually active and who harbor HPV before vaccination, as well as those who acquire the virus during the vaccination period, that even with inoculation they are susceptible to infection and neoplastic transformation, unlike those naïve to the vaccine-specific subtypes. Efficacy is still substantial, however—near 90% overall.
• If type-specific HPV testing becomes commercially available, counsel women who test positive for one of the four HPV subtypes targeted by the vaccine, as well as those with other HPV subtypes, that they are susceptible to neoplastic transformation even with the vaccine.
• Advise women who already have CIN, adenocarcinoma in situ, VIN, VAIN, or benign anogenital disease that the vaccine is not therapeutic and will not prevent the natural progression of these lesions toward cancer.
• Remember that few women harbor all four subtypes targeted by the vaccine. The vaccine may provide some marginal benefit to women already being treated for intraepithelial neoplasia, but each patient should be counseled about the potential lack of benefit.
• Be aware that there is clear benefit in the prevention of anogenital disease independent of the oncogenic risks associated with the virus.
• Don’t forget the other 13 known oncogenic HPV subtypes and the many more nononcogenic types identified so far. The effect of the vaccine is modestly reduced in women who harbor one or more of those subtypes when compared with its efficacy in uninfected recipients and virgins. Therefore, screening for cervical cancer and lower genital tract lesions should continue despite vaccination.
• In an editorial accompanying the FUTURE I and II trials, Sawaya and Smith-McCune observed that oncogenic HPV strains not targeted by the vaccine were responsible for a large number of CIN 2,3 and adenocarcinoma lesions in the FUTURE II trial.¹ Although there are no concrete data, the editorialists suggest that, as we vaccinate for known strains, existing strains that are not included or new strains that evolve may “fill the niche” and continue to cause incident cases of neoplasia despite vaccination. This is another reason to screen women cytologically or by direct visual or other in-vivo methods to detect neoplasia.

A. No. In the FUTURE I trial, among women who were naïve to all strains of the human papillomavirus (HPV) vaccine at the time of inoculation, the vaccine was 100% effective in preventing anogenital lesions, cervical intraepithelial neoplasia (CIN) 2,3, adenocarcinoma in situ, and cervical cancer. In FUTURE II, among the same population, it was 98% effective in preventing all cervical lesions.

However, in FUTURE I, when the groups comprising HPV-naïve and HPV-positive subjects and those with and without preexisting neoplasia were combined, the vaccine was 20% effective in preventing CIN 2,3, adenocarcinoma in situ, and cervical cancer, and 34% effective in preventing genital warts and vulvar and vaginal intraepithelial neoplasia and cancer due to vaccine and nonvaccine HPV types. In FUTURE II, when the same groups were included, the vaccine was 17% effective in preventing all cervical lesions (regardless of the causal HPV type).

The women involved in these trials fell within the target age range for prophylactic vaccination, with ages from 15 to 26 years.

Expert Commentary

Even females in the target population for HPV vaccination (ages 9 to 26) present with different histories and risk status. An individual may be a candidate for:

• true primary prevention (no evidence of any HPV subtype or neoplasia)
• primary prevention for the vaccine subtypes (ie, negative for HPV type 6, 11, 16, or 18)
• prevention despite the presence of HPV type 6, 11, 16, or 18
• prevention despite the presence of a subtype not covered in the vaccine
• vaccination despite existing vulvar, vaginal, or cervical neoplasia.

The effect of the vaccine on this last group would be considered both prophylactic and therapeutic, defined as secondary prevention of cervical cancer. Secondary prevention (reversal of HPV effect in CIN lesions, leading to regression) has not been demonstrated with the quadrivalent HPV vaccine (Gardasil).

Trials followed women over 3 years

In these randomized trials, both vaccine efficacy (lesions prevented) and safety (side effects) were evaluated.

FUTURE I enrolled nearly 5,500 young women within the advised age range for prophylaxis who were randomized to the quadrivalent HPV vaccine or placebo. Cervical screening and colposcopic biopsy (if indicated) were conducted at baseline, and HPV status was determined. Investigators studied the effect of prophylactic vaccination in women naïve to the four viral subtypes targeted by the vaccine (6, 11, 16, and 18), as well as women in each of the other groups listed above.

The principal aim of FUTURE I was to provide an “ideal” frequent visit schedule with broader referral to colposcopy and determine whether the vaccine would reduce the combined incidence of anogenital warts, vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), CIN 1,2,3, and cancer related to HPV subtypes 6, 11, 16, and 18.

FUTURE II involved 12,167 women and a wider visit interval more consistent with clinical practice than FUTURE I. The aim was to determine whether the quadrivalent vaccine would reduce the incidence of CIN 2,3, adenocarcinoma in situ, or invasive carcinoma of the cervix related to HPV subtypes 16 and 18.

In both trials, polymerase chain reaction was used to identify the HPV subtype associated with any CIN, adenocarcinoma in situ, or anogenital lesion that was biopsy-proven, and this information was correlated with the patient’s HPV status before and after vaccination. The baseline and postvaccination serological status against HPV subtypes was also measured.

Safety is not a concern thus far

There were no adverse events that caused death or withdrawal from the studies. The most common side effect was pain at the injection site, which occurred more frequently among vaccinated women.

Bottom line: Keep screening

The quadrivalent vaccine is not equally effective among all female candidates. I recommend the following:

• Encourage vaccination in very young girls and virgins. The vaccine is most effective in females who have not been exposed to any of the four subtypes targeted.
• A lack of type-specific, clinically available serology or lower genital tract screening in a woman who is already sexually active leaves the clinician in the dark about how to counsel her. Because most women I counsel do not harbor all four subtypes covered by the vaccine and lack anogenital disease, I offer the vaccine to all women in the age range that is indicated.
• Counsel women who are already sexually active and who harbor HPV before vaccination, as well as those who acquire the virus during the vaccination period, that even with inoculation they are susceptible to infection and neoplastic transformation, unlike those naïve to the vaccine-specific subtypes. Efficacy is still substantial, however—near 90% overall.
• If type-specific HPV testing becomes commercially available, counsel women who test positive for one of the four HPV subtypes targeted by the vaccine, as well as those with other HPV subtypes, that they are susceptible to neoplastic transformation even with the vaccine.
• Advise women who already have CIN, adenocarcinoma in situ, VIN, VAIN, or benign anogenital disease that the vaccine is not therapeutic and will not prevent the natural progression of these lesions toward cancer.
• Remember that few women harbor all four subtypes targeted by the vaccine. The vaccine may provide some marginal benefit to women already being treated for intraepithelial neoplasia, but each patient should be counseled about the potential lack of benefit.
• Be aware that there is clear benefit in the prevention of anogenital disease independent of the oncogenic risks associated with the virus.
• Don’t forget the other 13 known oncogenic HPV subtypes and the many more nononcogenic types identified so far. The effect of the vaccine is modestly reduced in women who harbor one or more of those subtypes when compared with its efficacy in uninfected recipients and virgins. Therefore, screening for cervical cancer and lower genital tract lesions should continue despite vaccination.
• In an editorial accompanying the FUTURE I and II trials, Sawaya and Smith-McCune observed that oncogenic HPV strains not targeted by the vaccine were responsible for a large number of CIN 2,3 and adenocarcinoma lesions in the FUTURE II trial.¹ Although there are no concrete data, the editorialists suggest that, as we vaccinate for known strains, existing strains that are not included or new strains that evolve may “fill the niche” and continue to cause incident cases of neoplasia despite vaccination. This is another reason to screen women cytologically or by direct visual or other in-vivo methods to detect neoplasia.