Laura Wilder, MLS

Evidence summary

Nonulcer dyspepsia is defined by upper abdominal symptoms (nausea, bloating, and abdominal pain) in the absence of an ulcer.¹ A prospective study evaluating the natural history of 209 Taiwanese patients with nonulcer dyspepsia found a 45% prevalence of H pylori. The patients presented with dyspeptic symptoms and had no history of peptic ulcer disease or treatment for H pylori. Investigators performed an initial endoscopy to establish a diagnosis of nonulcer dyspepsia and followed the patients for 24 months. Patients with H pylori infection were more likely to develop peptic ulcer disease (odds ratio [OR]=3.59; 95% confidence interval [CI], 1.07-12.05; P=.039).²

In addition, a prospective cohort study of Japanese patients with nonulcer dyspepsia found that 4.7% of patients infected with H pylori developed gastric cancer after 10 years.³

Eradicating H pylori doesn’t prevent peptic ulcer disease
A prospective, placebo-controlled trial found that therapy to eradicate H pylori didn’t reduce peptic ulcer disease in patients with functional dyspepsia. Investigators recruited 161 patients with H pylori infection who had had functional dyspepsia symptoms for 3 months and no peptic ulcer disease at baseline. They gave lansoprazole, metronidazole, and tetracycline for 1 week to the treatment group and placebo antibiotics and lansoprazole to the placebo group. Fewer of the treated patients developed peptic ulcers by 12 months, but the difference wasn’t significant (2.5% treatment vs 7.5% placebo; P=.167).⁴

Eradication improves symptoms, but not quality of life
A Cochrane systematic review of 17 RCTs (total N=3566) compared drugs known to eradicate H pylori with placebo or drugs known to be ineffective against H pylori for patients with nonulcer dyspepsia. Investigators evaluated individual and global dyspeptic symptom scores and quality-of-life measures. At 3 to 12 months of follow-up, treated patients reported improved symptom scores (number needed to treat=14; 95% CI, 10-25). Three studies that evaluated quality-of-life indicators found no significant benefit with H pylori eradication.⁵

Evidence for outcomes beyond 12 months is limited. An RCT evaluated 100 patients with nonulcer dyspepsia who received bismuth subcitrate for 4 weeks or metronidazole and tetracycline for 7 days or placebo. At 5 years, investigators performed urea breath testing on 64 patients and found that 67% were negative for H pylori. More H pylori-negative patients reported complete symptom resolution than patients who were still infected (34% vs 8.3%; chi-square <0.001). However, investigators grouped patients at 5-year follow-up according to their H pylori status at that time and not by their original treatment group.⁶

H pylori eradication is low cost
A 2000 systematic review with economic analysis found that eradicating H pylori would cost less than $50 per patient per year compared with antisecretory therapy alone.⁷

Recommendations

The European Helicobacter Study Group states that treatment of H pylori in nonulcer dyspepsia is appropriate.⁸ The American College of Gastroenterology agrees that offering treatment for H pylori in nonulcer dyspepsia is acceptable.⁹

The American Gastroenterological Association recommends a “test and treat” strategy for H pylori in dyspeptic patients.¹

Evidence summary

Nonulcer dyspepsia is defined by upper abdominal symptoms (nausea, bloating, and abdominal pain) in the absence of an ulcer.¹ A prospective study evaluating the natural history of 209 Taiwanese patients with nonulcer dyspepsia found a 45% prevalence of H pylori. The patients presented with dyspeptic symptoms and had no history of peptic ulcer disease or treatment for H pylori. Investigators performed an initial endoscopy to establish a diagnosis of nonulcer dyspepsia and followed the patients for 24 months. Patients with H pylori infection were more likely to develop peptic ulcer disease (odds ratio [OR]=3.59; 95% confidence interval [CI], 1.07-12.05; P=.039).²

In addition, a prospective cohort study of Japanese patients with nonulcer dyspepsia found that 4.7% of patients infected with H pylori developed gastric cancer after 10 years.³

Eradicating H pylori doesn’t prevent peptic ulcer disease
A prospective, placebo-controlled trial found that therapy to eradicate H pylori didn’t reduce peptic ulcer disease in patients with functional dyspepsia. Investigators recruited 161 patients with H pylori infection who had had functional dyspepsia symptoms for 3 months and no peptic ulcer disease at baseline. They gave lansoprazole, metronidazole, and tetracycline for 1 week to the treatment group and placebo antibiotics and lansoprazole to the placebo group. Fewer of the treated patients developed peptic ulcers by 12 months, but the difference wasn’t significant (2.5% treatment vs 7.5% placebo; P=.167).⁴

Eradication improves symptoms, but not quality of life
A Cochrane systematic review of 17 RCTs (total N=3566) compared drugs known to eradicate H pylori with placebo or drugs known to be ineffective against H pylori for patients with nonulcer dyspepsia. Investigators evaluated individual and global dyspeptic symptom scores and quality-of-life measures. At 3 to 12 months of follow-up, treated patients reported improved symptom scores (number needed to treat=14; 95% CI, 10-25). Three studies that evaluated quality-of-life indicators found no significant benefit with H pylori eradication.⁵

Evidence for outcomes beyond 12 months is limited. An RCT evaluated 100 patients with nonulcer dyspepsia who received bismuth subcitrate for 4 weeks or metronidazole and tetracycline for 7 days or placebo. At 5 years, investigators performed urea breath testing on 64 patients and found that 67% were negative for H pylori. More H pylori-negative patients reported complete symptom resolution than patients who were still infected (34% vs 8.3%; chi-square <0.001). However, investigators grouped patients at 5-year follow-up according to their H pylori status at that time and not by their original treatment group.⁶

H pylori eradication is low cost
A 2000 systematic review with economic analysis found that eradicating H pylori would cost less than $50 per patient per year compared with antisecretory therapy alone.⁷

Recommendations

The European Helicobacter Study Group states that treatment of H pylori in nonulcer dyspepsia is appropriate.⁸ The American College of Gastroenterology agrees that offering treatment for H pylori in nonulcer dyspepsia is acceptable.⁹

The American Gastroenterological Association recommends a “test and treat” strategy for H pylori in dyspeptic patients.¹

Evidence summary

Nonulcer dyspepsia is defined by upper abdominal symptoms (nausea, bloating, and abdominal pain) in the absence of an ulcer.¹ A prospective study evaluating the natural history of 209 Taiwanese patients with nonulcer dyspepsia found a 45% prevalence of H pylori. The patients presented with dyspeptic symptoms and had no history of peptic ulcer disease or treatment for H pylori. Investigators performed an initial endoscopy to establish a diagnosis of nonulcer dyspepsia and followed the patients for 24 months. Patients with H pylori infection were more likely to develop peptic ulcer disease (odds ratio [OR]=3.59; 95% confidence interval [CI], 1.07-12.05; P=.039).²

In addition, a prospective cohort study of Japanese patients with nonulcer dyspepsia found that 4.7% of patients infected with H pylori developed gastric cancer after 10 years.³

Eradicating H pylori doesn’t prevent peptic ulcer disease
A prospective, placebo-controlled trial found that therapy to eradicate H pylori didn’t reduce peptic ulcer disease in patients with functional dyspepsia. Investigators recruited 161 patients with H pylori infection who had had functional dyspepsia symptoms for 3 months and no peptic ulcer disease at baseline. They gave lansoprazole, metronidazole, and tetracycline for 1 week to the treatment group and placebo antibiotics and lansoprazole to the placebo group. Fewer of the treated patients developed peptic ulcers by 12 months, but the difference wasn’t significant (2.5% treatment vs 7.5% placebo; P=.167).⁴

Eradication improves symptoms, but not quality of life
A Cochrane systematic review of 17 RCTs (total N=3566) compared drugs known to eradicate H pylori with placebo or drugs known to be ineffective against H pylori for patients with nonulcer dyspepsia. Investigators evaluated individual and global dyspeptic symptom scores and quality-of-life measures. At 3 to 12 months of follow-up, treated patients reported improved symptom scores (number needed to treat=14; 95% CI, 10-25). Three studies that evaluated quality-of-life indicators found no significant benefit with H pylori eradication.⁵

Evidence for outcomes beyond 12 months is limited. An RCT evaluated 100 patients with nonulcer dyspepsia who received bismuth subcitrate for 4 weeks or metronidazole and tetracycline for 7 days or placebo. At 5 years, investigators performed urea breath testing on 64 patients and found that 67% were negative for H pylori. More H pylori-negative patients reported complete symptom resolution than patients who were still infected (34% vs 8.3%; chi-square <0.001). However, investigators grouped patients at 5-year follow-up according to their H pylori status at that time and not by their original treatment group.⁶

H pylori eradication is low cost
A 2000 systematic review with economic analysis found that eradicating H pylori would cost less than $50 per patient per year compared with antisecretory therapy alone.⁷

Recommendations

The European Helicobacter Study Group states that treatment of H pylori in nonulcer dyspepsia is appropriate.⁸ The American College of Gastroenterology agrees that offering treatment for H pylori in nonulcer dyspepsia is acceptable.⁹

The American Gastroenterological Association recommends a “test and treat” strategy for H pylori in dyspeptic patients.¹

Evidence summary

Patients with either IFG or IGT have a significant risk of progressing to diabetes. A recent Cochrane review evaluated studies that randomized patients to intensive exercise and diet counseling or standard advice with follow-up for 1 to 6 years.¹ Although treatment arms varied from study to study, exercise recommendations averaged at least 150 minutes a week and diet recommendations included counseling by dieticians. These lifestyle interventions reduced progression to diabetes by 37%. Another meta-analysis showed a relative risk reduction of 49% for lifestyle changes.²

Metformin is the most effective drug; acarbose and orlistat also help
This meta-analysis also encompassed 10 RCTs that evaluated the effectiveness of pharmacologic interventions, including oral diabetes drugs (metformin, phenformin, acarbose, glipizide, flumamine) and an antiobesity drug (orlistat).² Metformin was the most effective drug, with a 31% to 35% relative risk reduction (number needed to treat [NNT]=7-14), although acarbose and orlistat also produced significant reductions. In a small study, glipizide didn’t prevent development of diabetes.

A 2006 Cochrane review of acarbose encompassed 5 RCTs, including the Study to Prevent Non-Insulin-Dependent Diabetes (STOP-NIDDM), which showed a relative risk reduction of 22%.³

Rosiglitazone offers benefit, but also hazard
The Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM) Trial of 5269 participants with IGT or IFG compared treatment with rosiglitazone and placebo.⁴ Rosiglitazone reduced development of diabetes for participants (hazard ratio=0.40; 95% confidence interval [CI], 0.35-0.46; P<.0001; NNT=5).

However, the risk of heart failure was higher in the rosiglitazone arm, with a risk ratio of 7.00 (95% CI, 1.59-30.76) and a number needed to harm of 250. No statistically significant difference was noted in cardiovascular-related deaths. This trial is consistent with recent evidence showing an increased risk of fluid overload and heart failure in patients with diabetes who take thiazolidinediones.⁵

ACE inhibitors aren’t routinely recommended
Early evidence suggested that blockade of the renin-angiotensin system might delay the onset of diabetes.⁶ The DREAM trial included a ramipril arm to evaluate for this effect in IGT and IFG.⁷ After 3 years of follow-up, no significant decrease in the incidence of diabetes was found among participants taking ramipril compared with placebo.

However, a significant regression to normoglycemia was observed in participants taking ramipril, which suggests that ACE inhibitors may have a modest favorable effect on glucose metabolism. Routine use of ACE inhibitors for the express purpose of preventing diabetes isn’t indicated at this time.

Recommendations

The American Diabetes Association’s (ADA) 2009 position statement recommends starting treatment for IGT or IFG with intensive lifestyle modifications, including referral to an effective ongoing support program for loss of 5% to 10% of body weight and increasing exercise to at least 150 minutes a week of moderate aerobic activity (50%-70% of maximum heart rate).⁸ Follow-up counseling is important for success.

Metformin can be considered in addition to lifestyle interventions for patients at high risk for progression to diabetes, defined as:

• both IGT and IFG plus 1 other risk factor, such as hemoglobin A1C >6%, hypertension, low levels of high-density lipoprotein, elevated triglycerides, or diabetes in a first-degree relative
• obesity
• <60 years of age.

The ADA recommends against using other drugs for diabetes prevention because of issues of cost, side effects, and failure to produce a persistent pharmacologic effect. Patients with prediabetes should be monitored annually for progression to diabetes, using either fasting glucose or a 2-hour oral glucose tolerance test.

Evidence summary

Patients with either IFG or IGT have a significant risk of progressing to diabetes. A recent Cochrane review evaluated studies that randomized patients to intensive exercise and diet counseling or standard advice with follow-up for 1 to 6 years.¹ Although treatment arms varied from study to study, exercise recommendations averaged at least 150 minutes a week and diet recommendations included counseling by dieticians. These lifestyle interventions reduced progression to diabetes by 37%. Another meta-analysis showed a relative risk reduction of 49% for lifestyle changes.²

Metformin is the most effective drug; acarbose and orlistat also help
This meta-analysis also encompassed 10 RCTs that evaluated the effectiveness of pharmacologic interventions, including oral diabetes drugs (metformin, phenformin, acarbose, glipizide, flumamine) and an antiobesity drug (orlistat).² Metformin was the most effective drug, with a 31% to 35% relative risk reduction (number needed to treat [NNT]=7-14), although acarbose and orlistat also produced significant reductions. In a small study, glipizide didn’t prevent development of diabetes.

A 2006 Cochrane review of acarbose encompassed 5 RCTs, including the Study to Prevent Non-Insulin-Dependent Diabetes (STOP-NIDDM), which showed a relative risk reduction of 22%.³

Rosiglitazone offers benefit, but also hazard
The Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM) Trial of 5269 participants with IGT or IFG compared treatment with rosiglitazone and placebo.⁴ Rosiglitazone reduced development of diabetes for participants (hazard ratio=0.40; 95% confidence interval [CI], 0.35-0.46; P<.0001; NNT=5).

However, the risk of heart failure was higher in the rosiglitazone arm, with a risk ratio of 7.00 (95% CI, 1.59-30.76) and a number needed to harm of 250. No statistically significant difference was noted in cardiovascular-related deaths. This trial is consistent with recent evidence showing an increased risk of fluid overload and heart failure in patients with diabetes who take thiazolidinediones.⁵

ACE inhibitors aren’t routinely recommended
Early evidence suggested that blockade of the renin-angiotensin system might delay the onset of diabetes.⁶ The DREAM trial included a ramipril arm to evaluate for this effect in IGT and IFG.⁷ After 3 years of follow-up, no significant decrease in the incidence of diabetes was found among participants taking ramipril compared with placebo.

However, a significant regression to normoglycemia was observed in participants taking ramipril, which suggests that ACE inhibitors may have a modest favorable effect on glucose metabolism. Routine use of ACE inhibitors for the express purpose of preventing diabetes isn’t indicated at this time.

Recommendations

The American Diabetes Association’s (ADA) 2009 position statement recommends starting treatment for IGT or IFG with intensive lifestyle modifications, including referral to an effective ongoing support program for loss of 5% to 10% of body weight and increasing exercise to at least 150 minutes a week of moderate aerobic activity (50%-70% of maximum heart rate).⁸ Follow-up counseling is important for success.

Metformin can be considered in addition to lifestyle interventions for patients at high risk for progression to diabetes, defined as:

• both IGT and IFG plus 1 other risk factor, such as hemoglobin A1C >6%, hypertension, low levels of high-density lipoprotein, elevated triglycerides, or diabetes in a first-degree relative
• obesity
• <60 years of age.

The ADA recommends against using other drugs for diabetes prevention because of issues of cost, side effects, and failure to produce a persistent pharmacologic effect. Patients with prediabetes should be monitored annually for progression to diabetes, using either fasting glucose or a 2-hour oral glucose tolerance test.

Evidence summary

Patients with either IFG or IGT have a significant risk of progressing to diabetes. A recent Cochrane review evaluated studies that randomized patients to intensive exercise and diet counseling or standard advice with follow-up for 1 to 6 years.¹ Although treatment arms varied from study to study, exercise recommendations averaged at least 150 minutes a week and diet recommendations included counseling by dieticians. These lifestyle interventions reduced progression to diabetes by 37%. Another meta-analysis showed a relative risk reduction of 49% for lifestyle changes.²

Metformin is the most effective drug; acarbose and orlistat also help
This meta-analysis also encompassed 10 RCTs that evaluated the effectiveness of pharmacologic interventions, including oral diabetes drugs (metformin, phenformin, acarbose, glipizide, flumamine) and an antiobesity drug (orlistat).² Metformin was the most effective drug, with a 31% to 35% relative risk reduction (number needed to treat [NNT]=7-14), although acarbose and orlistat also produced significant reductions. In a small study, glipizide didn’t prevent development of diabetes.

A 2006 Cochrane review of acarbose encompassed 5 RCTs, including the Study to Prevent Non-Insulin-Dependent Diabetes (STOP-NIDDM), which showed a relative risk reduction of 22%.³

Rosiglitazone offers benefit, but also hazard
The Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM) Trial of 5269 participants with IGT or IFG compared treatment with rosiglitazone and placebo.⁴ Rosiglitazone reduced development of diabetes for participants (hazard ratio=0.40; 95% confidence interval [CI], 0.35-0.46; P<.0001; NNT=5).

However, the risk of heart failure was higher in the rosiglitazone arm, with a risk ratio of 7.00 (95% CI, 1.59-30.76) and a number needed to harm of 250. No statistically significant difference was noted in cardiovascular-related deaths. This trial is consistent with recent evidence showing an increased risk of fluid overload and heart failure in patients with diabetes who take thiazolidinediones.⁵

ACE inhibitors aren’t routinely recommended
Early evidence suggested that blockade of the renin-angiotensin system might delay the onset of diabetes.⁶ The DREAM trial included a ramipril arm to evaluate for this effect in IGT and IFG.⁷ After 3 years of follow-up, no significant decrease in the incidence of diabetes was found among participants taking ramipril compared with placebo.

However, a significant regression to normoglycemia was observed in participants taking ramipril, which suggests that ACE inhibitors may have a modest favorable effect on glucose metabolism. Routine use of ACE inhibitors for the express purpose of preventing diabetes isn’t indicated at this time.

Recommendations

The American Diabetes Association’s (ADA) 2009 position statement recommends starting treatment for IGT or IFG with intensive lifestyle modifications, including referral to an effective ongoing support program for loss of 5% to 10% of body weight and increasing exercise to at least 150 minutes a week of moderate aerobic activity (50%-70% of maximum heart rate).⁸ Follow-up counseling is important for success.

Metformin can be considered in addition to lifestyle interventions for patients at high risk for progression to diabetes, defined as:

• both IGT and IFG plus 1 other risk factor, such as hemoglobin A1C >6%, hypertension, low levels of high-density lipoprotein, elevated triglycerides, or diabetes in a first-degree relative
• obesity
• <60 years of age.

The ADA recommends against using other drugs for diabetes prevention because of issues of cost, side effects, and failure to produce a persistent pharmacologic effect. Patients with prediabetes should be monitored annually for progression to diabetes, using either fasting glucose or a 2-hour oral glucose tolerance test.

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence summary

A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.¹ This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).^2,3

At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis^4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).⁶ A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.⁷ The majority of patients used either form of treatment for 1 year.

Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.⁸ At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).

In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).⁹

The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.

Recommendations from others

In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.¹⁰ This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.

Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.

In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.

Evidence summary

A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.¹ This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).^2,3

At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis^4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).⁶ A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.⁷ The majority of patients used either form of treatment for 1 year.

Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.⁸ At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).

In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).⁹

The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.

Recommendations from others

In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.¹⁰ This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.

Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.

In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.

Evidence summary

A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.¹ This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).^2,3

At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis^4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).⁶ A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.⁷ The majority of patients used either form of treatment for 1 year.

Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.⁸ At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).

In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).⁹

The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.

Recommendations from others

In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.¹⁰ This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.

Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.

In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.

Evidence Summary

Both IGT and IFG are associated with a significant risk of developing diabetes and its associated cardiovascular comorbidities; thus, the primary goal for treatment is to prevent or delay the onset of diabetes. Recent well-designed studies have demonstrated benefits of lifestyle interventions for patients with IGT.

In the US Diabetes Prevention Program (DPP), 3234 patients with IGT and a body-mass index (BMI) of at least 24 kg/m² were randomly assigned to one of the following groups: placebo, metformin, or intensive lifestyle modification. After an average follow-up of 2.8 years, there was a 14% absolute risk reduction in the progression to diabetes in the lifestyle intervention group compared with placebo (number needed to treat [NNT]=7).¹ In the Finnish Diabetes Prevention Study, the lifestyle intervention group had a 12.5% absolute risk reduction compared with the control group (NNT=8).² Successful lifestyle interventions in these studies included weight loss of 5% to 7%, decreased fat intake, increased fiber intake, and 150 minutes of exercise per week.^1-2

Drug therapy with metformin, acarbose, and troglitazone has also been successful in preventing or delaying diabetes in people with IGT.^1,3,4 In the placebo-controlled DPP trial, metformin use was associated with a reduction in progression to diabetes mellitus (NNT=14).¹ In the STOP-NIDDM trial of 1429 persons over 3.3 years of follow-up, acarbose 100 mg 3 times daily resulted in a 9% reduction of progression to diabetes, compared with placebo (NNT=11).³

In the TRIPOD study, troglitazone use was associated with a 17% absolute risk reduction in the incidence of diabetes in high-risk Hispanic women (NNT=6 over an average of 30 months).⁴ The preventive effect of the drug was maintained more than 8 months after troglitazone therapy was discontinued (due to withdrawal from the US market). Current trials with other thiazolidinediones are underway.

TABLE
Comparison of major lifestyle and pharmacologic trials in IGT and IFG

Recommendations from others

The American Diabetes Association (ADA) recommends counseling on weight loss and instructing on increased physical activity in people with IGT.⁵ The United States Preventive Services Task Force recommends intensive programs of lifestyle modification (diet, exercise, and behavior) for patients who have pre-diabetes.⁶

The ADA recommends regular monitoring (every 1 to 2 years) for the development of diabetes in people with prediabetes, and prefers FPG to screen for diabetes since it is faster, cost-effective, and more reproducible than the more sensitive 2-hour oral glucose tolerance test.^5,7 The ADA also recommends that if the FPG is <126 mg/dL and there is a high suspicion for diabetes, a 2-hour oral glucose tolerance test should be performed.

Glycosylated hemoglobin (HbA_1C) is not recommended as a screening tool, because individuals with IFG or IGT may have normal or near-normal HbA_1C levels; these individuals often manifest hyperglycemia only when challenged with the oral glucose load use in the standardized oral glucose tolerance test.⁸

Evidence Summary

Both IGT and IFG are associated with a significant risk of developing diabetes and its associated cardiovascular comorbidities; thus, the primary goal for treatment is to prevent or delay the onset of diabetes. Recent well-designed studies have demonstrated benefits of lifestyle interventions for patients with IGT.

In the US Diabetes Prevention Program (DPP), 3234 patients with IGT and a body-mass index (BMI) of at least 24 kg/m² were randomly assigned to one of the following groups: placebo, metformin, or intensive lifestyle modification. After an average follow-up of 2.8 years, there was a 14% absolute risk reduction in the progression to diabetes in the lifestyle intervention group compared with placebo (number needed to treat [NNT]=7).¹ In the Finnish Diabetes Prevention Study, the lifestyle intervention group had a 12.5% absolute risk reduction compared with the control group (NNT=8).² Successful lifestyle interventions in these studies included weight loss of 5% to 7%, decreased fat intake, increased fiber intake, and 150 minutes of exercise per week.^1-2

Drug therapy with metformin, acarbose, and troglitazone has also been successful in preventing or delaying diabetes in people with IGT.^1,3,4 In the placebo-controlled DPP trial, metformin use was associated with a reduction in progression to diabetes mellitus (NNT=14).¹ In the STOP-NIDDM trial of 1429 persons over 3.3 years of follow-up, acarbose 100 mg 3 times daily resulted in a 9% reduction of progression to diabetes, compared with placebo (NNT=11).³

In the TRIPOD study, troglitazone use was associated with a 17% absolute risk reduction in the incidence of diabetes in high-risk Hispanic women (NNT=6 over an average of 30 months).⁴ The preventive effect of the drug was maintained more than 8 months after troglitazone therapy was discontinued (due to withdrawal from the US market). Current trials with other thiazolidinediones are underway.

TABLE
Comparison of major lifestyle and pharmacologic trials in IGT and IFG

Recommendations from others

The American Diabetes Association (ADA) recommends counseling on weight loss and instructing on increased physical activity in people with IGT.⁵ The United States Preventive Services Task Force recommends intensive programs of lifestyle modification (diet, exercise, and behavior) for patients who have pre-diabetes.⁶

The ADA recommends regular monitoring (every 1 to 2 years) for the development of diabetes in people with prediabetes, and prefers FPG to screen for diabetes since it is faster, cost-effective, and more reproducible than the more sensitive 2-hour oral glucose tolerance test.^5,7 The ADA also recommends that if the FPG is <126 mg/dL and there is a high suspicion for diabetes, a 2-hour oral glucose tolerance test should be performed.

Glycosylated hemoglobin (HbA_1C) is not recommended as a screening tool, because individuals with IFG or IGT may have normal or near-normal HbA_1C levels; these individuals often manifest hyperglycemia only when challenged with the oral glucose load use in the standardized oral glucose tolerance test.⁸

Evidence Summary

Both IGT and IFG are associated with a significant risk of developing diabetes and its associated cardiovascular comorbidities; thus, the primary goal for treatment is to prevent or delay the onset of diabetes. Recent well-designed studies have demonstrated benefits of lifestyle interventions for patients with IGT.

In the US Diabetes Prevention Program (DPP), 3234 patients with IGT and a body-mass index (BMI) of at least 24 kg/m² were randomly assigned to one of the following groups: placebo, metformin, or intensive lifestyle modification. After an average follow-up of 2.8 years, there was a 14% absolute risk reduction in the progression to diabetes in the lifestyle intervention group compared with placebo (number needed to treat [NNT]=7).¹ In the Finnish Diabetes Prevention Study, the lifestyle intervention group had a 12.5% absolute risk reduction compared with the control group (NNT=8).² Successful lifestyle interventions in these studies included weight loss of 5% to 7%, decreased fat intake, increased fiber intake, and 150 minutes of exercise per week.^1-2

Drug therapy with metformin, acarbose, and troglitazone has also been successful in preventing or delaying diabetes in people with IGT.^1,3,4 In the placebo-controlled DPP trial, metformin use was associated with a reduction in progression to diabetes mellitus (NNT=14).¹ In the STOP-NIDDM trial of 1429 persons over 3.3 years of follow-up, acarbose 100 mg 3 times daily resulted in a 9% reduction of progression to diabetes, compared with placebo (NNT=11).³

In the TRIPOD study, troglitazone use was associated with a 17% absolute risk reduction in the incidence of diabetes in high-risk Hispanic women (NNT=6 over an average of 30 months).⁴ The preventive effect of the drug was maintained more than 8 months after troglitazone therapy was discontinued (due to withdrawal from the US market). Current trials with other thiazolidinediones are underway.

TABLE
Comparison of major lifestyle and pharmacologic trials in IGT and IFG

Recommendations from others

The American Diabetes Association (ADA) recommends counseling on weight loss and instructing on increased physical activity in people with IGT.⁵ The United States Preventive Services Task Force recommends intensive programs of lifestyle modification (diet, exercise, and behavior) for patients who have pre-diabetes.⁶

The ADA recommends regular monitoring (every 1 to 2 years) for the development of diabetes in people with prediabetes, and prefers FPG to screen for diabetes since it is faster, cost-effective, and more reproducible than the more sensitive 2-hour oral glucose tolerance test.^5,7 The ADA also recommends that if the FPG is <126 mg/dL and there is a high suspicion for diabetes, a 2-hour oral glucose tolerance test should be performed.

Glycosylated hemoglobin (HbA_1C) is not recommended as a screening tool, because individuals with IFG or IGT may have normal or near-normal HbA_1C levels; these individuals often manifest hyperglycemia only when challenged with the oral glucose load use in the standardized oral glucose tolerance test.⁸

Evidence summary

Uterine myomas are usually diagnosed by incidental visualization during pelvic sonography or bimanual palpation of an enlarged, mobile uterus with irregular contours.¹ In a retrospective chart review of obese and nonobese patients with known uterine fibroids, clinical estimate of uterine size by bimanual examination correlated with both ultrasound fibroid sizing and posthysterectomy pathology analysis.² Additional diagnostic testing is indicated for patients with suspected fibroids and abnormal uterine bleeding, increased pelvic girth, pelvic pressure contributing to urinary frequency or constipation, or pelvic pain with intercourse or other physical activity.³

TVS has high sensitivity for detecting myomas in a uterus of <10-week size. The use of high-frequency probes improves the sensitivity for diagnosing small myomas, although their precise location with respect to the uterine cavity often remains uncertain. Localization of fibroids in a larger uterus or when there are many tumors is limited.⁴ Also, TVS may fail to detect small fibroids and subserosal myomas. A systematic review of 9 heterogeneous studies evaluating TVS found wide ranges for sensitivity and specificity (TABLE).⁵ The cost of TVS is less than half of sonohysterography or diagnostic hysteroscopy, based on Medicare allowable pricing data.⁶

SHG uses an intrauterine saline contrast medium with transvaginal ultrasonography. This office-based procedure is more invasive than TVS but requires no anesthesia. SHG is more sensitive and specific than TVS in detecting submucous myomas and focal endometrial lesions.⁷ In a prospective study of 81 symptomatic patients, using a gold standard of surgical pathology, SHG demonstrated more discriminating positive and negative likelihood ratios (LR+, LR–) for detecting myomata than did TVS or hysteroscopy.⁸ A prospective study of 56 symptomatic patients with a gold standard of hysteroscopic or surgical pathology similarly found SHG to be superior to TVS.⁷ In a systematic review of 7 studies, SHG demonstrated a clinically significant LR+ of 29.7. There was too much heterogeneity in the data to calculate an LR– (TABLE).⁵

Hysteroscopy is as accurate but more invasive than SHG in evaluating uterine myomata. In a systematic review of 4 studies, hysteroscopy had a pooled LR+ of 29.4 for diagnosing fibroids. Due to study heterogeneity, a pooled LR– could not be calculated.⁵ A prospective, blinded comparative study of SHG and hysteroscopy for diagnosing fibroids in 117 women found SHG to have a higher failure rate (22% vs 6%) but a statistically significant lower median pain score: 1.6 (interquartile range 0.48–3.03) vs 3.2 (1.58–5.18) (P<.001)—than hysteroscopy.⁹ Failure of SHG was most commonly due to cervical stenosis.

In a double-blinded comparative study of 106 consecutive premenopausal women undergoing hysterectomy for benign reasons, MRI and TVS detected myomas with equal precision (TABLE). MRI is preferred in cases for which exact myoma mapping is necessary and those with multiple myomas or large uteri who are scheduled for advanced surgical procedures.⁴ MRI costs up to twice as much as sonohysterography or diagnostic hysteroscopy, when comparing Medicare allowable pricing data.⁶

TABLE
Evaluations of diagnostic tools for fibroids

Recommendations from others

A 1994 American College of Obstetrics and Gynecology (ACOG) bulletin stated that uterine fibroids can be diagnosed with 95% certainty by examination alone.¹⁰ ACOG recommends augmenting physical examination with ultrasonography in cases involving obese women or when adnexal pathology cannot be excluded based on examination alone. This bulletin also points out that routine ultrasonography does not improve long-term clinical outcomes for fibroids. A more recent bulletin (2000) addressed management but not evaluation or diagnosis of leiomyomas.¹¹

A 2003 guideline from the Society of Obstetrics and Gynecology of Canada recommends against routine ultrasonography, since it rarely affects the clinical management of uterine fibroids. However, it emphasizes the importance of ruling out underlying endometrial pathology in women with abnormal uterine bleeding.¹²

Evidence summary

Uterine myomas are usually diagnosed by incidental visualization during pelvic sonography or bimanual palpation of an enlarged, mobile uterus with irregular contours.¹ In a retrospective chart review of obese and nonobese patients with known uterine fibroids, clinical estimate of uterine size by bimanual examination correlated with both ultrasound fibroid sizing and posthysterectomy pathology analysis.² Additional diagnostic testing is indicated for patients with suspected fibroids and abnormal uterine bleeding, increased pelvic girth, pelvic pressure contributing to urinary frequency or constipation, or pelvic pain with intercourse or other physical activity.³

TVS has high sensitivity for detecting myomas in a uterus of <10-week size. The use of high-frequency probes improves the sensitivity for diagnosing small myomas, although their precise location with respect to the uterine cavity often remains uncertain. Localization of fibroids in a larger uterus or when there are many tumors is limited.⁴ Also, TVS may fail to detect small fibroids and subserosal myomas. A systematic review of 9 heterogeneous studies evaluating TVS found wide ranges for sensitivity and specificity (TABLE).⁵ The cost of TVS is less than half of sonohysterography or diagnostic hysteroscopy, based on Medicare allowable pricing data.⁶

SHG uses an intrauterine saline contrast medium with transvaginal ultrasonography. This office-based procedure is more invasive than TVS but requires no anesthesia. SHG is more sensitive and specific than TVS in detecting submucous myomas and focal endometrial lesions.⁷ In a prospective study of 81 symptomatic patients, using a gold standard of surgical pathology, SHG demonstrated more discriminating positive and negative likelihood ratios (LR+, LR–) for detecting myomata than did TVS or hysteroscopy.⁸ A prospective study of 56 symptomatic patients with a gold standard of hysteroscopic or surgical pathology similarly found SHG to be superior to TVS.⁷ In a systematic review of 7 studies, SHG demonstrated a clinically significant LR+ of 29.7. There was too much heterogeneity in the data to calculate an LR– (TABLE).⁵

Hysteroscopy is as accurate but more invasive than SHG in evaluating uterine myomata. In a systematic review of 4 studies, hysteroscopy had a pooled LR+ of 29.4 for diagnosing fibroids. Due to study heterogeneity, a pooled LR– could not be calculated.⁵ A prospective, blinded comparative study of SHG and hysteroscopy for diagnosing fibroids in 117 women found SHG to have a higher failure rate (22% vs 6%) but a statistically significant lower median pain score: 1.6 (interquartile range 0.48–3.03) vs 3.2 (1.58–5.18) (P<.001)—than hysteroscopy.⁹ Failure of SHG was most commonly due to cervical stenosis.

In a double-blinded comparative study of 106 consecutive premenopausal women undergoing hysterectomy for benign reasons, MRI and TVS detected myomas with equal precision (TABLE). MRI is preferred in cases for which exact myoma mapping is necessary and those with multiple myomas or large uteri who are scheduled for advanced surgical procedures.⁴ MRI costs up to twice as much as sonohysterography or diagnostic hysteroscopy, when comparing Medicare allowable pricing data.⁶

TABLE
Evaluations of diagnostic tools for fibroids

Recommendations from others

A 1994 American College of Obstetrics and Gynecology (ACOG) bulletin stated that uterine fibroids can be diagnosed with 95% certainty by examination alone.¹⁰ ACOG recommends augmenting physical examination with ultrasonography in cases involving obese women or when adnexal pathology cannot be excluded based on examination alone. This bulletin also points out that routine ultrasonography does not improve long-term clinical outcomes for fibroids. A more recent bulletin (2000) addressed management but not evaluation or diagnosis of leiomyomas.¹¹

A 2003 guideline from the Society of Obstetrics and Gynecology of Canada recommends against routine ultrasonography, since it rarely affects the clinical management of uterine fibroids. However, it emphasizes the importance of ruling out underlying endometrial pathology in women with abnormal uterine bleeding.¹²

Evidence summary

Uterine myomas are usually diagnosed by incidental visualization during pelvic sonography or bimanual palpation of an enlarged, mobile uterus with irregular contours.¹ In a retrospective chart review of obese and nonobese patients with known uterine fibroids, clinical estimate of uterine size by bimanual examination correlated with both ultrasound fibroid sizing and posthysterectomy pathology analysis.² Additional diagnostic testing is indicated for patients with suspected fibroids and abnormal uterine bleeding, increased pelvic girth, pelvic pressure contributing to urinary frequency or constipation, or pelvic pain with intercourse or other physical activity.³

TVS has high sensitivity for detecting myomas in a uterus of <10-week size. The use of high-frequency probes improves the sensitivity for diagnosing small myomas, although their precise location with respect to the uterine cavity often remains uncertain. Localization of fibroids in a larger uterus or when there are many tumors is limited.⁴ Also, TVS may fail to detect small fibroids and subserosal myomas. A systematic review of 9 heterogeneous studies evaluating TVS found wide ranges for sensitivity and specificity (TABLE).⁵ The cost of TVS is less than half of sonohysterography or diagnostic hysteroscopy, based on Medicare allowable pricing data.⁶

SHG uses an intrauterine saline contrast medium with transvaginal ultrasonography. This office-based procedure is more invasive than TVS but requires no anesthesia. SHG is more sensitive and specific than TVS in detecting submucous myomas and focal endometrial lesions.⁷ In a prospective study of 81 symptomatic patients, using a gold standard of surgical pathology, SHG demonstrated more discriminating positive and negative likelihood ratios (LR+, LR–) for detecting myomata than did TVS or hysteroscopy.⁸ A prospective study of 56 symptomatic patients with a gold standard of hysteroscopic or surgical pathology similarly found SHG to be superior to TVS.⁷ In a systematic review of 7 studies, SHG demonstrated a clinically significant LR+ of 29.7. There was too much heterogeneity in the data to calculate an LR– (TABLE).⁵

Hysteroscopy is as accurate but more invasive than SHG in evaluating uterine myomata. In a systematic review of 4 studies, hysteroscopy had a pooled LR+ of 29.4 for diagnosing fibroids. Due to study heterogeneity, a pooled LR– could not be calculated.⁵ A prospective, blinded comparative study of SHG and hysteroscopy for diagnosing fibroids in 117 women found SHG to have a higher failure rate (22% vs 6%) but a statistically significant lower median pain score: 1.6 (interquartile range 0.48–3.03) vs 3.2 (1.58–5.18) (P<.001)—than hysteroscopy.⁹ Failure of SHG was most commonly due to cervical stenosis.

In a double-blinded comparative study of 106 consecutive premenopausal women undergoing hysterectomy for benign reasons, MRI and TVS detected myomas with equal precision (TABLE). MRI is preferred in cases for which exact myoma mapping is necessary and those with multiple myomas or large uteri who are scheduled for advanced surgical procedures.⁴ MRI costs up to twice as much as sonohysterography or diagnostic hysteroscopy, when comparing Medicare allowable pricing data.⁶

TABLE
Evaluations of diagnostic tools for fibroids

Recommendations from others

A 1994 American College of Obstetrics and Gynecology (ACOG) bulletin stated that uterine fibroids can be diagnosed with 95% certainty by examination alone.¹⁰ ACOG recommends augmenting physical examination with ultrasonography in cases involving obese women or when adnexal pathology cannot be excluded based on examination alone. This bulletin also points out that routine ultrasonography does not improve long-term clinical outcomes for fibroids. A more recent bulletin (2000) addressed management but not evaluation or diagnosis of leiomyomas.¹¹

A 2003 guideline from the Society of Obstetrics and Gynecology of Canada recommends against routine ultrasonography, since it rarely affects the clinical management of uterine fibroids. However, it emphasizes the importance of ruling out underlying endometrial pathology in women with abnormal uterine bleeding.¹²

Evidence summary

Constipation in toddlers is characterized by a delay or difficulty in defecation that is present for 2 or more weeks. It is a common problem, accounting for 3% of all general pediatric visits. In most children, constipation is functional without pathological cause. Treatment for pathologic constipation is not addressed here.

Laxative therapies were compared in 2 studies. An unblinded, randomized, crossover trial enrolled 37 children referred for subspecialty evaluation of functional constipation. It found that PEG 3350 and lactulose were equivalent in improving stool frequency, stool form, and ease of passage.

However, there was a significant difference in total stool transit time in subjects taking PEG compared with those taking lactulose (47.6 hours vs 55.3 hours, respectively; P=.038). In addition, twice as many parents and guardians rated PEG effective as those rating lactulose effective (84% vs 46%); and 73% of parents preferred PEG to lactulose.¹

A randomized trial compared PEG with milk of magnesia in 49 children with functional constipation and encopresis. Follow-up at 1, 3, 6, and 12 months revealed similar effectiveness in increasing bowel movement frequency, decreasing soiling episodes, and decreasing abdominal pain. It also revealed that PEG was more palatable and better-tolerated than milk of magnesia (33% of children refused to take milk of magnesia, whereas none refused PEG). No side effects from PEG were reported.²

Behavioral modification has been studied for constipation-related encopresis. A randomized controlled trial of 87 children with fecal soiling compared the effect of enhanced toilet training (including behavioral therapy) with aggressive medical management that included disimpaction, enemas, and regular laxative therapy. After 12 months, the enhanced toilet training with behavioral therapy was more effective in reducing daily frequency of soiling (78% of the children had significantly decreased average daily frequency of soiling compared with 41% in the aggressive medical management group; P<.0001; absolute risk reduction=0.37; number needed to treat for 1 year=2.7).³

Dietary management centers on a balanced diet with whole grains, fruits, and vegetables. A case-control study evaluated 291 subjects with constipation and compared their diet with 1602 controls. Mean daily fiber intake was lower in the constipation group. Compared with fiber intake of more than 29 g/d, the relative risk was 8.0 for fiber intake of less than 12.4 g/d.⁴

A nonrandomized, controlled trial of acupuncture treatment enrolled 17 children with history of constipation for a minimum of 6 months. Bowel movement frequency improved in both males (1.5 ± 0.1/week to 4.4 ± 0.6/week; P<.01) and females (1.4 ± 0.3/week to 5.6 ± 1.1/week; P<.01) after 10 acupuncture sessions. No other bowel movement parameter was reported.⁵

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) recommends parental education, initial disimpaction as needed, and maintenance therapy with a balanced diet, behavioral modification, and laxatives for all children aged >1 year. Recommended laxatives include mineral oil, magnesium hydroxide, lactulose, and sorbitol. Behavior modification includes regular toileting, unhurried time on the toilet after meals, diary of stool frequency, and a reward system.⁶ The American Academy of Pediatrics supports the above guidelines.

A multispecialty panel from the University of Michigan used a structured literature review as a basis for a consensus guideline. The resulting protocol was similar to the NASPGN protocol, with the addition of stool softeners as an alternative to laxatives.⁷

Evidence summary

Constipation in toddlers is characterized by a delay or difficulty in defecation that is present for 2 or more weeks. It is a common problem, accounting for 3% of all general pediatric visits. In most children, constipation is functional without pathological cause. Treatment for pathologic constipation is not addressed here.

Laxative therapies were compared in 2 studies. An unblinded, randomized, crossover trial enrolled 37 children referred for subspecialty evaluation of functional constipation. It found that PEG 3350 and lactulose were equivalent in improving stool frequency, stool form, and ease of passage.

However, there was a significant difference in total stool transit time in subjects taking PEG compared with those taking lactulose (47.6 hours vs 55.3 hours, respectively; P=.038). In addition, twice as many parents and guardians rated PEG effective as those rating lactulose effective (84% vs 46%); and 73% of parents preferred PEG to lactulose.¹

A randomized trial compared PEG with milk of magnesia in 49 children with functional constipation and encopresis. Follow-up at 1, 3, 6, and 12 months revealed similar effectiveness in increasing bowel movement frequency, decreasing soiling episodes, and decreasing abdominal pain. It also revealed that PEG was more palatable and better-tolerated than milk of magnesia (33% of children refused to take milk of magnesia, whereas none refused PEG). No side effects from PEG were reported.²

Behavioral modification has been studied for constipation-related encopresis. A randomized controlled trial of 87 children with fecal soiling compared the effect of enhanced toilet training (including behavioral therapy) with aggressive medical management that included disimpaction, enemas, and regular laxative therapy. After 12 months, the enhanced toilet training with behavioral therapy was more effective in reducing daily frequency of soiling (78% of the children had significantly decreased average daily frequency of soiling compared with 41% in the aggressive medical management group; P<.0001; absolute risk reduction=0.37; number needed to treat for 1 year=2.7).³

Dietary management centers on a balanced diet with whole grains, fruits, and vegetables. A case-control study evaluated 291 subjects with constipation and compared their diet with 1602 controls. Mean daily fiber intake was lower in the constipation group. Compared with fiber intake of more than 29 g/d, the relative risk was 8.0 for fiber intake of less than 12.4 g/d.⁴

A nonrandomized, controlled trial of acupuncture treatment enrolled 17 children with history of constipation for a minimum of 6 months. Bowel movement frequency improved in both males (1.5 ± 0.1/week to 4.4 ± 0.6/week; P<.01) and females (1.4 ± 0.3/week to 5.6 ± 1.1/week; P<.01) after 10 acupuncture sessions. No other bowel movement parameter was reported.⁵

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) recommends parental education, initial disimpaction as needed, and maintenance therapy with a balanced diet, behavioral modification, and laxatives for all children aged >1 year. Recommended laxatives include mineral oil, magnesium hydroxide, lactulose, and sorbitol. Behavior modification includes regular toileting, unhurried time on the toilet after meals, diary of stool frequency, and a reward system.⁶ The American Academy of Pediatrics supports the above guidelines.

A multispecialty panel from the University of Michigan used a structured literature review as a basis for a consensus guideline. The resulting protocol was similar to the NASPGN protocol, with the addition of stool softeners as an alternative to laxatives.⁷

Evidence summary

Constipation in toddlers is characterized by a delay or difficulty in defecation that is present for 2 or more weeks. It is a common problem, accounting for 3% of all general pediatric visits. In most children, constipation is functional without pathological cause. Treatment for pathologic constipation is not addressed here.

Laxative therapies were compared in 2 studies. An unblinded, randomized, crossover trial enrolled 37 children referred for subspecialty evaluation of functional constipation. It found that PEG 3350 and lactulose were equivalent in improving stool frequency, stool form, and ease of passage.

However, there was a significant difference in total stool transit time in subjects taking PEG compared with those taking lactulose (47.6 hours vs 55.3 hours, respectively; P=.038). In addition, twice as many parents and guardians rated PEG effective as those rating lactulose effective (84% vs 46%); and 73% of parents preferred PEG to lactulose.¹

A randomized trial compared PEG with milk of magnesia in 49 children with functional constipation and encopresis. Follow-up at 1, 3, 6, and 12 months revealed similar effectiveness in increasing bowel movement frequency, decreasing soiling episodes, and decreasing abdominal pain. It also revealed that PEG was more palatable and better-tolerated than milk of magnesia (33% of children refused to take milk of magnesia, whereas none refused PEG). No side effects from PEG were reported.²

Behavioral modification has been studied for constipation-related encopresis. A randomized controlled trial of 87 children with fecal soiling compared the effect of enhanced toilet training (including behavioral therapy) with aggressive medical management that included disimpaction, enemas, and regular laxative therapy. After 12 months, the enhanced toilet training with behavioral therapy was more effective in reducing daily frequency of soiling (78% of the children had significantly decreased average daily frequency of soiling compared with 41% in the aggressive medical management group; P<.0001; absolute risk reduction=0.37; number needed to treat for 1 year=2.7).³

Dietary management centers on a balanced diet with whole grains, fruits, and vegetables. A case-control study evaluated 291 subjects with constipation and compared their diet with 1602 controls. Mean daily fiber intake was lower in the constipation group. Compared with fiber intake of more than 29 g/d, the relative risk was 8.0 for fiber intake of less than 12.4 g/d.⁴

A nonrandomized, controlled trial of acupuncture treatment enrolled 17 children with history of constipation for a minimum of 6 months. Bowel movement frequency improved in both males (1.5 ± 0.1/week to 4.4 ± 0.6/week; P<.01) and females (1.4 ± 0.3/week to 5.6 ± 1.1/week; P<.01) after 10 acupuncture sessions. No other bowel movement parameter was reported.⁵

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) recommends parental education, initial disimpaction as needed, and maintenance therapy with a balanced diet, behavioral modification, and laxatives for all children aged >1 year. Recommended laxatives include mineral oil, magnesium hydroxide, lactulose, and sorbitol. Behavior modification includes regular toileting, unhurried time on the toilet after meals, diary of stool frequency, and a reward system.⁶ The American Academy of Pediatrics supports the above guidelines.

A multispecialty panel from the University of Michigan used a structured literature review as a basis for a consensus guideline. The resulting protocol was similar to the NASPGN protocol, with the addition of stool softeners as an alternative to laxatives.⁷

Evidence summary

Recommendations about antibiotic prophylaxis are based on several premises. Reflux predisposes children to acute pyelonephritis; reflux plus infection leads to reflux nephropathy and ultimately to renal scarring. In theory, if antibiotics could be initiated at the appropriate time and be maintained until reflux resolves, we could successfully prevent infection and scarring.⁴

A recent systematic review evaluated the use of antibiotics to prevent UTI in children.⁵ This review of 5 randomized controlled trials included a total of 463 children between the ages of 2 months to 16 years. Three out of 5 trials evaluated the effectiveness of antibiotic treatment for 2 to 6 months to prevent subsequent off-treatment recurrence. The 2 smaller trials (n=71) evaluated the use of low-dose long-term antibiotics to prevent UTI.

There was a clinically, but not statistically, significant trend towards reduced risk of UTI during long-term antibiotic treatment (risk reduction [RR]=0.31; 95% confidence interval [CI]=0.10–1.00); however, no sustained benefit was seen once antibiotics were stopped (RR=0.79; 95% CI, 0.61–1.02). There were many problems with the methodological quality of these trials, including significant heterogeneity. The researchers concluded that well-designed randomized controlled trails are still needed to evaluate this commonly used intervention in the pediatric population.⁴ Benefits for long-term prophylaxis are even less clear in children with low-grade reflux (I–II).⁵ Furthermore, no randomized controlled trials assess whether prophylaxis prevents the development of new renal scars in children.⁶

In addition, a recent systematic review of studies done in children with normal urinary tracts, as well in children with neurogenic bladders, found that the available evidence is of low quality. Only 6 out of 31 potential studies fulfilled the inclusion criteria. These were small (mean sample size was 28), and the quality scores of all 6 trials were low, indicating that the evidence may be unreliable.⁷

Two of 3 studies done in children with normal urinary tracts demonstrated statistically significant higher rates of UTI recurrence in control groups compared with treatment groups receiving 6 to 10 months of either nitrofurantoin or cotrimoxazole (RR=24–31). The third study showed no difference between groups.

One of 2 trials in children with neurogenic bladder demonstrated higher recurrence rates of 2.9 per 10 patient years for patients receiving antibiotics compared with 1.5 in the untreated group. The other study showed lower recurrence rates of 17.1 for patients receiving antibiotics, compared with 33 in the untreated group.⁷Neither of these findings were statistically significant.

A different meta-analysis of 15 controlled clinical trials in children with neurogenic bladder due to spinal cord dysfunction. This analysis showed that antibiotic prophylaxis was associated with a reduction in asymptomatic bacteruria among children with acute spinal cord injury (P<.05), but there was no significant reduction in symptomatic infections. Prophylaxis resulted in an approximately twofold increase in antimicrobial-resistant bacteria. The researchers concluded that although a clinically important effect has not been excluded, the regular use of antimicrobial prophylaxis for most patients who have neurogenic bladder caused by spinal cord dysfunction is not supported at this time.⁸

Poor compliance may be an issue with long-term prophylaxis and may represent patient or parent practice.⁹One study found that in children taking low-dose trimethoprim, 97% of the parents reported giving antibiotics on daily basis, but in 31% of subjects, trimethoprim was not detectable in the urine.⁶Risk of prophylaxis includes nausea, vomiting, and rash in 8% to 10% of patients; development of resistant organisms; and change in indigenous microflora.⁶ One study of resistance found that children who received antibiotics for more than 4 weeks in the previous 6 months were more likely to have resistant Escherichia coli isolates than children who had not received prolonged antibiotic treatment (odds ratio [OR]=13.9; 95% CI, 8.2–23.5). Children with abnormalities of the genitourinary tract were approximately 4 times more likely to have resistant isolates of E coli than children without abnormalities of the genitourinary tract (OR=3.9; 95% CI, 2.7–5.7).¹¹

Recommendations from others

The American Academy of Pediatrics, American Urological Association, and the Swedish Medical Research Council guidelines recommend prophylaxis for children with reflux ( Table ), but they all acknowledge that the recommendations are not supported by well-designed randomized controlled trials.^1-3 No guidelines are available for children with neurogenic bladder and recurrent urinary tract infections.⁷

TABLE
Oral antibiotics for prophylaxis of urinary tract infections in children

Evidence summary

Recommendations about antibiotic prophylaxis are based on several premises. Reflux predisposes children to acute pyelonephritis; reflux plus infection leads to reflux nephropathy and ultimately to renal scarring. In theory, if antibiotics could be initiated at the appropriate time and be maintained until reflux resolves, we could successfully prevent infection and scarring.⁴

A recent systematic review evaluated the use of antibiotics to prevent UTI in children.⁵ This review of 5 randomized controlled trials included a total of 463 children between the ages of 2 months to 16 years. Three out of 5 trials evaluated the effectiveness of antibiotic treatment for 2 to 6 months to prevent subsequent off-treatment recurrence. The 2 smaller trials (n=71) evaluated the use of low-dose long-term antibiotics to prevent UTI.

There was a clinically, but not statistically, significant trend towards reduced risk of UTI during long-term antibiotic treatment (risk reduction [RR]=0.31; 95% confidence interval [CI]=0.10–1.00); however, no sustained benefit was seen once antibiotics were stopped (RR=0.79; 95% CI, 0.61–1.02). There were many problems with the methodological quality of these trials, including significant heterogeneity. The researchers concluded that well-designed randomized controlled trails are still needed to evaluate this commonly used intervention in the pediatric population.⁴ Benefits for long-term prophylaxis are even less clear in children with low-grade reflux (I–II).⁵ Furthermore, no randomized controlled trials assess whether prophylaxis prevents the development of new renal scars in children.⁶

In addition, a recent systematic review of studies done in children with normal urinary tracts, as well in children with neurogenic bladders, found that the available evidence is of low quality. Only 6 out of 31 potential studies fulfilled the inclusion criteria. These were small (mean sample size was 28), and the quality scores of all 6 trials were low, indicating that the evidence may be unreliable.⁷

Two of 3 studies done in children with normal urinary tracts demonstrated statistically significant higher rates of UTI recurrence in control groups compared with treatment groups receiving 6 to 10 months of either nitrofurantoin or cotrimoxazole (RR=24–31). The third study showed no difference between groups.

One of 2 trials in children with neurogenic bladder demonstrated higher recurrence rates of 2.9 per 10 patient years for patients receiving antibiotics compared with 1.5 in the untreated group. The other study showed lower recurrence rates of 17.1 for patients receiving antibiotics, compared with 33 in the untreated group.⁷Neither of these findings were statistically significant.

A different meta-analysis of 15 controlled clinical trials in children with neurogenic bladder due to spinal cord dysfunction. This analysis showed that antibiotic prophylaxis was associated with a reduction in asymptomatic bacteruria among children with acute spinal cord injury (P<.05), but there was no significant reduction in symptomatic infections. Prophylaxis resulted in an approximately twofold increase in antimicrobial-resistant bacteria. The researchers concluded that although a clinically important effect has not been excluded, the regular use of antimicrobial prophylaxis for most patients who have neurogenic bladder caused by spinal cord dysfunction is not supported at this time.⁸

Poor compliance may be an issue with long-term prophylaxis and may represent patient or parent practice.⁹One study found that in children taking low-dose trimethoprim, 97% of the parents reported giving antibiotics on daily basis, but in 31% of subjects, trimethoprim was not detectable in the urine.⁶Risk of prophylaxis includes nausea, vomiting, and rash in 8% to 10% of patients; development of resistant organisms; and change in indigenous microflora.⁶ One study of resistance found that children who received antibiotics for more than 4 weeks in the previous 6 months were more likely to have resistant Escherichia coli isolates than children who had not received prolonged antibiotic treatment (odds ratio [OR]=13.9; 95% CI, 8.2–23.5). Children with abnormalities of the genitourinary tract were approximately 4 times more likely to have resistant isolates of E coli than children without abnormalities of the genitourinary tract (OR=3.9; 95% CI, 2.7–5.7).¹¹

Recommendations from others

The American Academy of Pediatrics, American Urological Association, and the Swedish Medical Research Council guidelines recommend prophylaxis for children with reflux ( Table ), but they all acknowledge that the recommendations are not supported by well-designed randomized controlled trials.^1-3 No guidelines are available for children with neurogenic bladder and recurrent urinary tract infections.⁷

TABLE
Oral antibiotics for prophylaxis of urinary tract infections in children

Evidence summary

Recommendations about antibiotic prophylaxis are based on several premises. Reflux predisposes children to acute pyelonephritis; reflux plus infection leads to reflux nephropathy and ultimately to renal scarring. In theory, if antibiotics could be initiated at the appropriate time and be maintained until reflux resolves, we could successfully prevent infection and scarring.⁴

A recent systematic review evaluated the use of antibiotics to prevent UTI in children.⁵ This review of 5 randomized controlled trials included a total of 463 children between the ages of 2 months to 16 years. Three out of 5 trials evaluated the effectiveness of antibiotic treatment for 2 to 6 months to prevent subsequent off-treatment recurrence. The 2 smaller trials (n=71) evaluated the use of low-dose long-term antibiotics to prevent UTI.

There was a clinically, but not statistically, significant trend towards reduced risk of UTI during long-term antibiotic treatment (risk reduction [RR]=0.31; 95% confidence interval [CI]=0.10–1.00); however, no sustained benefit was seen once antibiotics were stopped (RR=0.79; 95% CI, 0.61–1.02). There were many problems with the methodological quality of these trials, including significant heterogeneity. The researchers concluded that well-designed randomized controlled trails are still needed to evaluate this commonly used intervention in the pediatric population.⁴ Benefits for long-term prophylaxis are even less clear in children with low-grade reflux (I–II).⁵ Furthermore, no randomized controlled trials assess whether prophylaxis prevents the development of new renal scars in children.⁶

In addition, a recent systematic review of studies done in children with normal urinary tracts, as well in children with neurogenic bladders, found that the available evidence is of low quality. Only 6 out of 31 potential studies fulfilled the inclusion criteria. These were small (mean sample size was 28), and the quality scores of all 6 trials were low, indicating that the evidence may be unreliable.⁷

Two of 3 studies done in children with normal urinary tracts demonstrated statistically significant higher rates of UTI recurrence in control groups compared with treatment groups receiving 6 to 10 months of either nitrofurantoin or cotrimoxazole (RR=24–31). The third study showed no difference between groups.

One of 2 trials in children with neurogenic bladder demonstrated higher recurrence rates of 2.9 per 10 patient years for patients receiving antibiotics compared with 1.5 in the untreated group. The other study showed lower recurrence rates of 17.1 for patients receiving antibiotics, compared with 33 in the untreated group.⁷Neither of these findings were statistically significant.

A different meta-analysis of 15 controlled clinical trials in children with neurogenic bladder due to spinal cord dysfunction. This analysis showed that antibiotic prophylaxis was associated with a reduction in asymptomatic bacteruria among children with acute spinal cord injury (P<.05), but there was no significant reduction in symptomatic infections. Prophylaxis resulted in an approximately twofold increase in antimicrobial-resistant bacteria. The researchers concluded that although a clinically important effect has not been excluded, the regular use of antimicrobial prophylaxis for most patients who have neurogenic bladder caused by spinal cord dysfunction is not supported at this time.⁸

Poor compliance may be an issue with long-term prophylaxis and may represent patient or parent practice.⁹One study found that in children taking low-dose trimethoprim, 97% of the parents reported giving antibiotics on daily basis, but in 31% of subjects, trimethoprim was not detectable in the urine.⁶Risk of prophylaxis includes nausea, vomiting, and rash in 8% to 10% of patients; development of resistant organisms; and change in indigenous microflora.⁶ One study of resistance found that children who received antibiotics for more than 4 weeks in the previous 6 months were more likely to have resistant Escherichia coli isolates than children who had not received prolonged antibiotic treatment (odds ratio [OR]=13.9; 95% CI, 8.2–23.5). Children with abnormalities of the genitourinary tract were approximately 4 times more likely to have resistant isolates of E coli than children without abnormalities of the genitourinary tract (OR=3.9; 95% CI, 2.7–5.7).¹¹

Recommendations from others

The American Academy of Pediatrics, American Urological Association, and the Swedish Medical Research Council guidelines recommend prophylaxis for children with reflux ( Table ), but they all acknowledge that the recommendations are not supported by well-designed randomized controlled trials.^1-3 No guidelines are available for children with neurogenic bladder and recurrent urinary tract infections.⁷

TABLE
Oral antibiotics for prophylaxis of urinary tract infections in children

Evidence summary

The prevalence of urinary tract infection in childhood has been estimated to be roughly 1%.¹ For those children with asymptomatic bacteriuria, fewer than 10% progress to symptomatic urinary tract infections.² The prevalence of other glomelonephropathies is <0.05%.^3,4 Currently vailable screening urinalyses using chemical dipstick testing have reported sensitivities ranging from 53% to 93% and specificities of 72% to 98% for detecting significant bacteriuria.⁵ All positive screening tests for acteriuria require confirmation by standard urine culture.

No prospective randomized trials of screening urinalysis in childhood have been published to date. Expert opinion varies as to the necessity of screening urinalysis. No prospective randomized trials demonstrate improved outcomes, and limited evidence suggests that detection and treatment of asymptomatic bacteriuria improves long-term outcomes such as renal scarring, hypertension, or pyelone phritis.⁶

Recommendations from others

The American Academy of Pediatrics recommends 1 screening dipstick urinalysis at age 5.⁷ The American Academy of Family Physicians,⁸ Bright Futures,⁹ Canadian Task Force on the Periodic Health xamination,¹⁰ and the United States Preventive Services Task Force¹¹ do not recommend screening for asymptomatic bacteriuria in children. The Institute for Clinical Systems Improvement recommends that consideration be given to eliminating routine urinalyses in asymptomatic children.¹²

Evidence summary

The prevalence of urinary tract infection in childhood has been estimated to be roughly 1%.¹ For those children with asymptomatic bacteriuria, fewer than 10% progress to symptomatic urinary tract infections.² The prevalence of other glomelonephropathies is <0.05%.^3,4 Currently vailable screening urinalyses using chemical dipstick testing have reported sensitivities ranging from 53% to 93% and specificities of 72% to 98% for detecting significant bacteriuria.⁵ All positive screening tests for acteriuria require confirmation by standard urine culture.

No prospective randomized trials of screening urinalysis in childhood have been published to date. Expert opinion varies as to the necessity of screening urinalysis. No prospective randomized trials demonstrate improved outcomes, and limited evidence suggests that detection and treatment of asymptomatic bacteriuria improves long-term outcomes such as renal scarring, hypertension, or pyelone phritis.⁶

Recommendations from others

The American Academy of Pediatrics recommends 1 screening dipstick urinalysis at age 5.⁷ The American Academy of Family Physicians,⁸ Bright Futures,⁹ Canadian Task Force on the Periodic Health xamination,¹⁰ and the United States Preventive Services Task Force¹¹ do not recommend screening for asymptomatic bacteriuria in children. The Institute for Clinical Systems Improvement recommends that consideration be given to eliminating routine urinalyses in asymptomatic children.¹²

Evidence summary

The prevalence of urinary tract infection in childhood has been estimated to be roughly 1%.¹ For those children with asymptomatic bacteriuria, fewer than 10% progress to symptomatic urinary tract infections.² The prevalence of other glomelonephropathies is <0.05%.^3,4 Currently vailable screening urinalyses using chemical dipstick testing have reported sensitivities ranging from 53% to 93% and specificities of 72% to 98% for detecting significant bacteriuria.⁵ All positive screening tests for acteriuria require confirmation by standard urine culture.

No prospective randomized trials of screening urinalysis in childhood have been published to date. Expert opinion varies as to the necessity of screening urinalysis. No prospective randomized trials demonstrate improved outcomes, and limited evidence suggests that detection and treatment of asymptomatic bacteriuria improves long-term outcomes such as renal scarring, hypertension, or pyelone phritis.⁶

Recommendations from others

The American Academy of Pediatrics recommends 1 screening dipstick urinalysis at age 5.⁷ The American Academy of Family Physicians,⁸ Bright Futures,⁹ Canadian Task Force on the Periodic Health xamination,¹⁰ and the United States Preventive Services Task Force¹¹ do not recommend screening for asymptomatic bacteriuria in children. The Institute for Clinical Systems Improvement recommends that consideration be given to eliminating routine urinalyses in asymptomatic children.¹²

Evidence summary

Osteoporosis results in significant morbidity and mortality. In a prospective observational study of women over 50 years of age, 39.6% had osteopenia and 7.2% had osteoporosis. Osteoporosis was associated with a fracture rate 4 times that of normal bone mineral density.¹ People with vertebral or hip fractures have a reduced relative 5-year survival of 0.81. Excess mortality occurred within the first 6 months following fracture.²

One prospective cohort study identified 14 independent risk factors for hip fracture.³ The best predictors were female gender, age, low weight, and no current estrogen use. For women aged >65 years with no other risks, 12% to 28% have osteoporosis.⁴ Multiple risk assessment scales have been studied to identify women aged >65 years who are at increased risk; however, none of the scales had good discriminatory performance.⁵ As a result, it is unclear which factors for women under 65 years should trigger screening.

While multiple technologies exist to measure bone mineral density, dual-energy x-ray absorptiometry (DEXA) has been the most validated test for predicting fractures. A meta-analysis of 11 prospective cohort trials showed that all sites of bone mineral density measurements correlated with fractures (relative risk [RR], 1.5; 95% confi-dence interval [CI], 1.4–1.6.). However, DEXA of the femoral neck predicted hip fracture better than other measures (RR, 2.6; 95% CI, 2.0–3.5).⁶

Additionally, heel ultrasonography was compa-rable with hip DEXA for predicting hip fractures for women over 65 years (probability of fracture 0.018 vs. 0.023); no studies have compared effec-tiveness for women under 65 years.

Multiple therapeutic interventions for osteo-porosis have been demonstrated to reduce frac-tures. Adequate calcium and vitamin D appear to prevent fractures. Alendronate and rise-dronate are the only prescription medications with evidence showing they prevent hip fractures.

A meta-analysis of 11 randomized controlled trials including 11,808 women found fewer hip fractures in women taking 10 mg/day of alendronate (RR, 0.51; 95% CI, 0.38–0.69; number needed to treat [NNT]=24), and fewer vertebral fractures in women taking 5 mg/day of alendronate (RR, 0.52; 95% CI, 0.43–0.65; NNT=72).⁷

For these results to apply to screening, study participants must be similar to those identified by general population screening. All trials included healthy women with low bone mineral density who were not using estrogen, which is similar to women identified by general screening. However, 57% of women recruited for the second Fracture Intervention Trial (FIT-II), the largest study, were classified as ineligible. This raises concern about the study’s generalizability.⁸

The US Preventive Services Task Force did an outcomes estimation of screening effectiveness, combining all of the above data (Table).⁹ Screening 731 women aged 65 to 69 years would prevent 1 hip fracture if those with indications for treat-ment took it; screening 248 women would prevent 1 vertebral fracture. As the table demonstrates, benefits increase with age. For women under 65 years, benefits are relatively small, unless they have other risk factors for osteoporosis.

TABLE
Hip and vertebral fracture outcomes for osteoporosis screening in 10,000 postmenopausal women ⁹

Recommendations from others

Based on their outcomes model, the US Preventive Services Task Force recommends screening for women aged >65 years, and those aged 60 to 65 years who have risk factors.⁹ In 1998, the National Osteoporosis Foundation, in collaboration with many other professional organ-izations, recommended bone mineral density test-ing for all women aged >65 years and younger postmenopausal women who have had or are at risk for fractures.¹⁰ The 2000 Consensus Development Conference from the National Institutes of Health recommended an individual-ized approach to screening, stating evidence for universal osteoporosis screening is inconclusive.¹¹ The American Association of Clinical Endo-crinologists revised guidelines in 2001 to include screening younger postmenopausal women with a body weight <127 lbs or a family history of nontraumatic spine or hip fracture.¹²

Evidence summary

Osteoporosis results in significant morbidity and mortality. In a prospective observational study of women over 50 years of age, 39.6% had osteopenia and 7.2% had osteoporosis. Osteoporosis was associated with a fracture rate 4 times that of normal bone mineral density.¹ People with vertebral or hip fractures have a reduced relative 5-year survival of 0.81. Excess mortality occurred within the first 6 months following fracture.²

One prospective cohort study identified 14 independent risk factors for hip fracture.³ The best predictors were female gender, age, low weight, and no current estrogen use. For women aged >65 years with no other risks, 12% to 28% have osteoporosis.⁴ Multiple risk assessment scales have been studied to identify women aged >65 years who are at increased risk; however, none of the scales had good discriminatory performance.⁵ As a result, it is unclear which factors for women under 65 years should trigger screening.

While multiple technologies exist to measure bone mineral density, dual-energy x-ray absorptiometry (DEXA) has been the most validated test for predicting fractures. A meta-analysis of 11 prospective cohort trials showed that all sites of bone mineral density measurements correlated with fractures (relative risk [RR], 1.5; 95% confi-dence interval [CI], 1.4–1.6.). However, DEXA of the femoral neck predicted hip fracture better than other measures (RR, 2.6; 95% CI, 2.0–3.5).⁶

Additionally, heel ultrasonography was compa-rable with hip DEXA for predicting hip fractures for women over 65 years (probability of fracture 0.018 vs. 0.023); no studies have compared effec-tiveness for women under 65 years.

Multiple therapeutic interventions for osteo-porosis have been demonstrated to reduce frac-tures. Adequate calcium and vitamin D appear to prevent fractures. Alendronate and rise-dronate are the only prescription medications with evidence showing they prevent hip fractures.

A meta-analysis of 11 randomized controlled trials including 11,808 women found fewer hip fractures in women taking 10 mg/day of alendronate (RR, 0.51; 95% CI, 0.38–0.69; number needed to treat [NNT]=24), and fewer vertebral fractures in women taking 5 mg/day of alendronate (RR, 0.52; 95% CI, 0.43–0.65; NNT=72).⁷

For these results to apply to screening, study participants must be similar to those identified by general population screening. All trials included healthy women with low bone mineral density who were not using estrogen, which is similar to women identified by general screening. However, 57% of women recruited for the second Fracture Intervention Trial (FIT-II), the largest study, were classified as ineligible. This raises concern about the study’s generalizability.⁸

The US Preventive Services Task Force did an outcomes estimation of screening effectiveness, combining all of the above data (Table).⁹ Screening 731 women aged 65 to 69 years would prevent 1 hip fracture if those with indications for treat-ment took it; screening 248 women would prevent 1 vertebral fracture. As the table demonstrates, benefits increase with age. For women under 65 years, benefits are relatively small, unless they have other risk factors for osteoporosis.

TABLE
Hip and vertebral fracture outcomes for osteoporosis screening in 10,000 postmenopausal women ⁹

Recommendations from others

Based on their outcomes model, the US Preventive Services Task Force recommends screening for women aged >65 years, and those aged 60 to 65 years who have risk factors.⁹ In 1998, the National Osteoporosis Foundation, in collaboration with many other professional organ-izations, recommended bone mineral density test-ing for all women aged >65 years and younger postmenopausal women who have had or are at risk for fractures.¹⁰ The 2000 Consensus Development Conference from the National Institutes of Health recommended an individual-ized approach to screening, stating evidence for universal osteoporosis screening is inconclusive.¹¹ The American Association of Clinical Endo-crinologists revised guidelines in 2001 to include screening younger postmenopausal women with a body weight <127 lbs or a family history of nontraumatic spine or hip fracture.¹²

Evidence summary

Osteoporosis results in significant morbidity and mortality. In a prospective observational study of women over 50 years of age, 39.6% had osteopenia and 7.2% had osteoporosis. Osteoporosis was associated with a fracture rate 4 times that of normal bone mineral density.¹ People with vertebral or hip fractures have a reduced relative 5-year survival of 0.81. Excess mortality occurred within the first 6 months following fracture.²

One prospective cohort study identified 14 independent risk factors for hip fracture.³ The best predictors were female gender, age, low weight, and no current estrogen use. For women aged >65 years with no other risks, 12% to 28% have osteoporosis.⁴ Multiple risk assessment scales have been studied to identify women aged >65 years who are at increased risk; however, none of the scales had good discriminatory performance.⁵ As a result, it is unclear which factors for women under 65 years should trigger screening.

While multiple technologies exist to measure bone mineral density, dual-energy x-ray absorptiometry (DEXA) has been the most validated test for predicting fractures. A meta-analysis of 11 prospective cohort trials showed that all sites of bone mineral density measurements correlated with fractures (relative risk [RR], 1.5; 95% confi-dence interval [CI], 1.4–1.6.). However, DEXA of the femoral neck predicted hip fracture better than other measures (RR, 2.6; 95% CI, 2.0–3.5).⁶

Additionally, heel ultrasonography was compa-rable with hip DEXA for predicting hip fractures for women over 65 years (probability of fracture 0.018 vs. 0.023); no studies have compared effec-tiveness for women under 65 years.

Multiple therapeutic interventions for osteo-porosis have been demonstrated to reduce frac-tures. Adequate calcium and vitamin D appear to prevent fractures. Alendronate and rise-dronate are the only prescription medications with evidence showing they prevent hip fractures.

A meta-analysis of 11 randomized controlled trials including 11,808 women found fewer hip fractures in women taking 10 mg/day of alendronate (RR, 0.51; 95% CI, 0.38–0.69; number needed to treat [NNT]=24), and fewer vertebral fractures in women taking 5 mg/day of alendronate (RR, 0.52; 95% CI, 0.43–0.65; NNT=72).⁷

For these results to apply to screening, study participants must be similar to those identified by general population screening. All trials included healthy women with low bone mineral density who were not using estrogen, which is similar to women identified by general screening. However, 57% of women recruited for the second Fracture Intervention Trial (FIT-II), the largest study, were classified as ineligible. This raises concern about the study’s generalizability.⁸

The US Preventive Services Task Force did an outcomes estimation of screening effectiveness, combining all of the above data (Table).⁹ Screening 731 women aged 65 to 69 years would prevent 1 hip fracture if those with indications for treat-ment took it; screening 248 women would prevent 1 vertebral fracture. As the table demonstrates, benefits increase with age. For women under 65 years, benefits are relatively small, unless they have other risk factors for osteoporosis.

TABLE
Hip and vertebral fracture outcomes for osteoporosis screening in 10,000 postmenopausal women ⁹

Recommendations from others

Based on their outcomes model, the US Preventive Services Task Force recommends screening for women aged >65 years, and those aged 60 to 65 years who have risk factors.⁹ In 1998, the National Osteoporosis Foundation, in collaboration with many other professional organ-izations, recommended bone mineral density test-ing for all women aged >65 years and younger postmenopausal women who have had or are at risk for fractures.¹⁰ The 2000 Consensus Development Conference from the National Institutes of Health recommended an individual-ized approach to screening, stating evidence for universal osteoporosis screening is inconclusive.¹¹ The American Association of Clinical Endo-crinologists revised guidelines in 2001 to include screening younger postmenopausal women with a body weight <127 lbs or a family history of nontraumatic spine or hip fracture.¹²