Clinical Inquiries

Evidence summary

Major depressive disorder is common among adolescents and is associated with significant morbidity, including substance abuse and eating disorders. One study of survey data from 1769 adolescents found a lifetime prevalence of 15.3% for major depression. The majority of those reporting episodes of major depression in this study had recurrent symptoms and impairment in work or school.¹

Fluoxetine and therapy together have the best results

A large, multicenter, randomized controlled trial evaluated the effectiveness of fluoxetine (Prozac), cognitive behavioral therapy (CBT), or the combination of the 2. Researchers evaluated improvement with the Children’s Depression Rating Scale–Revised (CDRSR). The CDRS-R uses adolescent and parent interviews to rate 17 symptom areas: impaired schoolwork, difficulty having fun, social withdrawal, appetite disturbance, sleep disturbance, excessive fatigue, physical complaints, irritability, excessive guilt, low self-esteem, depressed feelings, morbid ideas, suicidal ideas, excessive weeping, depressed facial affect, listless speech, and hypoactivity. Combination treatment with fluoxetine and CBT was statistically superior to placebo, CBT alone, or fluoxetine alone. In addition, fluoxetine alone was superior to CBT alone.²

A meta-analysis including both published and unpublished trials of SSRI medications found that fluoxetine was more likely than placebo to cause remission of symptoms after 7 to 8 weeks of treatment (number needed to treat [NNT]=6). Fluoxetine treatment was also associated with a reduction in symptom scores as measured with the CDRS-R (NNT=5).³

Data were conflicting for the efficacy of paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa).^3,4 No data were available for escitalopram (Lexapro).

But are SSRIs safe for adolescents?

Considerable controversy surrounds the safety of SSRIs in children due to reports of increased suicidal behavior. In 2004, the FDA conducted a meta-analysis of the suicide related adverse events from the published and unpublished trials of SSRIs including fluoxetine, sertraline, paroxetine, fluvoxamine (Luvox), and citalopram. A team of experts reviewed the adverse events from each trial to evaluate for suicidality including suicidal ideation, preparatory acts, self-injurious behavior, or suicide attempts. They found a risk ratio of 1.66 (95% confidence interval, 1.02–2.68) for suicidality in the treatment arms compared with placebo. There were no completed suicides in any study.⁵

This review led to the FDA’s October 2004 “black box” warning regarding suicidality and antidepressant medication in adolescents. However, an ecological analysis of prescription data and US Census data found an overall decline in suicide rates as the rate of prescriptions for SSRI medications increased, suggesting a beneficial correlation of SSRI medications on suicide rates.⁶

Recommendations from others

The American Academy of Child and Adolescent Psychiatry (AACAP) recommends psychosocial and pharmacologic intervention for depression, with psychotherapy as the preferred initial treatment for most adolescent patients.⁴ This organization reviewed the current published and unpublished data including the FDA analysis to formulate its conclusions regarding safety and efficacy. AACAP concluded that fluoxetine is effective for the treatment of depression in children and adolescents.

Evidence summary

Major depressive disorder is common among adolescents and is associated with significant morbidity, including substance abuse and eating disorders. One study of survey data from 1769 adolescents found a lifetime prevalence of 15.3% for major depression. The majority of those reporting episodes of major depression in this study had recurrent symptoms and impairment in work or school.¹

Fluoxetine and therapy together have the best results

A large, multicenter, randomized controlled trial evaluated the effectiveness of fluoxetine (Prozac), cognitive behavioral therapy (CBT), or the combination of the 2. Researchers evaluated improvement with the Children’s Depression Rating Scale–Revised (CDRSR). The CDRS-R uses adolescent and parent interviews to rate 17 symptom areas: impaired schoolwork, difficulty having fun, social withdrawal, appetite disturbance, sleep disturbance, excessive fatigue, physical complaints, irritability, excessive guilt, low self-esteem, depressed feelings, morbid ideas, suicidal ideas, excessive weeping, depressed facial affect, listless speech, and hypoactivity. Combination treatment with fluoxetine and CBT was statistically superior to placebo, CBT alone, or fluoxetine alone. In addition, fluoxetine alone was superior to CBT alone.²

A meta-analysis including both published and unpublished trials of SSRI medications found that fluoxetine was more likely than placebo to cause remission of symptoms after 7 to 8 weeks of treatment (number needed to treat [NNT]=6). Fluoxetine treatment was also associated with a reduction in symptom scores as measured with the CDRS-R (NNT=5).³

Data were conflicting for the efficacy of paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa).^3,4 No data were available for escitalopram (Lexapro).

But are SSRIs safe for adolescents?

Considerable controversy surrounds the safety of SSRIs in children due to reports of increased suicidal behavior. In 2004, the FDA conducted a meta-analysis of the suicide related adverse events from the published and unpublished trials of SSRIs including fluoxetine, sertraline, paroxetine, fluvoxamine (Luvox), and citalopram. A team of experts reviewed the adverse events from each trial to evaluate for suicidality including suicidal ideation, preparatory acts, self-injurious behavior, or suicide attempts. They found a risk ratio of 1.66 (95% confidence interval, 1.02–2.68) for suicidality in the treatment arms compared with placebo. There were no completed suicides in any study.⁵

This review led to the FDA’s October 2004 “black box” warning regarding suicidality and antidepressant medication in adolescents. However, an ecological analysis of prescription data and US Census data found an overall decline in suicide rates as the rate of prescriptions for SSRI medications increased, suggesting a beneficial correlation of SSRI medications on suicide rates.⁶

Recommendations from others

The American Academy of Child and Adolescent Psychiatry (AACAP) recommends psychosocial and pharmacologic intervention for depression, with psychotherapy as the preferred initial treatment for most adolescent patients.⁴ This organization reviewed the current published and unpublished data including the FDA analysis to formulate its conclusions regarding safety and efficacy. AACAP concluded that fluoxetine is effective for the treatment of depression in children and adolescents.

Evidence summary

Major depressive disorder is common among adolescents and is associated with significant morbidity, including substance abuse and eating disorders. One study of survey data from 1769 adolescents found a lifetime prevalence of 15.3% for major depression. The majority of those reporting episodes of major depression in this study had recurrent symptoms and impairment in work or school.¹

Fluoxetine and therapy together have the best results

A large, multicenter, randomized controlled trial evaluated the effectiveness of fluoxetine (Prozac), cognitive behavioral therapy (CBT), or the combination of the 2. Researchers evaluated improvement with the Children’s Depression Rating Scale–Revised (CDRSR). The CDRS-R uses adolescent and parent interviews to rate 17 symptom areas: impaired schoolwork, difficulty having fun, social withdrawal, appetite disturbance, sleep disturbance, excessive fatigue, physical complaints, irritability, excessive guilt, low self-esteem, depressed feelings, morbid ideas, suicidal ideas, excessive weeping, depressed facial affect, listless speech, and hypoactivity. Combination treatment with fluoxetine and CBT was statistically superior to placebo, CBT alone, or fluoxetine alone. In addition, fluoxetine alone was superior to CBT alone.²

A meta-analysis including both published and unpublished trials of SSRI medications found that fluoxetine was more likely than placebo to cause remission of symptoms after 7 to 8 weeks of treatment (number needed to treat [NNT]=6). Fluoxetine treatment was also associated with a reduction in symptom scores as measured with the CDRS-R (NNT=5).³

Data were conflicting for the efficacy of paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa).^3,4 No data were available for escitalopram (Lexapro).

But are SSRIs safe for adolescents?

Considerable controversy surrounds the safety of SSRIs in children due to reports of increased suicidal behavior. In 2004, the FDA conducted a meta-analysis of the suicide related adverse events from the published and unpublished trials of SSRIs including fluoxetine, sertraline, paroxetine, fluvoxamine (Luvox), and citalopram. A team of experts reviewed the adverse events from each trial to evaluate for suicidality including suicidal ideation, preparatory acts, self-injurious behavior, or suicide attempts. They found a risk ratio of 1.66 (95% confidence interval, 1.02–2.68) for suicidality in the treatment arms compared with placebo. There were no completed suicides in any study.⁵

This review led to the FDA’s October 2004 “black box” warning regarding suicidality and antidepressant medication in adolescents. However, an ecological analysis of prescription data and US Census data found an overall decline in suicide rates as the rate of prescriptions for SSRI medications increased, suggesting a beneficial correlation of SSRI medications on suicide rates.⁶

Recommendations from others

The American Academy of Child and Adolescent Psychiatry (AACAP) recommends psychosocial and pharmacologic intervention for depression, with psychotherapy as the preferred initial treatment for most adolescent patients.⁴ This organization reviewed the current published and unpublished data including the FDA analysis to formulate its conclusions regarding safety and efficacy. AACAP concluded that fluoxetine is effective for the treatment of depression in children and adolescents.

Evidence summary

Findings from 2 studies support the notion that the treatment of gestational diabetes decreases neonatal morbidity and mortality (TABLE).^1,2 Both studies found a decrease in neonatal morbidity and mortality for those patients treated either with diet or insulin. One study found a higher rate of NICU admission in the treatment group, but the authors attributed this to physician awareness of the patient having gestational diabetes.¹

TABLE
Treatment of gestational diabetes reduces neonatal morbidity and mortality

Glyburide vs insulin

A high-quality randomized controlled trial comparing glyburide with insulin among 404 women found no difference in maternal hypoglycemia, neonatal mortality, or neonatal features and outcomes (including birthweight, NICU admissions, hyperbilirubinemia, and hypoglycemia; P ≥.25).³ Although this was a fairly large trial, it may have been underpowered since it found small differences in such rare outcomes.

Similarly, a retrospective study comparing glyburide with insulin in 584 women found little difference between the 2 approaches. Women in the glyburide group had better glycemic control, but the women in the insulin group started with higher initial blood sugars.⁴ The glyburide group had fewer NICU admissions than the insulin group (number needed to treat [NNT]=11), but higher rates of jaundice (number needed to harm [NNH]=25), pre-eclampsia (NNH=17), and maternal hypoglycemia (NNH=8). All other neonatal outcomes were similar between groups.

Diet alone vs diet + insulin

A meta-analysis combined 6 RCTs comparing diet alone with diet plus insulin in a total of 1281 women.⁵ Insulin was moderately superior to diet in preventing fetal macrosomia (NNT=11; 95% confidence interval, 6–36), but not in rates of hypoglycemia, hypocalcemia, hyperbilirubinemia, or congenital malformations.

Recommendations from others

The American Diabetes Association (ADA) recommends that women diagnosed with gestational diabetes by a 3-hour glucose tolerance test receive nutritional counseling from a registered dietician. The ADA also recommends insulin therapy if diet is unsuccessful in achieving fasting glucose <105 mg/dL, 1-hour postprandial <155 mg/dL, or 2-hour postprandial <130 mg/dL.⁶

The American College of Obstetricians and Gynecologists (ACOG) recommends the use of diet or insulin to achieve 1-hour postprandial blood sugar of 130 mg/dL.⁷ Both ADA and ACOG indicate that further studies are needed to establish the safety of glyburide before general use can be recommended.

Evidence summary

Findings from 2 studies support the notion that the treatment of gestational diabetes decreases neonatal morbidity and mortality (TABLE).^1,2 Both studies found a decrease in neonatal morbidity and mortality for those patients treated either with diet or insulin. One study found a higher rate of NICU admission in the treatment group, but the authors attributed this to physician awareness of the patient having gestational diabetes.¹

TABLE
Treatment of gestational diabetes reduces neonatal morbidity and mortality

Glyburide vs insulin

A high-quality randomized controlled trial comparing glyburide with insulin among 404 women found no difference in maternal hypoglycemia, neonatal mortality, or neonatal features and outcomes (including birthweight, NICU admissions, hyperbilirubinemia, and hypoglycemia; P ≥.25).³ Although this was a fairly large trial, it may have been underpowered since it found small differences in such rare outcomes.

Similarly, a retrospective study comparing glyburide with insulin in 584 women found little difference between the 2 approaches. Women in the glyburide group had better glycemic control, but the women in the insulin group started with higher initial blood sugars.⁴ The glyburide group had fewer NICU admissions than the insulin group (number needed to treat [NNT]=11), but higher rates of jaundice (number needed to harm [NNH]=25), pre-eclampsia (NNH=17), and maternal hypoglycemia (NNH=8). All other neonatal outcomes were similar between groups.

Diet alone vs diet + insulin

A meta-analysis combined 6 RCTs comparing diet alone with diet plus insulin in a total of 1281 women.⁵ Insulin was moderately superior to diet in preventing fetal macrosomia (NNT=11; 95% confidence interval, 6–36), but not in rates of hypoglycemia, hypocalcemia, hyperbilirubinemia, or congenital malformations.

Recommendations from others

The American Diabetes Association (ADA) recommends that women diagnosed with gestational diabetes by a 3-hour glucose tolerance test receive nutritional counseling from a registered dietician. The ADA also recommends insulin therapy if diet is unsuccessful in achieving fasting glucose <105 mg/dL, 1-hour postprandial <155 mg/dL, or 2-hour postprandial <130 mg/dL.⁶

The American College of Obstetricians and Gynecologists (ACOG) recommends the use of diet or insulin to achieve 1-hour postprandial blood sugar of 130 mg/dL.⁷ Both ADA and ACOG indicate that further studies are needed to establish the safety of glyburide before general use can be recommended.

Evidence summary

Findings from 2 studies support the notion that the treatment of gestational diabetes decreases neonatal morbidity and mortality (TABLE).^1,2 Both studies found a decrease in neonatal morbidity and mortality for those patients treated either with diet or insulin. One study found a higher rate of NICU admission in the treatment group, but the authors attributed this to physician awareness of the patient having gestational diabetes.¹

TABLE
Treatment of gestational diabetes reduces neonatal morbidity and mortality

Glyburide vs insulin

A high-quality randomized controlled trial comparing glyburide with insulin among 404 women found no difference in maternal hypoglycemia, neonatal mortality, or neonatal features and outcomes (including birthweight, NICU admissions, hyperbilirubinemia, and hypoglycemia; P ≥.25).³ Although this was a fairly large trial, it may have been underpowered since it found small differences in such rare outcomes.

Similarly, a retrospective study comparing glyburide with insulin in 584 women found little difference between the 2 approaches. Women in the glyburide group had better glycemic control, but the women in the insulin group started with higher initial blood sugars.⁴ The glyburide group had fewer NICU admissions than the insulin group (number needed to treat [NNT]=11), but higher rates of jaundice (number needed to harm [NNH]=25), pre-eclampsia (NNH=17), and maternal hypoglycemia (NNH=8). All other neonatal outcomes were similar between groups.

Diet alone vs diet + insulin

A meta-analysis combined 6 RCTs comparing diet alone with diet plus insulin in a total of 1281 women.⁵ Insulin was moderately superior to diet in preventing fetal macrosomia (NNT=11; 95% confidence interval, 6–36), but not in rates of hypoglycemia, hypocalcemia, hyperbilirubinemia, or congenital malformations.

Recommendations from others

The American Diabetes Association (ADA) recommends that women diagnosed with gestational diabetes by a 3-hour glucose tolerance test receive nutritional counseling from a registered dietician. The ADA also recommends insulin therapy if diet is unsuccessful in achieving fasting glucose <105 mg/dL, 1-hour postprandial <155 mg/dL, or 2-hour postprandial <130 mg/dL.⁶

The American College of Obstetricians and Gynecologists (ACOG) recommends the use of diet or insulin to achieve 1-hour postprandial blood sugar of 130 mg/dL.⁷ Both ADA and ACOG indicate that further studies are needed to establish the safety of glyburide before general use can be recommended.

Evidence summary

Toothpaste as effective as rinse or gel

A large Cochrane review evaluated topical fluoride therapy in the form of toothpaste, mouth rinse, varnish, or gel. Based on 133 randomized or quasi-randomized controlled trials (n=65,169), the meta-analysis indicated a 26% (95% confidence interval [CI], 24%–29%) reduction in decayed, missing, and filled tooth surfaces in children.¹ Another Cochrane review found 17 randomized controlled trials comparing different methods of topical fluoride application in children. The limited data suggested that fluoride toothpaste is as effective as mouth rinse or gel.² Depending on the prevalence of caries in the population, between 1.6 and 3.7 children need to use a fluoride toothpaste to prevent 1 decayed, missing, or filled tooth.³

The risk of fluorosis

Topical fluoride use has been associated with dental fluorosis, which causes staining or pitting of the enamel tooth surface. The incidence of significant dental fluorosis varies in children—from 5% to 7% with 1450 ppm fluoride toothpaste to 2% to 4% with 440 ppm fluoride toothpaste (number needed to harm [NNH]=20–100).^4,5

High-fluoride concentrations

High-fluoride-concentration toothpastes (1000 ppm F) prevent 14% more caries than low-fluoride-concentration toothpastes (250 ppm F).⁶ Another randomized controlled trial, carried out in an area without fluoridated water, found the high-fluoride-concentration toothpaste (1450 ppm F) resulted in 16% fewer caries in children, while the low-fluoride-concentration toothpaste (440 ppm F) was no different than placebo.⁷

When there’s fluoridated water

A meta-analysis found that the effect of topical fluoride was independent of water fluoridation, suggesting that topical fluoride toothpaste has a beneficial effect even in communities with fluoridated water.³ No relevant studies comparing topical fluoride toothpaste with oral fluoride supplementation were found.

Recommendations from others

Both the American Academy of Pediatric Dentistry (AAPD) and the Centers for Disease Control and Prevention (CDC) recommend topical fluoride toothpaste for children as an adjunct to oral fluoride intake. The AAPD⁸ recommends a “pea-sized” amount of toothpaste for children under 6 years of age. The CDC⁹ recommends that you weigh the risks and possible other sources of fluoride in children under age 2, and using a pea-sized amount of toothpaste with supervised brushing for children 2 to 6 years of age.

The TABLE shows the AAPD’s recommended daily dose of fluoride supplementation based on the fluoride concentration in the local water.

TABLE
Oral fluoride dosing: Recommendations from the American Academy of Pediatric Dentistry⁸

Evidence summary

Toothpaste as effective as rinse or gel

A large Cochrane review evaluated topical fluoride therapy in the form of toothpaste, mouth rinse, varnish, or gel. Based on 133 randomized or quasi-randomized controlled trials (n=65,169), the meta-analysis indicated a 26% (95% confidence interval [CI], 24%–29%) reduction in decayed, missing, and filled tooth surfaces in children.¹ Another Cochrane review found 17 randomized controlled trials comparing different methods of topical fluoride application in children. The limited data suggested that fluoride toothpaste is as effective as mouth rinse or gel.² Depending on the prevalence of caries in the population, between 1.6 and 3.7 children need to use a fluoride toothpaste to prevent 1 decayed, missing, or filled tooth.³

The risk of fluorosis

Topical fluoride use has been associated with dental fluorosis, which causes staining or pitting of the enamel tooth surface. The incidence of significant dental fluorosis varies in children—from 5% to 7% with 1450 ppm fluoride toothpaste to 2% to 4% with 440 ppm fluoride toothpaste (number needed to harm [NNH]=20–100).^4,5

High-fluoride concentrations

High-fluoride-concentration toothpastes (1000 ppm F) prevent 14% more caries than low-fluoride-concentration toothpastes (250 ppm F).⁶ Another randomized controlled trial, carried out in an area without fluoridated water, found the high-fluoride-concentration toothpaste (1450 ppm F) resulted in 16% fewer caries in children, while the low-fluoride-concentration toothpaste (440 ppm F) was no different than placebo.⁷

When there’s fluoridated water

A meta-analysis found that the effect of topical fluoride was independent of water fluoridation, suggesting that topical fluoride toothpaste has a beneficial effect even in communities with fluoridated water.³ No relevant studies comparing topical fluoride toothpaste with oral fluoride supplementation were found.

Recommendations from others

Both the American Academy of Pediatric Dentistry (AAPD) and the Centers for Disease Control and Prevention (CDC) recommend topical fluoride toothpaste for children as an adjunct to oral fluoride intake. The AAPD⁸ recommends a “pea-sized” amount of toothpaste for children under 6 years of age. The CDC⁹ recommends that you weigh the risks and possible other sources of fluoride in children under age 2, and using a pea-sized amount of toothpaste with supervised brushing for children 2 to 6 years of age.

The TABLE shows the AAPD’s recommended daily dose of fluoride supplementation based on the fluoride concentration in the local water.

TABLE
Oral fluoride dosing: Recommendations from the American Academy of Pediatric Dentistry⁸

Evidence summary

Toothpaste as effective as rinse or gel

A large Cochrane review evaluated topical fluoride therapy in the form of toothpaste, mouth rinse, varnish, or gel. Based on 133 randomized or quasi-randomized controlled trials (n=65,169), the meta-analysis indicated a 26% (95% confidence interval [CI], 24%–29%) reduction in decayed, missing, and filled tooth surfaces in children.¹ Another Cochrane review found 17 randomized controlled trials comparing different methods of topical fluoride application in children. The limited data suggested that fluoride toothpaste is as effective as mouth rinse or gel.² Depending on the prevalence of caries in the population, between 1.6 and 3.7 children need to use a fluoride toothpaste to prevent 1 decayed, missing, or filled tooth.³

The risk of fluorosis

Topical fluoride use has been associated with dental fluorosis, which causes staining or pitting of the enamel tooth surface. The incidence of significant dental fluorosis varies in children—from 5% to 7% with 1450 ppm fluoride toothpaste to 2% to 4% with 440 ppm fluoride toothpaste (number needed to harm [NNH]=20–100).^4,5

High-fluoride concentrations

High-fluoride-concentration toothpastes (1000 ppm F) prevent 14% more caries than low-fluoride-concentration toothpastes (250 ppm F).⁶ Another randomized controlled trial, carried out in an area without fluoridated water, found the high-fluoride-concentration toothpaste (1450 ppm F) resulted in 16% fewer caries in children, while the low-fluoride-concentration toothpaste (440 ppm F) was no different than placebo.⁷

When there’s fluoridated water

A meta-analysis found that the effect of topical fluoride was independent of water fluoridation, suggesting that topical fluoride toothpaste has a beneficial effect even in communities with fluoridated water.³ No relevant studies comparing topical fluoride toothpaste with oral fluoride supplementation were found.

Recommendations from others

Both the American Academy of Pediatric Dentistry (AAPD) and the Centers for Disease Control and Prevention (CDC) recommend topical fluoride toothpaste for children as an adjunct to oral fluoride intake. The AAPD⁸ recommends a “pea-sized” amount of toothpaste for children under 6 years of age. The CDC⁹ recommends that you weigh the risks and possible other sources of fluoride in children under age 2, and using a pea-sized amount of toothpaste with supervised brushing for children 2 to 6 years of age.

The TABLE shows the AAPD’s recommended daily dose of fluoride supplementation based on the fluoride concentration in the local water.

TABLE
Oral fluoride dosing: Recommendations from the American Academy of Pediatric Dentistry⁸

Evidence summary

Systematic reviews analyzing the modification of early feeding practices to prevent atopic disease have all been limited by a paucity of double-blinded RCTs of sufficient duration.^1-3

Breastfeeding, hydrolyzed formulas confer lowest atopy risk

Breastfeeding and the use of hydrolyzed protein formulas confer the lowest risk of atopy in high-risk children when compared with cow’s milk or soy-based formulas.^1,3 The relative risk for wheeze or asthma in the first year of life was 0.4 (95% confidence interval [CI] 0.19–0.85) for children fed hydrolyzed protein formulas when compared with cow’s milk.¹ Studies have not found a significant difference among these forms of milk for infants without a strong family history of atopic disease.³

Delaying solid food may reduce allergies

There is speculation that introducing certain solid foods early increases the risk of allergies to these foods, as well as causing generalized atopic symptoms. Few studies have examined this, and no systematic reviews focus on atopic disease.⁴

A cohort study (n=1265) comparing children who had been given 4 or more types of solid food before 4 months of age with those whose caregivers delayed solid foods showed an increased incidence of eczema by 10 years of age (relative risk=2.35; P<.05) in the early feeding group.⁵

However, a prospective interventional cohort study using a retrospective cohort as a control (n=375) compared children who had strictly avoided fish and citrus products until 1 year of age with those who had an unrestricted diet. There was no difference in the frequency of allergy to these foods as quantified by history and positive challenge test, although the authors did not include a statistical analysis of their results.⁶

Another study randomized 165 high-risk children into groups with standard feeding practices or an allergy prophylaxis regimen, which included avoidance of milk protein until age 1 year, eggs until 2 years, and fish and peanuts until 3 years. Although prophylaxis decreased the prevalence of atopic disorders at 1 year, there was no difference in any atopic disease between the 2 groups at age 7.⁷

Recommendations from others

The American Academy of Pediatrics recommends that for high-risk infants, solid foods should not be introduced into the diet until 6 months of age, with dairy products delayed until 1 year, eggs until 2 years, and peanuts, tree nuts, and fish until 3 years of age.⁸

Evidence summary

Systematic reviews analyzing the modification of early feeding practices to prevent atopic disease have all been limited by a paucity of double-blinded RCTs of sufficient duration.^1-3

Breastfeeding, hydrolyzed formulas confer lowest atopy risk

Breastfeeding and the use of hydrolyzed protein formulas confer the lowest risk of atopy in high-risk children when compared with cow’s milk or soy-based formulas.^1,3 The relative risk for wheeze or asthma in the first year of life was 0.4 (95% confidence interval [CI] 0.19–0.85) for children fed hydrolyzed protein formulas when compared with cow’s milk.¹ Studies have not found a significant difference among these forms of milk for infants without a strong family history of atopic disease.³

Delaying solid food may reduce allergies

There is speculation that introducing certain solid foods early increases the risk of allergies to these foods, as well as causing generalized atopic symptoms. Few studies have examined this, and no systematic reviews focus on atopic disease.⁴

A cohort study (n=1265) comparing children who had been given 4 or more types of solid food before 4 months of age with those whose caregivers delayed solid foods showed an increased incidence of eczema by 10 years of age (relative risk=2.35; P<.05) in the early feeding group.⁵

However, a prospective interventional cohort study using a retrospective cohort as a control (n=375) compared children who had strictly avoided fish and citrus products until 1 year of age with those who had an unrestricted diet. There was no difference in the frequency of allergy to these foods as quantified by history and positive challenge test, although the authors did not include a statistical analysis of their results.⁶

Another study randomized 165 high-risk children into groups with standard feeding practices or an allergy prophylaxis regimen, which included avoidance of milk protein until age 1 year, eggs until 2 years, and fish and peanuts until 3 years. Although prophylaxis decreased the prevalence of atopic disorders at 1 year, there was no difference in any atopic disease between the 2 groups at age 7.⁷

Recommendations from others

The American Academy of Pediatrics recommends that for high-risk infants, solid foods should not be introduced into the diet until 6 months of age, with dairy products delayed until 1 year, eggs until 2 years, and peanuts, tree nuts, and fish until 3 years of age.⁸

Evidence summary

Systematic reviews analyzing the modification of early feeding practices to prevent atopic disease have all been limited by a paucity of double-blinded RCTs of sufficient duration.^1-3

Breastfeeding, hydrolyzed formulas confer lowest atopy risk

Breastfeeding and the use of hydrolyzed protein formulas confer the lowest risk of atopy in high-risk children when compared with cow’s milk or soy-based formulas.^1,3 The relative risk for wheeze or asthma in the first year of life was 0.4 (95% confidence interval [CI] 0.19–0.85) for children fed hydrolyzed protein formulas when compared with cow’s milk.¹ Studies have not found a significant difference among these forms of milk for infants without a strong family history of atopic disease.³

Delaying solid food may reduce allergies

There is speculation that introducing certain solid foods early increases the risk of allergies to these foods, as well as causing generalized atopic symptoms. Few studies have examined this, and no systematic reviews focus on atopic disease.⁴

A cohort study (n=1265) comparing children who had been given 4 or more types of solid food before 4 months of age with those whose caregivers delayed solid foods showed an increased incidence of eczema by 10 years of age (relative risk=2.35; P<.05) in the early feeding group.⁵

However, a prospective interventional cohort study using a retrospective cohort as a control (n=375) compared children who had strictly avoided fish and citrus products until 1 year of age with those who had an unrestricted diet. There was no difference in the frequency of allergy to these foods as quantified by history and positive challenge test, although the authors did not include a statistical analysis of their results.⁶

Another study randomized 165 high-risk children into groups with standard feeding practices or an allergy prophylaxis regimen, which included avoidance of milk protein until age 1 year, eggs until 2 years, and fish and peanuts until 3 years. Although prophylaxis decreased the prevalence of atopic disorders at 1 year, there was no difference in any atopic disease between the 2 groups at age 7.⁷

Recommendations from others

The American Academy of Pediatrics recommends that for high-risk infants, solid foods should not be introduced into the diet until 6 months of age, with dairy products delayed until 1 year, eggs until 2 years, and peanuts, tree nuts, and fish until 3 years of age.⁸

Evidence summary

Numerous reports and guidelines indicate that if a nevus is even slightly suspicious for malignancy, it should be removed by excisional biopsy or sampled for diagnosis by punch or incisional biopsy. There are no randomized controlled trials or cohort studies comparing techniques for removing raised nevi from the face.

Shave biopsy has good outcomes

Expert opinion and individual prospective case series show acceptable outcomes for shave biopsy. One prospective study followed 55 patients after removal of nevi from the head and neck. These nevi were removed using a shave procedure with a#15 scalpel and hot cautery for bleeding. Of the 55 sites, 4 retained pigment and 30 had a visible scar with a mean diameter of 5 mm at 6- to 8-month follow-up.¹ The mean diameter of the original lesions was 6 mm. There was no difference between the size of those lesions that scarred and those that didn’t.

Researchers conducting a second retrospective study, done at least 1 year after the procedure, used a questionnaire to ask 76 patients (with a total of 83 nevi removed from the face by shave excision) about their perceptions of the scar.² Patients described their lesions as: no scar (33%), white and flat (25%), depressed (19%), raised (15%), and pigmented (7%). Eighty-six percent thought their scars looked better than the nevus and 79% were “happy with the way the scar looks now.” Two additional studies, based on both patient and provider perceptions, with similar conclusions, are presented in the (TABLE).^3,4

TABLE
Favorable cosmetic results following shave biopsy of facial nevi

Atypical lesions should be excised

Atypical lesions require excisional biopsy. The depth and architecture of the lesion, if melanoma, cannot be determined by shave biopsy, and both treatment and prognosis depend on those characteristics.

These guidelines derive from well-designed, nonexperimental descriptive studies.⁵ However, a recent retrospective study compared the Breslow depth determination of 4 different biopsy techniques, performed by experienced dermatologists, with the subsequent depth on definitive surgery for melanoma. This study found that superficial shave, deep shave, and punch biopsy predicted the Breslow depth 88% (95/108) of the time.⁶ As expected, excisional biopsy predicted the depth 100% (30/30) of the time. The location of the biopsy sites were not reported. The choice of biopsy was influenced by the suspicion of melanoma; thin (< 1 mm) melanomas were more likely to be superficially shaved than deep-shaved or punched.

Recommendations from others

Guidelines on nevocellular nevi from the American Academy of Dermatology recommend a simple excisional or incisional biopsy; they do not discuss the method of removal for benign appearing facial lesions.⁷

The UK Guidelines for the Management of Cutaneous Melanoma recommend that suspicious lesions be excised completely (excisional biopsy) and sent for confirmatory histopathological examination.⁵ A biopsy that transects the depth of the lesion (for example, superficial shave biopsy) should be avoided because histological depth of invasion is the basic criterion for staging and shave biopsy makes the staging impossible in some cases.

Evidence summary

Numerous reports and guidelines indicate that if a nevus is even slightly suspicious for malignancy, it should be removed by excisional biopsy or sampled for diagnosis by punch or incisional biopsy. There are no randomized controlled trials or cohort studies comparing techniques for removing raised nevi from the face.

Shave biopsy has good outcomes

Expert opinion and individual prospective case series show acceptable outcomes for shave biopsy. One prospective study followed 55 patients after removal of nevi from the head and neck. These nevi were removed using a shave procedure with a#15 scalpel and hot cautery for bleeding. Of the 55 sites, 4 retained pigment and 30 had a visible scar with a mean diameter of 5 mm at 6- to 8-month follow-up.¹ The mean diameter of the original lesions was 6 mm. There was no difference between the size of those lesions that scarred and those that didn’t.

Researchers conducting a second retrospective study, done at least 1 year after the procedure, used a questionnaire to ask 76 patients (with a total of 83 nevi removed from the face by shave excision) about their perceptions of the scar.² Patients described their lesions as: no scar (33%), white and flat (25%), depressed (19%), raised (15%), and pigmented (7%). Eighty-six percent thought their scars looked better than the nevus and 79% were “happy with the way the scar looks now.” Two additional studies, based on both patient and provider perceptions, with similar conclusions, are presented in the (TABLE).^3,4

TABLE
Favorable cosmetic results following shave biopsy of facial nevi

Atypical lesions should be excised

Atypical lesions require excisional biopsy. The depth and architecture of the lesion, if melanoma, cannot be determined by shave biopsy, and both treatment and prognosis depend on those characteristics.

These guidelines derive from well-designed, nonexperimental descriptive studies.⁵ However, a recent retrospective study compared the Breslow depth determination of 4 different biopsy techniques, performed by experienced dermatologists, with the subsequent depth on definitive surgery for melanoma. This study found that superficial shave, deep shave, and punch biopsy predicted the Breslow depth 88% (95/108) of the time.⁶ As expected, excisional biopsy predicted the depth 100% (30/30) of the time. The location of the biopsy sites were not reported. The choice of biopsy was influenced by the suspicion of melanoma; thin (< 1 mm) melanomas were more likely to be superficially shaved than deep-shaved or punched.

Recommendations from others

Guidelines on nevocellular nevi from the American Academy of Dermatology recommend a simple excisional or incisional biopsy; they do not discuss the method of removal for benign appearing facial lesions.⁷

The UK Guidelines for the Management of Cutaneous Melanoma recommend that suspicious lesions be excised completely (excisional biopsy) and sent for confirmatory histopathological examination.⁵ A biopsy that transects the depth of the lesion (for example, superficial shave biopsy) should be avoided because histological depth of invasion is the basic criterion for staging and shave biopsy makes the staging impossible in some cases.

Evidence summary

Numerous reports and guidelines indicate that if a nevus is even slightly suspicious for malignancy, it should be removed by excisional biopsy or sampled for diagnosis by punch or incisional biopsy. There are no randomized controlled trials or cohort studies comparing techniques for removing raised nevi from the face.

Shave biopsy has good outcomes

Expert opinion and individual prospective case series show acceptable outcomes for shave biopsy. One prospective study followed 55 patients after removal of nevi from the head and neck. These nevi were removed using a shave procedure with a#15 scalpel and hot cautery for bleeding. Of the 55 sites, 4 retained pigment and 30 had a visible scar with a mean diameter of 5 mm at 6- to 8-month follow-up.¹ The mean diameter of the original lesions was 6 mm. There was no difference between the size of those lesions that scarred and those that didn’t.

Researchers conducting a second retrospective study, done at least 1 year after the procedure, used a questionnaire to ask 76 patients (with a total of 83 nevi removed from the face by shave excision) about their perceptions of the scar.² Patients described their lesions as: no scar (33%), white and flat (25%), depressed (19%), raised (15%), and pigmented (7%). Eighty-six percent thought their scars looked better than the nevus and 79% were “happy with the way the scar looks now.” Two additional studies, based on both patient and provider perceptions, with similar conclusions, are presented in the (TABLE).^3,4

TABLE
Favorable cosmetic results following shave biopsy of facial nevi

Atypical lesions should be excised

Atypical lesions require excisional biopsy. The depth and architecture of the lesion, if melanoma, cannot be determined by shave biopsy, and both treatment and prognosis depend on those characteristics.

These guidelines derive from well-designed, nonexperimental descriptive studies.⁵ However, a recent retrospective study compared the Breslow depth determination of 4 different biopsy techniques, performed by experienced dermatologists, with the subsequent depth on definitive surgery for melanoma. This study found that superficial shave, deep shave, and punch biopsy predicted the Breslow depth 88% (95/108) of the time.⁶ As expected, excisional biopsy predicted the depth 100% (30/30) of the time. The location of the biopsy sites were not reported. The choice of biopsy was influenced by the suspicion of melanoma; thin (< 1 mm) melanomas were more likely to be superficially shaved than deep-shaved or punched.

Recommendations from others

Guidelines on nevocellular nevi from the American Academy of Dermatology recommend a simple excisional or incisional biopsy; they do not discuss the method of removal for benign appearing facial lesions.⁷

The UK Guidelines for the Management of Cutaneous Melanoma recommend that suspicious lesions be excised completely (excisional biopsy) and sent for confirmatory histopathological examination.⁵ A biopsy that transects the depth of the lesion (for example, superficial shave biopsy) should be avoided because histological depth of invasion is the basic criterion for staging and shave biopsy makes the staging impossible in some cases.

Evidence summary

Morbidity profile makes LEEP appear best

Similar efficacy. All 7 available surgical techniques were found to have similar efficacy, in a 2005 Cochrane review of 28 randomized trials.¹ Resolution of CIN 2 or 3 lesions was 77% to 98%, using knife cone biopsy, laser conization, loop excision, laser ablation, cryotherapy, or 2 techniques not used commonly in the US, cold coagulation and radical diathermy. Surgical techniques were tested in various combinations, but no trial compared all of the techniques with one another. Most studies were underpowered, limiting the results.

 

CERVICAL SCREENING AND PREVENTION

Pap test: Good, but underused We’ve made great progress. What was the 2nd leading cancer in US women in incidence and mortality is now 11th in incidence and 13th in mortality. Yet, even with perfect attendance at annual screenings, women still get cervical cancer. And many still do not have screenings—they account for about half of all cervical cancers. The Pap, as good as it is, has flaws. The test is subjective, and sensitivity varies from lab to lab. ⁹

Dr. J. Thomas cox, university of California. Member, American Cancer society Cervical guidelines Committee, the 2002 Bethesda Workshop; ACS HPV vaccine Advisory Committee; author, ASCCP guidelines Committee

Each year in the united states approximately 500,000 women are diagnosed with high-grade cervical cancer precursor lesions, CIN 2 and CIN III.⁴ If left untreated, 22% of CIN 2 lesions progress to carcinoma in situ or invasive cervical cancer, 43% regress, and 35% persist at the same level. Fourteen percent of untreated CIN 3 lesions progress, 32% regress, and 56% persist at the same level.

HPV vaccine: Won’t replace prevention or protection Although an effective vaccine is a major advance in the prevention of genital HPV and cervical cancer, it will not replace other prevention strategies, such as cervical cancer screening for women or protective sexual behaviors. Women should continue to get Pap tests as a safeguard against cervical cancer.

Dr. Anne Schuchat, Director, CDC National Center for Immunization and respiratory Diseases, June 29, 2006 press release (www.cdc.gov/od/oc/media/pressrel/r060629.htm)

The HPV vaccine (Gardasil) that prevents the development of lesions caused by HPV types 6, 11, 16, and 18, was approved by the us Food and Drug Administration in June 2006 for use in females 9 to 26 years oof age. Shortly after, the Advisory Committee on Immunization Practices issued guidelines, stating that vaccination is recommended for all women <26 years of age. (www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm).

HPV testing: Adjunct to cytology The United States is falling behind other countries in assessing how best to utilize HPV testing for screening. Ongoing trials in The Netherlands, Italy, United Kingdom, Canada, and Finland are evaluating whether cytology can be replaced by HPV DNA testing for screening. Currently, HPV testing is only approved as an adjunct to cytology for cervical cancer screening in the United States, and no similar trials are underway. ¹⁰

Dr. Thomas C. Wright, Columbia university. Author, 2001 Consensus guidelines on Managing Women with Cytological and Histological Abnormalities, the 2004 Interim guidance for use of HPV DNA testing for Primary screening, and the 2001 Bethesda system

Least morbidity with LEEP. Morbidity was compared with one-on-one trials of different techniques ( TABLE 1 ). The review noted that LEEP has the least morbidity (such as hemorrhage, infection, cervical stenosis, and midtrimester pregnancy loss) while providing the most reliable histology by excising tissue without causing thermal artifact ( FIGURE ).

Higher rate of hemorrhage with cone biopsy. Another systematic review of 21 controlled trials comparing treatments for CIN 2 or 3 found a similar efficacy of all the modalities, including cone biopsy, cryotherapy, laser ablation, and LEEP. However, it also found a trend toward a higher rate of significant hemorrhage among women who received cone biopsies compared with women who received either laser ablation or LEEP.²

FIGURE
CIN 2 and 3 and its treatment by LEEP

TABLE 1
CIN 2 and 3 treatment options: An outcomes comparison

Surgical treatment raises obstetric risks

There is a concern regarding future obstetric outcomes for women who have undergone surgical treatment of a high-grade cervical lesion. A recent meta-analysis of 27 controlled cohort studies found that cold knife conization and LEEP were associated with increased obstetrical risks, such as delivery at less than 37 weeks’ gestation and a birth weight <2500 g ( TABLE 2 ). Any resection that was more than 10 mm deep increased the risk of prematurity with future pregnancies (pooled relative risk=2.6; 95%] CI, 1.3–5.3).³

TABLE 2
Obstetrical outcomes for CIN 2 and 3 treatment options

Recommendations from others

Consensus guidelines from the American Society for Colposcopy and Cervical Pathology (ASCCP) and a practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) both recommend immediate removal of the entire transformation zone, with either ablative or excisional treatment as initial treatment of CIN 2 and 3 for patients who are not pregnant.^4,5

Value of excisional treatment. The ASCCP guidelines note that there is a benefit to excisional treatment, as it allows pathologic assessment of the excised tissue. Some of the ASCCP guideline authors recommend excisional procedures for the management of large CIN 2 and 3 lesions, which are at increased risk of having microinvasive disease.⁴

For women with unsatisfactory colposcopy and biopsy-proven CIN 2 or 3, there is up to a 7% risk for an occult invasive cervical carcinoma.^1,4 Performing a diagnostic excisional procedure is recommended on these patients.^4,6

ASCCP and ACOG make special recommendations for both adolescents and pregnant women.

For adolescent patients with biopsy-proven CIN 2, a recent ACOG Committee Opinion recommends close follow-up—with Pap smears or colposcopies every 4 to 6 months—due to the high rates of resolution of CIN 2 in adolescents.⁷

For pregnant patients, diagnostic excisional procedures are associated with complications such as bleeding and preterm delivery, while there is minimal risk of CIN 2 or 3 progressing to invasive cervical cancer.^4,8 In pregnancy, follow CIN 2 and 3 with colposcopy each trimester, and reevaluate at 6 to 12 weeks postpartum. Limit any diagnostic excisional procedures to cases where you cannot rule out invasive cancer.^4,5

Evidence summary

Morbidity profile makes LEEP appear best

Similar efficacy. All 7 available surgical techniques were found to have similar efficacy, in a 2005 Cochrane review of 28 randomized trials.¹ Resolution of CIN 2 or 3 lesions was 77% to 98%, using knife cone biopsy, laser conization, loop excision, laser ablation, cryotherapy, or 2 techniques not used commonly in the US, cold coagulation and radical diathermy. Surgical techniques were tested in various combinations, but no trial compared all of the techniques with one another. Most studies were underpowered, limiting the results.

 

CERVICAL SCREENING AND PREVENTION

Pap test: Good, but underused We’ve made great progress. What was the 2nd leading cancer in US women in incidence and mortality is now 11th in incidence and 13th in mortality. Yet, even with perfect attendance at annual screenings, women still get cervical cancer. And many still do not have screenings—they account for about half of all cervical cancers. The Pap, as good as it is, has flaws. The test is subjective, and sensitivity varies from lab to lab. ⁹

Dr. J. Thomas cox, university of California. Member, American Cancer society Cervical guidelines Committee, the 2002 Bethesda Workshop; ACS HPV vaccine Advisory Committee; author, ASCCP guidelines Committee

Each year in the united states approximately 500,000 women are diagnosed with high-grade cervical cancer precursor lesions, CIN 2 and CIN III.⁴ If left untreated, 22% of CIN 2 lesions progress to carcinoma in situ or invasive cervical cancer, 43% regress, and 35% persist at the same level. Fourteen percent of untreated CIN 3 lesions progress, 32% regress, and 56% persist at the same level.

HPV vaccine: Won’t replace prevention or protection Although an effective vaccine is a major advance in the prevention of genital HPV and cervical cancer, it will not replace other prevention strategies, such as cervical cancer screening for women or protective sexual behaviors. Women should continue to get Pap tests as a safeguard against cervical cancer.

Dr. Anne Schuchat, Director, CDC National Center for Immunization and respiratory Diseases, June 29, 2006 press release (www.cdc.gov/od/oc/media/pressrel/r060629.htm)

The HPV vaccine (Gardasil) that prevents the development of lesions caused by HPV types 6, 11, 16, and 18, was approved by the us Food and Drug Administration in June 2006 for use in females 9 to 26 years oof age. Shortly after, the Advisory Committee on Immunization Practices issued guidelines, stating that vaccination is recommended for all women <26 years of age. (www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm).

HPV testing: Adjunct to cytology The United States is falling behind other countries in assessing how best to utilize HPV testing for screening. Ongoing trials in The Netherlands, Italy, United Kingdom, Canada, and Finland are evaluating whether cytology can be replaced by HPV DNA testing for screening. Currently, HPV testing is only approved as an adjunct to cytology for cervical cancer screening in the United States, and no similar trials are underway. ¹⁰

Dr. Thomas C. Wright, Columbia university. Author, 2001 Consensus guidelines on Managing Women with Cytological and Histological Abnormalities, the 2004 Interim guidance for use of HPV DNA testing for Primary screening, and the 2001 Bethesda system

Least morbidity with LEEP. Morbidity was compared with one-on-one trials of different techniques ( TABLE 1 ). The review noted that LEEP has the least morbidity (such as hemorrhage, infection, cervical stenosis, and midtrimester pregnancy loss) while providing the most reliable histology by excising tissue without causing thermal artifact ( FIGURE ).

Higher rate of hemorrhage with cone biopsy. Another systematic review of 21 controlled trials comparing treatments for CIN 2 or 3 found a similar efficacy of all the modalities, including cone biopsy, cryotherapy, laser ablation, and LEEP. However, it also found a trend toward a higher rate of significant hemorrhage among women who received cone biopsies compared with women who received either laser ablation or LEEP.²

FIGURE
CIN 2 and 3 and its treatment by LEEP

TABLE 1
CIN 2 and 3 treatment options: An outcomes comparison

Surgical treatment raises obstetric risks

There is a concern regarding future obstetric outcomes for women who have undergone surgical treatment of a high-grade cervical lesion. A recent meta-analysis of 27 controlled cohort studies found that cold knife conization and LEEP were associated with increased obstetrical risks, such as delivery at less than 37 weeks’ gestation and a birth weight <2500 g ( TABLE 2 ). Any resection that was more than 10 mm deep increased the risk of prematurity with future pregnancies (pooled relative risk=2.6; 95%] CI, 1.3–5.3).³

TABLE 2
Obstetrical outcomes for CIN 2 and 3 treatment options

Recommendations from others

Consensus guidelines from the American Society for Colposcopy and Cervical Pathology (ASCCP) and a practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) both recommend immediate removal of the entire transformation zone, with either ablative or excisional treatment as initial treatment of CIN 2 and 3 for patients who are not pregnant.^4,5

Value of excisional treatment. The ASCCP guidelines note that there is a benefit to excisional treatment, as it allows pathologic assessment of the excised tissue. Some of the ASCCP guideline authors recommend excisional procedures for the management of large CIN 2 and 3 lesions, which are at increased risk of having microinvasive disease.⁴

For women with unsatisfactory colposcopy and biopsy-proven CIN 2 or 3, there is up to a 7% risk for an occult invasive cervical carcinoma.^1,4 Performing a diagnostic excisional procedure is recommended on these patients.^4,6

ASCCP and ACOG make special recommendations for both adolescents and pregnant women.

For adolescent patients with biopsy-proven CIN 2, a recent ACOG Committee Opinion recommends close follow-up—with Pap smears or colposcopies every 4 to 6 months—due to the high rates of resolution of CIN 2 in adolescents.⁷

For pregnant patients, diagnostic excisional procedures are associated with complications such as bleeding and preterm delivery, while there is minimal risk of CIN 2 or 3 progressing to invasive cervical cancer.^4,8 In pregnancy, follow CIN 2 and 3 with colposcopy each trimester, and reevaluate at 6 to 12 weeks postpartum. Limit any diagnostic excisional procedures to cases where you cannot rule out invasive cancer.^4,5

Evidence summary

Morbidity profile makes LEEP appear best

Similar efficacy. All 7 available surgical techniques were found to have similar efficacy, in a 2005 Cochrane review of 28 randomized trials.¹ Resolution of CIN 2 or 3 lesions was 77% to 98%, using knife cone biopsy, laser conization, loop excision, laser ablation, cryotherapy, or 2 techniques not used commonly in the US, cold coagulation and radical diathermy. Surgical techniques were tested in various combinations, but no trial compared all of the techniques with one another. Most studies were underpowered, limiting the results.

 

CERVICAL SCREENING AND PREVENTION

Pap test: Good, but underused We’ve made great progress. What was the 2nd leading cancer in US women in incidence and mortality is now 11th in incidence and 13th in mortality. Yet, even with perfect attendance at annual screenings, women still get cervical cancer. And many still do not have screenings—they account for about half of all cervical cancers. The Pap, as good as it is, has flaws. The test is subjective, and sensitivity varies from lab to lab. ⁹

Dr. J. Thomas cox, university of California. Member, American Cancer society Cervical guidelines Committee, the 2002 Bethesda Workshop; ACS HPV vaccine Advisory Committee; author, ASCCP guidelines Committee

Each year in the united states approximately 500,000 women are diagnosed with high-grade cervical cancer precursor lesions, CIN 2 and CIN III.⁴ If left untreated, 22% of CIN 2 lesions progress to carcinoma in situ or invasive cervical cancer, 43% regress, and 35% persist at the same level. Fourteen percent of untreated CIN 3 lesions progress, 32% regress, and 56% persist at the same level.

HPV vaccine: Won’t replace prevention or protection Although an effective vaccine is a major advance in the prevention of genital HPV and cervical cancer, it will not replace other prevention strategies, such as cervical cancer screening for women or protective sexual behaviors. Women should continue to get Pap tests as a safeguard against cervical cancer.

Dr. Anne Schuchat, Director, CDC National Center for Immunization and respiratory Diseases, June 29, 2006 press release (www.cdc.gov/od/oc/media/pressrel/r060629.htm)

The HPV vaccine (Gardasil) that prevents the development of lesions caused by HPV types 6, 11, 16, and 18, was approved by the us Food and Drug Administration in June 2006 for use in females 9 to 26 years oof age. Shortly after, the Advisory Committee on Immunization Practices issued guidelines, stating that vaccination is recommended for all women <26 years of age. (www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm).

HPV testing: Adjunct to cytology The United States is falling behind other countries in assessing how best to utilize HPV testing for screening. Ongoing trials in The Netherlands, Italy, United Kingdom, Canada, and Finland are evaluating whether cytology can be replaced by HPV DNA testing for screening. Currently, HPV testing is only approved as an adjunct to cytology for cervical cancer screening in the United States, and no similar trials are underway. ¹⁰

Dr. Thomas C. Wright, Columbia university. Author, 2001 Consensus guidelines on Managing Women with Cytological and Histological Abnormalities, the 2004 Interim guidance for use of HPV DNA testing for Primary screening, and the 2001 Bethesda system

Least morbidity with LEEP. Morbidity was compared with one-on-one trials of different techniques ( TABLE 1 ). The review noted that LEEP has the least morbidity (such as hemorrhage, infection, cervical stenosis, and midtrimester pregnancy loss) while providing the most reliable histology by excising tissue without causing thermal artifact ( FIGURE ).

Higher rate of hemorrhage with cone biopsy. Another systematic review of 21 controlled trials comparing treatments for CIN 2 or 3 found a similar efficacy of all the modalities, including cone biopsy, cryotherapy, laser ablation, and LEEP. However, it also found a trend toward a higher rate of significant hemorrhage among women who received cone biopsies compared with women who received either laser ablation or LEEP.²

FIGURE
CIN 2 and 3 and its treatment by LEEP

TABLE 1
CIN 2 and 3 treatment options: An outcomes comparison

Surgical treatment raises obstetric risks

There is a concern regarding future obstetric outcomes for women who have undergone surgical treatment of a high-grade cervical lesion. A recent meta-analysis of 27 controlled cohort studies found that cold knife conization and LEEP were associated with increased obstetrical risks, such as delivery at less than 37 weeks’ gestation and a birth weight <2500 g ( TABLE 2 ). Any resection that was more than 10 mm deep increased the risk of prematurity with future pregnancies (pooled relative risk=2.6; 95%] CI, 1.3–5.3).³

TABLE 2
Obstetrical outcomes for CIN 2 and 3 treatment options

Recommendations from others

Consensus guidelines from the American Society for Colposcopy and Cervical Pathology (ASCCP) and a practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) both recommend immediate removal of the entire transformation zone, with either ablative or excisional treatment as initial treatment of CIN 2 and 3 for patients who are not pregnant.^4,5

Value of excisional treatment. The ASCCP guidelines note that there is a benefit to excisional treatment, as it allows pathologic assessment of the excised tissue. Some of the ASCCP guideline authors recommend excisional procedures for the management of large CIN 2 and 3 lesions, which are at increased risk of having microinvasive disease.⁴

For women with unsatisfactory colposcopy and biopsy-proven CIN 2 or 3, there is up to a 7% risk for an occult invasive cervical carcinoma.^1,4 Performing a diagnostic excisional procedure is recommended on these patients.^4,6

ASCCP and ACOG make special recommendations for both adolescents and pregnant women.

For adolescent patients with biopsy-proven CIN 2, a recent ACOG Committee Opinion recommends close follow-up—with Pap smears or colposcopies every 4 to 6 months—due to the high rates of resolution of CIN 2 in adolescents.⁷

For pregnant patients, diagnostic excisional procedures are associated with complications such as bleeding and preterm delivery, while there is minimal risk of CIN 2 or 3 progressing to invasive cervical cancer.^4,8 In pregnancy, follow CIN 2 and 3 with colposcopy each trimester, and reevaluate at 6 to 12 weeks postpartum. Limit any diagnostic excisional procedures to cases where you cannot rule out invasive cancer.^4,5

Evidence summary

Acetaminophen, while widely used, is hepatotoxic in supra-therapeutic doses.³ Many studies purporting to show evidence of hepatic damage from therapeutic doses of acetaminophen have also been reported. Particularly in the 1970s and 1980s, there were a number of case reports and small literature reviews indicating that hepatic injury among regular users of alcohol (particularly chronic alcoholics) who take acetaminophen with therapeutic intent could be a “therapeutic misadventure.”⁴

Recent studies suggest short-term safety

• A systematic review (published in 2000) identified reports of acetaminophen toxicity, poisoning, or adverse events for alcohol patients.⁵
• In a randomized, double-blinded, placebo-controlled study, 102 alcoholic patients were given 4 g of acetaminophen daily for 2 days.⁶

Recommendations from others

American College of Gastroenterology. The American College of Gastroenterology states that it’s generally safe to take acetaminophen in the amount specified in the package labeling. Furthermore, they recommend that patients diagnosed with liver conditions consult their physician for advice on dosing for acetaminophen or any other pain reliever.⁷

In Liver and Biliary Disease, the author concludes that chronic alcoholics are at increased risk for hepatotoxicity secondary to acetaminophen even at therapeutic doses; therefore, advise them to take no more than 2 g daily.⁸

Evidence summary

Acetaminophen, while widely used, is hepatotoxic in supra-therapeutic doses.³ Many studies purporting to show evidence of hepatic damage from therapeutic doses of acetaminophen have also been reported. Particularly in the 1970s and 1980s, there were a number of case reports and small literature reviews indicating that hepatic injury among regular users of alcohol (particularly chronic alcoholics) who take acetaminophen with therapeutic intent could be a “therapeutic misadventure.”⁴

Recent studies suggest short-term safety

• A systematic review (published in 2000) identified reports of acetaminophen toxicity, poisoning, or adverse events for alcohol patients.⁵
• In a randomized, double-blinded, placebo-controlled study, 102 alcoholic patients were given 4 g of acetaminophen daily for 2 days.⁶

Recommendations from others

American College of Gastroenterology. The American College of Gastroenterology states that it’s generally safe to take acetaminophen in the amount specified in the package labeling. Furthermore, they recommend that patients diagnosed with liver conditions consult their physician for advice on dosing for acetaminophen or any other pain reliever.⁷

In Liver and Biliary Disease, the author concludes that chronic alcoholics are at increased risk for hepatotoxicity secondary to acetaminophen even at therapeutic doses; therefore, advise them to take no more than 2 g daily.⁸

Evidence summary

Acetaminophen, while widely used, is hepatotoxic in supra-therapeutic doses.³ Many studies purporting to show evidence of hepatic damage from therapeutic doses of acetaminophen have also been reported. Particularly in the 1970s and 1980s, there were a number of case reports and small literature reviews indicating that hepatic injury among regular users of alcohol (particularly chronic alcoholics) who take acetaminophen with therapeutic intent could be a “therapeutic misadventure.”⁴

Recent studies suggest short-term safety

• A systematic review (published in 2000) identified reports of acetaminophen toxicity, poisoning, or adverse events for alcohol patients.⁵
• In a randomized, double-blinded, placebo-controlled study, 102 alcoholic patients were given 4 g of acetaminophen daily for 2 days.⁶

Recommendations from others

American College of Gastroenterology. The American College of Gastroenterology states that it’s generally safe to take acetaminophen in the amount specified in the package labeling. Furthermore, they recommend that patients diagnosed with liver conditions consult their physician for advice on dosing for acetaminophen or any other pain reliever.⁷

In Liver and Biliary Disease, the author concludes that chronic alcoholics are at increased risk for hepatotoxicity secondary to acetaminophen even at therapeutic doses; therefore, advise them to take no more than 2 g daily.⁸

Evidence summary

VVC is a common cause of vaginitis; Candida albicans accounts for 85% to 90% of cases. Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics.¹ Incidence increases with onset of sexual activity, but there is no direct evidence it is sexually transmitted.¹ About 75% of women experience 1 VVC episode during their lifetime, 40% to 45% have 2 or more, and 5% to 8% have recurrent VVC (defined as 4 or more annually).^1,2

The candidiasis/antibiotics link

A 2003 systematic review found the evidence supporting the association between antibiotics and VVC limited and contradictory.³ Most were case-control or cohort studies with small sample sizes. No RCTs compare the incidence of culture-confirmed VVC among women receiving antibiotics or placebo.

Nineteen reports of 18 original studies had sufficient data to calculate a relative risk or odds ratio for antibiotic-associated VVC. Thirteen of the 19 reports showed an increase (around twofold; range, 0.43–5) in vaginal Candida prevalence; however, 3 of the 13 reports had no mycological culture data. Six studies did not show significant association between antibiotics and vaginal yeast.³

Antibiotics are thought to increase risk of VVC by killing endogenous vaginal flora (particularly Lactobacillus), allowing microorganisms resistant to the antibiotics, like Candida, to flourish.¹ Yet there is evidence that numbers of genital Lactobacillus are similar for women with and without symptomatic VVC.⁴ Further, decreasing Lactobacillus does not increase the risk of VVC.⁵

Topical and oral antifungals—both do the job

For the treatment of uncomplicated VVC, both topical and oral antifungals are clinically and mycologically effective, with comparable clinical cure rates >80%.⁶ No difference in persistent symptoms between single and multiple doses, or different durations of multiple dose regimens have been found, but samples may have been too small to detect clinically significant effects. An RCT found less nausea, headache, and abdominal pain with intravaginal imidazoles, but more vulvar irritation and vaginal discharge than oral fluconazole.⁶

For treatment of recurrent VVC, RCTs have shown the effectiveness of oral fluconazole and itraconazole maintenance therapy taken for 6 months after an initial regimen.^7,8 Treating male sexual partners did not significantly improve resolution of the woman’s symptoms or reduce the rate of symptomatic relapse.⁹

Yogurt may not live up to its rep

Two poor-quality crossover RCTs provided insufficient evidence regarding effectiveness of a diet containing oral Lactobacillus yogurt to prevent recurrent VVC.⁹ A recent RCT of 278 women on short courses of antibiotics were randomized to oral lactobacilli or placebo and vaginal lactobacilli or placebo.¹⁰ The study was stopped early because there was no effect seen. Overall, 23% developed symptomatic vulvovaginitis.

Recommendations from others

The Infectious Diseases Society of America¹¹ recommends treating uncomplicated VVC with short-course of oral or topical antifungals; treating complicated VVC with antimycotic therapy for 7 days, either daily as topical therapy or as two 150-mg doses of fluconazole 72 hours apart; treating non-albicans species of Candida with topical boric acid (600 mg/day for 14 days) or topical flucytosine; and treating recurrent VVC with induction therapy with 2 weeks of a topical or oral azole followed by a maintenance regimen for 6 months (fluconazole once a week or itraconazole twice a week).¹¹

Evidence summary

VVC is a common cause of vaginitis; Candida albicans accounts for 85% to 90% of cases. Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics.¹ Incidence increases with onset of sexual activity, but there is no direct evidence it is sexually transmitted.¹ About 75% of women experience 1 VVC episode during their lifetime, 40% to 45% have 2 or more, and 5% to 8% have recurrent VVC (defined as 4 or more annually).^1,2

The candidiasis/antibiotics link

A 2003 systematic review found the evidence supporting the association between antibiotics and VVC limited and contradictory.³ Most were case-control or cohort studies with small sample sizes. No RCTs compare the incidence of culture-confirmed VVC among women receiving antibiotics or placebo.

Nineteen reports of 18 original studies had sufficient data to calculate a relative risk or odds ratio for antibiotic-associated VVC. Thirteen of the 19 reports showed an increase (around twofold; range, 0.43–5) in vaginal Candida prevalence; however, 3 of the 13 reports had no mycological culture data. Six studies did not show significant association between antibiotics and vaginal yeast.³

Antibiotics are thought to increase risk of VVC by killing endogenous vaginal flora (particularly Lactobacillus), allowing microorganisms resistant to the antibiotics, like Candida, to flourish.¹ Yet there is evidence that numbers of genital Lactobacillus are similar for women with and without symptomatic VVC.⁴ Further, decreasing Lactobacillus does not increase the risk of VVC.⁵

Topical and oral antifungals—both do the job

For the treatment of uncomplicated VVC, both topical and oral antifungals are clinically and mycologically effective, with comparable clinical cure rates >80%.⁶ No difference in persistent symptoms between single and multiple doses, or different durations of multiple dose regimens have been found, but samples may have been too small to detect clinically significant effects. An RCT found less nausea, headache, and abdominal pain with intravaginal imidazoles, but more vulvar irritation and vaginal discharge than oral fluconazole.⁶

For treatment of recurrent VVC, RCTs have shown the effectiveness of oral fluconazole and itraconazole maintenance therapy taken for 6 months after an initial regimen.^7,8 Treating male sexual partners did not significantly improve resolution of the woman’s symptoms or reduce the rate of symptomatic relapse.⁹

Yogurt may not live up to its rep

Two poor-quality crossover RCTs provided insufficient evidence regarding effectiveness of a diet containing oral Lactobacillus yogurt to prevent recurrent VVC.⁹ A recent RCT of 278 women on short courses of antibiotics were randomized to oral lactobacilli or placebo and vaginal lactobacilli or placebo.¹⁰ The study was stopped early because there was no effect seen. Overall, 23% developed symptomatic vulvovaginitis.

Recommendations from others

The Infectious Diseases Society of America¹¹ recommends treating uncomplicated VVC with short-course of oral or topical antifungals; treating complicated VVC with antimycotic therapy for 7 days, either daily as topical therapy or as two 150-mg doses of fluconazole 72 hours apart; treating non-albicans species of Candida with topical boric acid (600 mg/day for 14 days) or topical flucytosine; and treating recurrent VVC with induction therapy with 2 weeks of a topical or oral azole followed by a maintenance regimen for 6 months (fluconazole once a week or itraconazole twice a week).¹¹

Evidence summary

VVC is a common cause of vaginitis; Candida albicans accounts for 85% to 90% of cases. Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics.¹ Incidence increases with onset of sexual activity, but there is no direct evidence it is sexually transmitted.¹ About 75% of women experience 1 VVC episode during their lifetime, 40% to 45% have 2 or more, and 5% to 8% have recurrent VVC (defined as 4 or more annually).^1,2

The candidiasis/antibiotics link

A 2003 systematic review found the evidence supporting the association between antibiotics and VVC limited and contradictory.³ Most were case-control or cohort studies with small sample sizes. No RCTs compare the incidence of culture-confirmed VVC among women receiving antibiotics or placebo.

Nineteen reports of 18 original studies had sufficient data to calculate a relative risk or odds ratio for antibiotic-associated VVC. Thirteen of the 19 reports showed an increase (around twofold; range, 0.43–5) in vaginal Candida prevalence; however, 3 of the 13 reports had no mycological culture data. Six studies did not show significant association between antibiotics and vaginal yeast.³

Antibiotics are thought to increase risk of VVC by killing endogenous vaginal flora (particularly Lactobacillus), allowing microorganisms resistant to the antibiotics, like Candida, to flourish.¹ Yet there is evidence that numbers of genital Lactobacillus are similar for women with and without symptomatic VVC.⁴ Further, decreasing Lactobacillus does not increase the risk of VVC.⁵

Topical and oral antifungals—both do the job

For the treatment of uncomplicated VVC, both topical and oral antifungals are clinically and mycologically effective, with comparable clinical cure rates >80%.⁶ No difference in persistent symptoms between single and multiple doses, or different durations of multiple dose regimens have been found, but samples may have been too small to detect clinically significant effects. An RCT found less nausea, headache, and abdominal pain with intravaginal imidazoles, but more vulvar irritation and vaginal discharge than oral fluconazole.⁶

For treatment of recurrent VVC, RCTs have shown the effectiveness of oral fluconazole and itraconazole maintenance therapy taken for 6 months after an initial regimen.^7,8 Treating male sexual partners did not significantly improve resolution of the woman’s symptoms or reduce the rate of symptomatic relapse.⁹

Yogurt may not live up to its rep

Two poor-quality crossover RCTs provided insufficient evidence regarding effectiveness of a diet containing oral Lactobacillus yogurt to prevent recurrent VVC.⁹ A recent RCT of 278 women on short courses of antibiotics were randomized to oral lactobacilli or placebo and vaginal lactobacilli or placebo.¹⁰ The study was stopped early because there was no effect seen. Overall, 23% developed symptomatic vulvovaginitis.

Recommendations from others

The Infectious Diseases Society of America¹¹ recommends treating uncomplicated VVC with short-course of oral or topical antifungals; treating complicated VVC with antimycotic therapy for 7 days, either daily as topical therapy or as two 150-mg doses of fluconazole 72 hours apart; treating non-albicans species of Candida with topical boric acid (600 mg/day for 14 days) or topical flucytosine; and treating recurrent VVC with induction therapy with 2 weeks of a topical or oral azole followed by a maintenance regimen for 6 months (fluconazole once a week or itraconazole twice a week).¹¹

Evidence summary

Guaifenesin, available in numerous preparations (eg, Mucinex, Robitussin), is one of the most commonly used over-the-counter medications in pregnancy. The National Birth Defects Prevention Study surveyed 2970 pregnant women from 1997 to 2001; 6.2% reported taking guaifenesin during pregnancy.¹ A second survey evaluated 7563 mothers from 1998 to 2004; 9.2% of the mothers reported that they took it during pregnancy.¹

A weak link to inguinal hernias

Guaifenesin use in pregnancy has been associated with inguinal hernias in newborns. From 1958 to 1965, the Collaborative Perinatal Project recruited 132,500 women to participate in a multicenter study; however, selection and exclusion criteria were not consistent. From this initial group, only 50,282 mother-child pairs were studied. Trained examiners interviewed the women at the child’s 4, 8, 12, and 24-month visits, and then annually thereafter to 8 years of age.

The examiners identified 7 children with inguinal hernias among 197 mothers who had used guaifenesin during their first trimester (standardized relative risk [RR] of 2.6; no CI or P value reported). Twenty children had inguinal hernias among the 1337 mothers who had used guaifenesin during any trimester of their pregnancy (RR=1.1; no confidence interval [CI] or P value reported).² The authors acknowledged that reporting bias among the participating centers prevented them from drawing any conclusions from the data.

A possible trend toward neural tube defects?

Guaifenesin use in pregnancy may also be associated with neural tube defects. In a case-control study, researchers identified 538 fetuses and live-born infants with neural tube defects between 1989 and 1991.³ Twelve patients with neural tube defects were exposed to guaifenesin during gestation; 6 in the control group reported exposure.

The authors reported a trend towards increased risk of neural tube defects in offspring of guaifenesin-exposed mothers (odds ratio=2.04; 95% CI, 0.79–5.28).³ However, since the results were not statistically significant, the authors concluded that guaifenesin had not contributed to the occurrence of neural tube defects.

In a study evaluating 6509 women whose pregnancies resulted in live births, 241 women reported first-trimester exposure to guaifenesin.⁴ Five of the guaifenesin-exposed infants (2.1%) had 1 of the birth defects studied (types of disorders not reported). The calculated RR of birth defect after in utero guaifenesin exposure was 1.3 (no CIs or P values reported); the authors concluded that there was no strong association between guaifenesin and the malformations studied.⁴

Interpret results with caution

Because of the significant potential for recall bias, interpret the findings of these case-control studies with caution.⁵ The mother of a child with a birth defect may search her memory more aggressively for potential causes than a mother of a healthy infant, leading to different rates of recalled, rather than actual, exposures. In the absence of confirmatory prospective data, such as medication diaries or pharmacy databases, recall bias accounts for many spurious positive findings in case control studies.

Recommendations from others

Food and Drug Administration. The FDA assigned guaifenesin to category C—that is, its risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk or lacking. Guaifenesin is recommended if the benefit to the pregnant woman warrants the risk to the fetus.⁶

ACOG. The American College of Obstetricians and Gynecologists (ACOG) makes no recommendation.⁷ The textbook Drugs in Pregnancy and Lactation reports that guaifenesin use during pregnancy exhibits very low risk to the fetus.⁶ The National Collaborating Centre for Women’s and Children’s Health suggests that guaifenesin be used sparingly during pregnancy.⁸

Evidence summary

Guaifenesin, available in numerous preparations (eg, Mucinex, Robitussin), is one of the most commonly used over-the-counter medications in pregnancy. The National Birth Defects Prevention Study surveyed 2970 pregnant women from 1997 to 2001; 6.2% reported taking guaifenesin during pregnancy.¹ A second survey evaluated 7563 mothers from 1998 to 2004; 9.2% of the mothers reported that they took it during pregnancy.¹

A weak link to inguinal hernias

Guaifenesin use in pregnancy has been associated with inguinal hernias in newborns. From 1958 to 1965, the Collaborative Perinatal Project recruited 132,500 women to participate in a multicenter study; however, selection and exclusion criteria were not consistent. From this initial group, only 50,282 mother-child pairs were studied. Trained examiners interviewed the women at the child’s 4, 8, 12, and 24-month visits, and then annually thereafter to 8 years of age.

The examiners identified 7 children with inguinal hernias among 197 mothers who had used guaifenesin during their first trimester (standardized relative risk [RR] of 2.6; no CI or P value reported). Twenty children had inguinal hernias among the 1337 mothers who had used guaifenesin during any trimester of their pregnancy (RR=1.1; no confidence interval [CI] or P value reported).² The authors acknowledged that reporting bias among the participating centers prevented them from drawing any conclusions from the data.

A possible trend toward neural tube defects?

Guaifenesin use in pregnancy may also be associated with neural tube defects. In a case-control study, researchers identified 538 fetuses and live-born infants with neural tube defects between 1989 and 1991.³ Twelve patients with neural tube defects were exposed to guaifenesin during gestation; 6 in the control group reported exposure.

The authors reported a trend towards increased risk of neural tube defects in offspring of guaifenesin-exposed mothers (odds ratio=2.04; 95% CI, 0.79–5.28).³ However, since the results were not statistically significant, the authors concluded that guaifenesin had not contributed to the occurrence of neural tube defects.

In a study evaluating 6509 women whose pregnancies resulted in live births, 241 women reported first-trimester exposure to guaifenesin.⁴ Five of the guaifenesin-exposed infants (2.1%) had 1 of the birth defects studied (types of disorders not reported). The calculated RR of birth defect after in utero guaifenesin exposure was 1.3 (no CIs or P values reported); the authors concluded that there was no strong association between guaifenesin and the malformations studied.⁴

Interpret results with caution

Because of the significant potential for recall bias, interpret the findings of these case-control studies with caution.⁵ The mother of a child with a birth defect may search her memory more aggressively for potential causes than a mother of a healthy infant, leading to different rates of recalled, rather than actual, exposures. In the absence of confirmatory prospective data, such as medication diaries or pharmacy databases, recall bias accounts for many spurious positive findings in case control studies.

Recommendations from others

Food and Drug Administration. The FDA assigned guaifenesin to category C—that is, its risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk or lacking. Guaifenesin is recommended if the benefit to the pregnant woman warrants the risk to the fetus.⁶

ACOG. The American College of Obstetricians and Gynecologists (ACOG) makes no recommendation.⁷ The textbook Drugs in Pregnancy and Lactation reports that guaifenesin use during pregnancy exhibits very low risk to the fetus.⁶ The National Collaborating Centre for Women’s and Children’s Health suggests that guaifenesin be used sparingly during pregnancy.⁸

Evidence summary

Guaifenesin, available in numerous preparations (eg, Mucinex, Robitussin), is one of the most commonly used over-the-counter medications in pregnancy. The National Birth Defects Prevention Study surveyed 2970 pregnant women from 1997 to 2001; 6.2% reported taking guaifenesin during pregnancy.¹ A second survey evaluated 7563 mothers from 1998 to 2004; 9.2% of the mothers reported that they took it during pregnancy.¹

A weak link to inguinal hernias

Guaifenesin use in pregnancy has been associated with inguinal hernias in newborns. From 1958 to 1965, the Collaborative Perinatal Project recruited 132,500 women to participate in a multicenter study; however, selection and exclusion criteria were not consistent. From this initial group, only 50,282 mother-child pairs were studied. Trained examiners interviewed the women at the child’s 4, 8, 12, and 24-month visits, and then annually thereafter to 8 years of age.

The examiners identified 7 children with inguinal hernias among 197 mothers who had used guaifenesin during their first trimester (standardized relative risk [RR] of 2.6; no CI or P value reported). Twenty children had inguinal hernias among the 1337 mothers who had used guaifenesin during any trimester of their pregnancy (RR=1.1; no confidence interval [CI] or P value reported).² The authors acknowledged that reporting bias among the participating centers prevented them from drawing any conclusions from the data.

A possible trend toward neural tube defects?

Guaifenesin use in pregnancy may also be associated with neural tube defects. In a case-control study, researchers identified 538 fetuses and live-born infants with neural tube defects between 1989 and 1991.³ Twelve patients with neural tube defects were exposed to guaifenesin during gestation; 6 in the control group reported exposure.

The authors reported a trend towards increased risk of neural tube defects in offspring of guaifenesin-exposed mothers (odds ratio=2.04; 95% CI, 0.79–5.28).³ However, since the results were not statistically significant, the authors concluded that guaifenesin had not contributed to the occurrence of neural tube defects.

In a study evaluating 6509 women whose pregnancies resulted in live births, 241 women reported first-trimester exposure to guaifenesin.⁴ Five of the guaifenesin-exposed infants (2.1%) had 1 of the birth defects studied (types of disorders not reported). The calculated RR of birth defect after in utero guaifenesin exposure was 1.3 (no CIs or P values reported); the authors concluded that there was no strong association between guaifenesin and the malformations studied.⁴

Interpret results with caution

Because of the significant potential for recall bias, interpret the findings of these case-control studies with caution.⁵ The mother of a child with a birth defect may search her memory more aggressively for potential causes than a mother of a healthy infant, leading to different rates of recalled, rather than actual, exposures. In the absence of confirmatory prospective data, such as medication diaries or pharmacy databases, recall bias accounts for many spurious positive findings in case control studies.

Recommendations from others

Food and Drug Administration. The FDA assigned guaifenesin to category C—that is, its risk cannot be ruled out. Human studies are lacking, and animal studies are either positive for fetal risk or lacking. Guaifenesin is recommended if the benefit to the pregnant woman warrants the risk to the fetus.⁶

ACOG. The American College of Obstetricians and Gynecologists (ACOG) makes no recommendation.⁷ The textbook Drugs in Pregnancy and Lactation reports that guaifenesin use during pregnancy exhibits very low risk to the fetus.⁶ The National Collaborating Centre for Women’s and Children’s Health suggests that guaifenesin be used sparingly during pregnancy.⁸

Evidence summary

Orbital cellulitis is a serious soft-tissue infection of childhood with very different etiologies.

• Periorbital (or preseptal) cellulitis is synonymous with stage I orbital cellulitis, in which there is induration, erythema, warmth, and tenderness of the periorbital soft tissues, usually secondary to external inoculation, but the inflammation does not extend into the bony orbit.
• Stages II, III, and IV orbital cellulitis are progressively more invasive infections that generally arise from the sinuses; they may involve the retro-orbital area. These stages of orbital cellulitis can cause proptosis, decrease visual acuity, or appear as abscesses on computed tomography scan.^1,2

Staged treatment

Many retrospective studies of stage II–IV orbital cellulitis with relatively few subjects and small prospective case series have been published with common themes for management recommendations:

• early intravenous antibiotics (likely for an inpatient), and
• involvement of otolaryngology and ophthalmology specialists.

No head-to-head trials have been completed to evaluate efficacy of specific antimicrobial regimens.

Oral antibiotics. First, treat stage I orbital cellulitis with oral antibiotics.

IV antibiotics. Modify treatment to intravenous antibiotics when there is no improvement within 24 hours or if you discover any characteristic of more severe orbital cellulitis.

Medical management of stage II–IV orbital cellulitis with intravenous antibiotics is the current standard of care until it is clear that one of the following is present:

• no improvement by 24 to 48 hours
• visual impairment
• complete ophthalmoplegia, or
• well-defined periosteal abscess.^1,2

Surgery. For refractory cases, surgical decompression will likely be required.

The evidence. A small case series (n=9) found 21 children admitted to hospital for preseptal cellulitis, of whom 4 later were diagnosed with orbital cellulitis. There was a total of 9 cases of orbital cellulitis; however, only 1 required operative management of orbital cellulitis.³ In a prospective study to evaluate medical management (n=23), 87% of patients responded to intravenous antibiotics.⁴ No statistically significant long-term difference in subperiosteal abscesses (as a complication of orbital cellulitis) was found in another retrospective study comparing medical to surgical management.⁵

Target the likely pathogens

Direct antimicrobial therapy toward common pathogens for likely sources of infection, paying attention to local resistance patterns and the pathogens usually associated with sinusitis (TABLE).^1,2,6-8

A retrospective case series of 94 patients of all ages in China implicated Staphylococcus aureus and streptococcal species based on cultures taken from eye purulence and abscesses.⁶ Another retrospective case series from Vanderbilt (n=80) found streptococci as the most common cause, based on blood and wound cultures in the Hib vaccination era; however, only 12 wounds returned positive cultures.⁷

TABLE
Choose antibiotic based on cause and likely pathogen^1,2,6-8

Steroids have no proven benefit

Systemic steroids have no proven benefit in the treatment of pediatric orbital cellulitis with subperiosteal abscess.

A small retrospective cohort study of the benefit of intravenous steroids in addition to antibiotics showed no decrease in hospital stay or need for surgical decompression (n=23, P=.26 and .20, respectively).⁹ Without prospective data and a power analysis, lack of benefit of steroids cannot be definitively shown.

Recommendations from others

Infectious Disease Society of America. The guidelines for the management of skin and soft-tissue infections implicate β-hemolytic streptococci as the most common cellulitis pathogen, but also recommend empiric coverage against S aureus.

Periorbital and orbital cellulitis are not specifically addressed in these guidelines, but oral dicloxacillin, cephalexin, clindamycin, or erythromycin are recommended for superficial cellulitis, provided there is no known resistance to these antibiotics.

Intravenous penicillinase-resistant penicillins (nafcillin) or a first-generation cephalosporin (cefazolin) may be used for more severe infections.

For penicillin-allergic patients, the IDSA recommends clindamycin or vancomycin.¹⁰

Sanford Guide to Antimicrobial Therapy. Nafcillin plus ceftriaxone and metronidazole is the recommended treatment for orbital cellulitis.

For patients allergic to penicillin, vancomycin plus levofloxacin and metronidazole are recommended.⁸

Neither the American Academy of Ophthalmology nor the International Council of Ophthalmology offers clinical statements on orbital cellulitis.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical service or the US Air Force at large.

Evidence summary

Orbital cellulitis is a serious soft-tissue infection of childhood with very different etiologies.

• Periorbital (or preseptal) cellulitis is synonymous with stage I orbital cellulitis, in which there is induration, erythema, warmth, and tenderness of the periorbital soft tissues, usually secondary to external inoculation, but the inflammation does not extend into the bony orbit.
• Stages II, III, and IV orbital cellulitis are progressively more invasive infections that generally arise from the sinuses; they may involve the retro-orbital area. These stages of orbital cellulitis can cause proptosis, decrease visual acuity, or appear as abscesses on computed tomography scan.^1,2

Staged treatment

Many retrospective studies of stage II–IV orbital cellulitis with relatively few subjects and small prospective case series have been published with common themes for management recommendations:

• early intravenous antibiotics (likely for an inpatient), and
• involvement of otolaryngology and ophthalmology specialists.

No head-to-head trials have been completed to evaluate efficacy of specific antimicrobial regimens.

Oral antibiotics. First, treat stage I orbital cellulitis with oral antibiotics.

IV antibiotics. Modify treatment to intravenous antibiotics when there is no improvement within 24 hours or if you discover any characteristic of more severe orbital cellulitis.

Medical management of stage II–IV orbital cellulitis with intravenous antibiotics is the current standard of care until it is clear that one of the following is present:

• no improvement by 24 to 48 hours
• visual impairment
• complete ophthalmoplegia, or
• well-defined periosteal abscess.^1,2

Surgery. For refractory cases, surgical decompression will likely be required.

The evidence. A small case series (n=9) found 21 children admitted to hospital for preseptal cellulitis, of whom 4 later were diagnosed with orbital cellulitis. There was a total of 9 cases of orbital cellulitis; however, only 1 required operative management of orbital cellulitis.³ In a prospective study to evaluate medical management (n=23), 87% of patients responded to intravenous antibiotics.⁴ No statistically significant long-term difference in subperiosteal abscesses (as a complication of orbital cellulitis) was found in another retrospective study comparing medical to surgical management.⁵

Target the likely pathogens

Direct antimicrobial therapy toward common pathogens for likely sources of infection, paying attention to local resistance patterns and the pathogens usually associated with sinusitis (TABLE).^1,2,6-8

A retrospective case series of 94 patients of all ages in China implicated Staphylococcus aureus and streptococcal species based on cultures taken from eye purulence and abscesses.⁶ Another retrospective case series from Vanderbilt (n=80) found streptococci as the most common cause, based on blood and wound cultures in the Hib vaccination era; however, only 12 wounds returned positive cultures.⁷

TABLE
Choose antibiotic based on cause and likely pathogen^1,2,6-8

Steroids have no proven benefit

Systemic steroids have no proven benefit in the treatment of pediatric orbital cellulitis with subperiosteal abscess.

A small retrospective cohort study of the benefit of intravenous steroids in addition to antibiotics showed no decrease in hospital stay or need for surgical decompression (n=23, P=.26 and .20, respectively).⁹ Without prospective data and a power analysis, lack of benefit of steroids cannot be definitively shown.

Recommendations from others

Infectious Disease Society of America. The guidelines for the management of skin and soft-tissue infections implicate β-hemolytic streptococci as the most common cellulitis pathogen, but also recommend empiric coverage against S aureus.

Periorbital and orbital cellulitis are not specifically addressed in these guidelines, but oral dicloxacillin, cephalexin, clindamycin, or erythromycin are recommended for superficial cellulitis, provided there is no known resistance to these antibiotics.

Intravenous penicillinase-resistant penicillins (nafcillin) or a first-generation cephalosporin (cefazolin) may be used for more severe infections.

For penicillin-allergic patients, the IDSA recommends clindamycin or vancomycin.¹⁰

Sanford Guide to Antimicrobial Therapy. Nafcillin plus ceftriaxone and metronidazole is the recommended treatment for orbital cellulitis.

For patients allergic to penicillin, vancomycin plus levofloxacin and metronidazole are recommended.⁸

Neither the American Academy of Ophthalmology nor the International Council of Ophthalmology offers clinical statements on orbital cellulitis.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical service or the US Air Force at large.

Evidence summary

Orbital cellulitis is a serious soft-tissue infection of childhood with very different etiologies.

• Periorbital (or preseptal) cellulitis is synonymous with stage I orbital cellulitis, in which there is induration, erythema, warmth, and tenderness of the periorbital soft tissues, usually secondary to external inoculation, but the inflammation does not extend into the bony orbit.
• Stages II, III, and IV orbital cellulitis are progressively more invasive infections that generally arise from the sinuses; they may involve the retro-orbital area. These stages of orbital cellulitis can cause proptosis, decrease visual acuity, or appear as abscesses on computed tomography scan.^1,2

Staged treatment

Many retrospective studies of stage II–IV orbital cellulitis with relatively few subjects and small prospective case series have been published with common themes for management recommendations:

• early intravenous antibiotics (likely for an inpatient), and
• involvement of otolaryngology and ophthalmology specialists.

No head-to-head trials have been completed to evaluate efficacy of specific antimicrobial regimens.

Oral antibiotics. First, treat stage I orbital cellulitis with oral antibiotics.

IV antibiotics. Modify treatment to intravenous antibiotics when there is no improvement within 24 hours or if you discover any characteristic of more severe orbital cellulitis.

Medical management of stage II–IV orbital cellulitis with intravenous antibiotics is the current standard of care until it is clear that one of the following is present:

• no improvement by 24 to 48 hours
• visual impairment
• complete ophthalmoplegia, or
• well-defined periosteal abscess.^1,2

Surgery. For refractory cases, surgical decompression will likely be required.

The evidence. A small case series (n=9) found 21 children admitted to hospital for preseptal cellulitis, of whom 4 later were diagnosed with orbital cellulitis. There was a total of 9 cases of orbital cellulitis; however, only 1 required operative management of orbital cellulitis.³ In a prospective study to evaluate medical management (n=23), 87% of patients responded to intravenous antibiotics.⁴ No statistically significant long-term difference in subperiosteal abscesses (as a complication of orbital cellulitis) was found in another retrospective study comparing medical to surgical management.⁵

Target the likely pathogens

Direct antimicrobial therapy toward common pathogens for likely sources of infection, paying attention to local resistance patterns and the pathogens usually associated with sinusitis (TABLE).^1,2,6-8

A retrospective case series of 94 patients of all ages in China implicated Staphylococcus aureus and streptococcal species based on cultures taken from eye purulence and abscesses.⁶ Another retrospective case series from Vanderbilt (n=80) found streptococci as the most common cause, based on blood and wound cultures in the Hib vaccination era; however, only 12 wounds returned positive cultures.⁷

TABLE
Choose antibiotic based on cause and likely pathogen^1,2,6-8

Steroids have no proven benefit

Systemic steroids have no proven benefit in the treatment of pediatric orbital cellulitis with subperiosteal abscess.

A small retrospective cohort study of the benefit of intravenous steroids in addition to antibiotics showed no decrease in hospital stay or need for surgical decompression (n=23, P=.26 and .20, respectively).⁹ Without prospective data and a power analysis, lack of benefit of steroids cannot be definitively shown.

Recommendations from others

Infectious Disease Society of America. The guidelines for the management of skin and soft-tissue infections implicate β-hemolytic streptococci as the most common cellulitis pathogen, but also recommend empiric coverage against S aureus.

Periorbital and orbital cellulitis are not specifically addressed in these guidelines, but oral dicloxacillin, cephalexin, clindamycin, or erythromycin are recommended for superficial cellulitis, provided there is no known resistance to these antibiotics.

Intravenous penicillinase-resistant penicillins (nafcillin) or a first-generation cephalosporin (cefazolin) may be used for more severe infections.

For penicillin-allergic patients, the IDSA recommends clindamycin or vancomycin.¹⁰

Sanford Guide to Antimicrobial Therapy. Nafcillin plus ceftriaxone and metronidazole is the recommended treatment for orbital cellulitis.

For patients allergic to penicillin, vancomycin plus levofloxacin and metronidazole are recommended.⁸

Neither the American Academy of Ophthalmology nor the International Council of Ophthalmology offers clinical statements on orbital cellulitis.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical service or the US Air Force at large.